AusPAR Attachment 2

Extract from the Clinical Evaluation

Report for Fomepizole

Proprietary Product Name: Antizol

Sponsor: AFT Pharmaceuticals Pvt Ltd

Date of first round report: 6 April 2016

Date of second round report: 3 August 2016
 Therapeutic Goods Administration

About the Therapeutic Goods Administration (TGA)

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About the Extract from the Clinical Evaluation Report

• This document provides a more detailed evaluation of the clinical findings, extracted
from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not
include sections from the CER regarding product documentation or post market
activities.
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Contents
List of common abbreviations_______________________________________________ 5
1. Introduction _____________________________________________________________ 7
1.1. Drug Class and Therapeutic Indication_______________________________________ 7
1.2. Dosage Forms and Strengths __________________________________________________ 7
1.3. Dosage and Administration ___________________________________________________ 7
2. Clinical rationale _______________________________________________________ 7
3. Contents of the clinical dossier_______________________________________ 8
3.1. Scope of the clinical dossier ___________________________________________________ 8
3.2. Paediatric data _________________________________________________________________ 9
3.3. Good clinical practice __________________________________________________________ 9
4. Pharmacokinetics ____________________________________________________ 10
4.1. Studies providing pharmacokinetic data ___________________________________ 10
4.2. Summary of pharmacokinetics _____________________________________________ 11
4.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 22
5. Pharmacodynamics __________________________________________________ 24
5.1. Studies providing pharmacodynamic data _________________________________ 24
5.2. Summary of pharmacodynamics ___________________________________________ 24
5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 27
6. Dosage selection for the pivotal studies __________________________ 27
7. Clinical efficacy _______________________________________________________ 28
7.1. Treatment of ethylene glycol poisoning____________________________________ 28
7.2. Treatment of methanol poisoning __________________________________________ 47
8. Clinical safety__________________________________________________________ 65
8.1. Studies providing evaluable safety data____________________________________ 65
8.2. Pivotal studies that assessed safety as a primary outcome _______________ 66
8.3. Patient exposure _____________________________________________________________ 66
8.4. Integrated summary of safety (ISS) ________________________________________ 74
8.5. Post-marketing experience__________________________________________________ 76
8.6. Safety issues with the potential for major regulatory impact ____________ 76
8.7. Other safety issues ___________________________________________________________ 77
8.8. Evaluator’s overall conclusions on clinical safety _________________________ 77
9. First round benefit-risk assessment ______________________________ 78
9.1. First round assessment of benefits _________________________________________ 78
9.2. First round assessment of risks _____________________________________________ 78

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9.3. First round assessment of benefit-risk balance ___________________________ 79

10. First round recommendation regarding authorisation________ 80
11. Clinical questions _____________________________________________________ 80
11.1. Pharmacokinetics __________________________________________________________ 80
11.2. Pharmacodynamics ________________________________________________________ 80
11.3. Efficacy ______________________________________________________________________ 80
11.4. Safety ________________________________________________________________________ 81
12. Second round evaluation of clinical data submitted in response to
questions______________________________________________________________________ 81
12.1. Pharmacokinetics __________________________________________________________ 81
12.2. Pharmacodynamics ________________________________________________________ 82
12.3. Efficacy ______________________________________________________________________ 82
12.4. Safety ________________________________________________________________________ 84
13. Second round benefit-risk assessment ___________________________ 84
13.1. Second round assessment of benefits_____________________________________ 84
13.2. Second round assessment of risks ________________________________________ 84
13.3. Second round assessment of benefit-risk balance _______________________ 84
14. Second round recommendation regarding authorisation ____ 84
15. References _____________________________________________________________ 84

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List of common abbreviations

Abbreviations Meaning

AACT American Academy of Clinical Toxicology

ADH aldehyde dehydrogenase

AE Adverse event

AUC area under curve

APACHE II Acute Physiology and Chronic Health Evaluation II

BD base deficit

BP Blood pressure

bpm beats per minute

BUN Blood urea nitrogen

Cmax maximum plasma concentration

CI Confidence Interval

CVVH continuous-venovenous haemofiltration

CVVHD/HDF continuous veno-venous haemodialysis/ haemodiafiltration

DSW Distilled water

EAPCCT European Association of Poisons Centres and Clinical Toxicologists

ECG Electrocardiogram

EEG Electroencephalogram

EG ethylene glycol

IHD intermittent haemodialysis

IV Intravenous

IQR Inter quartile range

GCP Good Clinical Practice

4MP 4-MethylPyrazole (Fomepizole)

Kg kilogram

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Abbreviations Meaning

L litre

LLN Lower limit of normal

mg milligram

ml millilitre

NS Normal Saline

NCC-MERP National Coordinating Council for Medication Error Reporting and Prevention

OG Osmolar Gap

PK Pharmacokinetic

PD Pharmacodynamic

PO Per Oral

SD Standard deviation

SE Standard error

SEM Standard error of mean

ULN Upper limit of normal

µmol micromoles

mmol millimole

Vd volume of distribution

Tmax Time to maximum plasma concentration

T1/2 half life

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1. Introduction
This is a Category 1 application for registration of a new chemical entity, Antizol Fomepizole
liquid for dilution for infusion, 1.5g/1.5 mL vial.

1.1. Drug Class and Therapeutic Indication

Antizol is a pyrazole derivative, and a competitive inhibitor of the alcohol dehydrogenase (ADH)
enzyme. The proposed indication for Antizol is:
Antizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning,
either alone or in combination with haemodialysis.

1.2. Dosage Forms and Strengths

The submission proposes registration of the following dosage forms and strengths: Antizol® is
supplied as a sterile, preservative-free solution for intravenous use. The proposed marketed drug
product, fomepizole for injection, is supplied in 2 mL glass vials containing 1.5 mL sterile liquid
fomepizole free base as the drug substance. There are no diluents or additives. It is supplied in
packages of four vials or one vial. Each vial contains 1.5 mL (1 g/mL) of fomepizole.

1.3. Dosage and Administration

Preparation of fomepizole for intravenous infusion involves withdrawing the dose from the vial
and injecting it into 100 mL of 0.9% sterile sodium chloride for injection, or into dextrose 5% in
water.
A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 h
for 4 doses, then 15 mg/kg every 12 h thereafter until ethylene glycol or methanol
concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is
asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion
over 30 minutes.
Dosage with Renal Dialysis: Antizol (fomepizole) Injection is dialysable and the frequency of
dosing should be increased to every 4 h during haemodialysis.

2. Clinical rationale
Prior to the availability of specific therapies, approximately two-thirds of ethylene glycol (EG)
poisoned patients died, even with supportive therapy. No specific therapies existed until 1965,
when ethanol was used in the successful treatment of two cases of EG poisoning (Wacker WC, et
al, 1965). Ethanol is a better substrate for alcohol dehydrogenase (ADH) than EG and prevents
EG from being metabolised to its toxic metabolites while EG itself is being eliminated by the
kidneys. Around this time, dialysis also became available. The outcome of a patient with EG
poisoning depends on three primary factors: 1) the amount of time between ingestion of the
poison and the initiation of treatment, 2) the degree of metabolic acidosis and 3) the serum EG
level at presentation. Of these factors, the first two are the most important in determining the
patient’s outcome. The use of ethanol and haemodialysis has proven relatively effective,
particularly for patients being treated by physicians familiar with these poisonings.
Methanol is the primary component of windshield washer fluid. Considering its widespread use,
methanol poisoning is relatively rare and these poisonings are a result of accidental or
intentional ingestion of methanol. Since ingestion of a small amount of methanol is potentially

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fatal, immediate effective treatment is essential. Initially, methanol is metabolised by the

enzyme ADH to formaldehyde with subsequent rapid oxidation via ADH to its toxic metabolite,
formic acid or formate, depending on pH. Formate production is responsible for the severe
metabolic acidosis and progressive visual toxicities associated with methanol poisoning.
Historically, clinical management of methanol poisoning has focussed on three major areas:
sodium bicarbonate therapy for correction of metabolic acidosis, ethanol therapy to limit the
conversion of methanol to its toxic metabolites, formate; and haemodialysis for elimination of
methanol and/or formate. If left untreated or treatment is delayed, methanol poisoning can be
lethal. The lethal dose of methanol is approximately 1.4 mL/kg or about 100 mL for a 70 kg
person. Due to its ability to competitively bind with ADH, ethanol has been the antidote
treatment of choice for EG and methanol poisoning for many decades.
However, the use of ethanol in the treatment of EG poisoning requires constant monitoring of
the patient. If the dose of ethanol is too high, its depressive effects can add dangerously to those
of EG and its metabolites. If the dose of ethanol is too low, the enzyme ADH will not be inhibited
and toxic metabolites will accumulate. Thus, hourly ethanol plasma level determinations with
frequent adjustments to the ethanol infusion are necessary to maintain efficacious ethanol
levels. Additionally, ethanol is eliminated rapidly from the blood with considerable inter-
individual variability and finally, ethanol is a significant hepatotoxin. Similar limitations apply to
the use of ethanol for treatment of methanol poisoning.
Fomepizole or 4 Methypyrazole (4MP) is a competitive inhibitor of ADH and offers a substantial
improvement over the use of ethanol in the treatment of EG and methanol poisonings.

3. Contents of the clinical dossier

3.1. Scope of the clinical dossier

This product was originally developed and approved in the USA and Canada in the late 1990’s
and early 2000’s, before ICH guidelines came into force. Thus, the clinical studies and
nonclinical data that were provided with this dossier are quite old, and therefore CRFs are not
available for all clinical studies To bridge this time gap, the sponsors have conducted systematic
literature reviews, the strategies of which have been approved by the TGA.
Comment: The search strategy described provides a comprehensive and broad search selecting
relevant studies. However most of the available literature is case reports.
The submission contained the following clinical information:
• 10 clinical studies have been conducted to evaluate the pharmacokinetic parameters of
fomepizole in healthy volunteers and in patients with ethylene glycol and methanol
poisoning to determine optimum dosing recommendation, interactions with ethanol, and
the effects of renal dialysis on fomepizole plasma levels, since dialysis is commonly used as a
component of the treatment for both EG and methanol poisonings.
• Three pivotal efficacy/safety studies conducted by the manufacturer: Studies S7 (OMC-4MP-
3), S8 (OMC-4MP-1) and S13 (OMC-4MP-2).
• Other efficacy/safety studies: these include many published studies and case reports.
• 272 literature references
Comment: The clinical overview was well written and the evaluators have no major
disagreement with the contents of the document. The clinical summaries were not
well-written with many grammatical and typographical errors.

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The clinical submission had studies which were not labelled correctly. There was no
consistency between study report numbers and actual reports presented.
Furthermore, the actual reports were not in alignment with the Table of Contents
(ToC). This made it very difficult for the evaluator to navigate through the dossier.
There were 5 integrated summaries for Fomepizole:
 a 3-page integrated summary of benefits and risks of fomepizole in treatment of EG
poisoning.
 an integrated summary of effectiveness data: This was submitted as a supplemental
NDA to the FDA to seek approval for fomepizole for treatment of methanol
poisoning.
 an integrated summary of safety.
 an integrated summary of effectiveness data, but this document could not be
accessed.
 an integrated summary of safety data. However, this was just a 2-page document
with an index of the actual integrated summary of safety that was provided in
Section 8.8 above.
– There were 272 literature references: these were submitted under 7 subheadings:
 ‘LBS’ had approximately 40 literature references, all of which were reviewed,
evaluated and summarised in the report.
 ‘References provided with dossier clinical trial data’ about 10 references which were
all reviewed and evaluated.
 ‘Diethylene glycol references’ about 8 of these were provided and read but none of
these were directly relevant to this submission and so were not evaluated.
 ‘Historical control comparison references’ about 54 references and 5 case reports
were provided which were reviewed and those relevant to this submission were
evaluated and summarised in the report.
 ‘Human PK references’ about 17 references some of which were animal studies;
these were read and when relevant evaluated.
 ‘Methanol references’ about 34 references majority of which were dated before
1980 with some as early as 1941. These were read but none were considered
directly relevant to this submission.
 ‘Section 8.13’ Approximately 100 references were submitted in this section of the
dossier and these were read and relevant ones evaluated and summarised in the
evaluation report.

3.2. Paediatric data

The submission did not include any paediatric clinical studies (conducted by the manufacturer).
However, some case reports and case series of use of fomepizole in treatment of EG and
methanol poisoning in infants and children were provided.

3.3. Good clinical practice

The 3 main studies submitted by the manufacturer were conducted according to GCP ICH
guidelines. Most of the other published studies were conducted with ethics approval from the
investigating centre.

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4. Pharmacokinetics

4.1. Studies providing pharmacokinetic data

Table 1 below shows the studies relating to each pharmacokinetic topic.
Table 1: Submitted pharmacokinetic studies

PK topic Subtopic Study ID

PK in healthy General PK - Single dose S-2

adults
S-3
Maraffa, 2008
Jacobsen, 1996

- Multi-dose McMartin , 2012

Bioequivalence† - Single dose S-2

- Multi-dose S-3

Food effect Not applicable.

PK in special Target population - Single dose S1

populations
S11

- Multi-dose S8 (EG poisoning)

S13 (methanol poisoning)

Hepatic impairment None

Renal impairment S12- Jobard, 1996

Neonates/infants/children/adolescents None

Elderly None

Gender related Males vs. females None

PK interactions Drug interaction study with ethanol Jacobsen, 1990 (Study S4)
Jacobsen, 1996

Drug interaction study with EG Studies S1 and S11

Population PK Healthy subjects None

analyses
Target population None

† Bioequivalence of different formulations.

§ Subjects who would be eligible to receive the drug if approved for the proposed indication.

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None of the pharmacokinetic studies had deficiencies that excluded their results from
consideration.

4.2. Summary of pharmacokinetics

The information in the following summary is derived from conventional pharmacokinetic
studies unless otherwise stated.
4.2.1. Pharmacokinetics in healthy subjects
Comment: 6 studies in healthy subjects (S-2, S-3, Jacobsen, 1990, Jacobsen 1996, Maraffa, 2008
McMartin, 2012). However, it is important to note that detailed study reports and
subsequent published articles were provided for studies S2 and S31 only.
It has been stated that Study S4 is actually the Jacobsen, 1990 reference, but this
was provided under ‘study report 6’. It appears that Study S6 is the Jacobsen, 1996
reference, but this is not clearly stated in the dossier and the sponsors have been
asked to clarify. Furthermore, there was no Study S5 submitted in the dossier
although it is mentioned in the various summaries.
4.2.2. Absorption
4.2.2.1. Sites and mechanisms of absorption
Results from studies S2 and S3 (described below) indicate that fomepizole (4MP) is rapidly and
completely absorbed following both oral and IV dosing such that plasma concentrations of 4MP
were identical within 30 minutes of administration of the oral and IV doses.
4.2.2.2. Bioavailability
Results from the Phase I single-dose, crossover Study S-2 in 6 healthy males showed that the
oral doses of 4MP were rapidly and completely absorbed, with a bioavailability of one. When the
same acute dose (7 mg/kg) was given by either IV or oral routes, comparable AUC's were
obtained reflecting similar plasma values after 30 minutes which may allow for the oral safety
data from the rest of the studies in this section to be supportive of the IV use of fomepizole
(Figure 1). Following absorption and distribution, 4MP was eliminated primarily by metabolism
to 4-carboxypyrazole 4-CP, which was excreted in the urine. The rate of 4-CP excretion in the
urine and of 4MP elimination from the plasma was identical after both oral and IV doses.
Figure 1: IV study Group averages of plasma 4MP levels over time

1 S3 study report was the basis of two publications:

-Jacobsen et al. ‘4-methylpyrazole: a controlled study of safety in healthy human subjects after single,
ascending doses.’ Alcoholism, Clinical and Experimental Research, 1988; 12(4) :516-22.
- Jacobsen D, et al. ‘Non-linear kinetics of 4-methylpyrazole in healthy human subjects.’ Eur J Clin
Pharmacal 1989; 37:599-604.

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In Study S3 after oral administration, 4MP was rapidly absorbed and then slowly eliminated
(Figure 2). In all dose groups, the time to peak plasma concentration was about 0.5 to 2 h. The
mean peak plasma concentrations of 4MP (SEM) were 132 (17), 326 (18), 759 (196) and 1425
(49) µmol/L after doses of 10, 20, 50 and 100 mg/kg, respectively. Thus each mg/kg of 4MP
dose produced an increase in the 4MP peak plasma concentration of about 13-16 µM.
Figure 2: Non-linear 4MP kinetics (Jacobsen et al)

Jacobsen, et al (1990): A placebo-controlled, double blind, multiple dose, sequential, ascending-

dose study was performed to determine the tolerance of 4MP in 21 healthy volunteers. Oral
loading doses of 4MP were followed by supplemental doses every 12 h through 5 days,
producing plasma levels in the therapeutic range. Dose schedule in Group 3 (oral loading dose
of 10 mg/kg, plus 5mg/kg every 12 h up to 36 h and then 10 mg/kg every 12 h up to 96 h)
appeared to be the best at maintaining therapeutic levels for up to 5 days (Figure 3).
Figure 3: Plasma elimination profile of 4MP in heathy males given multiple doses.

Limitations of this study

This study only evaluated oral dosing with fomepizole and was mainly a tolerability study. It
showed results which appear to be identical to those reported by McMartin, 2012.The sponsors
have been asked to clarify this.
McMartin, 2012 reported a single dose, crossover study in 5 healthy male subjects followed by a
double-blind, and multiple dose study in 21 healthy male subjects.
In the single dose study, the initial absorption and distribution of fomepizole was extremely
rapid following oral and IV single dosing and there were virtually no differences in the plasma

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concentrations after the different routes of administration within 15 minutes of dosing (Figure
1). The PK parameters after the oral and IV doses, calculated by regression analysis of the zero
order elimination, show that the Vd and the AUC IV (0.58 + 0.03 L/kg and 1885 + 121) were
virtually identical to that determined by the nonlinear model simulations (0.57+ 0.03 L/kg and
1851+130) indicating compatibility between the two analyses.
In the multiple dose study, in Group 1 (loading dose of 4MP of 10 mg/kg followed by
supplemental doses of 3 mg/kg every 12 h up to 96 h) and Group 2 (loading dose of 15 mg/kg
plus 5 mg/kg/12 h up to 96 h), the plasma levels remained in the 50 to 150 µM range for about
36 to 60 h. Then the levels decreased markedly so that 4MP was detectable for only 8 h after the
last administration. Thus, in order to produce relatively constant plasma levels throughout 5
days of treatment, the supplemental doses of 4MP were increased for subjects in Group 3 after
36 h of treatment (loading dose of 10 mg/kg, plus 5 mg/kg/12 h up to 36 h and then 10
mg/kg/12 h up to 96 h) (Figure 4). Such a dosing schedule generally maintained plasma levels
in the 100 to 200 µmol range throughout the 5 day treatment. Overall, the dose schedule in
Group 3 (loading dose of 10 mg/kg, plus 5 mg/kg/12 h up to 36 h and then 10 mg/kg/12 h up to
96 h) seems to be the best at maintaining therapeutic levels for up to 5 days. One of the original
goals of the present study was to evaluate the effect of 4MP on the ethanol elimination rate as a
model for its effect on ADH activity. Therefore, ethanol, 0.5 mg/kg, was given orally at 74 h to
the subjects in Group 1 (Figure 4). This interaction was, however, difficult to interpret because
the plasma 4MP levels were very low at 74 h. Thus, no ethanol was given to subjects in Groups 2
and 3. The 4MP and ethanol interaction was investigated in a separate study (Jacobsen, 1996)
which is discussed below.

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Figure 4: Plasma profile of 4MP in heathy males given multiple doses

Comment: Overall results from this well-conducted study confirmed that fomepizole is
eliminated in human subjects following therapeutic doses by saturable, nonlinear
kinetics and that, when humans are given multiple doses of fomepizole over a 5-day
period, the rate of elimination of fomepizole was increased markedly (2- to 3-fold)
within 3 days of such multiple dosing. This increase in the elimination of fomepizole
was associated with an enhanced urinary excretion of 4-CP, the primary urinary
metabolite of fomepizole, thus indicating most probably an induction of metabolism
of fomepizole. Supplemental doses of fomepizole need to be increased at the time
that the enhanced elimination occurs (about 36 – 48 h) in order to maintain
therapeutic fomepizole concentrations and validate the currently recommended
dosing schedule for fomepizole in EG/methanol poisoned patients.
Marrafa J, et al (2008) reported a prospective, randomised, crossover trial in 10 healthy
volunteers to describe comparative PKs of fomepizole after single oral and IV dose. Each
received 15 mg/kg fomepizole, PO and by 30 minute IV infusion. PO fomepizole was rapidly
absorbed with a bioavailability of ~100%. After oral and intravenous administration, the KM

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ranged from 0.24 to 3.1 μmol/L (mean = 0.94; SD 0.98) and the Vmax ranged from 6.5–31.4
μmol/L/hr (mean = 18.6; SD 9.6). The kinetics best fit a 2-compartment model with Michaelis-
Menten elimination, which is consistent with previous studies in humans and animals showing a
zero-order elimination process. The time above the presumed minimum effective concentration
of 10 µmol/L ranged from 24 to 36 h (mean = 32.4 h; SD: 5.8), for both routes of administration
(Figure 5).
Figure 5: Mean IV and PO fomepizole serum concentration over time

Comment: This was the first study that effectively determined a human Vmax and Km for PO
and IV fomepizole. Oral and IV administration of fomepizole resulted in similar
pharmacokinetic parameters.
4.2.2.3. Distribution
Volume of distribution
Both oral and IV doses were rapidly distributed, apparently to total body water (volume of
distribution of 0. 6 L/kg). These data would imply that 4MP would gain access to and rapidly
inhibit ADH activity in all tissues in the body including the main metabolic organ, the liver, and
the potential target organs, the CNS, eyes and kidneys (Study S-2).
4.2.2.4. Metabolism
Interconversion between enantiomers
Not applicable.
Sites of metabolism and mechanisms / enzyme systems involved
Although there are no studies in humans showing that fomepizole is metabolised by cytochrome
P-450, studies in rats and mice have shown that the primary metabolites of fomepizole are 4-
hydoxymethylpyrazole (4-OHMP) and 4-CP with smaller amounts of an N-glucuronide.
Following absorption and distribution, 4MP was eliminated primarily by metabolism to 4-
carboxypyrazole (4-CP), which was excreted in the urine. The rate of 4-CP excretion in the urine
and of 4MP elimination from the plasma was identical after both oral and IV doses (S-2).
Metabolites identified in humans
Up to 80 to 85% of a dose of fomepizole was collected in the urine as the primary metabolite (S-
2), 4- carboxypyrazole (4-CP). 4-CP is not an inhibitor of alcohol dehydrogenase. Other minor
metabolites of fomepizole are 4- hydroxymethylpyrazole, N-glucuronide conjugates of 4-
carboxypyrazole and 4-hydroxymethylpyrazole (Weintraub and Standish, 1988). These
metabolites are either inactive or are so weak (4-hydroxymethylpyrazole) that they could not
contribute significantly to the inhibition of ADH seen with doses of fomepizole used clinically.

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4.2.2.5. Excretion
Routes and mechanisms of excretion
In Study S-2, the urinary excretion of unchanged 4MP is not a major route of elimination as the
total amount of 4MP recovered unchanged in the urine ranged from l to 3 % of the administered
dose. No difference in urinary 4MP excretion was seen between subjects when treated that is,
and orally. In earlier studies in human subjects, the primary metabolite of 4MP in the urine was
4-carboxypyrazole (4-CP), which accounted for about 72-86 % of the dose. There were no
differences in the production and excretion of 4-CP between the two routes of administration,
both in terms of the rate and of the total amount of excretion. 4-CP excretion was complete
within 36 h in all subjects, except IV-3 who showed excretion through 48 h. As in previous
studies, the major metabolite of 4MP was 4-CP, accounting for 54-82 % of the dose (mean, 65-
66%).
S3 was the Phase I, placebo-controlled single dose, sequential, ascending dose study in 22
healthy males to determine the tolerability of 4MP at dose levels of 10 (n=4), 20 (n=4), 50 (n=4)
and 100 mg/kg (n=3). Along with each dose group, there were two placebos except with the 100
mg/kg group where there was only one placebo. Single oral dose of 4MP (10-20 mg/kg)
produced plasma levels within a probable therapeutic range. After oral administration, 4MP was
rapidly absorbed and then slowly eliminated (Figure 2). In the 10 and 20 mg/kg groups, the
elimination of 4MP from the plasma followed non-linear kinetics with mean rates of
concentration decline of 3.66 and 5.05µmol/L/h, respectively. In the two highest dose groups,
the elimination also appeared to be non-linear although PK sampling was not done long enough
to confirm this. The average renal clearance of 4MP was low (0.016 mL/min) and only 3% of the
administered dose was excreted unchanged in the urine, indicating metabolism as the major
route of elimination.
Comment: Overall, results from this study showed that elimination of 4MP represented zero-
order kinetics at the two lowest doses (10 and 20 mg/kg). At the 2 highest doses (50
and 100 mg/kg), the elimination of 4MP was most likely zero order although this
could not be determined since the plasma concentration decline was not followed
long enough. Hence, multiple dose studies would be required to confirm PKs of
fomepizole at proposed dosing schedules.
It is important to note that the study report was the basis of 2 publications:
i. Jacobsen et al. ‘4-methylpyrazole: a controlled study of safety in healthy human
subjects after single, ascending doses. ‘Alcoholism, Clinical and Experimental
Research, 1988; 12(4):516-22.
ii. Jacobsen D, et al. ‘Non-linear kinetics of 4-methylpyrazole in healthy human
subjects.’ Eur J Clin Pharmacol 1989; 37:599-604.
Renal clearance
Renal clearance of fomepizole after acute treatment accounted for 1.4 to 3.5% of the dose across
all studies and was not affected by the size of the dose. Significantly more of the metabolite 4-CP
was excreted in the urine after higher doses. The rate of 4-CP excretion, however, was similar
among the high and low dose groups, suggesting saturation kinetics occurs in the pathway of 4-
CP formation and excretion.
4.2.2.6. Intra- and inter-individual variability of pharmacokinetics
The plasma half-life of Antizol varies with dose, even in patients with normal renal function;
intra and inter-individual variability has not been calculated.

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4.2.3. Pharmacokinetics in the target population

4.2.3.1. S1
The first pharmacokinetic data for 4MP in patients with ethylene glycol poisoning was reported
by Beng, et al, 1992. An initial dose of 10 to 20 mg/kg permits the achievement of plasma
concentrations >10 µmol/L, which are therapeutically effective. This level can be maintained by
the injection of lower doses every 12 h. The distribution volume of 4MP was 1 L/kg. Its body
clearance is 0.70 mL/min/kg and renal clearance is much lower (0.03 mL/min/kg). Its kinetics
is complex and dose dependent. It is first order at low doses (2-4 mg/kg) and zero order at high
doses (8-16 mg/kg) (Figure 6). These same results were presented in another figure using
Cartesian coordinates, the time being recorded for each dose starting from its moment of
administration. It can be seen that in the elimination phase, for at least seven h, the lowering of
the blood concentration for high doses is proportional to time, and depends little on the
concentration indicating zero order elimination kinetics. Similar results have been observed in
healthy subjects treated with 4MP.
Figure 6: Trend in the plasma concentration of 4MP with time. Each arrow head indicates
administration of a new 4MP dose. Cp=f(t)

4.2.3.2. S11
The single case report of ethylene poisoning in a 30-year old male showed that the EG half-life
was 16 h during 4MP treatment compared to a normal half-life of 3h. Such a prolonged half-life
especially strongly suggests reduced hepatic metabolism of ethylene glycol as a direct result of
the presence of 4MP. Absence of ethanol in the plasma of this patient eliminated the possibility
of ethanol contributing to the therapeutic effect of 4MP. It is important to note that the patient
was conscious, had only mild acidosis and normal renal function on admission and was also
administered 4MP within 3 h of accidental ingestion of ethylene glycol.
4.2.3.3. S8
In Study S-8 (discussed in detail in section Other efficacy studies), six of the seven patients
consistently had plasma levels of fomepizole that were therapeutic (>10 µmol/L or >0.82
mg/L). One of these six patients had a transient rise in plasma glycolate levels after levels fell
following the initiation of fomepizole therapy (Figure 7. This occurred when his plasma
fomepizole level had fallen to 118 µmol/L (9.7 mg/L), one of the lower levels observed for
patients in this trial, although still well in excess of the fomepizole plasma level believed to be
therapeutic (Figure 7). The two possibilities that would most likely explain this observation are
1) haemodynamic instability preventing clearance of any glycolate formed because of decreased
delivery of the metabolite to the kidneys and dialyser, and/or 2) insufficient inhibition of
ethylene glycol metabolism at this plasma level of fomepizole. This patient was in cardiogenic
shock at the time of enrolment. At the time this elevated glycolate measurement was detected,
he was hypotensive and it is likely that this contributed to the observed rise in plasma glycolate.

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This conclusion is supported by the next plasma glycolate determination which showed a
profound fall despite lower fomepizole levels (85.7 µmol/L or 7.0 mg/L).
Figure 7: PK results from patients poisoned with ethylene glycol in Study S8

Another patient had low measured plasma fomepizole levels at 2 h (10.8 µmol/L or 0.89 mg/L)
and 4 h (0 µmol/L) after his loading dose, despite being apparently administered an appropriate
dose (Figure 7). This patient refused further blood sampling after 4 h and subsequent
fomepizole levels were not obtained. This patient presented with a baseline EG level of 51.0
mg/dL and had no detectable ethanol in his system. The patient was placed on dialysis but not
until 8 h after the loading dose of trial drug was given. Both EG and plasma glycolate levels
dropped for this patient prior to haemodialysis. The EG level dropped from 51 mg/dL to 18
mg/dL within the first 8 h. Similarly, the plasma glycolate levels dropped from 10 to 5.9 µmol/L
within the first 4 h after the administration of the loading dose. It is unknown whether a
dispensing error caused him to have such a low level. Despite the low levels of fomepizole in
this patient, he did well and had no sequelae from his poisoning. The fomepizole level of 10.8
µmol/L (0.89 mg/L) obtained at two h post-loading dose, while less than predicted, should have
been sufficient in inhibit EG metabolism. Fomepizole levels fell faster during haemodialysis than
due to endogenous clearance alone. During haemodialysis, levels fell at a median rate of 0.80
µmol/L/minute (range 0.27 to 4.4). In the absence of haemodialysis, levels fell at a median rate
of 0.33 µmol/L/minute (range 0.1 to 0.83). Fomepizole appeared to be effectively removed by
haemodialysis and median clearance of fomepizole by dialysis was 183 mL/min (range 129 to
218).
Comment: Overall, data on fomepizole plasma levels from Study S-8 in seven patients treated
with fomepizole for EG poisoning demonstrated that a loading dose of 15 mg/kg
and supplemental dosing with 10 to 15 mg/kg every 12 h maintained fomepizole
levels in the therapeutic range. Fomepizole was cleared more rapidly following
haemodialysis suggesting that no frequent dosing with fomepizole may be required
to maintain therapeutic levels.
4.2.3.4. S-13
In Study S-13, the fomepizole dosing regimen used in 11 patients with methanol poisoning
consistently maintained plasma levels of fomepizole that were considered therapeutic (>10
µmol/L or >0.82 mg/L). Except for one patient 2, all patients received an initial fomepizole dose
as a 30-minute infusion of 15 mg/kg (182.7µmol/kg). Subsequent dosing with fomepizole

2Due to the comatose status of Patient [information redacted], an error was made in estimating the patient's weight
so that he actually received a loading dose of 22.0 mg/kg.

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occurred via a defined protocol, but was somewhat variable among the patients due to
variations in the timing and duration of haemodialysis periods, which influenced the fomepizole
dosing. Hence, it was not possible to summarise plasma levels of fomepizole at designated time
intervals. Cmax ranged from 173-560 µmol/L, with mean and median values of 310 and 272,
respectively. The peak often occurred following the initial dose (six of 11 patients), but
sometimes after subsequent doses. Mean and median time to maximum concentration levels
(Tmax) values were 12.1 and 3.8 h, respectively. Because of the repeated fomepizole dosing, there
were defined peaks and troughs in the plasma concentration profile in nine of 11 subjects. The
trough level of fomepizole at steady state could be determined (Cmin at time Tmin). The mean and
median Cmin were 86 and 61µmol/L, while the mean and median minimum times Tmin were 18.4
and 12 h, respectively. The number of blood sampling points after each dose of fomepizole was
limited in Study S-13 because of the anticipated poor medical condition of many of these
patients. Hence, the data points are insufficient to calculate the Michaelis-Menten parameters
(Km and Vmax). However, the zero-order elimination phase could be computed in most cases after
at least one dose of fomepizole to assess the nonlinear elimination of fomepizole in these
patients.
These rates of elimination were determined repeatedly after multiple doses in some of the
patients and were very consistent within each patient. The mean and median rates of
fomepizole elimination were 13.0 and 14.8 umo1/L/h, respectively. The rate of fomepizole
elimination in these patients was somewhat greater than those determined in healthy
individuals after intravenous administration of 5 or 7 mg/kg doses of fomepizole (5.8 µmol/L/h
in Jacobsen, 1989). During the haemodialysis periods, the total plasma clearance of fomepizole
was primarily determined by dialysis, which is a first-order kinetic process. Hence, during the
haemodialysis periods, the kinetic parameters demonstrated linear pharmacokinetics and the
plasma clearance was approximately three times faster in patients undergoing dialysis than in
undelayed patients. The mean and median Vct were 0.68 and 0.66 L/kg, respectively suggesting
that fomepizole is distributed to the total body water in these patients and is similar to the Vd in
healthy (0.74L/kg in Jacobsen, 1989).
4.2.4. Pharmacokinetics in other special populations
4.2.4.1. Pharmacokinetics in subjects with impaired hepatic function
Not evaluated.
4.2.4.2. Pharmacokinetics in subjects with impaired renal function
Jobard, 1996 (Study S12) reported two cases of severe ethylene glycol poisoning with renal
failure who were treated with 4MP and haemodialysis; due to elimination of 4MP in the
dialysate, a loading dose of 4MP 10-20 mg/kg was followed by continuous IV infusion of 1 to
1.5mg/kg/h during the 8-12 h of haemodialysis. The patient characteristics and clinical
outcomes in these patients were summarised. S-12 determined PK parameters for fomepizole
when used during dialysis in two aneuric patients. The plasma 4MP concentrations were 9 and
25.6mg/L at the beginning of dialysis in Patients 1 and 2 who received a loading dose of 10 and
20 mg/kg of 4MP, respectively. During dialysis, the plasma 4MP concentrations fell rapidly. In
Patient 1, a 4MP infusion of 2.5 mg/kg/h for 2 h was needed to compensate the decrease of 4MP
concentrations after four h of haemodialysis. Despite this infusion, the plasma 4MP
concentrations were very low at the end of dialysis, but this was not deleterious for the patient
because plasma EG concentrations were also very low over the same period. In contrast in
Patient 2, continuous infusion of 4MP at a rate of 1.5 mg/kg/h during dialysis after a loading
dose maintained plasma 4MP concentrations above 14 mg/L (Figure 8). The death of this
patient admitted very late after massive EG ingestion with a flat electroencephalogram cannot
be attributed to failure of treatment. The calculated volume of distribution of 4MP was 0.8 L/kg.
The amount of 4MP eliminated in the dialysate reached about 45% of the total elimination of
4MP for 12 and 8 h of haemodialysis for Patients 1 and 2, respectively.

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Figure 8: Plasma 4MP and EG versus Duration of haemolysis

4.2.4.3. Pharmacokinetics according to age

Not evaluated.
4.2.4.4. Pharmacokinetics related to genetic factors
Not applicable.
4.2.4.5. Pharmacokinetics {in other special population / according to other
population characteristic}
None.
4.2.5. Pharmacokinetic interactions
4.2.5.1. Pharmacokinetic interactions demonstrated in human studies
Fomepizole and ethylene glycol
Two publications, S-1 and S-11, describe drug interactions during the successful use of
fomepizole to treat single cases of ethylene glycol poisoning. Ethylene glycol decreased the renal
clearance of fomepizole from values of 1-2.5 mL/min in volunteers (S-2 and S-3) to 0.032
mL/min in a single reported case of poisoning treated with fomepizole (S-1). Likewise, it was
shown that fomepizole prolonged the half-life of ethylene glycol in a single reported case of
ethylene glycol poisoning from the reported values in the literature of approximately 3 h to
approximately 16 h (S-11).

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Fomepizole and ethanol

Previous studies in rats have shown that very large doses of ethanol can inhibit the elimination
of 4MP from the plasma, presumably by inhibiting the cytochrome P-450 mediated oxidation of
4MP. Many patients poisoned with methanol or ethylene glycol will also exhibit moderate
amounts of ethanol in the bodies (blood levels of 50 to 150 mg/dL), either because of co-
consumption or because of initial therapeutic use of ethanol.
One of the original goals of the study reported by Jacobsen (1990) was to evaluate the effect of
4MP on the ethanol elimination rate as a model for its effect on ADH activity. Therefore, ethanol,
0.5 mg/kg, was given orally at 74 h to the subjects in Group 1. This interaction was, however,
difficult to interpret because the plasma 4MP levels were very low at 74 h. Thus, no ethanol was
given to subjects in Groups 2 and 3. The 4MP and ethanol interaction was investigated in a
separate study which is discussed below.
Jacobsen D, 1996 was a study which examined whether moderate amounts of ethanol would
alter 4MP elimination in healthy human subjects. This study was conducted in 2 parts:
Study A showed that single oral therapeutic doses of 4MP (10, 15 and 20 mg/kg) inhibited
ethanol elimination in healthy humans by approximately 40%; 4MP concentrations in the range
of 120 to 260 pmol/L were sufficient to inhibit ethanol elimination, thus to inhibit ADH activity.
In Study B, ethanol was administered in doses that would produce moderate blood levels likely
to be observed in clinical situations. The ethanol dose schedule was sufficient to maintain blood
ethanol levels in the range of 50 to 150 mg/dL for at least 6 h. This duration was needed to test
for an effect on 4MP elimination, which was known to be slow and nonlinear. The inhibitory
effect of ethanol was not readily apparent until 8 h after dosing (Figure 9).
Figure 9: Effect of ethanol on 4MP plasma concentration in healthy humans

Kinetic analysis of the plasma levels during the apparent zero-order elimination phase showed
that ethanol inhibited the rate of concentration decline of 4MP by 50%. Ethanol did not alter the
volume of distribution of 4MP. Ethanol significantly inhibited the rate of 4-CP excretion in the
urine during the initial 10 h. After ethanol was cleared from the body, there was an apparent
rebound in 4-CP excretion. Also, the total recovery of 4-CP was not affected by ethanol (51.0 2
6.8% of dose vs. 51.2 2 8.5% for placebo subjects). Neither the rate nor the total urinary
excretion of unchanged 4MP (accounting for -2% of the dose) was affected by ethanol.
Comment: Overall, results from this study showed that that socially relevant concentrations of
ethanol can inhibit the elimination of 4MP, most likely by inhibiting the metabolism
of 4MP to 4-CP. Such an interaction should enhance the effectiveness of 4MP by
increasing the duration of inhibition of ADH activity.
As methanol has a much lower (-1/10) affinity for ADH, such doses of 4MP will most
likely cause a marked inhibition of methanol metabolism in humans. Ethylene glycol

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has an even lower affinity for ADH, and the inhibition of its metabolism should be
more complete, as has been demonstrated in clinical studies and case reports in this
submission. Drug interaction studies were not conducted to evaluate effects of other
ADH inhibitors and induction of the elimination of fomepizole by other enzyme
inducers that affect the cytochrome P-450 enzyme system.
4.2.5.2. Clinical implications of in vitro findings
Not applicable.

4.3. Evaluator’s overall conclusions on pharmacokinetics

4.3.1. Absorption and bioavailability
Although fomepizole is intended for use by the IV route in ethylene glycol and methanol
poisoning it has also been studied by the oral route. Single acute oral doses (7 to 50 mg/kg)
were rapidly absorbed (S-2, S-3, S-4, S-6) reaching maximum plasma concentrations in
volunteers between 1 to 2 h after dosing. T-max occurred at various times later in studies of
multiple oral doses (S-4), depending on the magnitude of the doses. Study S-2 demonstrates that
when the same acute dose (7 mg/kg) was given by either IV or oral routes, comparable AUC's
were obtained reflecting similar plasma values after 30 minutes. This allows for the oral safety
data from the rest of the studies in this section to be supportive of the IV use of fomepizole.
4.3.2. Distribution
Fomepizole distributed rapidly and widely to the total body water with a volume of distribution
between 0.60 to 1.0 L/kg depending on the study and subjects evaluated (healthy or patients
with ethylene glycol/ methanol poisoning) (Table 2).
Table 2: Plasma 4MP levels oral dosing 7 mg/kg (85.3 µmol/kg)

4.3.3. Metabolism and excretion

Fomepizole induced its own metabolism after 36 h of repeated dosing (S-4). After auto-
induction, a first order kinetic model more closely described the elimination of fomepizole. 4-CP
is formed from fomepizole after an initial cytochrome P-450 mediated hydroxylation that is
followed by further oxidation. Up to 80% to 85% of a dose of fomepizole was collected in the
urine as the primary metabolite (S-2), 4- carboxypyrazole (4-CP). 4-CP is not an inhibitor of
ADH. Other minor metabolites of fomepizole are 4- hydroxymethylpyrazole, N-glucuronide
conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole (Weintraub and Standish,
1988). These metabolites are either inactive or are so weak (4-hydroxymethylpyrazole) that

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they could not contribute significantly to the inhibition of ADH seen with doses of fomepizole
used clinically.
Fomepizole is eliminated in human subjects following therapeutic doses by saturable nonlinear
kinetics. Furthermore, when humans are given multiple doses of fomepizole over a 5-day
period, the rate of elimination of fomepizole was increased markedly (2- to 3-fold) within 3 days
of such multiple dosing. This increase in the elimination of fomepizole was associated with an
enhanced urinary excretion of 4-CP, the primary urinary metabolite of fomepizole, thus
indicating most probably an induction of metabolism of fomepizole. Only 1 to 3.8% of the
administered dose of fomepizole was excreted unchanged in the urine (S-2, S-3, S-4, S-5, S-6, S-
11) regardless of the dose magnitude.
The plasma half-life of Antizol varies with dose, even in patients with normal renal function;
intra- and inter-individual variability has not been calculated.
Most pharmacokinetic studies in humans have also suggested that fomepizole is eliminated by
saturable, nonlinear kinetics after doses in the therapeutic range. This elimination is most likely
due to metabolism since < 5% of the given dose is excreted unchanged in the urine.
4.3.4. PK data to support proposed dosing recommendations for fomepizole
In Study S3, the rate of elimination of fomepizole was increased markedly (2 to 3-fold) within 3
days of multiple dosing. This increase in the elimination of fomepizole was associated with an
enhanced urinary excretion of 4-CP, the primary urinary metabolite of fomepizole, thus
indicating most probably an induction of metabolism of fomepizole. Hence, supplemental doses
of fomepizole need to be increased at the time that the enhanced elimination occurs (about 36-
48 h) in order to maintain therapeutic fomepizole concentrations. Data from the multiple dose
part of study (Jacobsen, 1990) demonstrated that the 4MP dosing schedule that seems to be the
best at maintaining therapeutic levels for up to 5 days was: loading dose of 10 mg/kg, plus 5
mg/kg/12 h up to 36 h and then 10 mg/kg/12 h up to 96 h. The IV dosage of fomepizole
proposed in this submission is 15 mg/kg as a loading dose, followed by 10 mg/kg every 12 h, if
indicated, for 4 doses (to 48 h) and 15 mg/kg thereafter until blood levels of ethylene glycol are
<20 mg/L. Oral dosing studies (S-3, S-4, S-6) that included doses of up to 100 mg/kg support the
proposed clinical IV dosage.
4.3.5. Drug interactions
Results of Study S6 (Jacobsen, 1996) in healthy subjects showed that that socially relevant
concentrations of ethanol can inhibit the elimination of 4MP, most likely by inhibiting the
metabolism of 4MP to 4-CP. Such an interaction should enhance the effectiveness of 4MP by
increasing the duration of inhibition of ADH activity. As methanol has a much lower (-1/10)
affinity for ADH, such doses of 4MP will most likely cause a marked inhibition of methanol
metabolism in humans. Ethylene glycol has an even lower affinity for ADH, and the inhibition of
its metabolism should be more complete, as has been demonstrated in clinical studies and case
reports in this submission. Drug interaction studies were not conducted to evaluate effects of
other ADH inhibitors or induction of the elimination of fomepizole by other enzyme inducers
that affect the cytochrome P-450 enzyme system.

4.3.6. Limitations of the pharmacokinetic data

Drug interaction studies were not conducted to evaluate effects of other ADH inhibitors and
induction of the elimination of fomepizole by other enzyme inducers that affect the cytochrome
P-450 enzyme system.
No specific PK studies were conducted in patients with renal hepatic impairment or in the
paediatric population.

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5. Pharmacodynamics

5.1. Studies providing pharmacodynamic data

No specific pharmacodynamics studies were conducted in humans.
Reports of 9 studies that evaluated the safety and/or the pharmacological activity of fomepizole
in normal healthy subjects or in patients poisoned with ethylene glycol/ methanol have been
discussed in Section 4 above.

5.2. Summary of pharmacodynamics

5.2.1. Mechanism of action
Antizol (fomepizole) is a competitive inhibitor of alcohol dehydrogenase (ADH) which catalyses
the oxidation of ethanol to acetaldehyde. ADH also catalyses the initial steps in the metabolism
of ethylene glycol and methanol to their toxic metabolites. Fomepizole (4MP) has been shown in
vitro to block ADH enzyme activity in dog, monkey and human liver. The concentration of
fomepizole at which ADH is inhibited by 50% in vitro is approximately 0.1 µmol/L.
Ethylene glycol, the main component of most antifreezes and coolants, is metabolised to
glycoaldehyde and oxalate. Glycolate and oxalate are the metabolic by-products primarily
responsible for the metabolic acidosis and renal damage seen ethylene glycol toxicoses. The
lethal dose of ethylene glycol in humans is approximately 1.4 mL/kg. Methanol, the main
component of windshield wiper fluid, is slowly metabolised via alcohol dehydrogenase to yield
formic acid. Formic acid is primarily responsible for the metabolic acidosis and visual
disturbances (for example, decreased visual activity and potential blindness) associated with
methanol poisoning. A lethal dose of methanol in humans is approximately 1- 2 mL/kg.
5.2.2. Pharmacodynamic effects
5.2.2.1. Primary pharmacodynamic effects
Fomepizole has been shown in vitro to block ADH enzyme activity in dog, monkey and human
liver. The concentration of fomepizole at which ADH is inhibited by 50% in vitro is
approximately 0.1 µmol/L.
No specific PD studies were conducted in humans. Results from preliminary studies in patients
(S10, S11, S12; Table 3) provide evidence that Antizol blocks ethylene glycol and methanol
metabolism mediated by ADH in the clinical setting. Plasma concentrations of toxic metabolites
of ethylene glycol and methanol failed to rise in the initial phases of fomepizole treatment.
However, interpretation of the relationship of this effect to fomepizole therapy was confounded
by haemodialysis and significant blood ethanol concentrations in many of the patients.
Nevertheless, in the post-dialysis period(s), when ethanol concentrations were insignificant and
the concentrations of ethylene glycol or methanol were > 20 mg/dL, the administration of
fomepizole alone blocked any rise in glycolate or formate concentrations, respectively.
Table 3: Studies S10, S11 and S12: case reports of 4MP treatment of ethylene glycol

Authors, Details of case Treatment Clinical Conclusion

publication reports given course/ s/
sequelae comments

Baud, et al. In a suicide Initial treatment Clinical Repeated IV

“Treatment of attempt, a consisted of course was administrati
ethylene glycol previously healthy gastric uneventful; on of 4MP
poisoning with 42-year-old man aspiration, oral patient was

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Authors, Details of case Treatment Clinical Conclusion

publication reports given course/ s/
sequelae comments
intravenous 4- ingested Approx. administration regained full effective in
methylpyrazole.” 1.5L of antifreeze of activated consciousnes this case of
New England solution containing charcoal. 4MP s, no EG
Journal of 92.9% EG (23,500 dose of 9.5, 7, seizures, EEG poisoning
Medicine, Vol. mmol, or 1457 g). 3.5, 1.2 and normal; although
319, No. 2, July Vomiting and 0.5mg/kg at 9, metabolic normal
1988. polyuria soon 21, 33, 45 and acidosis did renal
developed. On 56 hrs till only not recur; function and
Reported as
admission to the traces of EG serum rapid
Study S10 in the
hospital 4.5 hours were present in creatinine clinical
dossier
later, the patient plasma samples. remained improveme
was drowsy. His normal nt are
plasma throughout necessary to
bicarbonate level hospitalisati allow use of
was 13mmol/L on; patient specific
with an anion gap discharged antidotal
of 17.5 mmol/L, from ICU treatment
and his serum after 3 days alone.
creatinine and from
concentration was hospital after
82 µmol/L. 7 days.

Harry et al, 30-year-old man, Given gastric Elevated The EG half-

“Efficacy of 4- 74kg, mentally lavage and anion gap life was 16 h
methylpyrazole retarded and activated and during 4MP
in ethylene slightly deaf charcoal on metabolic treatment.
glycol poisoning: accidentally admission. First acidosis Compared
Clinical and ingested 100 g IV dose of 4MP disappeared to normal
toxicokinetic ethylene glycol; pt was 1200mg within 4 h; half-life of
aspects.” Human was conscious at infused over no renal, 3hrs. The
and admission. Initial 30mins within neurological prolonged
experimental EG plasma level 3hrs of and cardiac half-life
toxicology: was 3.5g/L with no intoxication; toxicity due suggests
1994, 13: 61-64. ethanol. subsequent to hepatic EG reduced
doses of 4MP metabolites hepatic
Reported as
were 600, 400, and metabolism
Study S11 in the
200 and 100mg haemodialysi of EG as a
dossier
given every 12 s was not direct result
hours till plasma required. of the
concentration of Urinary presence of
EG was <0.1g/L. oxalate 4MP.
excretion Prompt
and serum treatment
calcium with IV 4MP
remained in a patient
normal with EG
throughout poisoning
the first 20 h. with normal
Osmotic renal
diuresis was function
observed was
which led to effective
moderately

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Authors, Details of case Treatment Clinical Conclusion

publication reports given course/ s/
sequelae comments
severe and safe.
dehydration.

Jobard, et al. “4- Both patients The 30 yr old Data from

Methylpyrazole intubated, man recovered these 2
and ventilation; 30 yr from coma in 48 patients
haemodialysis in old man given IV h, anuria and suggested
ethylene glycol loading dose of 10 haemodialysis that in cases
poisoning.” mg/kg 4MP, then given for 8 days; of severe EG
Clinical haemodialysis hospital stay of poisoning
Toxicology, started; between 14 days and with toxic
34(4), 373-377 4-6hr of dialysis, complete plasma EG
(1996). infusion of 2.5 recovery levels and
mg/kg/h of 4MP observed. renal failure,
Reported as
given to a 4MP
Study S12 in the The 50yr old
compensate for loading dose
dossier man had flat
loss of 4MP in of 10-
EEG and QRS
dialysate. The 20mg/kg
complexes along
50yr old man given followed by
with severe
4MP loading dose continuous
acidosis, anuria
of 20mg/kg, one hr infusion of 1
on admission,
later to
despite
haemodialysis 1.5mg/kg/h
symptomatic
started and during the 8-
treatment- he
maintenance dose 12 hrs of
had
of 4MP haemodialysi
haemodynamic
1.5mg/kg/h s may be
instability and
infused during effective.
died 48hr after
haemodialysis.
admission due
to multiorgan
failure and
disseminated
intravascular
coagulation.

5.2.2.2. Secondary pharmacodynamic effects

Not evaluated.
5.2.2.3. Time course of pharmacodynamic effects
In the study reported by McMartin, 2012 (in healthy subjects, the time above the presumed
minimum effective concentration of 10µmol/L ranged from 24 to 36 h (mean = 32.4 h; SD: 5.8),
for both oral and IV routes of administration (Figure 1).
5.2.2.4. Relationship between drug concentration and pharmacodynamic effects
Based on animal studies, the presumed minimum effective concentration of fomepizole in
humans is 10 µmol/L. These concentrations were associated with inhibition of metabolism of
ethylene glycol in some preliminary studies in patients with ethylene glycol poisoning (refer
section Summary of pharmacokinetics above).

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In Study S11, the half-life of ethylene glycol was prolonged to 16 h during fomepizole treatment
compared to a normal half-life of 3 h. Such a prolonged half-life suggests reduced hepatic
metabolism of ethylene glycol as a direct result of the presence of fomepizole.
5.2.3. Genetic-, gender- and age-related differences in pharmacodynamic response
Not evaluated.
5.2.4. Pharmacodynamic interactions
Fomepizole can inhibit the metabolism of ethanol and ethylene glycol, and these substances in
turn inhibit the elimination of fomepizole. Study S6 evaluated the inhibitory or interaction
effects of fomepizole, ethanol and ethylene glycol all of which are substrate inhibitors of ADH.
Results of this study in healthy subjects showed that socially relevant concentrations of ethanol
can inhibit the elimination of 4MP, most likely by inhibiting the metabolism of 4MP to 4-CP. Such
an interaction should enhance the effectiveness of 4MP by increasing the duration of inhibition
of ADH activity. Drug interactions with other ADH inhibitors and induction of the elimination of
fomepizole by other enzyme inducers that affect the cytochrome P-450 enzyme system would
be expected but were not specifically evaluated.

5.3. Evaluator’s overall conclusions on pharmacodynamics

Fomepizole has been shown in vitro to block ADH enzyme activity in dog, monkey and human
liver. The concentration of fomepizole at which ADH is inhibited by 50% in vitro is
approximately 0.1 µmol/L. No specific pharmacodynamics studies were conducted in humans.
However, preliminary studies in patients with ethylene glycol/ methanol poisoning (S10, S11,
S12) provided evidence to support the mechanism of action of fomepizole in the proposed
indications.

6. Dosage selection for the pivotal studies

Fomepizole has been shown in vitro to block ADH activity in dog, monkey and human liver. The
concentration of fomepizole at which alcohol dehydrogenase is inhibited by 50% in vitro is
approximately 0.1 µmol/L.
In a study of dogs given a lethal dose of ethylene glycol, three animals each were administered
fomepizole, ethanol or left untreated (control group). The three animals in the untreated group
became progressively obtunded, moribund, and died. At necropsy, all three dogs had severe
renal tubular damage. Fomepizole or ethanol, given 3 h after ethylene glycol ingestion,
attenuated the metabolic acidosis and prevented the renal tubular damage associated with
ethylene glycol intoxication.
Several studies have demonstrated that Antizol plasma concentrations of approximately 10
µmol/L (0.82 mg/L) in monkeys are sufficient to inhibit methanol metabolism to formate, which
is also mediated by ADH. Based in these results, concentrations of Antizol in humans in the
range of 100 to 300 µmol/L (8.6–24.6 mg/L) have been targeted to assure adequate plasma
concentrations for the effective inhibition of ADH.
In healthy volunteers, oral doses of Antizol (10–20 mg/kg) significantly reduced the rate of
elimination of moderate doses of ethanol, which is also metabolised through the action of ADH.
No specific studies were conducted to determine dosage selection for the pivotal studies.

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7. Clinical efficacy

7.1. Treatment of ethylene glycol poisoning

7.1.1. Pivotal efficacy studies (submitted by the Manufacturer)
7.1.1.1. Study S7 (OMC-4MP-3)
Study design, objectives, locations and dates
S-7 was a retrospective, open label study for patients treated in France with 4-methylpyrazole
(4MP) for ethylene glycol poisoning. The main objectives of this study were: (1) To determine
the- efficacy, safety, tolerance and PK profile of 4MP in ethylene glycol poisoned patients, (2) To
determine the safety, tolerance and PK profile of 4MP in patients with suspected ethylene glycol
poisoning, but who in fact were later determined to have no ethylene glycol poisoning, (3) To
determine the efficacy, safety, tolerance and PK profile of 4MP in patients with methanol
poisoning.
The first patient was treated in January 1982 and the last patient in December 1995.
Retrospective data collection took place at one study centre in France during a six-month period
from April 1996 to September 1996. Data was collected on paper Case Report Form from
original patient case records and was entered into a single database on an ongoing basis. The
database was frozen on October 14, 1996, after which study data was analysed.
Comment: Due to the retrospective nature of the study, patients were treated on
‘compassionate grounds’ and were not part of a prospective well-defined research
program and were not subject to French GCP regulations. No ethics approval or
informed consent was considered necessary since the anonymity of the patients
was confirmed and the confidential nature of the documents seen and used in this
study was respected at all times.
Inclusion and exclusion criteria
Data from a patient were to be collected if the patient was given 4MP therapeutically as an
antidote for suspected ethylene glycol or methanol poisoning from 1981 to 1995. Patients were
to be included whether or not they were actually confirmed to be poisoned with EG or
methanol. The following data regarding how the diagnosis of EG poisoning was established
were collected (if available): serum or blood EG level, urine EG level, osmolar gap, anion gap,
arterial pH, serum bicarbonate, presence of oxalate crystals in urine.
The investigators assessed the clinical severity of intoxication based on blood and urine
concentrations of EG or methanol, time of presentation after exposure and laboratory values,
such as anion gap, pH and serum creatinine; the overall severity of the intoxication was based
on the highest value found in any category.
Study treatments
4MP was administered as emergency treatment for acute EG poisoning according to the
experience and normal practice of the treating physician. As far as possible, the following data
related to 4MP treatment were collected for each patient eligible for the data collection: loading
dose and all supplemental doses, amount of 4MP dose (mg/kg), time of dose, 4MP preparation
(hydrochloride or sulphate salt), administration route (oral, IV), length of time of infusion,
diluent used for administration, reason for discontinuation of 4MP dosing (for example, EG level
below detectable limits).
Efficacy variables and outcome
The following data were collected while the patient was being treated with 4MP (if available):
Clinical laboratory assessments: 4MP levels, EG levels (plasma or serum), urinary/ plasma
oxalate level, ethanol level, arterial blood gases, lactate level, chemistry profile including

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electrolytes, complete blood count, urinalysis, ECG, vital sign measurements and adverse events
(AEs). If patients required haemodialysis as part of their treatment, the criteria for its initiation
and its duration were recorded. After dosing with 4MP had been discontinued, the clinical
laboratory assessments mentioned above were again collected.
The efficacy of 4MP treatment was based on the ability of 4MP to prevent mortality and severe
morbidity associated with EG poisoning including kidney and cardiac function abnormalities.
Secondary efficacy analyses included evaluations of the effect of 4MP on metabolic acidosis
caused by EG ingestion.
Analysis populations, statistical methods
Data on 38 patients was collected, of whom 26 subjects presented with confirmed EG poisoning
and were treated with 4MP (Cohort A). Five patients were treated with 4MP for methanol
poisoning, all of whom had documented methanol levels in the blood (Cohort B). A further seven
patients were treated with 4MP for suspected but later unconfirmed EG poisoning (Cohort C).
The efficacy analysis was performed on patients treated with 4MP for confirmed EG poisoning
(Cohort A). The safety analysis was performed on an Intention-to-Treat basis and included data
from all 38 patients. Demographic, diagnostic, efficacy and safety data were presented in the
form of tables, described by percentages for qualitative variables, and mean, standard deviation,
median, maximum and minimum for quantitative variables.
Baseline data
Majority of the population of patients treated with 4MP for suspected EG poisoning were male
(74%); the mean age of the patients was 39 years, ranging from 15 to 71 years. The criteria used
to initiate dosing with 4MP were summarised; 34 of 38 patients (89%) were treated for
suspected or documented EG poisoning. Documented plasma or serum EG levels were available
at entry for only 5 patients and ranged from 3.9 to 200 mg/dL. Patient history alone was used to
initiate dosing of 4MP in 12 cases (31.5%). At entry, 13 patients (34%) presented with
metabolic acidosis with arterial pH ranging from 7.03 to 7.34. The serum bicarbonate level was
below the lower normal limit (22 mmol/L) for all of these patients. An elevated anion gap was
noted for 12 patients (31.6%), ranging from I8 to 40 mmol/L. Four of the 5 patients with
documented or suspected methanol ingestion had methanol levels ranging from 10 to 269
mg/dL at entry. The history of intoxication was summarised; the type of product ingested was
known for 11 of 29 patients. In general, the product most commonly ingested was liquid
antifreeze (21 patients; 55%). Ethanol was noted as a co-ingestant for seven patients (18%)
while 3 patients had other co-ingestants (flunitrazepam, benzodiazepine and chloroform).
Seventeen patients (45%) consumed the intoxicating product(s) unintentionally, 10 patients
(26%) consumed that: intoxicating product deliberately for self-harm reasons. The reason for
intake was not known for 11 patients (29%).
The mean time between intoxication (date of product ingestion) and treatment with 4MP (date
of entry into trial) for the 38 patients treated was less than one day (0.61 ± 0.84 days: data
available for 31 patients). Five patients had a time-lag more than one day between intoxication
and treatment with 4MP (one patient died and 2 presented sequelae at follow-up). The median
serum or blood EG level at baseline for all 37 patients with EG data was 2.7 mg/dL (range from
0 to 830.8 mg/dL). The median serum or blood EG level in Cohort A at baseline was 10.4 mg/dL;
majority (15/26: 58%) had blood EG levels < 20 mg/dL, with 11/26 (42%) of patients having
EG levels of under 5mg/dL. Four patients had EG levels over 100 mg/dL at baseline. Vital signs
at baseline were summarised. In Cohort A, 65% of patients were awake, 27% were comatose
and 3% were lethargic. Plasma oxalate data were only available for 6 patients of whom 3 had
levels higher than ULN and all 3 patients had confirmed EG poisoning (Cohort A). Ethanol was
detected in the blood of 15 patients (45%) and baseline blood ethanol levels ranged from 0.46
to 180 mg/dL. In Cohort A. the mean blood pH at baseline was 7.3, ranging from 7.1 to 7.5; 8
patients (36%) had blood pH below the normal limit. In Cohort A, majority (94%) of patients

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with data available presented blood lactate levels above ULN (mean blood lactate was 7.5
mmol/L, ranging from 1.5 to 44 mmol/L), had low serum bicarbonate levels (mean of 20.4
mmol/L), mean BUN was 5.3 mmol/L with 5/26 (19%) of patients having BUN above ULN;
creatinine concentrations were high with 9/23 (39%) having levels above ULN. Patients also
tended to be hypocalcemic (data available for 21 patients) and majority of patients (61.9%)
presented serum calcium below the LLN (2.3 mmol/L) and 4 patients had serum calcium levels
under 2.0 mmol/L.
At entry, 7 patients (18%) were noted to have received treatment with ethanol as an antidote
before arrival at the hospital and a further 4 patients (l0.5%) received ethanol during 4MP
treatment. Two different preparations of 4MP were used to treat patients with suspected or
confirmed EG intoxication: 8 of 30 (21%) were treated with 4MP hydrochloride (4MP HCI)
while remaining 30 patients (79%) were treated with 4MP sulphate (4MP SO4) was given orally
to 13 of 38 patients (34%), while 20 patients (68%) received 4MP intravenously; one patient
was initially given 4MP by mouth with subsequent doses given IV. Treatment with 4MP was
initiated based on the estimated EG intake and the clinical status of the patient The mean
loading dose of 4MP given for all patients was 11 mg/kg, ranging from 0.2 to 19.5 mg/kg with
similar doses used in Cohort A. Overall, 10 patients received just 1 dose of 4MP, while all other
received multiple doses (mean number of doses was 3 with maximum of 13 doses given to one
patient). The doses of 4MP were administered in 0.9% sodium chloride injection, and 5%
dextrose injection, as the investigator deemed appropriate. When administered intravenously, it
was infused over 45 minutes. Doses were given at regular intervals (ranging from 1 hour to 12
h) while treatment periods ranged from one dose on one day to 13 injections over 7 days. The
mean duration of treatment was 2.1 days; 17 patients (45%) treated with 4MP received
treatment for less than 12 h (including the 10 patients treated with just one dose of 4MP), 8
patients (21%) received treatment for 24-48 h and 5 patients were treated for 48-72 h (13%) 3.
The mean total dose of 4MP administered per patient was 1565.8 mg for all patients (ranging
from 200 to 6000mg) and it was l674 mg in Cohort A.
Efficacy results (in Cohort A or 26 patients with confirmed EG poisoning)
The mean concentration of EG at baseline for the 26 patients in Cohort A was 82.0 mg/dL which
decreased over the treatment period and was negligible at the end of follow-up (median was
0.3mg/dL ranging from 0 to 16.4mg/dL) with 50% of patients being 0 mg/dL.
The mean blood pH also returned to within normal limits by the end of 4MP treatment. The
serum bicarbonate levels which were low at inclusion (mean=20.4 mmol/L for the 25 patients
with data available, 12 patients had levels under LLN) had increased to 26.4 mmol/L at
endpoint (last recorded measurement) with majority of patients (60%: missing data for 1
patient) having serum bicarbonate levels within the normal range.
The final outcome status for the 26 patients with confirmed EG intoxication showed that the
majority of patients were alive with no sequelae (73%). One patient died as a result of the
intoxication. Review of the death narrative revealed that this [information redacted] year old
patient with multiple product intoxication was comatose with multiple complications and only
started 4MP treatment, 2 days after the intoxication. Four patients (15%) were reported to
present sequelae upon discharge. The investigator considered that 4MP was definitely effective
in preventing or diminishing toxicity in 10 cases (38.5%) and was possibly effective in
preventing or diminishing toxicity in 9 cases (34.6%). Seven patients (27%) were noted to have
no apparent beneficial effect from treatment with 4MP: 2 patients had not consumed sufficient
EG to be judged intoxicated, 3 patients were only mildly intoxicated at admission. Both patients
without benefit (1 death and 1 long-term sequelae) were treated with 4MP more than 24 h after
the intoxication. No differences in clinical outcome was observed between the 4MP HCL (n=8)

3 One patient had undetermined duration of treatment as time of administration were not available.

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and 4MP SO4 (n=30) preparations or between patients treated with oral or intravenous 4MP
preparation.
Six patients underwent haemodialysis (16%). Four of these six patients were dialysed due to
renal insufficiency caused by EG ingestion, one patient was dialysed due to an extremely high
level of EG in the plasma (830 mg/dL) and the remaining patient was dialysed for methanol
ingestion. The number of haemodialysis required ranged from 1 to 8 (mean number
administered was 2.8); the mean duration of the first haemodialysis was 6.1 h.
Comment: In this pivotal retrospective study involving 26 patients with confirmed EG
intoxication, the median baseline EG concentration was 10.4 mg/dL, ranging from
1.0 to 830.8 mg/dL. Patients were, on the whole, treated rapidly after intoxication
although 5 patients received therapeutic intervention more than 24 h after
ingestion of intoxicant. Fifty-eight percent (58%) of the patients in Cohort A were
mildly intoxicated or presented with no clinical signs of intoxication and severe
intoxication was reported for seven cases (27%). The dosages and routes of 4MP
administration in this study, varied depending on the amount of toxin ingested,
length of time between exposure and treatment and mental status of the patient.
Overall prognostic outcome for the patients with confirmed EG intoxication treated
with 4MP was very good as 73% of patients survived and had no sequelae of
intoxication at endpoint. A further 15% of patients survived but presented with
some sequelae at endpoint, although these conditions tended to be mild and
improved or resolved during patient follow-up. One death was reported in the study
occurring after late therapeutic intervention for a severe multi-substance
intoxication (EG, flunitrazepam, sodium hydroxide). Seven patients were noted to
have no apparent beneficial effect from treatment with 4MP: 2 patients had not
consumed sufficient EG to be judged intoxicated, 3 patients were only mildly
intoxicated at admission. Both patients without benefit (1 death and 1 long-term
sequelae) were treated with 4MP more than 24 h after the intoxication. Hence, the
effectiveness of 4MP in the treatment of EG intoxication appears to be closely
related to the time at which the treatment is administered following intoxication. If
treatment can be initiated very rapidly after ingestion of EG, its metabolism can be
slowed and exposure to the toxic metabolites reduced.
However, interpretation of results from this study was limited by the following
confounded factors:
i. 7 patients (18%) were noted to have received treatment with ethanol as an
antidote before arrival at the hospital and a further 4 patients (10.5%) received
ethanol during 4MP treatment,
ii. Haemodialysis was used along with 4MP treatment in 7 patients,
iii. Retrospective nature of the study (important information may have been missed
in the data collection).
7.1.1.2. Study S-8 (OMC-4MP-1)
Study design, objectives, locations and dates
S-8 was an open label, multi-dose, multi-centre, Phase III pivotal trial of the antidotal efficacy
and pharmacokinetic profile of fomepizole for the treatment of patients with confirmed EG
poisoning.
The objectives of this study were to determine the efficacy and tolerance of fomepizole in the
treatment of EG poisoned patients; to determine the relationship between the time-response
curve of fomepizole and its pharmacokinetic profile; to correlate the pharmacokinetic profile of

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fomepizole with its inhibitory effects on EG metabolism; and to determine the safety of
fomepizole administration in EG poisoned patients.
The first patient was treated on 5 November 1995 and the last patient was treated on 15 July
1996. Twenty-one trial centres in USA were initiated as potential enrolment sites. For purposes
of this interim report (dated 29 October, 1996), only four of those sites actually enrolled
patients into the trial. This trial was conducted according to Good Clinical Practices (GCP)
guidelines.
Inclusion and exclusion criteria
The main inclusion criteria were: Male and female patients, over 12 years of age, who presented
with a documented serum EG level of >20 mg/dL; OR a history (or strong clinical suspicion) of
EG ingestion along with arterial pH< 7.3, serum bicarbonate <20 mEq/L, osmolar gap by
freezing point depression >10 mOsm/L, and/or oxalate crystals in urine; OR recent (<1 hour)
documented history of a potentially toxic amount of EG and osmolar gap >10 mOsm/L, were
eligible for participation in the trial. Signed written consent was also required prior to initiation
of the trial. The main exclusion criteria were: administration of ethanol to the patient at the
investigator’s hospital; known adverse reaction to pyrazoles and pregnant females.
Study treatments
The study treatment was fomepizole (4-methylpyrazole, 4MP) at a concentration of 1000
mg/mL in single unit-dose 5 mL amber glass vials containing 1.5 mL sterile fomepizole. Loading
dose: fomepizole 15 mg/kg diluted in 100 mL normal saline (NS) delivered intravenously (IV)
over 30 minutes. Supplemental doses: fomepizole 10 mg/kg (in 100 mL NS, IV over 30 min)
every 12 h for 4 doses, then 15 mg/kg (in 100 mL NS, IV over 30 min) thereafter. Duration of
treatment was dependent on severity of poisoning and resulting clinical condition (estimated to
be 2-4 days).
In addition to the fomepizole treatment described above, a standardised treatment protocol was
to be followed until 6 h after the final fomepizole dose. This protocol included establishing a
primary IV line to deliver 5% dextrose/normal saline at a rate determined by investigator;
administration of potassium supplementation to keep serum potassium in the normal range;
and administration of intravenous bicarbonate therapy to keep arterial pH >7.3. The amount of
bicarbonate administered was to be at the discretion of the investigator considering the
patient's age, cardiovascular and renal status, and base deficit. Magnesium and further vitamin
supplementation were administered at the discretion of the investigator. All patients were kept
on a cardiac monitor for the duration of the trial, and arterial oxygenation was to be maintained
at 290% (unless this degree of oxygen saturation was unobtainable with artificial ventilation).
Blood pressure support and general supportive care were provided as deemed appropriate by
the investigator.
In cases of severe EG poisoning, haemodialysis was required. Patients who presented with an
EG level of >50 mg/dL, or who met one of several criteria representing severe metabolic
acidosis or renal failure, were treated with haemodialysis in addition to fomepizole therapy. The
dialysability of fomepizole is significant, and for this reason, the dosing of fomepizole was
adjusted to account for haemodialysis. Patients were dosed with every four h during the dialysis
procedure. Dosing at the termination of haemodialysis was dependent on the length of time that
haemodialysis lasted. Patients who were dialysed for less than one hour, continued per protocol
with the next dose 12 h after the last dose. Patients who were dialysed for one to three h were
given half of the next scheduled dose, and then continued the every 12 hour dosing protocol. For
those patients who were dialysed for greater than three h, the next dose of fomepizole was
administered at the end of haemodialysis and treatment continued following the every 12 hour
dosing protocol.

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Efficacy variables and outcomes

Measurements related to the reversal of metabolic acidosis included serum pH and serum
bicarbonate. Measurements related to the inhibition of EG metabolism were plasma glycolate
and urinary oxalate levels. Assessments related to the morbidity associated with EG poisoning
included collection of adverse experiences associated with the poisoning. Of specific interest
were measurements associated with renal function including BUN, serum creatinine, and
urinalysis. Assessments related to cardiac function included monitoring of vital signs and
electrocardiograms. Cranial nerve assessments were also conducted.
The efficacy outcomes evaluated were: Mortality, Morbidity (cardiac and renal), Metabolic
Acidosis and Clinical Outcome. The primary efficacy analysis included an assessment of the
ability of fomepizole to prevent the mortality and severe morbidity associated with EG
poisoning. The morbidity analyses also included assessments of the ability of fomepizole to
prevent potential abnormalities to renal function, cardiac function and the cranial nerves.
Secondary analyses included evaluations of 1) the metabolic acidosis, 2) EG and glycolate PKs
and 3) fomepizole PKs.
Safety parameters evaluated were: Adverse experiences, Clinical laboratory tests, Vital signs,
Electrocardiograms, Ophthalmic examinations, Cranial nerve examinations, Concomitant
medication use. PK parameters of EG, its metabolites and that of fomepizole were also
evaluated.
Analysis populations, sample size, statistical methods
This trial was designed to enrol ten (10) patients poisoned with EG. For the purpose of this
interim report, a total of seven (7) patients were enrolled. More patients are expected to be
enrolled. All seven patients enrolled in the trial were included in all of the efficacy analyses.
The sample size (n=10) was based on the number of patients that the sponsor anticipated could
be enrolled at the trial sites within 12 to 18 months. No statistical considerations were made
with respect to sample size. For efficacy analyses, tabulations and summary statistics were
calculated, where appropriate, related to evaluations of metabolic acidosis and fomepizole PKs.
Baseline data
The study included 7 patients (6 male and 1 female), the average age was 43.4 ± 12.5 years;
median age was 44 years (range: 28 to 60 years). Six of the patients treated were Caucasian; one
patient was Afro-American. Two of the seven patients were enrolled based on documented EG
poisoning with serum EG level of >20 mg/dL. The other five patients were enrolled based on a
suspicion of EG poisoning and clinical and laboratory evidence suggestive of EG poisoning. All
patients demonstrated evidence of metabolic acidosis (six severe) and five patients
demonstrated some level of renal function impairment at baseline. Six of 7 patients were
considered severely intoxicated upon presentation. Six of the seven patients ingested EG
intentionally for self-harm (suicide) and one patient ingested EG for an inebriating effect.
Antifreeze was confirmed as the ingestant in 4 of 7 patients, while the specific ingestant was not
known for the remaining 3 patients. Four of the 7 patients presented at outlying hospitals and 3
of 7 presented at the investigator's site. Each of the 4 patients that presented to an outlying
hospital was treated with ethanol prior to transfer and subsequent treatment with fomepizole.
The time between EG ingestion and treatment with fomepizole at the investigator's hospital was
not known for 2 patients and ranged from 10 to 40 h for the other patients.
All seven of the patients had baseline EG levels >20 mg/dL with mean of 107.5 ± 58.9 mg/dL. At
baseline, 3 of the patients presented comatose, 2 were lethargic, 1 was inebriated and 1 was
awake. At baseline, all 7 patients had arterial pH below the LLN and 6 of 7 had serum
bicarbonate below the LLN. These results are as expected in patients with metabolic acidosis.
Four of 7 patients had lactate levels above the ULN. BUN tended to be within the normal limits
although 1 of 7 patients had a BUN below the lower limit. Creatinine concentrations were above

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the ULN in 5 of 7 patients at baseline indicating abnormalities in renal function. Three of 6 had
their Total calcium below the LLN. Additionally, 4 of 7 patients had oxalate crystals detected in
their urine. Six of 7 patients presented with detectable ethanol levels and 3 of 7 patients had
ethanol levels in or above the therapeutic range (100 to 130 mg/dL) upon trial entry. No
abnormalities were observed for the vital signs at baseline. Six of the seven patients were
severely intoxicated at presentation; the seventh patient was only mildly intoxicated at
presentation, but given the EG level at baseline for this patient (171 mg/dL), it is expected that
this patient may have succumbed to the types of sequelae (acute renal failure or even death)
without treatment. The patients were given between 2 and 5 doses of fomepizole each. The total
fomepizole dose for these seven patients ranged from 1800 to 6750 mg (25. 8 to 45 mg/kg,
respectively); the highest single dose administered to a patient during this trial was 15.7 mg/kg.
Efficacy results
Clinical outcome

At trial completion, one patient was dead, four patients were alive with sequelae (acute renal
failure) and two patients were alive without sequelae. The patient that died and the four that
had renal injury at the end of the trial were severely intoxicated at baseline. Each of the patients
with acute renal failure had renal insufficiency upon presentation. Of the four patients with
acute renal failure at the end of the trial, all had complete to near complete resolution of their
renal failure within 2 to 7 weeks after trial discharge. Each required treatment with
haemodialysis after trial discharge but no longer required haemodialysis at last follow-up.
Six patients presented with severe metabolic acidosis and all six had resolution of their acidosis
as evidenced by a normal serum pH within 4 h of treatment with fomepizole. Only one patient
redeveloped of metabolic acidosis while receiving treatment; this patient developed a severe
lactic acidosis secondary to cardiogenic shock and hypotension. One patient who entered the
trial with mild metabolic acidosis had a normal pH within 2 h of trial drug administration. The
last measured values of pH showed that 5 of 6 patients had pH within the normal range. While
the serum bicarbonate levels had not yet normalised for all patients, significant improvement
was observed over the course of the trial.
Levels of glycolate prior to the administration of fomepizole ranged from not detectable (in one
patient) to 23.7 mmol/L. All patients had a rapid reduction in plasma glycolate levels after the
initiation of fomepizole therapy although one patient showed a rise in glycolate levels during
the trial. This patient had a rapid and progressive fall in glycolate levels from 23.7 mmol/L (pre-
fomepizole) to 9.5 mmol/L at 4.75 h after the initial of therapy. This was followed by a rise of
plasma glycolate concentration to 18.4 mmol/L 6 h after his fomepizole loading dose, at a time
when he was scheduled to receive his next dose. All subsequent plasma glycolate
determinations in this patient were lower and progressively fell. Three of the four patients with
microscopic oxaluria at presentation had their urines turn negative for oxalate during the trial
while one patient still had microscopic oxaluria at the end of study.
Morbidity Associated with Ethylene Glycol Poisoning: Two patients had normal serum
creatinine levels at enrolment into the trial and neither of them developed an abnormal serum
creatinine level over the course of the trial. The remaining five patients had signs of renal
insufficiency on presentation with baseline serum creatinine ranging from 1.5 to 3 mg/mL and
these progressively rose during the trial to a maximum of 2.5 to 14.7. All of these patients had
severe metabolic acidosis (pH 7.05 to 7.35, bicarbonate 6 to 10.8 mEq/L) at presentation.
Plasma glycolate levels were markedly elevated in 4 patients (median 16.8 mmol/L, range 12.9
to 23.7) and urine oxalate concentration was markedly elevated (5.19, 2.29, and 2.69 mmol/L)
in three patients and borderline (1.27 and 1.54 mmol/L) in two patients. One patient who was
in profound renal failure and cardiogenic shock at the time of presentation died shortly after
entry into the trial. All four surviving patients with renal injury had completed to near complete
resolution of their renal failure within 2 to 7 weeks after trial discharge. All no longer required
haemodialysis at last follow-up. No clinically significant systemic abnormalities were noted on

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cardiac function, as assessed by vital signs, serial clinical examinations, and daily
electrocardiograms. There were no cranial nerve abnormalities that developed over the course
of the trial.
Graphs of the plasma fomepizole, plasma EG, plasma glycolate and plasma ethanol levels over
time for each patient were presented and these indicate when fomepizole doses were
administered to each patient, and when haemodialysis was used. These figures demonstrate
that EG, plasma glycolate, ethanol, and fomepizole levels gradually declined prior to and
following haemodialysis and rapidly declined while the patients were on haemodialysis.
Comment: This was a prospective study in patients with severe EG poisoning and used the
proposed dosing schedule for fomepizole (identical to the dosing recommendations
in the proposed PI). Results of this study provided evidence to suggest that
fomepizole (4MP) would be effective in preventing metabolism of EG to its toxic
metabolites and that this would be evident in better clinical outcomes in terms of
reduced mortality, morbidity, reversal of metabolic acidosis.
However, interpretation of results was confounded by the following limitations:
i. The study enrolled only 7 patients,
ii. Concomitant ingestion of ethanol which is a generally accepted treatment for EG
poisoning. Ethanol often consumed prior to and along with EG ingestion, but in
this study ethanol was also administered as an emergency treatment at outlying
hospitals prior to patient’s transfer to the trial site for 4 of the 7 patients.
iii. Concomitant treatment with haemodialysis was another confounding factor.
Although the study design included an assumption that up to 50% of patients
would require haemodialysis, in fact all the patients in this study required
haemodialysis due to initial high levels of EG, unstable serum chemistry due to
metabolic acidosis and decreased renal function.
Due to concomitant use of ethanol and haemodialysis in conjunction with
fomepizole, it is very difficult to definitively assess the actual benefits of fomepizole
in treatment of EG poisoning. However, EG and plasma glycolate levels declined
prior to and following haemodialysis suggesting the role of fomepizole in blocking
the conversion of EG to its toxic metabolites.
7.1.1.3. Other efficacy studies
Efficacy from published studies
Methylpyrazole for Toxic Alcohols (META) Investigation (Brent et al. 1999)
Between 1995 and 1997, the authors studied 23 consecutive patients with confirmed or
possible EG poisoning (7 of which were included in S8). The study was well conducted at
centres in USA and used proposed doses of fomepizole (loading dose of 15 mg/kg followed by
10 mg/kg every 12 h till 48 h and then again 15mg/kg after that to compensate for increased
fomepizole metabolism). The inclusion/exclusion criteria were well-defined. Four of the 23
enrolled patients were found to not have EG poisoning (EG levels <20 mg/dL and did not meet
any other inclusion criteria either). The main endpoints of the study were the development of
renal injury (high serum creatinine concentrations), additional production of EG metabolites
(an increase in either the plasma glycolate concentration or the urinary excretion of oxalate
after the administration of fomepizole), and the development of cranial neuropathies.
At presentation, 7 of the 19 patients were awake, 7 were comatose, 3 were inebriated and 2
were lethargic. Nine patients had high serum creatinine concentrations, and 15 had metabolic
acidosis and low serum bicarbonate concentrations. The initial arterial pH value was inversely
correlated with the plasma glycolate concentration (r=¡0.84, P<0.05) (Figure 10).

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Figure 10: Plasma glycolate versus arterial pH at the time of enrolment in 18 patients

Seventeen patients underwent haemodialysis. Ethanol was detected in 12 patients and 4 of

them had therapeutic concentrations (>100 mg/dL). The 19 patients were given an average of
3.5 doses of fomepizole (range, 1 to 7) over an average of 17.8 h (range, 5 to 58).
Plasma glycolate concentrations decreased progressively in all the patients. Concomitantly,
arterial pH values and serum bicarbonate concentrations increased progressively (Figure 11).

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Figure 11: Mean plasma glycolate concentrations, arterial pH and serum bicarbonate
concentration over time on the first day of 4MP therapy in 19 patients

Clinical improvement was correlated with the normalisation of acid-base status. None of the
patients had a spontaneous deterioration in mental status or hypoglycemia after the initiation of
therapy. The plasma fomepizole concentration during therapy usually ranged from 15 to 30
μg/mL (183 to 366 μmol/L) but occasionally, the values were lower. The mean half-time of
elimination of EG from plasma was 19.7±1.3 h. None of the patients in whom plasma glycolate
concentrations were undetectable at enrolment had measurable concentrations during therapy.
Urinary oxalate excretion decreased in all the patients during treatment with fomepizole.
Eighteen of the 19 patients survived their acute illness. The patient who died had an arterial pH
of 7.05 and an acute myocardial infarction before enrolment. He died from cardiogenic shock 22
h later. None of the patients had cranial neuropathy. All nine patients with high serum
creatinine concentrations at enrolment had a further increase (peak value, 2.4 to 14.7 mg/dL
[212 to 1299 μmol/L) during treatment. These nine patients presented later and had more
severe acidosis at the time of presentation than those who had normal serum creatinine
concentrations. However, the serum creatinine concentration became normal in six of the nine
patients, and ranged from 1.5 to 3.8 mg/dL (133 to 336 μmol /L) in the other three patients at
the time of the last measurement. All the patients in whom renal injury developed had plasma
glycolate concentrations of at least 98 mg/dL (12.9 mmol/L) at enrolment. No signs of renal

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injury developed in any patient whose initial plasma glycolate concentration did not exceed
76.8 mg/dL (10.1 mmol/L) or whose initial serum creatinine concentration was normal.
Comment: Overall, the results of this study suggest that fomepizole is a safe and effective
antidote in the treatment of EG poisoning. The plasma concentration of fomepizole
that is necessary to inhibit ADH (approximately 0.8 μg/mL) was exceeded in this
study. The reduction in plasma glycolate concentrations and urinary oxalate
excretion indicated that the metabolism of EG was inhibited. Furthermore, the
inhibition of metabolite production coincided with the resolution of metabolic
acidosis, at a mean of three h after the initiation of therapy. Renal function
decreased during therapy in nine patients, all of whom had abnormal renal function
at enrolment. In contrast, the patients with normal serum creatinine concentrations
at enrolment had no change in renal function.
Data reported in the Methylpyrazole for Toxic Alcohols (META) investigation, led to
approval of fomepizole for the treatment of ethylene glycol poisoning in the United
States.
The main limitation of this study was the lack of a control group. However, due to
the morbidity and mortality associated with EG poisoning, inclusion of an untreated
control group was not possible. Furthermore, interpretation was confounded by
presence of therapeutic levels of ethanol in 4 patients and use of haemodialysis in
17 patients.
Retrospective study of Fomepizole (Levine et al. 2012)
Levine et al. (2012) performed a retrospective, multicentre cohort study of 40 patients older
than 15 years intoxicated with EG using data from 3 specialist centres in USA over 8 years. The
primary purpose of this study was to determine the elimination half-life of ethylene glycol when
fomepizole was used as monotherapy without haemodialysis. A secondary purpose was to
report mortality and development of renal failure in patients treated with this approach. It is
important to note that the decision to treat with fomepizole as monotherapy and not use
haemodialysis had not been based on any set criteria. The choice had been made at the
discretion of the medical toxicologist treating each patient. In general, toxicologists treated
patients with fomepizole alone when metabolic acidosis (pH<7.3; anion gap>25 mEq/L) or
renal dysfunction was absent on admission. The 40 patients included in this case series had a
median age of 42 years, median peak EG concentrations of 127mg/dL and median number of
doses of fomepizole per patient was 4 (3-5 doses); only 3-4 patients showed mild acidosis
(pH<7.3, anion gap>25mEq/L). The mean elimination half-life for EG was 14.2 h (SD 3.7 h), with
a 95% confidence interval of 13.1 to 15.3 h (Figure 12). Only 1 patient developed non-oliguric
renal insufficiency (peak serum creatinine of 2.1 mg/mL), who recovered and did not require
haemodialysis.
Figure 12: Serum EG elimination half-life (mean 14.2 h±3.7 SD) n=40

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Comment: The estimations of EG elimination half-life during fomepizole monotherapy have

previously been based on small numbers of patients. This case series of 40 patients
displayed a mean elimination half-life of 14.2 h, which is shorter than but similar to
the half-life of 16.9 h reported in the META study4 for patients without renal failure.
Another difference from the META study was that patients who received
concomitant ethanol were not excluded in this case series; 24 patients in this case
series (60%) had measurable serum ethanol concentration at presentation, the
median of which was 118 mg/dL. The remaining patients had no ethanol in the
blood at presentation and did not receive ethanol as an antidote.
This was a retrospective cohort study of patients treated with fomepizole
monotherapy rather than a prospective randomised controlled study. There were
no strict criteria mandating what pH level is considered too acidotic for
monotherapy and thus mandates haemodialysis. Nonetheless, no patient in this
series had profound metabolic acidosis or renal dysfunction and among patients
without any metabolic acidosis or acute kidney injury the use of fomepizole as
monotherapy without concurrent haemodialysis proved to be quite safe. However,
it is important to note that 60% of the patients had measurable ethanol
concentrations which were in the therapeutic range (median >100 mg/dL),
6confounding interpretations regarding actual efficacy of fomepizole as an antidote
for EG poisoning.
Efficacy in paediatric patients from published studies
In the retrospective study by Caravati, et al, 2004, six patients with an age range of 22 months to
14 years were admitted for treatment of EG poisoning over a four-year period. Initial serum EG
concentrations ranged from 62 to 304 mg/dL (mean 174.0 mg/dL). Only patients with EG
concentrations >50 mg/dL were used as haemodialysis is often considered at this level and this
study hoped to evaluate other treatment options in patients with severe EG poisoning. The
lowest measured individual serum bicarbonates ranged from 4 to 17mEq/L. Serum creatinine
of all patients was normal at presentation) and only 3 patients had 1+ oxalate crystaluria on
initial urinalysis. The severity of illness ranged from severe acidosis and lethargy to mild
acidosis and alertness. All patients were initially admitted to intensive care. One patient
received ethanol only, two patients received fomepizole only, and three patients received a
loading dose of ethanol and then were converted to fomepizole therapy. None of the patients
received haemodialysis. Treatment was continued until the serum EG was <10 mg/dL.
Metabolic acidosis resolved with intravenous fluid and supplemental bicarbonate within 24 h.
The mean length of stay in intensive care was 21h and in the ward was 33.7 h. One episode of
hypoglycemia occurred in a 22 month-old. All patients recovered without evidence of renal
insufficiency or other major complications.
Comment: Overall, this study provided preliminary evidence that haemodialysis with its
inherent risks (bleeding, infection, thrombosis, hypovolemic, hypotension, and
electrolyte abnormalities) may be avoided in select paediatric patients with EG
concentrations >50 mg/dL and normal renal function; the six paediatric patients
with very high EG concentrations, normal renal function, and varying degrees of
metabolic acidosis were successfully treated with fomepizole or ethanol (primarily
fomepizole) without haemodialysis and most were discharged from the hospital
within two to three days. However, this study did have some limitations:

4In the META study, among the 19 patients included in the final analysis, 17 patients also underwent
haemodialysis. With the data from patients who received fomepizole before receiving haemodialysis, the
ethylene glycol concentrations exhibited first-order elimination kinetics, with a mean elimination half-life
of 19.7 hours. Of patients with normal renal function, the elimination half-life was 16.8 hours.

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i. Retrospective data collection from medical records has limitations as all clinical
information may not be accurately recorded and several complications may have
been missed.
ii. Small number of patients and lack of long-term follow-up after discharge.
Brent, et al (2010) did computerised search of the U.S. National Academy of medicine and
Embassy databases to identify published cases of paediatric patients treated with fomepizole.
This search strategy identified 14 published cases: 10 due to EG poisoning, 1 due to diethylene
glycol poisoning, 1 due to butoxyethanol ingestion, and 2 due to methanol poisoning. The
median age of these cases was 5.5 years old. For the 10 ethylene glycol poisoned patients, the
median recorded values of their arterial pH was 7.27 (range 7.03–7.38), serum bicarbonate
concentration was 13 mEq/L (range 2–25), and EG concentration was 2,140 mg/L (range 130–
3,840). Eight of these patients were not haemodialysed (these 8 patients had EG levels as high
as 3,500 mg/L and serum bicarbonate concentrations as low as 4 mEq/L. All 10 patients with
EG poisoning had resolution of their metabolic acidosis and recovered without sequelae. The
half-times of EG elimination ranged from 9 to 15 h during fomepizole therapy, which is faster
than the 19.7 h reported in adults. The two patients who ingested diethylene glycol or
butoxyethanol all recovered without sequelae. One of the two children who ingested methanol
was haemodialysed although both cases had similar severity. Most cases used the current U.S.
approved regimen. Two cases were originally treated with ethanol but switched to fomepizole
because of adverse effects. In both cases, the adverse reactions to ethanol resolved once
fomepizole treatment was initiated.
Comment: Overall, the limited data available suggest that fomepizole, using the same dosage
regimen as that used for adults, is efficacious and well tolerated in paediatric
patients. In many cases of paediatric EG poisoning treated with fomepizole,
haemodialysis may not be necessary despite high concentrations and the presence
of metabolic acidosis.
Although the data reviewed here suggest that fomepizole is safe and effective in
paediatric patients, and that in the majority of cases of EG poisoning, haemodialysis
may not be necessary, the data may be skewed by publication bias if those patients
with bad outcomes were not published.
Baum, et al (2000) reported the first case of treatment with fomepizole in an infant with EG
poisoning: An 8 month old infant who drank up to 120 mL of EG and developed minor acidosis,
significantly elevated osmolal gap and oxalate crystaluria. He was treated with fomepizole and
haemodialysis. Even after the completion of haemodialysis, fomepizole appeared to effectively
block the production of EG toxic metabolites and to allow the resolution of acidosis;
Haemodialysis was used in this infant in light of evidence that significant EG had been ingested
and that some degree of EG conversion to toxic organic acids had occurred. The use of
fomepizole alone in this patient may have been effective, despite the prolongation of EG half-life
to approximately 9 h. The reduction in EG concentration accomplished by haemodialysis would
have required approximately 16 additional h if treated with fomepizole alone. The authors
suggest that future studies must weigh the benefits of a lengthier but less invasive treatment
with fomepizole alone against the risks associated with acute haemodialysis.
7.1.1.4. Case reports
There are 6 case reports in paediatric patients which have been summarised in Table 4 and
provide preliminary evidence of efficacy of fomepizole in treatment of EG poisoning in
paediatric patients.

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Table 4: Case reports of EG poisoning in paediatric patients.

Authors, Details of case Treatment Clinical Conclusions/

publication reports given course/ comments
sequelae

1 Baum, et al. This is the first Treated with The patient Fomepizole
2000. report of fomepizole: recovered appeared to
‘Fomepizole fomepizole loading dose of within 48 hrs. prevent the
treatment of treatment of EG 15mg/kg IV and IV fomepizole metabolism
EG poisoning poisoning in an haemodialysis. (total dose, 45 of EG to toxic
in an infant.’ infant. 8-month-old Even after the mg/kg) acids even
male infant who completion of appeared to after
Paediatrics
drank up to 120 mL haemodialysis, allow the haemodialysi
Vol. 106 No. 6
of EG & developed fomepizole correction of s was
December 1,
acidosis and oxalate appeared to metabolic discontinued.
2000
crystalluria. Renal effectively block acidosis even The authors
pp. 1489 - function was the production after suggest EG-
1491 normal, with serum of EG toxic completion of poisoned
BUN of 10 mg/mL metabolites and haemodialysis, patients who
and creatinine of to allow the and prolonged present with
0.2mg/mL. Arterial resolution of EG half-life to normal renal
blood gas pH of 7.32 acidosis. approx. 9 function and
, osmolal gap of hours acid-base
approx. 60 status might
mOsm/kg. do well when
treated with
fomepizole
but without
haemodialysi
s.

2 Benitez, et al. 6-year old Fluid- The child She

2000: presented to the resuscitated, recovered developed
‘Nystagmus emergency NaHCO3, uneventfully coarse
Secondary to department thiamine, and vertical
Fomepizole mottled, comatose pyridoxine. nystagmus
with Kussmaul Within 4 hours within 2
Administratio
respirations. Initial of admission, a hours of
n in a
arterial blood gases: loading dose of fomepizole
Pediatric
pH 7.11, PO2 200, fomepizole (15 infusion
Patient.’
HCO3 2, base excess mg/kg) was frequently
Clinical 229 and within 20 infused due to cited adverse
Toxicology, minutes her pH the severity of events, such
38(7), 795– dropped to 7.03. the patient’s as headache,
798 (2000) clinical status, nausea, and
haemodialysis dizziness was
was initiated not reported.
but
Overall,
discontinued
fomepizole
temporarily due
appeared safe
to catheter
in this patient
thrombus
although she
formation. The
developed
initial (3-hour
transient
post-admission)
nystagmus.
EG was 13

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Authors, Details of case Treatment Clinical Conclusions/

publication reports given course/ comments
sequelae

mg/dL. EG was
5 mg/dL 3
hours after
haemodialysis
this then was
discontinued.
No further
fomepizole was
administered

3 Boyer, 2001. 13-year-old female Ethanol was Discharged Authors

‘Severe EG ingested approx. 4 given at primary after 3 days suggest that
ingestion fluid ounces of hospital; Six hrs with no use of
treated antifreeze after EG sequelae. At fomepizole
without BUN=11.0 mg/dL, ingestion she discharge on averted IV
haemodialysis. creatinine 0.8 received the third ethanol
’ mg/dL, and glucose fomepizole 15 hospital day, infusion &
105 mg/dL. Anion mg/kg IV she had BUN= haemodialysi
Pediatrics
gap was 14 mg/dL. loading dose. 10 mg/ml & s, limited the
2001;107;172
An arterial blood Arterial pH serum duration of
gas showed pH 7.38, remained above creatinine = intensive care
osmolar gap of 53 7.35. 0.6 mg/mL monitoring &
mosM/L. The fomepizole, 10 decreased
measured serum EG mg/kg, was overall cost of
was 103 mg/dL. given every 12 treatment.
hrs for total of 5
However,
doses. Serum EG
important to
was after 23
note that
mg/mL after
patient had
24hrs after
normal renal
ingestion,
function at
13mg/ml by 36
admission.
hrs.

4 Detaille, 2004. 5-month old boy Antidotal The infant Although not
‘Fomepizole ingested 200ml of therapy with a made a yet approved
alone for antifreeze solution. total of seven complete for this
severe infant Presented with doses of recovery with indication in
EG poisoning.’ metabolic acidosis- fomepizole no change in the child,
Pediatr Crit bicarbonate=11.1m given IV with an renal function. fomepizole
Care Med mol/L, anion interval of 12 Discharged seemed safe
2004; 5:490 – gap=31mOsm/L, hrs (15 mg/kg after 96hrs. and effective
491 hypercalcaemia=4m as loading dose, Plasma and may
mol/L, plasma EG=- then 10 mg/kg). fomepizole simplify
56.4mmol/L; Total of 7 doses concentration treatment in
normal renal reqd. s ranged from selected cases
function. Haemodialysis 4.5 to 21 of EG
was not mg/mL during poisoning
performed the treatment, reducing
with a mean need for
peak haemodialysi
concentration s.
of 18.9+ 2.2

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Authors, Details of case Treatment Clinical Conclusions/

publication reports given course/ comments
sequelae

mg/ml.

5 Hann G, 2012. 2-year old fomepizole The child was Fomepizole,

‘Antifreeze on accidental ingestion infusion given discharged when
a freezing of antifreeze 4hrs after after 7 days, available, is a
morning: presented with arrival to having fully safe
ethylene severe metabolic hospital, After recovered alternative to
glycol acidosis; pH=7.24, the second dose with no ethanol in the
poisoning in a anion gap=16.7, of fomepizole, sequelae to EG treatment of
2-year-old’ lactate=20mmol/L, the EG level fell poisoning and children with
BMJ Case bicarbonate=9.1mm to 31 mg/l. Child no adverse EG poisoning.
Reports 2012; ol/L; continued to effects of
Comments:
doi:10.1136/b EG=84.6mg/ml improve fomepizole
Dose of
cr.07.2011.45 clinically. Two
fomepizole
09 more doses of
administered
fomepizole were
to the child
given over the
was not
next 24 h,
mentioned in
making a total of
the case
four doses, until
report.
the EG level was
undetectable

6 Harry, 1998. A 4yr old girl 4MP antidotal The child was The efficiency
‘Ethylene accidentally treatment given discharged on of 4MP
glycol ingested unknown 7hrs after EG the fourth day treatment
poisoning in a amount of ingestion by IV without was
child treated antifreeze & loading dose of metabolic, confirmed by
with 4MP. admitted 4hrs later. 15mg/kg given hepatic, renal, the rapid
’Pediatrics EG poisoning was over 1hr or correction of
1998;102;e31 confirmed by a followed by 2 hematologic metabolic
metabolic acidosis, doses of disturbance.9 acidosis
with an anion gap of 10mg/kg days later, without
29 mmol/L and an infused 12 and results of the alkalization
osmolar gap of 50 24hrs later. clinical and by the
mOsm/L. Seven examination increase in
No ethanol or
hours after were normal, EG half-life.
haemodialysis
ingestion, the and biological No adverse
was given.
metabolic acidosis parameters effect of 4MP
increased revealed no was observed
complications
of EG
poisoning nor
of 4MP
treatment

Baud et al, 1986 presented 3 cases of acute EG poisonings that were treated in the ICU of a
single hospital in France from 1981 to 1983. During that period, no patients admitted for EG
poisoning were treated with ethanol. This study reports the uneventful course of three cases of
acute accidental EG intoxication treated with oral administration of 4MP. The diagnosis of EG
intoxication was confirmed by the determination of plasma and urine EG concentrations. 4MP
was given orally at an initial dose of 15 mg/kg body weight followed by 5 mg/kg after 12 h and

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thereafter, 10 mg/kg 4MP was given orally every 12 h until plasma EG concentrations became
undetectable. Review of the detailed clinical history provided evidence to support efficacy and
safety of 4MP especially when given soon after EG intoxication (it was given 4, 16 and 6 h after
intoxication in the 3 cases respectively) but before convulsions, coma or renal failure have
occurred.
Comment: This literature reference was submitted as Study S9 in the dossier.
The uneventful recovery in these patients raises the question whether these EG
intoxications would have been life-threatening without 4MP treatment. However,
these 3 cases did show that 4MP helped in inhibiting EG metabolism evidenced by
reduced oxalemia.
Baud et al, 1988 reported successful treatment with 4MP in a 42-year old man who ingested 1.5
litres of antifreeze solution (in an suicide attempt) containing 92.9% ethylene glycol. No
haemodialysis was required and he was given 4MP nine h after EG ingestion and clinical course
was uneventful with patient discharged on third day from ICU and seventh day from hospital.
Similar results were reported in another case report (Harry, 1994).
Comment: The above single case reports by Baud (1988) and Harry (1994) were submitted as
studies S10 and S11, respectively in the dossier. Both these single case reports
(Baud, 1988 and Harry, 1994) suggested efficacy of early treatment with 4MP
without need for any other treatment in patients with EG poisoning with normal
renal function.
Two publications (Baud et al. 1986 and Baud et al. 1988) presented cases of
patients that made up part of the study population of the retrospective Study S-7.
Jobard, 1996 reported two cases of severe EG poisoning with renal failure that were treated
with 4MP and haemodialysis; due to elimination of 4MP in the dialysate, a loading dose of 4MP
10-20 mg/kg was followed by continuous IV infusion of 1 to 1.5mg/kg/h during the 8-12 h of
haemodialysis). Data from these 2 patients suggested that in cases of severe EG poisoning with
toxic plasma EG levels and renal failure, a 4MP loading dose of 10-20 mg/kg followed by
continuous infusion of 1 to 1.5 mg/kg/h during the 8-12 h of haemodialysis may be effective.
Comment: The Jobard (1996) literature reference was submitted as Study S12 in the dossier.
Case reports of ≤ 3 intoxicated patients
Comment: The sponsor’s Clinical summary of efficacy states that of the 27 cases identified in
20 case reports in the systematic review that concerned 3 or fewer patients per
publication. The baseline status of these patients, treatment and clinical outcome
was supposed to be summarised in an Appendix.
However this appendix was not provided in the dossier.
These case reports have been evaluated and summarised in Tables 2 and 3; 17 patients were
administered fomepizole IV by the intravenous route. 3 subjects were administered 4MP orally
via nasogastric tube and all three were reported in the same publication (Baud, 1986). One
study did not describe the method of administration (Ahmed, 2014). Overall, 19 of the 20
patients reported in the clinical case report literature of the use of fomepizole in the treatment
of EG poisoning survived, and 1 patient died 48 h after admission due to multiorgan failure. The
patient had a very high level of acidosis (pH 6.5) at presentation and the time between ingestion
and treatment was unknown (Jobard, 1996, S12).
Hovda, et al, 2011 summarised the case of a 26-year old female with a dissociative disorder who
was admitted with EG poisoning a total of 154 times. She was treated with fomepizole 99 times,
ethanol 60 times (with a combination of both six times) and dialysis 73 times. Her admission
data before initiation of treatment was summarised. This patient had potentially lethal
poisoning on most occasions but was usually admitted early. Early admission was also

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consistent with only 10 admissions with a renal impairment (creatinine above 80 μmol/L, max
155 μmol/L; her baseline creatinine seemed to be between 60 and 70 μmol/L). Her renal
function seemed to normalise after each of these 10 incidents. The correlation between serum-
EG and osmolar gap (OG) was good (r2 = 0.76) suggesting that OG is a good surrogate marker for
EG. Eventually she died with an EG concentration of 81 mmol/L (506 mg/dL). The frequent use
of fomepizole in this young patient was not associated with any detectable side effects; neither
on clinical examination and lab screening, nor on the later autopsy. Despite repeated episodes of
EG poisoning, her kidney function seemed to normalise after each overdose. She was treated
with buffer and antidote without haemodialysis 81 times without complications, supporting the
safety of this approach in selected cases.
Comment: This study provided information on intra-individual variations in kinetics of EG and
its metabolites. It also provided data on long-term effects of repeated use of
fomepizole or on the outcome frequent EG poisonings. Results suggest that
fomepizole appears to be safe even when used frequently in the same patient.
However, this is the only available evidence for safety / efficacy of repeated
administration of fomepizole in the same patient.
Since their earlier publications (case studies Baud et al. 1986, 1988), the authors treated 38
patients with fomepizole alone for clinical suspicion of EG poisoning. 11 patients had plasma EG
concentrations of >20 mg/dL. In these 11 patients, fomepizole was given orally in 4 cases,
intravenously in 6 cases and via both routes in 1 case. Fomepizole was administered every 12 h
until EG concentrations became undetectable. Median number of doses administered to each
patient was 3 and the median loading dose of fomepizole was 800 mg. Four patients had renal
injury (serum creatinine concentration of 100 μmol/L or more). Between patients with (n=4)
and without (n=7) renal injury, plasma ethylene glycol concentrations at admission were
similar (p=0.09), and arterial pH was significantly lower (p=0.04) reflecting the impact of the
duration of time between poisoning and administration of antidote. Early administration of
fomepizole is essential if toxic metabolism is to be prevented. Three of the 11 patients
underwent haemodialysis: two due to renal insufficiency and acidosis; another patient with
normal renal function but very high plasma EG concentration (8.31 g/L) was dialysed (Borron,
et al, 1999).
7.1.2. Analyses performed across trials (pooled analyses and meta-analyses)
Not applicable.
7.1.3. Evaluator’s conclusions on clinical efficacy for treatment of ethylene glycol
poisoning
The efficacy of fomepizole treatment as an antidote for ethylene glycol toxicity has been
documented in two uncontrolled studies provided by the manufacturer:
Study S8 was a prospective study in 7 patients with severe EG poisoning and used the proposed
dosing schedule for fomepizole (identical to the dosing recommendations in the proposed PI).
Results of this study provided evidence to suggest that fomepizole (4MP) would be effective in
preventing metabolism of EG to its toxic metabolites and that this would be evident in better
clinical outcomes in terms of reduced mortality, morbidity, reversal of metabolic acidosis.
Study S7 was a retrospective study which showed that prognostic outcome for the 26 patients
with confirmed EG intoxication treated with 4MP was very good as 73% of patients survived
with no sequelae, 15% of patients survived with some sequelae at endpoint (although these
conditions tended to be mild and improved or resolved during patient follow-up). Two patients
without benefit (1 death and 1 with long-term sequelae) were treated with 4MP more than 24 h
after the intoxication. Hence, the effectiveness of 4MP in the treatment of EG intoxication
appears to be closely related to the time at which the treatment is administered following
intoxication. If treatment can be initiated very rapidly after ingestion of EG, its metabolism can
be slowed and exposure to the toxic metabolites reduced.

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However, interpretation of results from both studies S7 and S8 was confounded by concomitant
use of ethanol and haemodialysis in conjunction with fomepizole, making it difficult to
definitively assess the actual benefits of fomepizole in treatment of EG poisoning. Nevertheless,
in the post-dialysis period(s), when ethanol concentrations were insignificant and the
concentrations of ethylene glycol were >20 mg/dL, the administration of Antizol alone blocked
any rise in glycolate or formate concentrations, respectively.
The systematic review of the literature identified a large number of case reports/series
documenting the efficacy of 4MP in the treatment of ethylene glycol poisoning. The data from
these publications provided supportive evidence of the efficacy of 4MP.
The META (Methylpyrazole for Toxic Alcohols) investigation by Brent et al (1999) in 19 patients
with EG poisoning provided evidence that fomepizole is a safe and effective antidote in
treatment of EG poisoning as data reported in this study led to approval of fomepizole for the
treatment of EG poisoning in the United States. The plasma concentration of fomepizole that is
necessary to inhibit ADH (approximately 0.8 μg/mL) was exceeded in this study and patients
treated with concomitant ethanol were excluded from the study. The reduction in plasma
glycolate concentrations and urinary oxalate excretion indicated that the metabolism of EG was
inhibited. Furthermore, the inhibition of metabolite production coincided with the resolution of
metabolic acidosis, which occurred at a mean of three h after the initiation of therapy. Renal
function decreased during therapy in nine patients, all of whom had had abnormal renal
function at enrolment. In contrast, the patients with normal serum creatinine concentrations at
enrolment had no change in renal function.
A retrospective cohort study of 40 patients treated with fomepizole monotherapy for EG
poisoning (Levine, et al, 2012) showed that the use of fomepizole as monotherapy without
concurrent haemodialysis proved to be quite safe among patients without any metabolic
acidosis or acute kidney injury. However, it is important to note that 60% of the patients had
measurable ethanol concentrations which were in the therapeutic range (median >100 mg/dL).
Interpretation was also limited due to retrospective, uncontrolled nature of the study;
furthermore, there were no strict criteria mandating what pH level is considered too acidotic for
fomepizole monotherapy and thus mandates haemodialysis.
Other case reports of EG poisoning treated with fomepizole suggest that fomepizole is
successful in preventing the metabolism of EG to its toxic metabolites, in reversing metabolic
acidosis and in preventing extensive renal damage. Furthermore, many of the case reports
suggested that fomepizole along with supportive care (without haemodialysis) may be effective
in patients with elevated EG levels, normal renal function and no metabolic acidosis at
admission.
Hovda, et al (2011) reported the case of a 26-year old female with dissociative disorder who
was admitted for EG poisoning a total of 154 times and was treated with fomepizole 99 times.
Results from this case report suggest that fomepizole appears to be safe even when used
frequently in the same patient. However, this is the only reference provided to support efficacy/
safety of repeated dosing with fomepizole.
Some studies/case reports were provided to support evidence of efficacy of fomepizole for
treatment of EG poisoning in paediatric patients. The retrospective study (Caravati, 2004) in 6
patients with age ranging from 22 months to 14 years) showed that haemodialysis with its
inherent risks may be avoided in select paediatric patients with EG concentrations >50 mg/dL
and normal renal function; the six paediatric patients with very high EG concentrations, normal
renal function, and varying degrees of metabolic acidosis were successfully treated with
fomepizole or ethanol (primarily fomepizole) without haemodialysis and most were discharged
from the hospital within two to three days. Brent (2010) identified 14 published cases of
paediatric patients treated with fomepizole. Six other case reports in paediatric patients are also
summarised in Table 2. Overall, the limited data available suggest that fomepizole, is effective

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and well tolerated in paediatric patients. Although the limited data reviewed here suggest that
fomepizole (using the same dosage regimen as that used for adults) is safe and effective in
paediatric patients and that in the majority of cases of EG poisoning, haemodialysis may not be
necessary, the data may be skewed by publication bias if those patients with bad outcomes were
not published.
There exist no well controlled studies of the use of fomepizole in the treatment of EG poisoning
because of the nature of these events. The efficacy/ safety of fomepizole were not specifically
evaluated in elderly or in patients with renal/hepatic impairment.
Overall, there was adequate evidence to support use of fomepizole in treatment of EG poisoning.
The amount of toxin ingested, clinical level of intoxication and time to intervention are
interrelated factors that influence the degree of treatment success.

7.2. Treatment of methanol poisoning

7.2.1. Pivotal efficacy studies (provided by the manufacturer)
7.2.1.1. Study S7 (Cohort B)
In addition to studying the effect of fomepizole on the treatment of EG poisoning, Study S7
(discussed above) also evaluated its efficacy in the treatment of methanol poisoning. Of the 38
patients initially enrolled, 5 were treated for methanol toxicity. These 5 patients were referred
to as cohort B in Study S7. Majority of patients in Cohort B were males (n=4, 80%) with mean
age of 47years (28-57years). At admission, the investigator assessed that 2 patients (40%) were
severely intoxicated, 2 patients (40%) were mildly intoxicated and l patient (20%) was not
intoxicated. Three of these patients were awake (60%), one was inebriated (20%) and one was
lethargic (20%). All 5 patients were treated with 4MP sulphate; 3 received IV 4MP while 2
patients received oral treatment. The mean loading dose of 4MP used was 11.1 mg/kg (700mg),
ranging from 9 to 16.3 mg/kg. Patients tended to receive multiple doses of 4MP, with the mean
number of doses being 4 (median: 2 doses). One patient received a total of 13 doses of 4MP over
a 7 day period. A mean cumulative total dose of 1935mg 4MP was administered (range: 500 mg
to 5050 mg).
Median baseline blood methanol was 102.1 mg/mL, ranging from I0 to 425.6 mg/mL. At the
final evaluation, no methanol was detected in the blood of any of the four intoxicated patients.
At baseline the mean blood pH was within normal range (mean pH 7.4) and only one patient
had clinically significant low pH (7.26) which returned to normal within 9 h of dosing with 4MP.
At baseline, three patients presented blood bicarbonate levels below the LLN; the mean serum
bicarbonate level for the population at entry into the study was low (15.1 mmol/L). At endpoint,
the level had increased and was within the normal range (22.5 mmol/L) and only 1 patient had
a serum bicarbonate concentration below the LLN (21.5 mmol/L). However, this was very close
to the normal limit (22 mmol/L) and was not clinically significant. The renal parameters were
normal at baseline and end of the study; calcium levels were low at baseline in 4 patients and
remained low in 3 of the 4 patients.
At the last study evaluation, four of the five patients in this study treated with 4MP for
suspected or documented methanol intoxication, were alive with no sequelae (80%) while one
patient was alive with sequelae due to intoxication (bilateral blindness after severe methanol
intoxication, although this condition was presented at hospital admission). The investigator
assessed that treatment with 4MP was definitely or possibly effective in preventing or
diminishing toxicity for four patients. No beneficial effect was noted for the fifth patient who
was considered by the investigator not to be intoxicated at admission to hospital.
Comment: Overall, the case-by-case analysis of the 4 patients with confirmed methanol
intoxication in Study S7 provided evidence to support efficacy and safety of 4MP in

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the treatment of methanol intoxication. However, interpretation was limited by

retrospective nature of study and small sample size (n=5).
7.2.1.2. Study S13 (OMC-4MP-2)
Study design, objectives, dates and locations
The second study, S13, was a prospective, Phase III, open-label, multicentre, uncontrolled study
to assess the safety and efficacy of Antizol (fomepizole) Injection in patients with methanol
poisoning. The objectives of this study were to: determine the efficacy and tolerance of Antizol
in the treatment of methanol poisoned patients; determine the relationship between the time
response curve of Antizol and its PK profile; correlate the PK profile of Antizol with its
inhibitory effects on methanol metabolism, and determine the safety of Antizol administration
in methanol poisoned patients. The study was conducted by Orphan Medical with patients
enrolled from January 1996 to October 1997 at 6 centres in USA. This trial was conducted in
accordance with the current guidelines for Good Clinical Practices (GCPs).
Inclusion/ exclusion criteria
The main inclusion criteria were: age ≥ 12 years; written informed consent and documented
serum methanol level >20 mg/dL or if methanol level was not immediately available, patients
with a history of methanol ingestion, or a strong clinical suspicion of methanol intoxication (if a
history was not obtainable) plus at least two of the four following criteria:
• Arterial pH <7.3
• Serum bicarbonate <20 mEq/L
• Osmolar gap by freezing point depression >10 mOsm/L
• Recent (less than 1 h) documented history of an ingestion of a potentially toxic amount of
methanol.
The main exclusion criteria were: Ethanol given therapeutically to the patient at the
investigator's hospital; Known adverse reaction to pyrazoles; Pregnant female.
Study treatments
The patients described in this report received an initial loading dose of Antizol administered at
a dose of 15 mg/kg followed by supplemental doses every 12-h until methanol levels were <20
mg/dL. Except for one patient, all patients received an initial Antizol dose as a 30 minute
infusion of 15 mg/kg (182.7 pmol/kg). Due to the comatose status of one patient, an error was
made in estimating the patient's weight so that he actually received a loading dose of 22.0
mg/kg. Patients with significant metabolic acidosis or visual sequelae (with severe intoxication)
and who met criteria for haemodialysis as defined in the protocol 5, were also medically
managed with haemodialysis. Additional patient management included bicarbonate therapy,
cardiac monitoring, vitamin supplementation, blood pressure support, and oxygenation as
appropriate.

5 Arterial pH <7.1; Drop in arterial pH > 0.05 units despite bicarbonate supplementation after completion

of the Antizol loading dose; Drop in serum bicarbonate of > 5 mEq/L despite bicarbonate
supplementation after completion of the initial loading dose of Antizol;; Inability to maintain arterial pH
>7.3 despite bicarbonate therapy; Measured methanol level of >50 mg/dL; Methanol levels declining at a
rate of <10 mg/dL/24-hours. Any of the following visual symptoms: a. Significant blurring of vision b.
Double vision c. Large number of spots before eyes d. Significant decrement in visual acuity (greater than
one line on a standard hand-held Snellen eye chart) ; e. Sense of seeing through a ‘snowfield’. Any of the
following visual signs: a. Peri-papillary oedema b. Hyperaemia of the optic discs. Markedly retarded
pupillary light reflex d. Central scotomata Any of the following visual signs: a. Peri-papillary oedema b.
Hyperaemia of the optic discs c. Markedly retarded pupillary light reflex. d.Central scotomata

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Efficacy endpoints, statistical considerations

The primary efficacy variables that were established a priori for this study were reversal of or
lack of development of metabolic acidosis, inhibition of methanol metabolism as assessed by
formate, and assessment of morbidities associated with methanol poisoning. The efficacy
analyses included an assessment of the ability of Antizol to prevent the mortality and severe
morbidity associated with methanol poisoning; tabulations and summary statistics were
calculated. No statistical considerations were made with respect to sample size. The sample size
was based on the number of patients that the sponsor anticipated could be enrolled at up to 25
sites within 12 to 18 months.
Participants
Fifteen patients were initially enrolled in this study. Due to laboratory error, it was
subsequently determined that four of these patients did not have documented blood methanol
concentration levels at baseline. Thus, 11 of the 15 patients were included as efficacy evaluable
patients. All 15 patients who were enrolled in this study were included in the assessment of
safety in the final clinical study report.
Baseline data
Majority of the patients were male (n=9), Caucasian (n=10) and the mean age was 38 years
(range: 18-61 years). Overall, 7/11 (64%) of the patients entered the study with moderate or
severe intoxication. The most common reason for methanol ingestion was suicide attempt (n=6)
followed by inebriating effect (n=2) and accidental (n=2). The time of methanol ingestion was
unknown for four of 11 patients (36%) For the remaining seven patients, treatment with
Antizol was initiated within 6 h for two patients (18%), between 6 and 12 h for one patient
(9%), between 12 and 24 h for three patients (27%) and > 24 h for one patient (9%). At
baseline, the median pH level was 7.38 (Range: 6.90- 7.46). Five of 11 patients (45%) had
arterial pH levels <7.35. The median serum bicarbonate level was 15.0 mEq/L (range 3.0- 22.5).
All eleven evaluable patients had baseline serum methanol levels > 20 mg/dL (median=71.3
mg/dL, range: 23.0 to 612.1 mg/dL). Seven of 11 patients (64%) presented with formate levels
in the non-detectable range (< 1 mmol/L). Among the remaining six patients, one (9%) had a
formate level in the moderate range (1 to 9 mmol/L) and the remaining five patients (45%) had
formate levels in the severe range (>9 mmol/L). All five of these patients received baseline
ocular scores indicative of severe intoxication. Five of 11 efficacy evaluable patients (45%)
presented with detectable ethanol levels and 3 patients (27%) had ethanol levels in or above
the presumed ethanol therapeutic range (100 to 125 mg/dL) upon study entry. All three had
received ethanol as a first line therapy at a referring hospital, prior to transport to the trial site.
Four patients (36%) had no visual abnormalities at baseline, one (9%) had mild to moderate
visual dysfunction 6, and one patient (9%) had severe visual dysfunction 7. Five patients (45%)
were not evaluable due to either coma (N=4) or uncooperative behaviour (N=1). Only 1 patient
was hypotensive with a baseline blood pressure of 100/38 mmHg. No other clinically significant
abnormalities were observed for vital sign measurements at baseline.
Results
Clinical outcome
At study completion, seven patients (64%) were alive without sequelae, three patients (27%)
were alive with sequelae, and one patient (9%) died. Five of the seven patients who ended the
trial alive and without sequelae had overall baseline severity scores of moderate (N=2) to
severe (N=3). Life support was terminated 20 days after completion of the study for one of the

6presented with a score of 20/100

7One patient could only count fingers and also presented with sluggish pupillary reactivity and peri-
papillary oedema of his right eye. {This patient had previously documented optic nerve damage in his
right eye and a prosthetic left eye)

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patients with sequelae at the end of the study, Cause of death was attributed to brain stem
herniation due to toxic encephalopathy secondary to severe methanol toxicity and this patient
entered the study comatose. The sequelae described by the Investigator's for the remaining two
patients were left lower lobe infiltrate for one patient (which was present at baseline and
continued throughout the study) and mild blurring of vision for another patient (unknown
aetiology although, the patient presented with hyperaemia of the optic disc at baseline).
Four of 11 patients (36%) were comatose at baseline. The time of methanol ingestion was
unknown for these patients. At the end of the trial, two of these patients showed marked
improvement in mental status, one patient died during the trial, and one patient remained
comatose and subsequently died post-trial due to severe methanol toxicity. Of the remaining
seven patients, the number of h from time of methanol ingestion to initiation of trial drug
therapy varied from 3.3 h to 26.75 h. For the 5 patients who were awake at baseline, mental
status remained unchanged at the end of the trial, even though the number of h to trial drug
initiation varied from 3.3 h to 23.5 h. For the remaining two patients, both demonstrated some
improvement in mental status by the end of the trial.
Nine of 11 (82%) efficacy evaluable patients had low serum bicarbonate levels, five (45%) had
low blood pH measurements, and eight (73%) had low PCo2 levels at baseline. At the end of the
study, the majority of patients had normal values for each of these parameters, demonstrating a
reversal of baseline metabolic acidosis.
Inhibition of methanol metabolism
Five patients (45%) presented with non-detectable (<1 mmol/L) plasma formate levels prior to
the administration of Antizol, one patient (9%) presented with a mild (1-9 mmol/L) severity
level, and five patients (45%) presented with severe toxic (>9 mmol/L) levels of formate. No
patient developed elevated formate levels after initiation of Antizol therapy. Levels decreased
within 4 h of initiation of Antizol therapy in all patients who presented with detectable baseline
plasma formate levels. All patients had non-detectable levels of formate at the end of the trial.
At the end of haemodialysis, four of seven patients still had methanol levels> 20 mg/dL (range:
21.7- 33.2 mg/dL), two of whom had detectable but non-therapeutic levels of ethanol (~ 16.5
mg/dL). All four patients ended haemodialysis with insignificant plasma formate levels (<1
mmol/L). Within 48 h after the end of haemodialysis, all four patients had methanol levels <20
mg/dL and none of these patients developed an increase in formate levels throughout the post-
haemodialysis period.
Presenting methanol levels for the 4 patients who did not receive haemodialysis in this study
were 37.4, 38.8, 36.7 and 23.0 mg/dL, respectively. Presenting ethanol levels were below the
accepted therapeutic range (67.8, 10.7, 0 and 0 mg/dL, respectively). In each case, plasma
formate levels quickly declined to non-detectable levels, or remained at non-detectable levels in
conjunction with reduction in methanol and ethanol levels throughout the course of treatment
with Antizol. Thus, treatment with Antizol, and not ethanol, played a primary role in the
prevention of any increase in the concentration levels of the toxic metabolite, formate.
Formate levels <1 mmol/L are considered to be background levels in these patients. The data
suggests that Antizol, in conjunction with supportive care with or without haemodialysis,
inhibits the conversion of methanol to its toxic metabolite, formate.
For the three patients that presented with normal visual acuity and were asymptomatic for
other visual signs or symptoms at baseline, none developed any visual changes throughout the
course of the study. For the four patients who could not be visually assessed at baseline, two
ended the study with normal visual acuity, one died during study and one died subsequent to
study. For the remaining patients, three showed signs of improvement by the end of the study
and one patient showed no signs of improvement until 48 h after the end of the study.

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Four patients had sinus tachycardia at study entry that resolved by the end of the study for 2 of
the patients. An ECG was not conducted at the end of the study for the other 2 patients. No
significant abnormalities were noted in cardiac function for the remaining seven efficacy
evaluable patients. There were no cranial nerve abnormalities other than ocular nerve findings
previously present that developed throughout the course of the study for any patient.
Comment: This was a well-conducted study which provided evidence for efficacy of fomepizole
(4MP) treatment in 11 patients with methanol poisoning. Overall, 7/11 patients
survived without sequelae, 3 patients survived with sequelae and there was 1
death. Fomepizole inhibited metabolism of methanol to toxic metabolites which was
demonstrated by reduction in serum formate in all patients with detectable formate
at baseline.
7.2.2. Other studies
7.2.2.1. Efficacy from published studies
Methylpyrazole for Toxic Alcohols (META) Investigation (Brent et al. 2001)
Study design, inclusion/ exclusion criteria
Brent and co-workers performed a prospective multicentre study of fomepizole treatment in 11
patients with methanol poisoning between 1995 and 1997. The main inclusion criteria were
patients aged > 12 years old with serum methanol >20 mg/dL (6.2 mmol/L) or if there was a
history or a strong suspicion of methanol ingestion, in addition to at least two of the following
three findings: an arterial pH <7.3, a serum bicarbonate concentration <20 mmol/L, or a serum
osmolality gap of >10 mOsm/kg of water. Main exclusion criteria were ethanol treatment,
known adverse reaction to pyrazoles and pregnancy.
Study treatment
Fomepizole was administered as a 15 mg/kg loading dose, followed by 3 doses of 10 mg/kg
every 12 h. From the fifth dose, 15 mg/kg was given to compensate for increased metabolism.
Endpoints, statistical considerations
Outcomes measured were preservation of visual acuity, resolution of metabolic acidosis,
inhibition of formic acid production, achievement of therapeutic plasma concentrations of
fomepizole with the dosing regimen, residual illness or disability and death. Mean values were
compared with use of Student’s unpaired t-test and nominal variables with use of Fisher’s exact
test. Correlations were determined with the Pearson correlation coefficient.
Baseline data
The mean (+SD) age of the 11 patients was 40±13 years. Of the 9 patients for whom the ingested
product was known, 8 had drunk windshield-wiper fluid, and one had ingested gas-line
antifreeze. Methanol was ingested to attempt suicide in six patients, to cause inebriation in two,
accidentally in two, and for unknown reasons in one. Three patients had initial plasma ethanol
concentrations of at least 100 mg/dL (21.7 mmol/L); all three had received ethanol at referring
hospitals before they were enrolled in the study. There was a strong inverse correlation
between the initial arterial pH values and the plasma formic acid concentration (r=0.92,
P<0.001). Of the three patients who had undetectable plasma formic acid concentrations at the
time of presentation, only one patient had a high plasma ethanol concentration. For the group as
a whole, there was no correlation between the initial plasma formic acid and ethanol
concentrations (P=0.96). Seven patients had visual abnormalities, manifested as symptoms,
decreased visual acuity, or other abnormal results on examination. The mean plasma formic
acid concentration in this group was 80 mg/dL (17.5 mmol/L) with a range of 0 to 198 mg/dL
(0 to 43.0 mmol/L), compared to a much lower 7.4 mg/dL (1.6 mmol/L) with a range of 0 to
24.5 mg/dL (0 to 5.33 mmol/L) in the patients with no visual abnormalities (P=0.08). All
patients who could be evaluated had normal extra ocular movements. No patient reported

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diplopia, seeing spots, or the sensation of seeing through a snowstorm. The median duration of
treatment with fomepizole was 30 h (range, 0.5 to 60), and the patients received a median of 4
doses (range, 1 to 10). The seven patients who underwent haemodialysis received a median of
one treatment (range, one to four). The median interval between enrolment and the initiation of
haemodialysis was 90 minutes (range, 14 to 160).
Results
After the institution of fomepizole therapy, plasma formic acid concentrations fell in all patients,
with simultaneous resolution of the metabolic acidosis and improvements in mental status and
visual symptoms and signs. No patient had hypoglycemia after the initiation of therapy.
Methanol elimination in patients who did not undergo dialysis followed first order kinetics with
a half-life of 54 h. Plasma fomepizole, measured a total of 155 times during therapy in all
patients, was at or above the target concentration of 0.8 μg/mL on all but three occasions. Nine
of the 11 patients survived. Seven patients who presented with visual disturbances due to
methanol poisoning recovered without visual impairment. The two patients that died were
comatose at presentation, had an unknown time from ingestion to treatment, had non-
detectable levels of ethanol in serum and had very high levels of serum formate at presentation.
Both patients died of anoxic brain injury.
Comment: This study was similar to the 2 pivotal studies evaluated above with similar study
design, endpoints and patient characteristics and the results of this prospective
study in 11 patients suggest that fomepizole is a safe and effective antidote for use
in the treatment of methanol poisoning.
7.2.2.2. Prospective case series study of severe methanol intoxications treated with
Fomepizole (Hovda et al. 2005)
Study design, objectives
Prospective case series study on methanol, formate and dialysis kinetics in 7 cases of severe
methanol poisoning treated with buffer, fomepizole and haemodialysis (average 7 h, range 5 –
8). The objective of this prospective kinetic study on methanol and formate in seven methanol-
poisoned patients was to evaluate role of haemodialysis when using the new antidote-
fomepizole and to find a possible new indication for dialysis based on the patient’s initial clinical
status.
Study participants
The patients were part of an outbreak where illegal spirit consisting of 20% methanol and 80%
ethanol were consumed.
Study treatments
Six patients were initially given sodium bicarbonate, while 1 patient received trometamol
(Tribonat) as a buffer. Two patients were given IV ethanol before being transferred to the
investigating hospital where they received fomepizole. Fomepizole (Fomepizole, OPI Orphan
Pharma international, Paris, France) was given as a bolus dose of 15 mg/kg IV diluted in
isotonic saline, and then 10 mg/kg every 12 h, all doses given over 30 minutes. From the fifth
dose and on, 15 mg/kg were given in order to compensate for increased metabolism. During
dialysis, fomepizole was given by 10 mg/kg every 4 h.
The doses were based on clinical studies [Jacobsen et al. 1990] and the META Study [Brent et al.
2001] and similar to the proposed doses for fomepizole. Haemodialysis was performed in all
patients for 5 to 8 h and when terminated, serum methanol was below 10 mmol/L. Four
patients were dialysed early after diagnosis was obtained, while three were dialysed ‘electively’
the next day. The decision for early or elective dialysis was done on the basis of the patients’
clinical condition; the degree of metabolic acidosis or visual disturbances present which did not
disappear with buffer and antidote alone. Of the 4 patients who received dialysis after diagnosis,

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3 also received massive supportive treatment due to their clinical condition (antibiotics for
sepsis; mechanical ventilation and vasopressors because of respiratory and circulatory failure).
Results
This study included 5 males and 2 females with ages ranging from 41 to 69 years. The severity
and outcome of methanol poisoning were correlated to the toxic effects of formate and the
degree of metabolic acidosis and not to the serum methanol, provided alkali and antidotal
treatment had been started. This was shown in this study by patients 6 and 7 who had the
highest serum methanol levels at admission, but no clinical features. The early acidosis is due to
the production of formic acid whereas lactic acid production occurring in the later stages of
poisoning is due to tissue hypoxia caused by formate uncoupling of cytochrome oxidase [Hovda
et al. 2005, Jacobsen and McMartin 1986, 1997].
Elimination kinetics for methanol and formate before, during and after haemodialysis in all 7
patients showed that the elimination rate of methanol was clearly increased during
haemodialysis and apparently followed first order kinetics with a mean R2 of 0.98 (range 0.96 –
1.00). No rebound effect in serum methanol due to redistribution was observed after dialysis
was terminated.
Despite similar dialysis clearance, the half-life of formate is shorter than that of methanol,
average being 1.7 and 2.5 h, respectively. This is explained by a higher intrinsic elimination of
formate (metabolism and a variable renal excretion), whereas methanol metabolism is blocked
and the renal and pulmonary excretion is small. As such, dialysis represents 83% of the total
body clearance of methanol and 68% of the total body clearance of formate in these patients.
The median dialysis clearance of methanol was 222 mL/min (range 204 – 232, n = 5) and for
formate 225 mL/min (range 220 – 229, n = 2). The potential benefit of dialysis is due to the
removal of methanol, the correction of the metabolic acidosis and removal of the toxic
metabolite formate. Due to their small molecular weight, small volume of distribution, and lack
of protein binding, both methanol and formate are easily dialysed [Jacobsen et al. 1990].
As demonstrated by the effective block of methanol metabolism by fomepizole in all 7 patients
and the clinical improvement after this treatment combined with aggressive correction of
acidosis, there is really no longer any recommended serum methanol concentration for
discontinuation of dialysis (for example, 10 mmol/L [Jacobsen and McMartin 1986, 1997]). The
efficacy of haemodialysis in removing methanol is undisputable. If methanol analyses are not
available, the length of haemodialysis may best be guided by calculations of the osmolality gaps
[Hovda et al. 2004, 2005].
Comment: The role of haemodialysis in methanol poisoning is well-established when ethanol is
the antidote but there are few reports and few kinetic data on dialysis when
fomepizole is used as an antidote. Although the phase III study leading to the FDA
approval of fomepizole in methanol poisoning included dialysed patients, they were
all dialysed according to the traditional dialysis indications from the time when
ethanol was the only antidote [Brent et al. 2001).
Based on data from the above prospective case series study and another
retrospective study discussed below [Megarbane et al. 2001, 2004], the authors
propose that the indications for haemodialysis in methanol poisoning using
fomepizole as the antidote may therefore be separated into two categories:
 The critically ill patient, with severe metabolic acidosis (base deficit > 20 mM)
and/or visual disturbances, should be given buffer, fomepizole and haemodialysis as
soon as possible. The main effect of dialysis is then to remove the toxic anion
formate and to assist in correcting the metabolic acidosis, thereby also reducing
formate toxicity. The removal of methanol per se is not life-saving in this setting,
because fomepizole prevents further production of formic acid.

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 The stable patient, with little to moderate metabolic acidosis and no visual
disturbances, should be given buffer and fomepizole. The indication for
haemodialysis should then be discussed with an experienced nephrologist and/or
clinical toxicologist.
The efficacy of fomepizole and the significant different side effect profile from
ethanol gives the treating physician the possibility to delay or even drop dialysis in
this setting, and thereby change the triage, as patients will not develop more clinical
features from methanol poisoning when fomepizole and bicarbonate is given.
However, the evidence for the above guidelines is only preliminary and would
require confirmation in prospective studies.
7.2.2.3. Retrospective study of methanol intoxications treated with Fomepizole
(Mégarbane et al., 2001)
Study design, objectives
This was a retrospective clinical study in three intensive care units in university-affiliated
teaching hospitals in France between 1987 and 1999. The objective was to assess the efficacy
and safety of fomepizole in methanol poisoning and to test the hypothesis that fomepizole
obviates the need for haemodialysis in selected patients.
Study participants
The study included 14 methanol-poisoned patients admitted to ICUs and treated with
fomepizole. Patients were classified according to requirement for dialysis and whether ethanol
was self-administered or prescribed.
Study treatments
Fomepizole was administered orally (n=4) or IV (n=10). The IV form was diluted in 250 mL
isotonic saline and infused over 45 mins by an infusion pump. Fomepizole dosing varied by
practitioner but was generally administered twice daily. A loading dose of 15 mg/kg was
followed by doses of 10 mg/kg every 12 hour until plasma methanol became undetectable.
Median dose was 10.8 mg/kg. Patients with a plasma methanol concentration of 50 mg/dL
received a median of 4 doses. Haemodialysis was performed only in the 4 patients with visual
disturbances. Two patients received sodium bicarbonate, seven folinic acid and eight thiamine
and pyridoxine. One patient underwent delayed peritoneal dialysis (28 h after initiation of
fomepizole therapy) for acute pancreatitis present on admission.
Baseline data
There were 9 men and 5 women with median age of 46 years. The ingested products were
cooking alcohol (n=7), pure methanol (n=4), windshield washing fluid (n=1) and undetermined
(n=2). There was a history of alcoholism in 12 cases. Reasons for methanol ingestion included
suicide (n=10), unintentional misuse (n=2) and unknown (n=2). The median delay between
intoxication and ICU admission was 13 h (range: 3-48 h). On admission, 9 patients were awake,
one inebriated, 2 lethargic and 2 comatose (both of whom required mechanical ventilation); 3
patients presented with bilateral blindness and one with colour vision impairment (optic nerve
damage on ophthalmological examination). Only 1 patient had hypotension and 3 had
tachycardia; median respiratory rate was 18/min (14-40) with 6 patients presenting with
tachypnoea (respiratory rate >20/min). Only 1 patient underwent gastric lavage and 3 received
activated charcoal prior to ICU admission. The median initial plasma methanol concentration
was 50 mg/mL (4-146 mg/dL). Eight patients co-ingested ethanol with median initial plasma
concentration of 195 mg/dL (12-530 mg/dL) and 3 patients received ethanol as initial
treatment. Median arterial pH was 7.34 (7.11-7.51), serum bicarbonate 17.5 mmol/L (3-25
mmol/L), anion gap 22.1 mmol/L (11.8-42.2), arterial lactate 2.2 mmol/L (0.7-6.9) and serum
creatinine 84 µmol/L (50-128).

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Results
Except for the 4 patients with visual disturbances at admission, all patients recovered without
sequelae. Visual disturbances improved in only 1 blind patient who could count fingers several
weeks after discharge. The median ICU stay was 5 days (2-20). The 6 that were not
haemodialysed with plasma methanol <50 mg/mL had uneventful hospital courses; 4 patients
with methanol of at least 50 mg/mL were not haemodialysed and recovered completely.
On admission, 8 patients had subnormal arterial pH which returned to normal with fomepizole
therapy within 6 h (5-12 h); 11 patients had subnormal bicarbonate which returned to normal
in 21 h (4-34 h) and 11 patients had elevated anion gaps which returned to normal within 26 h
(3-62 h). The 4 patients receiving haemodialysis had significantly lower pH, lower serum
bicarbonate and larger anion gaps despite insignificant differences in plasma methanol
concentration than the non-haemodialysed patients 8. These differences suggested a delay in
seeking treatment which likely contributed to their visual impairment. Neither fomepizole nor
haemodialysis improved visual impairment.
Comment: Results from this retrospective case series suggest that in patients presenting with
high methanol concentrations (>50 mg/dL) but without severe acidosis or visual
impairment may be successfully treated by repeated dosing with fomepizole
without dialysis. Although interpretation was limited due to retrospective nature of
this study, it did provide some evidence to support the findings observed in the
prospective case series study discussed in Hovda, 2005 above.
7.2.2.4. Combined retrospective and prospective case series study of methanol
poisonings from large outbreak in Norway 2002-2004 (Hovda 2005).
Study design, objectives
This was combined prospective and retrospective case series study of 51 hospitalised patients
in Norway who were confirmed poisoned with methanol. This was one of the largest study
where both serum methanol 9, acid-base status and in some cases, even serum formate levels
were measured. This was also the first large-scale outbreak in which fomepizole was used as an
antidote.
Patient characteristics, methods
Overall, 51 patients were admitted from September 2002 until December 2004, of who 33 were
admitted in 2002, 13 in 2003 and five in 2004. Nine patients died in hospital (hospital mortality
18%), five patients were discharged from hospital with sequelae (10%), whereas one died 1
year later from cerebral sequelae. Eight patients who died outside hospital were diagnosed as
methanol poisonings on autopsy. The patients were retrospectively separated into three groups
according to the outcome: Group I: patients who survived without sequelae; Group II: patients
who survived with sequelae; Group III: patients who died. Comparisons between the admission
data in the different groups were initially performed by the use of Kruskal–Wallis
nonparametric test. The statistically significant parameters were then compared group by
group using Mann–Whitney U-test. The significant parameters were separated by 25-, 50- and
75-percentiles in order to look for possible threshold values for the different parameters. The
correlation between pH and pCO2 was performed by interaction term using regression analysis.

8 The 2 subgroups of patients with and without haemodialysis were compared using the Mann-Whitney
test with the significance level set at p=0.05.
9 Methanol in serum was measured by a gas chromatographic method with flame ionization detection and

a headspace injector (sensitivity 1.3 mmol/ L and day-to-day coefficient of variation 5%).

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Study treatment
Patients were given buffer (bicarbonate or trometamol; Tribonat, Baxter Germany) aiming at a
full correction of acidosis within the first h. In addition, they were given ethanol (15 patients) or
fomepizole (36 patients) as antidotes, and haemodialysis (37 patients). Fomepizole
(Fomepizole, OPi Orphan Pharma International, Paris, France) was given as a bolus dose of 15
mg/kg IV diluted in isotonic saline, and then 10 mg/kg every 12 h, all doses given over 30 min.
From the fifth dose and on, 15 mg/kg was given in order to compensate for increased
metabolism. During dialysis, 10 mg/kg fomepizole was given every 4 h.
Results
There were 39 males and 12 females with a median age of 53 years. Median S-methanol in all
the groups on admission was 25.0 mmol/L (80 mg/dL) (range 3.1– 147.0 mmol/L). Of those 39
(77%) who were symptomatic upon admission, 28 patients (55%) presented with visual
disturbances, 21 (41%) with dyspnoea, 22 (43%) with gastrointestinal (GI) symptoms, 12
patients (24%) were comatose, six (12%) with chest pain and eight (16%) with other symptoms
(mainly fatigue). Eight patients (16%) presented with respiratory arrest.
Overall, 35/51 patients survived without sequelae, 7 patients survived with sequelae and 9
patients died. About 60% of the patients discharged with sequelae had visual disturbances on
admission, 40% had GI symptoms, dyspnoea, coma and respiratory arrest. Respiratory arrest
and coma on admission were robust markers of poor outcome: 6 of 8 (75%) patients admitted
with respiratory arrest died and 8 of 12 (67%) comatose patients died. Although the patients
with the most severe outcome also had the highest serum methanol, the differences between
the groups surviving without sequelae, surviving with sequelae, and the patients who died, were
not significant (P=0.289, using Kruskal–Wallis nonparametric test). The patients who died were
more acidotic [median pH 6.57, median base deficit (BD) 28 mmol/L) than the patients
discharged with sequelae and those discharged without. There was a significant difference
between these three groups regarding pH (P < 0.001) and BD (P=0.001), but not regarding HCO3
(P= 0.207). The three groups were further separated by the 25-, 50- and 75-percentiles, in order
to look for possible threshold values regarding different prognosis. It is important to note that
the 25-percentile (pH below 6.90) almost completely separated the dying patients (Group III)
from those surviving (Group I) 10. Amongst the patients surviving, there was a trend towards
decreased pCO2 when pH was decreasing, whilst the trend was opposite amongst the patients
dying, the difference between groups being highly significant (P < 0.001). In 13 of the dialysed
patients, serum methanol levels were obtained before start of, and after termination of,
haemodialysis. During dialysis the mean half-life of the serum methanol concentration was 2.4
h.
Comment: Epidemiological, clinical and prognostic features from the large methanol outbreak
in Norway in 2002-2004 provided evidence to support use of fomepizole in
treatment of methanol poisoning. Methanol poisoning still has a high mortality,
mainly because of delayed admission to hospital and late diagnosis. The use of
buffer, antidote (ethanol and fomepizole were used in this study) and haemodialysis
is effective if initiated early. Visual disturbances, dyspnoea (including
hyperventilation) and GI symptoms were the most frequent clinical features, whilst
severe metabolic acidosis (pH < 6.90, BD > 28 mmol/dL), coma and increased pCO2
(lack of compensatory hyperventilation) were associated with poor outcome. Most
of the patients who presented with symptoms were discharged without sequelae.

10The one patient dying in the 50-percentile group (pH 6.90–7.19), was admitted with the tentative
diagnosis of stroke and methanol poisoning was therefore diagnosed late. He is therefore an outlier
amongst the dead (pH 7.13, pCO2 2.0 kPa). This patient also explains one of the two deaths in the 50-
percentile of the BD values in Figure 4b, which without him would distinguish survivors well at a BD <28
mmol L.

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7.2.2.5. CZECH mass outbreak of Methanol poisonings (Zakharov, 2014)

Study design, objectives
This was a combined prospective and retrospective case series study of 121 patients with
confirmed methanol poisoning. A large outbreak of methanol poisonings in the Czech Republic
between September 2012 and January 2013 was attributed to the consumption of illegal
methanol-containing strong alcoholic beverages sold on the black market or at conventional
outlets. The objective of the present study was to report the data from the mass methanol
poisoning in the Czech Republic in 2012 addressing the general epidemiology, treatment, and
outcomes, and to present a protocol for the use of fomepizole ensuring that the antidote was
provided to the most severely poisoned patients in the critical phase.
Patient characteristics, methods:
Diagnosis was made when (i) a history of recent ingestion of illicit spirits was available and
serum methanol was higher than 20 mg/dL (6.24 mmol/L) and/or an osmolal gap >20
mOsm/kg/H2O (that could not be explained by ethanol) was found, or (ii) there was a
history/clinical suspicion of methanol poisoning; serum methanol was above the limit of
detection with at least two of the following: pH<7.3, serum bicarbonate<20 mmol/L (20
mEq/L), and anion gap (calculated with potassium) >20 mmol/L (20 mEq/L). Of the 121 cases
that were identified, 20 died out of hospital and 101 were hospitalised.
The clinical examination protocol included complete ocular examination with standard
ophthalmologic tests (visual acuity, visual fields, colour vision, contrast sensibility, fundoscopy),
cerebral computed tomography (CT) in symptomatic patients and standard neurological
examination. The patients were considered to have visual sequelae (VS) of acute methanol
poisoning if the symptoms of toxic neuropathy of the optic nerve were documented on
admission/ during hospitalisation, with pathologic findings on visual acuity, visual fields, colour
vision, and contrast sensitivity, or persisting lesions on fundoscopy with other symptoms of
visual damage on discharge from the hospitals. The patients were considered as having CNS
sequelae of poisoning if the symmetrical necrosis and haemorrhages of basal ganglia were
present on computed tomogram of the brain. The hospitalised patients were divided into three
groups according to the outcome: Group I: Survivors without sequelae; Group II: Survivors with
visual and/or CNS sequelae; Group III: Patients who died.
The admission laboratory data in the different groups were compared on a group by group basis
using Two-Sample Assuming Unequal Variances (Equal Means), Two-sample F-Test for
Variances, Bias test, and two-sample Kolmogorov–Smirnov test. Data was expressed as medians
with range and arithmetic means with confidence interval, as appropriate. For comparison of
the obtained results, common statistical tests have been used (t-Test: Two-Sample Assuming
Equal Variances, t-Test: Two-Sample Assuming Unequal Variances (Equal Means), Two-sample
F-Test for Variances, Bias test and ANOVA). Multivariate logistic regression was used to
evaluate the different independent variables for mortality, whereas cumulative logit
proportional odds model was used for various sequelae. The p-values were based on the
likelihood-ratio tests. For the multivariate regression analysis, the whole population of 101
hospitalised patients was used without stratification. All statistical calculations were carried out
with a level of significance α < 0.05.
Study treatment:
Bicarbonate was given as a buffer to patients with metabolic acidosis aiming at full correction;
ethanol and/or fomepizole were given as antidotes. Uniform indications were applied for
antidotal treatment and elimination techniques according to the AACT/EAPCCT practice
guidelines on the treatment of methanol poisoning. Because there was limited availability of
fomepizole, the following antidote-saving approach was used: a) if fomepizole was not available,
the standard scheme of ethanol administration to rapidly achieve the protective serum
concentration of 100–150 mg/dL (21.7 – 32.6 mmol/L) was initiated as soon as possible; b)

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fomepizole treatment was prioritised in patients with serum methanol >50 mg/dL (15.6
mmol/L) [or formate higher than 40 mg/dL (8.9 mmol/L)] and pH <7.0, or methanol >30 mg/dL
(9.4 mmol/L) and pH < 7.0 in patients unable to hyperventilate (pCO2 > 3.07 kPa or 23.0
mmHg); c) treatment with fomepizole was stopped and followed by ethanol administration
when methanol concentration decreased below 30 mg/dL (9.4 mmol/L) given a normal pH, or
20 mg/dL (6.2 mmol/L) if metabolic acidosis was not yet corrected.
The rationale for this approach was to decrease the risk of incomplete ADH blocking by possible
fluctuations of ethanol levels in the most severely poisoned patients, especially during
haemodialysis, and to avoid respiratory depression caused by ethanol in patients
hyperventilating to compensate the acidosis. Haemodialysis was performed if the patients
fulfilled any of the following criteria: serum methanol higher than 50 mg/dL (15.6 mmol/L),
metabolic acidosis with a pH<7.30, or had visual toxicity. The mode of dialysis, intermittent
haemodialysis (IHD) or continuous veno-venous haemodialysis/ haemodiafiltration
(CVVHD/HDF), was based on several factors, such as the haemodynamic stability of a patient on
admission, or the severity of poisoning, but availability also played an important role.
Results:
Of the 101 patients treated at hospitals, there were 80 males with median age of 53 (23-79)
years and 21 females with median age of 57 (16-69) years. Only 11% (n=11) of the patients
were admitted within 12 h after the methanol ingestion, 35% (n=35) within 48 h, and 37%
(n=37) later than 48 h and was unknown in 18% (n=18) of the cases. All of the patients who
died were admitted more than 24 h after ingestion. According to the history from the discharge
reports, 56% of the hospitalised patients were daily alcohol abusers. The type of toxic alcohol
was known in 78 cases, and the approximate quantity in 67 cases. The median amounts of toxic
spirits (volumes of the formulated spirits) consumed by males was 450 mL (range 100–1500
mL) and by females 200 mL (range 80–500 mL). Forty-one patients had detectable ethanol
before hospital antidote treatment, with a median concentration of 65 mg/dL (8–446 mg/mL),
that is, 14.1 mmol/L (1.7 – 96.8 mmol/L); 30 of them were administered ethanol as a ‘ first aid
antidote ‘ by ambulance medical staff during the transfer to a hospital and 6 patients were not
tested for serum ethanol before the antidote treatment was started Three patients were found
with negative methanol levels and positive formate and twelve were found with a methanol
concentration below the ‘ toxic limit ‘ (20 mg/dL or 6.24 mmol/L). On admission, 25/101 (25%)
of patients were asymptomatic, 18 of them with measurable ethanol in blood (all of them were
given pre-hospital ethanol). The most common clinical symptoms on admission are shown in
Table 5. Detailed information about the treatment given is presented in Table 6. In total 10/101
(10%) did not receive any antidote: 3 of these recovered without sequelae 11, 2 recovered with
sequelae 12 and 5 patients died 13. A total of 26/101 (26%) patients did not receive
haemodialysis: 21 of them did not meet criteria for haemodialysis and, all of them survived
without sequelae; two patients died upon admission and in 3 cases haemodialysis was not
applied because of the negative serum methanol, coma on admission, and severe metabolic
acidosis corrected by the bicarbonate infusions with no definite diagnosis of methanol
poisoning till death (the first cases in the outbreak). Overall, 26/101 (26%) did not receive
folate of whom 10 died, 3 survived with visual sequelae and 13 survived without sequelae.

11 All 3 had low serum methanol on admission (6, 10 and 20mg/dL) and no metabolic acidosis.
12 One patient with serum methanol of 17 mg/dL (5.3 mmol/L), pH 7.2, and serum ethanol of 228 mg/dL,
or 49.5 mmol/L (self-administered shortly before admission), and one patient admitted in coma with
severe metabolic acidosis and negative serum methanol
13 3 of them were diagnosed post-mortem and 2 patients died on admission before any specific treatment

was initiated.

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Table 5: Most common clinical symptoms on admission in 101 patients

Table 6: Treatment given in 101 patients separated by the three outcome groups

Outcome and prognosis:

There were 21 fatalities in hospital (hospital mortality 21%), other 20 patients died at home or
before reaching hospital, giving a total mortality of 34%. Twenty patients (20%) were
discharged from hospital with sequelae, with visual impairment diagnosed in nine, CNS
impairment in four cases and both visual and CNS sequelae in seven cases. Among the 25
asymptomatic patients on admission, there were 24 (96%) survivors without sequelae, one
patient got visual sequelae, and none died. The patients with symptoms of visual toxicity on
admission (42/101) got visual sequelae on discharge in 33% of cases, and died in 29% of cases.
On admission these patients had gastrointestinal symptoms in 71% of cases, dyspnoea in 55%,
and chest pain in 21%. Overall, 36% (15/42) of these patients became comatose during the
transfer to the hospitals or shortly upon admission to the emergency departments of hospitals,
5% of them had episodes of respiratory arrest. Most of these patients (83%) were administered
sodium bicarbonate to correct metabolic acidosis, 90% were treated with antidote (ethanol in
59% and fomepizole in 31% cases) and haemodialysis (CVVHD/ HDF in 59% and IHD in 31%)
and 71% of them were administered folate. The patients without visual sequelae on discharge
were significantly less acidotic than those with visual damage (p< 0.01), and had lower serum
methanol and formate (both p< 0.01). Coma upon admission was significantly more prevalent in
the patients with visual sequelae (p< 0.05). The hospital treatment measures (haemodialysis,
antidotes, folate substitution) in the patients without visual sequelae did not differ from the
other groups. The 21 patients who died were more acidotic than the survivors with and without
sequelae, and the difference in pH and base deficit was significant between all three groups.
Among the patients who recovered without sequelae, there was a trend toward lower pCO2
when pH was increasing, while the opposite trend was seen among the dying patients (pH
decreased/pCO2 increased) (p< 0.001). Multivariate regression analysis evaluating the partial
effect of laboratory and clinical features on mortality found coma, metabolic acidosis with
pH<7.0, and negative serum ethanol on admission to be the only independent parameters
predicting death. Arterial blood pH was the most important predicting parameter for the
multivariate logistic regression model (logit) of risk of death. The probability of death changed

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exponentially from approximately 77% for the cut-off pH of 6.6, 21% for the cut-off pH of 7.0.
For the serum ethanol concentration on admission as the independent parameter predicting
mortality the AUC was 0.77 (95% CI 0.68 – 0.86) There were no significant differences in
mortality rate between any of the treatment modalities (IHD vs. CVVHD/ HDF, ethanol vs.
fomepizole, or folate substitution ‘yes/ no’). In the survivors, the difference in the prevalence of
visual sequelae was not significant between those with and without folate therapy (p= 0.08).
Most of the survivors with folate substitution (48/63, 76%), and half of those without folate
therapy (8/16, 50%) were treated with haemodialysis.
Comment: Of the 101 patients treated at hospitals, 21 were administered fomepizole. There
were no significant differences in mortality rate between either of the antidote
treatment modalities (ethanol vs. fomepizole) despite fomepizole being reserved for
patients with more severe methanol poisonings. Severity of metabolic acidosis,
state of consciousness, and serum ethanol on admission were the only significant
parameters associated with mortality. The type of dialysis or antidote did not
appear to affect mortality. Recommendations that were issued for hospital triage of
fomepizole administration allowed conservation of this valuable antidote in this
massive poisoning outbreak for those patients most in need.
The main strengths of this study were:
i. The most comprehensive data ever presented after a methanol outbreak.
ii. Most of the essential clinical and laboratory data on admission were collected
during the hospitalisations using standardised forms distributed to the hospitals
by the TIC during the first weeks of the outbreak.
iii. The groups of patients were comparable by age, circumstances of poisoning,
latency period, and size; most of the collected data exhibited normal distribution.
iv. The effect of each treatment modality and laboratory parameter on outcome was
evaluated after adjustment for the effect of the remaining treatment modalities
and laboratory parameters within the multivariate regression analysis.
Some of the limitations of this study were:
v. Data on some patients (such as history of poisoning and clinical symptoms on
admission) were retrospective with their limitations.
vi. Possible variations in the time, amount and patterns of toxic spirits intake,
individual differences in the methanol and formate metabolism, as well as the
possible variations in the available modalities for treatment in different hospitals.
7.2.2.6. Zakharov et al, 2015: A prospective study in 38 patients with methanol
poisoning
Study design, objectives
This was a prospective, uncontrolled observational study based on data from the Czech
methanol mass poisoning in 2012 (Zakharov, 2014).
Patient characteristics, methods:
Patients were eligible if they met the following criteria: confirmed methanol poisoning,
documented circumstances of methanol ingestion and time to diagnosis, and sufficient
laboratory data, including arterial blood pH, serum methanol, and lactate and ethanol
concentrations on admission. A diagnosis of methanol poisoning was made based on similar
criteria to those described above in Zakharov, 2014. The patients were further divided into
three groups according to the outcome: Group I, survivors without health sequelae; Group II,
survivors with visual and/or central nervous system (CNS) sequelae; and Group III, patients

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who died. Study treatments, comparison of admission data and analysis of results were same as
that described for Zakharov, 2014 above.
Results
The 38 patients had a median age of 51 (37-62) years and included 28 males and 10 females.
Only 10% of the patients were admitted within 12 h after the methanol ingestion, 53% within
48 h and 37% later than 48 hr. The type of toxic alcohol was known in 34 cases and the
approximate quantity in 27 cases. The median amount of toxic spirits (volumes of the
formulated spirits) consumed was 450 mL (range 100–800 mL). The methanol poisoning
occurred due to unintentional ingestion of methanol-tainted ethanol in adulterated strong
alcoholic beverages. Ten (26%) patients had co-ingested other alcoholic beverages without
toxic amounts of methanol (wine, beer, whisky, home-made spirits) concomitantly.
The group of survivors without sequelae differed significantly in serum formate and lactate
concentrations from the two other groups. A significant correlation was found between the
aggregate concentration of serum formate and serum lactate and the severity of metabolic
acidosis. In two patients, the serum concentrations of methanol on admission were under the
limit of toxicity of 6.24 mmol/L. In both subjects 14, the measurement of formic acid proved to be
useful for diagnostics and clinical management. In 12 patients, the methanol concentrations
were under 15.6 mmol/L on admission, that is, under the serum level indicating haemodialysis;
nevertheless, the median formate concentration in these 12 cases was 8.6 mmol/L (range 4.1–
14.2 mmol/L), indicating the need for the application of enhanced elimination methods
according to the present AACT/EAPCCT practice guidelines on the treatment of methanol
poisoning.
The symptomatic patients had significantly higher serum formate concentrations than the
asymptomatic ones (median of 2 mmol/L): the median serum formate in the patients with
visual disturbance was 15.2 mmol/L (IQR 13.5–16.9 mmol/L), and in those with dyspnoea, it
was 15.4 mmol/L (IQR 12.1–18.0 mmol/L), but signs of visual toxicity were present in one
patient with serum formate as low as 3.7 mmol/L. Finally, the lowest serum formate
concentration in a patient with coma on admission was 9.3 mmol/L, and the median for
comatose patients was 15.7 mmol/L (IQR 12.8–18.5 mmol/L). The differences in serum formate
concentrations in symptomatic patients depending on clinical features were not significant (all
p > 0.05).
Most of the patients were severely acidotic on admission; therefore, bicarbonate was given
aiming for full correction of the metabolic acidosis. All the patients were administered antidotes
to block ADH, and ethanol was administered more often as a cheaper and more available
antidote, whereas fomepizole was applied mainly in severely ill patients.
There were six fatalities in hospital, 15 patients (39%) were discharged from hospital without
sequelae, and 17 patients (45%) had health sequelae of methanol poisoning. Among them,
visual impairment was diagnosed in three cases, CNS impairment in five cases and both visual
and CNS sequelae in nine cases. Patients with visual sequelae were found to have a median
serum formate concentration on admission of 16.1 mmol/L (IQR 14.3–19.9 mmol/L). Patients
with CNS sequelae had a median serum formate concentration of 15.9 mmol/L (IQR 14.2–19.5
mmol/L). The patients with both visual and CNS sequelae had a median serum formate
concentration of 19.1 mmol/L (IQR 14.3–20.6 mmol/L). Finally, those who died had a median
serum formate concentration of 15.2 mmol/L (IQR 13.8–15.9 mmol/L). The bivariate logistic
regression (logit) model showed that the probability of a poor outcome (death or survival with
sequelae) was higher than 90% in the patients with a serum formate concentration of at least
17.5 mmol/L, a serum lactate concentration of at least 7.0 mmol/L and/or an arterial blood pH

14In one case, the serum formate was very high, 15.2 mmol/L, confirming that in late-presenting patients, most of the
methanol might be bio transformed into this metabolite. In the other case, the serum formate was at the upper
reference limit, confirming minor methanol poisoning.

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lower than 6.87. Receiver operating characteristics (ROC) curve analysis was used to examine
how the serum formate concentration alone and combined with the serum lactate concentration
predicted survival without visual and CNS sequelae. It showed that the corresponding areas
under the curve (AUC) were 0.64 (95%CI 0.44–0.85) I for the serum formate and 0.75 (95% CI
0.56–0.93) for ‘S-formate + S-lactate’. The difference between the two was not significant (p =
0.23), because the analysis was based on data from only 38 patients.
Comment: This was the most comprehensive data on formate measurements after methanol
poisonings and results suggested that:
i. Serum formate concentration is a more reliable indicator of the severity of
poisoning in patients presenting 48 or more h after toxic spirit ingestion, when
much of the ingested methanol might already have been metabolised or in unclear
cases with the serum methanol concentrations are close to the toxic limit.
ii. Serum formate unlike serum methanol concentration alone or with serum lactate
concentration, as well as the severity of metabolic acidosis, should be used as
decisive parameters for the application of haemodialysis in subjects with serum
methanol <15.6 mmol/L in underdeveloped countries where resources are scarce,
checking methanol levels with gas chromatography may not be possible and the
enzymatic measurement of serum formate may be more practical.
Limitations of this study were as follows:
iii. Confounding factors due to nature of retrospective data (history, of poisoning,
amount of toxic spirits and clinical symptoms on admission).
iv. Individual differences in methanol and formate metabolism.
7.2.2.7. Paasma et al, 2012
Retrospective observation case series of methanol-poisoned patients from Norway (Hovda, et
al., 2005), Estonia, Tunisia and Iran who were identified by positive serum methanol and had a
blood acid-base status drawn on admission. Overall, 203 patients were included in the study, of
which 32 were given fomepizole and the remaining 171 were administered ethanol alone. There
were 48 deaths and 34 patients were discharged with neurological sequelae.
Using data from all patients, multiple-regression analysis and the ROC curve identified pH and
coma to be the strongest prognostic factors, which is consistent with results from previous
studies. A pH < 7.00 was found to be the strongest risk factor for poor outcome, along with coma
(Glasgow Coma Scale (GCS)< 8) and a pCO2> 3.1 kPa in spite of a pH< 7.00. Despite the low
number of patients in the fomepizole group, the analysis suggested a trend (non-significant)
toward a leftward shift in morbidity and mortality (that is, better outcomes) regarding the pH,
but this difference was not significant. In spite of the severe metabolic acidosis reflected by low
pH, more patients who were administered fomepizole survived with sequelae instead of dying
compared with patients with a similar pH treated with ethanol.
Due to the small number of fomepizole patients, the analysis was more sensitive to outliers,
such as one of the patients in the fomepizole Group III who died despite having a pH of 7.13 on
admission. The diagnosis of this patient was delayed, and treatment was not initiated until 6 h
after admission, at which time the patient was already much more acidotic (pH 6.8) and in a
coma. Without this one outlier, the difference between the two antidote groups would be
significant (p= 0.038). Further, there was a trend toward hyperkalaemia in the poor-outcome
fomepizole groups (Group II and III), whereas many of the surviving patients treated with
ethanol suffered from sequelae despite having a normal serum-K (not significant). Finally,
patients in the ethanol group seemed to die significantly more often despite (spontaneous)
hyperventilation relative to patients in the fomepizole group (p=0.034). The authors proposed a
risk assessment chart to predict the patient’s outcome based on admission data.

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Comment: Interpretation from the above analysis was confounded by the following factors:
i. Not possible to compare the outcomes from the two antidotes directly in
retrospective studies as the morbidity and mortality associated with methanol
poisoning depend on the time from methanol intake to the initiation of treatment,
the amount of formic acid produced and the degree of metabolic acidosis.
ii. Possible variations in the time from intake to the start of treatment, and the
available modalities for treatment (other than the antidote).
iii. The limited number of patients in the fomepizole group, the analysis was more
susceptible to the effects of outliers. Hence the positive trend observed in this
study would require a prospective study and also a larger fomepizole group to
confirm any benefits of fomepizole over ethanol.
7.2.3. Fomepizole treatment for methanol poisonings in paediatric patients
Brent et al. 2010 reviewed the published literature to identify published cases of paediatric
patients treated with fomepizole; 14 patients were identified as being of relevance to the topic,
of which 2 were intoxicated with methanol. Both cases had a similar degree of severity and one
was haemodialysed. Both patients recovered without reported sequelae and did not have any
reported adverse events of fomepizole administration (Brent, 2010).
Although fomepizole prevents the formation of toxic metabolites, dialysis is still required for
elimination of methanol which is distinct from EG intoxication, where fomepizole may eliminate
the need for dialysis (Brown, et al, 2001).
7.2.4. Other studies
Hovda 2005 report serum methanol kinetics in 8 patients treated with bicarbonate and
fomepizole only. This was a prospective case series study of 8 patients with methanol poisoning,
who were selected to fomepizole and bicarbonate treatment only, because of moderate
metabolic acidosis. Three of the patients were later dialysed, because of high serum methanol
concentrations and very slow methanol elimination.
7.2.4.1. Results
Upon admission the median pH was 7.27 (range 7.12–7.50), median base deficit was 15 mmol/L
(5–22 mmol/L) and median serum methanol was 20.4 mmol/L (65 mg/dL) (range 8.4–140.6
mmol/L). The kinetics of methanol during fomepizole treatment in six patients was best
described by a first-order elimination one-compartment model.
The mean correlation coefficient (R2) describing the first-order elimination model in all eight
patients was 0.95 (range 0.90–0.99). The mean plasma half-life (T1/2) of methanol during
fomepizole treatment was 52 h (range 22–87); the higher the serum methanol, the longer the
T1/2. Mean half-life of serum formate was 2.6 h, when methanol metabolism was assumed
blocked by fomepizole and no folinic acid was given. This rapid formate elimination in non-
acidotic patients may be explained by high renal excretion of formate.
Comment: Based on their data, the authors suggest that methanol-poisoned patients with
moderate metabolic acidosis (pH>7.10 and base deficit <22 mmol/L) and visual
disturbances that are reversed by the initial bicarbonate administration may safely
be treated with fomepizole only. However, it is important to note that dialysis does
shorten the period of hospitalisation when the serum methanol is high (>19
mmol/L or 60 mg/dL).
7.2.4.2. Case reports
From the literature, detailed information regarding 8 individual cases including 2 paediatric
methanol intoxications, were identified. These case reports also provided supportive evidence

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for efficacy of fomepizole in treatment of methanol poisoning. However, it is important to note

that dialysis was used in almost all of these patients.
7.2.5. Analyses performed across trials (pooled analyses and meta-analyses)
After approval of Antizol (fomepizole, 4MP) was granted by the FDA for treatment of ethylene
glycol poisoning, a supplemental NDA was submitted to seek approval for the use of Antizol as
an antidote for methanol or suspected methanol poisoning. This integrated summary was
provided in the sponsor’s submission.
7.2.6. Evaluator’s conclusions on clinical efficacy for treatment of methanol
poisoning
The evidence for efficacy of fomepizole treatment as an antidote for methanol toxicity was
provided by two uncontrolled studies provided by the manufacturer (S7 and S13) involving 16
patients with methanol poisoning.
S13 was a well-conducted, prospective study which provided evidence for efficacy of fomepizole
(4MP) treatment in 11 patients with methanol poisoning. Overall, 7/11 patients survived
without sequelae, 3 patients survived with sequelae and there was 1 death. Fomepizole
inhibited metabolism of methanol to toxic metabolites which was demonstrated by reduction in
serum formate in all patients with detectable formate at baseline. Hence results from this study
suggest that fomepizole, in conjunction with supportive care with or without haemodialysis,
inhibits the conversion of methanol to its toxic metabolite, formate.
The case-by-case analysis of the 4 patients with confirmed methanol intoxication in Study S7
provided evidence to support efficacy and safety of 4MP in the treatment of methanol
intoxication. However, interpretation was limited by retrospective nature of study and small
sample size.
These efficacy studies and pharmacokinetic data have shown the recommended loading dose to
be in the range of 10-20 mg/kg, followed by similar or lower doses every 12 h up to 48 h; then ,
due to enzyme induction, increased doses should be administered every 12 h until ethylene
glycol or methanol blood levels are <20 mg/dL. If dialysis is employed to remove toxic
metabolites of ethylene glycol or methanol, additional doses should be infused periodically
throughout dialysis to compensate for its loss in the dialysate.
In addition to full clinical study reports provided to the sponsor (AFT Pharmaceuticals) by the
manufacturer, the systematic review of the literature identified an additional two prospective
studies (Hovda et al 2005 and Brent et al. 2001) that documented the efficacy of fomepizole in
the treatment of poisoning associated with potentially fatal amounts of methanol in another 18
patients.
The role of haemodialysis in methanol poisoning is well-established when ethanol is the
antidote, but there are few reports and few kinetic data on dialysis when fomepizole is used as
an antidote. Although the phase III study (S13) leading to the FDA approval of fomepizole in
methanol poisoning included dialysed patients, they were all dialysed according to the
traditional dialysis indications from the time when ethanol was the only antidote Based on data
from the prospective case series study in 7 patients (Hovda, 2005) and another retrospective
study in 14 patients [Megarbane et al. 2001, 2004], the authors suggest that methanol poisoning
involving high methanol concentrations (>50 mg/dL) without severe acidosis or visual
impairment may be successfully treated by repeated dosing with fomepizole without dialysis.
Although fomepizole prevents the formation of toxic metabolites, dialysis is still required for
elimination of methanol which is distinct from EG intoxication, where fomepizole may eliminate
the need for dialysis (Brown, et al, 2001).
Three retrospective/prospective study reports on methanol poisoning outbreaks in Norway
(Hovda, 2005) and Czech Republic (Zakharov, 2014 and 2015) provided epidemiological,

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clinical and prognostic features from the large methanol outbreaks involving 210 patients.
Methanol poisoning still has a high mortality, mainly because of delayed admission to hospital
and late diagnosis. The use of buffer, antidote (ethanol and fomepizole were used in these
studies) and haemodialysis is effective if initiated early. Visual disturbances, dyspnoea
(including hyperventilation) and GI symptoms were the most frequent clinical features, whilst
severe metabolic acidosis (pH < 6.90, BD > 28 mmol/L), coma and increased pCO2 (lack of
compensatory hyperventilation) were associated with poor outcome. Most of the patients who
presented with symptoms were discharged without sequelae.
Other case report publications in adult (Table 2) and paediatric (Table 3) patients with
methanol poisonings also provided supportive evidence for efficacy of fomepizole in treatment
of methanol poisoning. However, it is important to note that dialysis was used in almost all of
these patients.
Fomepizole is not intended to substitute for haemodialysis in patients with methanol poisoning.
Concurrent haemodialysis is probably necessary to hasten removal of methanol in patients who
present with high methanol levels, even if they present before the development of metabolic
acidosis. However, fomepizole appears to be an easy and effective (although slightly expensive)
substitute for ethanol in patients with methanol poisoning. By inhibiting hepatic metabolism of
methanol and the accumulation of formic acid in the blood, it prevents the life- and vision-
threatening complications of methanol poisoning.

8. Clinical safety

8.1. Studies providing evaluable safety data

The following studies provided evaluable safety data:
8.1.1. Pivotal efficacy studies
Six studies conducted in 63 patients to assess the safety and efficacy of fomepizole therapy for
ethylene glycol poisoning (Studies S-7, S-8, S-9, S-10, S-11 and S-12), and interim safety data
generated from 15 patients enrolled in an ongoing clinical Study S13 to assess the safety and
efficacy of fomepizole in the treatment of suspected methanol poisoning.
8.1.2. Clinical pharmacology studies
Five clinical pharmacology studies conducted in 63 healthy subjects (identified in the NDA as
Studies S-2, S-3, S-4, S-5 and S-6). Studies S-2 through S-6 were clinical pharmacology studies
assessing the pharmacokinetic and pharmacodynamic parameters of fomepizole.
8.1.3. Pivotal studies that assessed safety as a primary outcome
None.
Comment: Due to complexity of this literature based dossier, the safety sections of this
evaluation report will be discussed as follows:
Section 8.4.1: evaluation and discussion of the safety results of the individual
clinical studies in patients.
Section 8.4.2: evaluation and discussion of the safety results from each of the
clinical pharmacology studies in healthy subjects.
Section 8.4.3: evaluation and discussion of the main safety results from other
important published studies and case reports.
Section 8.5: evaluation and discussion of the Integrated summary of safety in
combined dataset of 141 subjects (63 healthy subjects and 78 patients).

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The sponsors have stated that the adverse reaction data in the proposed PI was
based on data generated from this combined safety dataset of 141 (63 healthy
subjects and 78 patients).

8.2. Pivotal studies that assessed safety as a primary outcome

None.

8.3. Patient exposure

8.3.1.1. In healthy volunteers
Overall, 53 healthy male subjects received fomepizole in the placebo-controlled Studies S2, S3,
S4, S5 and S6. However, two of the cross-over studies (S-2 and S-5) involved two fomepizole
treatment periods. In study S-2, six patients received fomepizole IV in one treatment period
(with concomitant oral placebo) and oral fomepizole (with concomitant IV placebo) in another.
In Study S-5, five patients received fomepizole and ‘placebo’ (in place of ethanol) in one period
and 4 of the 5 received fomepizole and ethanol in another (the fifth patient dropped out prior to
the second period). Thus, there were a total of 63 fomepizole subject-treatments (12 with
fomepizole placebo concomitantly, five with ethanol ‘placebo’ concomitantly, and 46 without
placebo) and 25 placebo subject-treatments (without fomepizole) in the five studies combined.
Twelve of the fomepizole subject-treatments (S-2) involved both fomepizole and placebo (by
different routes). Overall, 32 subjects received either single oral doses (n=27) or single IV doses
(n=5) of fomepizole; 6 subjects received both IV and oral single doses in a cross-over study and
15 additional subjects received multiple oral doses every 12 h for up to 96 h.
It is important to note that only 5 subjects in the clinical pharmacology studies were treated
with the proposed IV route of administration.
8.3.1.2. In patients with EG and methanol poisoning
Table 3 summarises the studies in patients which provided safety data. Study S-7 was a
retrospective study of 38 patients treated for various poisonings over 14 years at a single centre
in France. Cohort A included 26 patients treated for EG poisoning, Cohort B included 5 patients
treated for methanol poisoning, and Cohort C included 7 patients treated for suspected but later
unconfirmed EG poisoning. Study S-8 was a prospective study of 22 EG poisoned patients
conducted by the sponsor in the U.S. Studies S-9 and S-10 were published reports that contained
detailed descriptions of 4 patients whose data was also included in Study S-7. Studies S-11 and
S-12 were published case reports of three additional patients poisoned with EG. Majority of
dosing with fomepizole was by IV administration in all the EG/methanol poisoning studies
(Table 3).

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Table 3: Main studies in patients which provided safety data with brief summary of safety
results

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Table 3 continued: Main studies in patients which provided safety data with brief
summary of safety results

Dosing characteristics varied among patients in the two pivotal methanol studies. In the
retrospective study S-7 (Cohort B), fomepizole dosages and routes of administration varied
depending upon the amount of toxin ingested, length of time between exposure and treatment,
and mental status of the patient. In the prospective study (S-13), all patients were to receive IV
fomepizole at an initial dose of 15 mg/kg, followed by 4 doses of 10 mg/kg every 12 hours, and
15 mg/kg every 12 h thereafter until methanol levels were <20 mg/dL. Patients receiving
haemodialysis were given an additional dose before dialysis if more than 6 h had elapsed since
their last dose, and this dose was to be repeated every 4 h during dialysis. Those receiving
dialysis for longer than one hour were also to receive an additional fomepizole dose at the end
of dialysis in addition to the next regularly scheduled dose, according to the following schedule:
1-3 hours: one-half of the next scheduled dose
>3 hours: full dose equivalent to the next scheduled dose.
In Study S-7, three patients (60%) received IV fomepizole; the other two patients received an
oral formulation. In Study S-13, all patients received the IV fomepizole formulation. The median
loading dose of fomepizole for the 20 patients with suspected methanol poisoning was 15
mg/kg with a range of 9 to 22 mg/kg. Treatment periods ranged from single doses in seven
patients to 13 doses over seven days in one patient. The highest cumulative dose administered
was 8445 mg or 102.8 mg/kg (Table 4).

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Table 4: Integrated fomepizole dosing characteristics

The ongoing study S13 in patients with suspected methanol poisoning used the proposed
dosing regimen for fomepizole (including during haemodialysis) as reflected in the ‘Dosage and
administration’ section of the proposed PI.
8.3.2. Safety results of the individual pivotal studies in patients
Brief summary of the safety results in studies in patients was provided in Pivotal efficacy
studies above.
8.3.2.1. Study S7
All 38 patients that received fomepizole regardless of actual intoxication status were included in
the analysis of safety; 25/38 patients (66%) reported 84 AEs including headache, vomiting,
abdominal pain anaemia and fever. Ten AEs were reported in 3/5 patients (60%) of patients in
Cohort B. The majority of these AEs were judged by the investigator to be mild to moderate. No
serious adverse events were reported and no patient discontinued the trial. No clinically
significant laboratory abnormalities were noted at last evaluation.
8.3.2.2. Study S8
Overall, 22 patients were treated for suspected or confirmed EG poisoning in this open-label,
prospective study. All patients received 4MP via intravenous infusion; loading dose 15 mg/kg,
then 10 mg/kg q12h for 4 doses then 15 mg/kg until EG <20 mg/dL. The most frequent AE was
acute renal failure which occurred in patient who had signs of established renal insufficiency at
presentation and was not related to treatment as renal injury is the most common major
complication of EG poisoning. There was one death which was attributed to the severe
intoxication and significant time delay to treatment and unrelated to the treatment regimen.
One case of hypotension also occurred in this patient and the relationship with the study drug
was deemed unknown by the investigator and occurred in a patient who had evidence of a
concurrent acute myocardial infarction on presentation. The patient rapidly developed
cardiogenic shock and died; this patient also experienced seizure. Four other AEs were judged
to be related to the study drug by the investigator, of which each occurred once over the course
of the study. These were emesis, headache, abdominal pain and vertigo. Other AEs were
unrelated to study medication as judged by the investigators. There were non-clinically
significant abnormalities noted for ECG, cranial nerve assessments, or ophthalmic evaluations.
With the exception of the hypotension noted for one patient, no clinically significant vital sign
abnormalities were observed. No clinically significant laboratory abnormalities were noted with
the exception of those related to the effect of the EG poisoning itself. In contrast to the
observations in earlier studies in healthy subjects (S2 and S4), no elevations in liver enzymes
were observed in this trial.

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8.3.2.3. Study S13

The highest cumulative dose of fomepizole in this study was 8445 mg. Due to the comatose
status of one patient an error was made in estimating the patient’s weight so that he actually
received a loading dose of 22 mg/kg. The patient tolerated the dose well and completed the
study alive with ongoing baseline sequelae of lower left lung infiltrate. Overall, 37 AEs were
reported by 13/15 patients (87%). The majority were mild to moderate and considered related
to concurrent illness (67%). The most frequently reported AEs were agitation (33.3%) anxiety
(20%), fever (20%) and headache (13.3%). Three SAEs were reported by two patients (toxic
encephalopathy, rhabdomyolysis and right deep vein thrombosis) and both patients died (one
patient during the study and the other patient 20 days after end of the trial). Both deaths were
due to toxic encephalopathy secondary to severe methanol poisoning. No patients discontinued
due to an AE. There were no clinically significant abnormalities for cranial nerve assessment,
vital signs or physical examinations.
8.3.2.4. Study S10
Baud et al, 1986: The only obvious AE in this study was a skin rash in one of three patients and
possible eosinophilia in two others.
8.3.2.5. Study S11
Harry, et al, 1994: This was a case of a 30 year old male with EG poisoning treated with IV
fomepizole (loading doses of 16.2 mg/kg or followed by q12h doses of 8.1, 5.4, 2.7 and 1.35
mg/kg). During 5 days of hospitalisation the only observed AE of 4MP treatment was a mild
transient elevation in AST activity to 36 IU/L on the third day (normal <30 IU/L). Examination
of the patient 15 days later revealed no clinical or biochemical abnormality.
8.3.2.6. Study S12
Jobard, et al, 1996: This study reported the cases of two patients severely intoxicated with EG.
The first patient made a full clinical recovery without any AEs. The second patient suffered
multiorgan failure and death. The authors concluded that the death of this patient admitted very
late after massive EG ingestion with a flat electroencephalogram cannot be attributed to failure
of treatment
8.3.3. Safety results of the individual clinical pharmacology studies in healthy
subjects
8.3.3.1. Study S2
Safety and PK study of 6 healthy males between the ages of 23 and 35 using single IV bolus or
oral doses of 7 mg/kg. Safety results included mild and brief instances of light-headedness, skin
rash, venous irritation, phlebosclerosis, nausea and headache after IV doses. Some elevation in
triglycerides, CPK and ketonuria was observed, although none were clinically significant.
8.3.3.2. Study S3: Jacobsen et al, 1988 and 1989
Single ascending oral dose study of the safety of fomepizole (10, 20, 50 and 100 mg/kg) in 22
healthy males ages 20-40: No side effects were observed at 20 mg/kg dose. Slight nausea
observed at 10 mg/kg. At 50 or 100 mg/kg nausea, vertigo, dizziness, feeling of drunkenness,
loss of appetite and increases uric acid were reported. Slight transient liver impairment
(elevation of liver transaminases) was observed but was not consistent with increasing doses of
fomepizole (4MP given orally).
8.3.3.3. Study S4: Jacobsen, 1990
Subjective side effects were reported in 50% of the placebos (3/6) and 47% of the drug subjects
(7/15). The side effects reported at various times in both groups were dizziness, light-
headedness, diarrhoea and headache. All effects were rated mild and of short duration and no
relationship with the study drug as apparent. Six (40%) of the drug subjects had an increase in

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one or both serum transaminase levels. The elevation was mild, and in all of these subjects the
follow-up values had not returned to normal when measured about 1 to 2 weeks following
completion of the study.
8.3.3.4. Study S5
All subjects subjectively evaluate their side effects on a 1-3 scale. All subjects were also checked
for objective signs or side effects at each vital sign checkpoint. Other than the predictable side
effects related to moderate ethanol consumption, the side effects reported by these subjects
were abnormal taste and small, local tingling, mild nausea, dizziness, headache and diarrhoea.
An instance of hyperglycaemia was also reported. There was no irritation or phlebosclerosis
reported in the 9 subjects who were given fomepizole as a 30 minute IV infusion.
8.3.3.5. Study S6 (Jacobsen, 1996)
This was a study which evaluated the mutual inhibitory effect between ethanol and 4MP on
their elimination following single oral doses of 10, 15 and 20 mg/kg of 4MP with and without
ethanol in a double-blind, placebo controlled, crossover study; the second part of the study
involved IV 4MP with oral ethanol or placebo.
Comment: The actual reference provided by the sponsor did not provide any safety results for
this study. However, the following was provided in the sponsor’s Summary of
clinical safety: ‘The major AEs experienced by these subjects were related to the
moderate intoxication produced by the ethanol. The subjects all reported subjective
effects that would be considered characteristics of ethanol, but with equivalent
occurrence whether given 4MP or placebo. Side effects observed included lethargy,
facial flush, nausea, vomiting, blurred vision, hangover and diarrhoea. No laboratory
abnormalities related to 4MP were observed.’ However, the source of this data was
not provided and the sponsors have been requested to clarify.
8.3.4. Additional Safety results from the published studies and case reports
8.3.4.1. Prospective and retrospective studies:
In the single patient that was treated for EG poisoning 154 times (99 of which were with
fomepizole only, and 6 with combination fomepizole and ethanol), except for renal impairment
(most probably caused by the calcium monohydrate crystals from EG metabolism), there were
no signs of organ damage after repetitive use of fomepizole as judged from findings on
admission to hospital, on discharge from hospital, and on the autopsy performed at her eventual
death. This suggested that the use of fomepizole is safe even when used frequently (Hovda, et al,
2011).
Of the 38 patients administered fomepizole for clinical suspicion of EG poisoning and reported
by Borron et al. 1999, side-effects that were regarded as possibly related to fomepizole occurred
in four patients, probably related in 1 patient and definitely related in one patient. Side-effects
included two events each of pain/inflammation at the site of injection and transient
eosinophilia, and one event of generalised cutaneous eruption.
In patients treated for EG poisoning reported by the Methylpyrazole for Toxic Alcohols (META)
study group (Brent et al., 1999), no AEs were rated as definitely or probably related to
fomepizole. Adverse events that were possibly related to fomepizole were bradycardia (2
patients), seizure (2 patients) and headache (2 patients).
In the META study for methanol poisoning (Brent et al., 2001), AEs in six patients were
classified by the treating physicians as possibly related to fomepizole. These were phlebitis,
dyspepsia, anxiety, agitation, hiccups, reaction at the infusion site, transient tachycardia,
transient rash and a ‘strange’ feeling. Each of these events occurred in only one patient, except
for agitation, which was reported by two patients. The rash that occurred after four doses of
fomepizole in one patient who had a history of allergic reactions to sulphonamide drugs and

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who was also receiving methadone, clonidine, lorazepam, and vitamins. He received two
additional doses of fomepizole, with no recurrence of the rash.
Levine et al. (2012) did not report any AEs that were related to treatment with fomepizole in 40
patients with EG intoxication without haemodialysis.
In another retrospective study for the treatment of methanol poisoning (Mégarbane et al.,
2001), most patients received between 1 and 4 doses of fomepizole. However, three patients
received 5, 6 and 16 doses, representing total doses of 4000, 6000, and 5025 mg (57.1, 88.2 and
75.0 mg/kg), respectively. Despite these relatively high cumulative doses, AEs were rare.
Nausea and headache occurred in one patient, lymphangitis, a burning skin sensation and mild
transient eosinophilia in the patient receiving 16 doses, and fever was observed in two patients
(one of whom received 4 doses). During fomepizole treatment, prothrombin time, liver function
tests, creatine phosphokinase and platelet and white blood cell counts remained stable.
8.3.4.2. Adverse drug events associated with the use of ethanol vs. fomepizole
Lepik, et al (2009) reported a cohort study which investigated patients aged ≥ 13 years if they
were hospitalised between 1996–2005 for methanol or ethylene glycol poisoning and treated
with at least 1 dose of ethanol or fomepizole. The primary outcome was at least 1 adverse drug
event, expressed as adverse drug event rate per person-day of antidote treatment. Association
between time to first adverse drug event and antidote type was modelled by Cox regression,
adjusted for confounders. Overall, 223 charts were reviewed and 172 analysed. The fomepizole
treated cases had higher pre-treatment APACHE II scores 15 than the ethanol-treated cases,
indicating more severe illness at baseline. Use of non-antidote treatments was similar between
treatment types, although a higher proportion of fomepizole treated cases receiving
haemodialysis and sodium bicarbonate. All fomepizole- and 115 (88%) of ethanol-treated cases
received antidote exclusively by the intravenous route. Median antidote duration was
approximately 24 h for both groups. Fifteen cases received both antidotes, all switched from
ethanol to fomepizole. Toxicologists identified at least 1 adverse drug event in 74 of 130 (57%)
ethanol-treated and 5 of 42 (12%) fomepizole-treated cases. CNS symptoms accounted for most
adverse drug events (48% ethanol-treated, 2% fomepizole treated). Severe adverse drug events
occurred in 26 of 130 (20%) ethanol-treated (coma, extreme agitation, cardiovascular) and 2 of
42 (5%) fomepizole-treated (coma, cardiovascular). Serious (life-threatening) adverse drug
events occurred in 11 of 130 (8%) ethanol-treated (respiratory depression, hypotension) and 1
of 42 (2%) fomepizole-treated (hypotension, bradycardia) cases. Median adverse drug event
onset was within 3 h after the start of either antidote. Ethanol and fomepizole adverse drug
event rates were 0.93 and 0.13 adverse drug events per treatment-day, respectively. Adjusted
hazard ratio was 0.16 (95% confidence interval 0.06, 0.40) suggesting a 6-fold reduction in AEs
rate in the fomepizole group compared with ethanol.
Comment: The above results should be interpreted with caution due to the following
limitations of this cohort study:
i. This was an observational study and cases were not randomised to treatment
groups.
ii. Number of patients in the fomepizole group was much lesser compared to the
ethanol group (40 vs 130).
iii. Use of hospital chart data, which are susceptible to misclassification (for example,
incorrect documentation of symptom onset times) and missing information
(which could underestimate event frequency).
iv. Chart abstracters and reviewers were not blinded to the study.

15Acute physiology and Chronic Health Evaluation II is a severity of disease classification system (Kraus, et al, 1985)
and is one of the several ICU scoring systems;

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v. Overall, it is very difficult to come to any definitive conclusions regarding

comparative safety of fomepizole vs ethanol as an antidote for EG/methanol
poisonings due to co-ingestants, other treatments, effects of toxic alcohol
poisoning and other medical conditions.
Lepik, et al (2011) described and compared the frequency, type, outcome and underlying causes
of medication errors associated with ethanol and fomepizole. Using the same cohort as the
previous study (Lepik et al. 2009) the authors used Fisher’s exact test to determine differences
in the proportion of ethanol and fomepizole treated cases with medication error and univariate
logistic regression to identify risk factors associated with harmful dosage errors.
There were 145 ethanol- and 44 fomepizole-treated cases with similar baseline characteristics
with exception of fact that voluntary poison control service consultation occurred in 100% of
fomepizole- but only 50% of ethanol-treated cases. There was ≥ 1 medication error in 113/145
(78%) ethanol- and 20/44 (45%) fomepizole-treated cases (p = 0.0001) with more ethanol-
related errors involving excessive dose, inadequate monitoring and inappropriate antidote
duration. Harmful errors occurred in 19% of ethanol and 7% of fomepizole-treated cases
(p=0.06) and were largely due to excessive antidote dose or delayed antidote initiation.
Occurrence of harmful dosage error was reduced in cases with Poison Control Centre
consultation, odds ratio (95% CI) 0.39 (0.17, 0.91), haemodialysis 0.37 (0.16, 0.88), or
fomepizole versus ethanol 0.24 (0.06, 1.04). Poison Control Centre consultation and
haemodialysis treatment had a significant protective effect against harmful dosage errors, with
odds ratios (OR), (95% CI) of 0.39 (0.17, 0.91) and 0.37 (0.16, 0.88), respectively. Use of
fomepizole reduced the risk of harmful dosage error relative to ethanol, OR (CI 95%) 0.24 (0.06,
1.04), but did not achieve statistical significance. Overall, the authors concluded that fomepizole
was less prone to medication error than ethanol. Error-related harm was most commonly due to
excessive antidote dose or delayed antidote initiation.
Comment: Overall, fomepizole was less prone to medication error than ethanol. Error-related
harm was most commonly due to excessive antidote dose or delayed antidote
initiation. However, the above results should be interpreted with caution due to the
following limitations of the above study:
i. This was an observational study and cases were not randomised to treatment
groups.
ii. Number of patients in the fomepizole group was much lesser compared to the
ethanol group (44 vs 145).
iii. Poison Control Centre consultation occurred in 100% of fomepizole-treated
patients compared to only 50% of the ethanol-treated patients; this is especially
important as consultation had a significant protective effect against harmful
dosage errors.
iv. Documentation of medication errors by hospital chart review is susceptible to
missing information. Information was less complete for ethanol than for
fomepizole-treated cases.
v. Chart abstracters and reviewers were not blinded to the study.
8.3.4.3. Case reports
In addition to the case reports provided by the manufacturer, two other case reports identified
in the systematic review presented treatment emergent AEs associated with fomepizole.
Transient nystagmus within 2 h of IV infusion of 15 mg/kg fomepizole in a 6-year old girl that
ingested ethylene glycol and the event lasted one hour. However, the more commonly cited AEs
associated with fomepizole, such as headache, nausea and dizziness were not obvious in this
patient (Benitez, 2000).

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Lepik et al (2008) reported a case of hypotension and bradycardia associated with IV

fomepizole infusion. A 59-year old man presented to hospital 10 years after EG ingestion with
ataxia, slurred speech, metabolic acidosis, heart rate 70/min, blood pressure 160/100 mmHg.
Treatment with haemodialysis and fomepizole began 7.5 h after admission. Severe bradycardia
(29/min) and hypotension (69 mmHg systolic) occurred immediately following a 30 minute IV
infusion of the first (19 mg/kg) fomepizole dose, but was rapidly corrected with 1 mg atropine.
Transient bradycardia (48/min) and hypotension (89/57 mmHg) recurred immediately after
the second (10 mg/kg) fomepizole dose, also given during dialysis. There was a dose dependent
symptoms intensity and recurrence with rechallenge (with fomepizole) that suggest a causal
relationship between fomepizole and the adverse events experienced. The authors concluded
that the patient probably suffered an idiosyncratic reaction to fomepizole. This patient was
included in the cohort of patients in subsequent publications by these authors (Lepik et al. 2009,
2011).
The other case reports did not provide safety data.

8.4. Integrated summary of safety (ISS)

The objective of the ISS provided was to integrate AE data generated from the 12 clinical studies
conducted to assess the safety of fomepizole in the treatment of EG and methanol poisonings. In
USA, this integrated data was used to update the Adverse reactions section of the current
package insert (already approved for EG poisoning) upon marketing approval of Antizol for
treatment of methanol or suspected methanol poisoning.
8.4.1. Adverse events:
8.4.1.1. AEs in patients
Overall, 60 of the 78 patients (76.9%) experienced at least one AE. The 60 patients included 25
of the 38 patients in Study S-7 (84 events), 19 of the 22 patients in Study S-8 (69 events), 13 of
the 15 patients in Study S-13 (27 events), and all three patients reported in Study S-11 and
Study S-12 (4 events). A total of 184 AEs were reported. The body systems most affected were
Body as a Whole (51.3%), Nervous System (33.3%), Respiratory System (30.8%), Digestive
System (26.9%), Urogenital System (25.6%) and Cardiovascular System (23.1%). The most
frequently reported AEs were fever (14.1%) and acute renal failure (14.1%). Other common
AEs were headache (11.5%), vomiting (7.7%) and agitation (7.7%).
8.4.1.2. AEs in healthy subjects 16
The most common AE was nausea, which occurred in 14 subjects receiving fomepizole (22%)
and in one subject (4%) on placebo. Headache was reported by 13 fomepizole subjects (21%)
and two placebo subjects (8%). Although these events occurred with greater frequency among
fomepizole-treated subjects, the temporal relationship to dosing was not consistent. An
unpleasant taste was sometimes associated with both oral and intravenous administration of
fomepizole (8 subjects, 13%); 3 subjects (5%) complained of an abnormal smell with IV dosing.
Dizziness was reported by 9 subjects who received fomepizole (14%), especially at higher oral
dosage levels (50 and 100 mg/kg) and by one placebo subject (4%).
8.4.1.3. AEs in combined healthy subjects and patients (n=141)
Overall 138 of the 141 (97.9%) combined subject/patient population reported at least one AE. A
total of 262 events were reported. The body systems most often involved were Body as a Whole
(38.3%), Nervous System (37.6%) and Digestive System (29.1%). The most frequently reported

16 AEs that occurred in healthy subjects were counted for each specific treatment period during which the

event occurred. Thus, identical events occurring in the same subject during different treatments were
counted once for each treatment period.

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AEs were headache (n=22; 15.6%), nausea (n=16; 11.3%), fever (n=11, 7.8%), acute renal
failure (n=11, 7.8%), dizziness (n=10; 7.1%), increased drowsiness (n=9; 6.4%), bad metallic
taste (n=8; 5.7%), vomiting (n=7; 5.0%) and agitation (6; 4.3%). Anaemia and abdominal
pain/tenderness were each reported in five patients (3.5%). Hypotension, rash, feeling of
burn/tingling in vein, diarrhoea, and light-headedness each were reported in four patients
(2.8%). All other events were reported in <2.1% of patients.
8.4.2. Drug-related AEs
8.4.2.1. AEs in patients
Overall, 53 of the 78 patients (67.8%) experienced 53 drug related AEs. The body systems most
affected were Body as a Whole (23.1%), Nervous System (11.5%), Cardiovascular (7.7%) and
Hemic/Lymphatic (7.7%). The most frequently reported drug-related AEs were headache (n=7;
9.0%), abdominal pain (n=4; 5.1%), vomiting (n=3, 3.8%) and fever (n=3, 3.8%). Majority of AEs
for which severity assessments were' made were mild or moderate in intensity. Hypotension
and seizure in Study S-8 were rated severe with unknown relationship to study drug. The severe
hiccups (possibly related to study drug) reported in Study S13 resolved three days after
fomepizole dosing had been discontinued. The remaining AEs were not rated in intensity or
relationship to study drug by the Investigator and were entered into the database as ‘unknown’
for both of these categories. These included agitation, anxiety, dyspepsia, headache (N=1),
multiorgan system failure, disseminated intravascular coagulation, anuria and lymphangitis.
8.4.2.2. AEs in healthy subjects 17
AEs were not rated for intensity or by relationship to study drug per FDA guidelines in the
healthy subject studies (N=63). Brief periods of light-headedness, decreased environmental
awareness, and a feeling of drunkenness were also reported with IV and high oral doses. These
events correlated with high plasma levels of fomepizole and were probably drug-related.
However, concomitant ethanol administration in some subjects reporting these AEs made
assessment of causality difficult. The only events definitely attributed to treatment with
fomepizole were phlebosclerosis, abnormal smell, and bad taste, the latter occurring during
both IV and oral administration. Phlebosclerosis occurred only in subjects receiving a 25
mg/mL bolus injection over 5 minutes (Study S-2). This concentration and infusion rate was
higher than those used in the subsequent intravenous study, S-5 (2 mg/mL over 30 minutes).
None of the five subjects in S-5 developed phlebosclerosis in either fomepizole treatment
period.
8.4.2.3. AEs in combined healthy subjects and patients (n=141)
Overall, 134 of the 141 subjects/ patients (95%) experienced 134 drug-related AEs. The body
systems most affected were Nervous System (25.5%), Body as a Whole (22.7%), Digestive
System (17.7%) and Special Senses (11.3%). The most frequently reported drug-related AEs
were headache (n=20; 14.2%), nausea (n=15; 10.6%), dizziness (n=9; 6.4%), increased
drowsiness (n=8, 5.7%) and bad taste/metallic taste (n=8, 5.7%). The incidence of all remaining
events was <2.8% and included application site reaction, vomiting, rash, and abnormal smell.
AEs were not rated for intensity or by relationship to study drug per FDA guidelines in the
healthy subject studies (N=63). Therefore, all events noted in this group were included as
‘unknowns.
8.4.3. Deaths, SAEs and discontinuations due to AE
Six deaths were reported during fomepizole treatment: one in Study S7, 3 in Study S8, 1 each in
studies S12 and S13. Two additional deaths were reported post study (a patient in Study S13

17AEs that occurred in healthy subjects were counted for each specific treatment period during which the event
occurred. Thus, identical events occurring in the same subject during different treatments were counted once for
each treatment period.

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died 20 days post-study and another patient in Study S7 died 11 months after treatment.
Review of the death narratives suggested that the deaths did not appear to be related to
fomepizole treatment.
AEs collected in Study S7 were not assessed for seriousness according to the FDA definition.
However, six serious events that resulted in the death of one patient were life-threatening
(metabolic acidosis, collapse, acute renal failure, anuria- all present prior to fomepizole
administration; convulsions and fever) and the investigator rated all of these events as severe
and not related to study drug. Three other patients in Study S7 were transferred to other
facilities for continuing treatment of adverse experiences. Prolongation of hospitalisation would
be considered as serious by the FDA definition. The events were fever, gastric pain, and
vomiting in one patient; pre-existing tuberculosis in another patient; and acute pancreatitis and
alcoholic ketoacidosis (both pre-existing) and suspicion of bacteraemia in a third patient. All
three patients were lost to long term follow-up.
Thirteen AEs that occurred in ten patients in Study S8 were considered serious. All 13 of these
events (liver failure, myocardial infarction, and cerebral oedema in one patient each and acute
renal failure in ten patients) were judged by the Investigator to be due to EG or acetaminophen
poisoning, and unrelated to fomepizole treatment.
In Study S12, the events leading to death in one case were multi-organ system failure and
disseminated intravascular coagulation, which were life-threatening, although no assessment of
seriousness was reported by the Investigator.
There were 3 SAEs reported by two patients in Study S13: toxic encephalopathy in one patient
and rhabdomyolysis and right deep vein thrombosis in the second patient. All three events were
coded by the Investigator as severe and not related to study drug. Both patients subsequently
died.
One patient in Study S7 was discontinued from treatment with fomepizole after two doses but
no details were available. In Studies S8 and S13, seven patients were discontinued after being
enrolled and after receiving a loading dose of fomepizole and repeat laboratory reports
indicated that none of these patients had ingested ethylene glycol (N=3) or methanol (N=4) . All
patients were included in safety assessments of the respective study reports. No patient
discontinued due to an AE.

8.5. Post-marketing experience

No PSURs were provided in this submission.

8.6. Safety issues with the potential for major regulatory impact
8.6.1. Liver toxicity
Mild, transient elevations in liver transaminases were reported in the earlier studies in healthy
subjects but similar findings were not observed in the studies in patients.
8.6.2. Haematological toxicity
Eosinophilia is a known AE associated with fomepizole treatment.
8.6.3. Serious skin reactions
None.
8.6.4. Cardiovascular safety
None.

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8.6.5. Unwanted immunological events

Venous irritation and phlebosclerosis were noted in two of six normal volunteers given bolus
injections (over 5 minutes) Antizol at a concentration of 25 mg/mL. Minor allergic reactions
(mild rash, eosinophilia) have been reported in a few patients receiving Antizol. Therefore,
patients should be monitored for signs of allergic reactions.

8.7. Other safety issues

8.7.1. Safety in special populations
8.7.1.1. Paediatric patients
Brent et al (2010) reported 14 published cases related to fomepizole treatment in paediatric
patients with EG (N=10), methanol (n=2) or other (diethylene glycol & butoxyethanol, n=2)
poisoning. The one adverse effect reported during fomepizole therapy was transient nystagmus
in a 6-year-old with a serum EG concentration of 130 mg/L and a serum bicarbonate
concentration of 2 mEq/L.
8.7.1.2. Elderly patients
Not evaluated.
8.7.1.3. Renal, Hepatic impairment
Not evaluated.
8.7.2. Safety related to drug-drug interactions and other interactions
No specific studies were conducted to evaluate safety of fomepizole when administered with
other ADH inhibitors or drugs that act on the CYP-450 enzyme system.
8.7.3. Overdose, abuse potential
Nausea, dizziness and vertigo were noted in healthy volunteers receiving 50 and 100 mg/kg
doses of Antizol (at plasma concentration of 290–520 μmol/L, 23.8 – 42.6 mg/L). These doses
are 3-6 times the recommended dose. This dose-dependent CNS effect was short-lived in most
subjects and lasted up to 30 h in one subject. Antizol is dialysable, and haemodialysis may be
useful in treating cases of overdosing.
Fomepizole is not recommended in pregnant/ nursing women or paediatric population unless
the benefits outweigh the risks.

8.8. Evaluator’s overall conclusions on clinical safety

Adverse effects reported with fomepizole use in adults include dizziness, lightheadedness,
diarrhoea and headache. Elevation in blood pressure was observed in one report, but was also
noted with equal frequency in placebo- administered volunteers. Transient elevation of liver
transaminases (40%), serum triglycerides (30%), cholesterol (10%), phosphorous, and
bilirubin was associated with multiple-dose fomepizole administration in Phase I studies,
although lipid changes also appeared in placebo studies. Clinical use of fomepizole in adults
showed only minimal adverse effects consisting of transient transaminase elevation, skin rash
and eosinophilia. Besides the report of nystagmus and one AE of hypotension/bradycardia
which appeared to be directly related to IV fomepizole administration, no other major AEs were
reported in the case reports.
The observational cohort studies comparing the safety (AEs and medication errors) of antidotal
treatment with fomepizole versus ethanol in patients with EG/methanol poisoning (Lepik, 2009
and 2011). Although the results suggested a significantly worse side effect profile and higher
rate of medication errors (including harmful errors) with ethanol compared to fomepizole,

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interpretation was limited by many confounding factors (discussed in section 8.4.2 above).
Despite this and acknowledging that it would be very difficult to conduct prospective clinical
trials comparing ethanol with fomepizole in these patients, the safety profile of fomepizole does
appear to be more acceptable compared to that of ethanol.
No definitive clinical trials were conducted to evaluate safety in paediatric patients, elderly or
patients with renal/ hepatic impairment.
The sponsors have stated that the objective of the ISS provided was to integrate AE data
generated from the 12 clinical studies conducted to assess the safety of fomepizole in the
treatment of EG and methanol poisonings. In USA, this integrated data was used to update the
Adverse reactions section of the current package insert (already approved for EG poisoning)
upon marketing approval of Antizol for treatment of methanol or suspected methanol
poisoning. However, the safety section of the proposed Australian PI does not include this
information and should be modified to incorporate these AEs.

9. First round benefit-risk assessment

9.1. First round assessment of benefits

The benefits of fomepizole in the proposed usage are:
• Fomepizole or 4 Methylpyrazole (4MP) is a competitive inhibitor of alcohol dehydrogenase
(ADH) and the affinity of fomepizole for human ADH is 80,000 and 8,000 times greater than
methanol and ethanol, respectively.
• Fomepizole was effective in preventing metabolism of EG to its toxic metabolites showing
better clinical outcomes in terms of reduced mortality, morbidity, reversal of metabolic
acidosis.
• In some cases of EG poisoning with normal renal function and no metabolic acidosis on
presentation, fomepizole may obviate the need for haemodialysis.
• Fomepizole, in conjunction with supportive care with or without haemodialysis, inhibits the
conversion of methanol to its toxic metabolite, formate. By inhibiting hepatic metabolism of
methanol and the accumulation of formic acid in the blood, it prevents the life- and vision-
threatening complications of methanol poisoning.
• Fomepizole has no central nervous system depressant effects are observed at therapeutic
doses.
• Monitoring of fomepizole blood levels is not necessary.
• Since fomepizole has a slower rate of elimination than ethanol, it has a stronger and more
consistent duration of effective inhibitory activity
• Fomepizole requires less frequent dosing to maintain effective blood levels.

9.2. First round assessment of risks

The risks of fomepizole in the proposed usage are:
• Lack of adequate prospective randomised controlled clinical trials but this would be difficult
considering the acute nature and occurrence of proposed indications of EG or methanol
poisonings.
• Lack of data on long-term safety implications including possible increase in sensitivity due
to repeat exposure.

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• Lack of definitive PK studies in patients with renal/hepatic impairment.

• Interactions may occur with concomitant use of Antizol and drugs that increase or inhibit
the cytochrome P450 system (for example, phenytoin, carbamazepine, cimetidine,
ketoconazole), though this has not been studied.
• Expensive compared to ethanol.
• Venous irritation and phlebosclerosis; this was mainly seen following bolus injections over
5mins at 25mg/mL.
• Common AEs associated with fomepizole treatment were vertigo, nausea, vomiting,
abdominal pain, headache, unpleasant taste/ smell, eosinophilia and rash.

9.3. First round assessment of benefit-risk balance

Fomepizole has been shown to be a potent inhibitor of ADH, the enzyme responsible for the
metabolism of ethylene glycol to its toxic metabolites, which can produce metabolic acidosis,
severe CNS impairment, renal failure, and frequently death. In some cases of EG poisoning with
normal renal function and no metabolic acidosis on presentation, fomepizole may obviate the
need for haemodialysis.
Fomepizole, in conjunction with supportive care with or without haemodialysis also inhibits the
conversion of methanol to its toxic metabolite, formate. By inhibiting hepatic metabolism of
methanol and the accumulation of formic acid in the blood, it prevents the life and vision-
threatening complications of methanol poisoning. Fomepizole is not intended to substitute for
haemodialysis in patients with methanol poisoning. Concurrent haemodialysis is probably
necessary to hasten removal of methanol in patients who present with high methanol levels,
even if they present before the development of metabolic acidosis.
The reported clinical use of 4MP has preceded the usual phase I to III clinical studies for new
drugs, and therefore little is known about the optimal dosing in humans. However, several PK
studies, literature references and clinical studies (retrospective and prospective) have
established that the proposed dose of fomepizole (15 mg/kg loading doses followed by 10
mg/kg every 12 h with more frequent dosing during haemodialysis) is effective in maintaining
therapeutic concentrations of fomepizole which inhibits ADH and hence biotransformation of
EG and methanol to their toxic metabolites. The amount of toxin ingested, clinical level of
intoxication, and time to intervention are interrelated factors that influence the degree of
treatment success.
Overall, few clinically relevant AEs have been observed with fomepizole treatment. Potentially
drug-related AEs include dizziness, lightheadedness, feeling of intoxication, vertigo, nausea,
vomiting, abdominal pain, headache, unpleasant taste/smell, eosinophilia, rash and local
inflammatory reactions to venous infusion. Additionally, hypotension and seizure are of
unknown relationship to fomepizole. Although these can be serious AEs, they are potential
symptoms of ethylene glycol poisoning, and assessment of their relationship to fomepizole is
confounded in these severely intoxicated and metabolically compromised patients. Laboratory
abnormalities possibly related to treatment include slight transient increases in liver enzymes,
eosinophilia, and elevated triglycerides and/or cholesterol, all without clinical manifestations.
The efficacy of fomepizole treatment as an antidote for ethylene glycol and methanol toxicity
has been documented in multiple uncontrolled studies (both published and unpublished) and
publications of individual patient case histories. Fomepizole has been shown to be successful in
preventing the metabolism of ethylene glycol and methanol to their toxic metabolites, in
reversing metabolic acidosis, and in preventing extensive renal damage and visual impairment.
Ethanol, which has been the standard antidote for EG poisoning over the last 10-15 years, works
by the same mechanism as fomepizole. However, the amount given must be carefully controlled,

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since ethanol itself is a hepatotoxin and CNS depressant. Patient management with ethanol is
difficult because patients must be kept intoxicated for several days. Furthermore, ethanol is
rapidly and erratically metabolised, requiring frequent dose adjustments to maintain
therapeutic levels. Therapeutic blood levels of fomepizole can be maintained with twice daily
dosing. Furthermore, only relatively mild CNS effects have been attributed to its use at
therapeutic levels. Therefore, fomepizole is much safer and easier to use than ethanol.
Overall, the benefit-risk balance of Antizol (fomepizole, 4MP), given the proposed usage for
treatment of ethylene glycol and methanol poisoning, is favourable.

10. First round recommendation regarding authorisation

It is recommended that Antizol (fomepizole, 4MP) be approved for the proposed indication of:
‘Antizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning
either alone or in combination with haemodialysis (see Dosage and administration).’
However, the approval is subject to incorporation of suggested changes to the proposed PI, CMI
and adequate response to clinical questions in section 11 of this evaluation report.

11. Clinical questions

11.1. Pharmacokinetics
2. It appears that Study S6 is the Jacobsen, 1996 reference. However, this is not clearly stated in
the dossier and in fact the clinical summary of safety in Module 2 mentions that Study S5 is
Jacobsen, 1996 which contradicts with the tabular summary provided in the ISS. Furthermore,
there was no Study S5 submitted in the dossier although it is mentioned in the various tabular
summaries. Could the sponsors provide clarification on the identity and location of these PK
studies in the dossier?
3. The actual reference (Jacobsen, 1996) provided did not provide any safety results for Study
S6. However, the following was provided in the sponsor’s Summary of clinical safety: ‘The
major AEs experienced by these subjects were related to the moderate intoxication produced
by the ethanol. The subjects all reported subjective effects that would be considered
characteristics of ethanol, but with equivalent occurrence whether given 4MP or placebo. Side
effects observed included lethargy, facial flush, nausea, vomiting, blurred vision, hangover and
diarrhoea. No laboratory abnormalities related to 4MP were observed.’ However, the source
of this data was not provided and it is requested that the sponsors provide clarification.

11.2. Pharmacodynamics
None.

11.3. Efficacy
Paediatric methanol or ethylene glycol poisonings: Brent et al. 2010 reviewed the published
literature to identify published cases of paediatric patients treated with fomepizole. Fourteen
patients were identified as being of relevance to the topic, of which 210 were intoxicated with
ethylene glycol. (sponsor’s Clinical summary of efficacy)

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4. There appears to be a typographical error in the above statement which should read 10 of the
14 patients. Could the sponsors please confirm this?
Study report of OMC-4MP-2 had the following: ‘Seven of 11 patients (64%) presented with
formate levels in the non-detectable range (less than 1 mmol/L). Among the remaining six
patients, one (9%) had a formate level in the moderate range (1 to 9 mmol/L) and the remaining
five patients (45%) had formate levels in the severe range (>9 mmol/L).’
5. The above paragraph is inaccurate as there were only 11 patients in all. Please provide
clarification.
Jacobsen, et al (1990) reported placebo-controlled, double blind, multiple dose, sequential,
ascending-dose study has been performed to determine the tolerance of 4MP in 21 healthy
volunteers. Oral loading doses of 4MP were followed by supplemental doses every 12 h through
5 days, producing plasma levels in the therapeutic range. Dose schedule in Group 3 (oral loading
dose of 10 mg/kg, plus 5 mg/kg every 12 h up to 36 h and then 10 mg/kg every 12 h up to 96 h)
seems to be the best at maintaining therapeutic levels for up to 5 days.
6. Results of the Jacobsen, 1990 study appear to be identical to those reported by McMartin,
2012. The sponsors have been asked to clarify this.
In the pivotal, Phase III, open-label Study S8 (OMC-4MP-2), the study reports submitted
mentions that 21 trial centres in USA were initiated as potential enrolment sites. For purposes
of this interim report (dated 29 October, 1996), only four of those sites actually enrolled
patients into the trial.
6. Did this study continue to enrol patients and if so could the sponsors provide an updated final
study report?
Brown, 2001. ‘Childhood methanol ingestion treated with fomepizole and haemodialysis.’
Paediatrics 2001;108;e77. This literature reference in Module 5.4 has the following sentence on
page 2 of 5: ‘Serum methanol concentration measured by gas chromatography was 35 g/dL’
7. There appears to be an error as it should read 35 mg/dL. Could the sponsors please provide
clarification?

11.4. Safety
None.

12. Second round evaluation of clinical data submitted in

response to questions
The clinical questions raised by the evaluators in first round evaluation report are mentioned
first followed by the sponsor’s response and then the evaluator’s comments on the sponsor’s
response.

12.1. Pharmacokinetics
12.1.1. Question 1
It appears that Study S6 is the Jacobsen, 1996 reference. However, this is not clearly stated in the
dossier and in fact the sponsor’s Clinical summary of safety mentions that Study S5 is Jacobsen,
1996 which contradicts with the tabular summary provided in the ISS. Furthermore, there was no
Study S5 submitted in the dossier although it is mentioned in the various tabular summaries. Could
the sponsors provide clarification on the identity and location of these PK studies in the dossier?

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Sponsor response:
Please note that there are two different studies both by Jacobsen in 1996 that have very similar
formats. One (S5) was provided in section 5351 (study report 3) and S6 was provided in section
5351 (study report 4).
Evaluation of response:
The sponsor’s response is satisfactory.
12.1.2. Question 2
The actual reference (Jacobsen 1996) provided did not provide any safety results for Study S6.
However, the following was provided in Module 2 summary of clinical safety: ‘The major AEs
experienced by these subjects were related to the moderate intoxication produced by the ethanol.
The subjects all reported subjective effects that would be considered characteristics of ethanol, but
with equivalent occurrence whether given 4MP or placebo. Side effects observed included lethargy,
facial flush, nausea, vomiting, blurred vision, hangover and diarrhoea. No laboratory
abnormalities related to 4MP were observed.’ However the source of this data was not provided
and it is requested that the sponsors provide clarifications.
Sponsor response:
Safety data is only provided in S6. In the summary of safety, there is a heading ‘S5/Jacobsen
1996’. This is incorrect, this should just be S5. Reference to S5 is not extensive in the clinical
overview and clinical summary. Also in the summary of safety there is a heading ‘s6’. Safety data
is only in the full clinical S6 study report, which is why only S6 is mentioned.
Evaluator of response:
The sponsor’s response is satisfactory.

12.2. Pharmacodynamics
None.

12.3. Efficacy
12.3.1. Question 3
Paediatric methanol or ethylene glycol poisonings: Brent et al 2010 reviewed the published
literature to identify published cases of paediatric patients treated with fomepizole. Fourteen
patients were identified as being of relevance to the topic, of which 210 were intoxicated with
ethylene glycol.
There appears to be a typographic error in the above statement which should read 10 of the 14
patients. Could the sponsors please confirm this?
Sponsor response:
This was a simple typographic error, and should read ‘10 of the 14 patients’.
Evaluation of response:
The sponsor’s response is satisfactory.
12.3.2. Question 4
Study report of OMC-4MP-2 had the following: ‘Seven of 11 patients (64%) presented with formate
levels in the non-detectable range (less than 1 mmol/L). Among the remaining six patients, one
(9%) had a formate level in the moderate range (1 to 9 mmol/L) and the remaining five patients
(45%) had formate levels in the severe range (>9 mmol/L).

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The above paragraph is inaccurate as there were only 11 patients in all. Please provide
clarification.
Sponsor response:
The sponsor agrees there seems to be an error in calculation. Unfortunately, the raw data
cannot be located.
Evaluation of response:
The sponsor’s response is satisfactory.
12.3.3. Question 5
Jacobsen et al (1990) reported placebo-controlled, double blind, multiple dose, sequential,
ascending-dose study has been performed to determine the tolerance of 4MP in 21 healthy
volunteers. Oral loading doses of 4MP were followed by supplemental doses every 12 h through 5
days, producing plasma levels in the therapeutic range. Dose schedule in Group 3 (oral loading
dose of 10 mg/kg, plus 5 mg/kg every 12 h up to 36 h and then 10 mg/kg every 12 h up to 96 h)
seems to be the best at maintaining therapeutic levels for up to 5 days.
Results of the Jacobsen 1990 study appear to be identical to those reported by McMartin 2012. The
sponsors have been asked to clarify this.
Sponsor response:
Jacobsen 1990 and McMartin 2012 do provide the exact same results and are likely the same
patients (both studies were done with 21 patients in Shreveport, Louisiana). For whatever
reason, McMartin 2012 does not reference Jacobsen 1990 and the main authors are the same.
Evaluation of response:
The sponsor’s response is satisfactory.
12.3.4. Question 6
In the pivotal, Phase III, open-label Study S8 (OMC-4MP-2), the study reports mentions that 21 trial
centres in US were initiated as potential enrolment sites. For purposes of this interim report (dated
29 October 1996), only four of those sites actually enrolled patients into the trial. Did this study
continue to enrol patients and if so could the sponsors provide an updated final study report.
Sponsor response:
The sponsors provided an updated final study report.
Review of this updated report indicated that the efficacy and safety results were identical to
those already discussed in section 7.2.1.1. Of the 15 enrolled patients at 6 study sites, only 11
were evaluated for efficacy. Overall, the updated study report did not provide any new
information and this Phase III open-label study provided evidence to support the efficacy/
safety of fomepizole in treatment of methanol poisoning.
12.3.5. Question 7
Brown 2001. ‘Childhood methanol ingestion treated with fomepizole and haemodialysis’.
Paediatrics 2001; 10; e 77. This literature reference has the following sentence on page 2 of 5:
‘Serum methanol concentration measured by gas chromatography was 35 g/dL’.
There appears to be an error as it should read 35 mg/dL. Could the sponsors please provide
clarification?

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Sponsor’s response:
This was a simple typographic error and should read 35 mg/dL.
Evaluator’s comments:
The sponsor’s response is satisfactory.

12.4. Safety
None.

13. Second round benefit-risk assessment

13.1. Second round assessment of benefits

After consideration of the responses to clinical questions, the benefits of fomepizole in the
proposed usage are unchanged to those identified in Section 9.1.

13.2. Second round assessment of risks

After consideration of the responses to clinical questions, the risks of fomepizole in the
proposed usage are unchanged to those identified in Section 9.2.

13.3. Second round assessment of benefit-risk balance

The benefit-risk balance of fomepizole, given the proposed usage is favourable.

14. Second round recommendation regarding

authorisation
It is recommended that Antizol (fomepizole, 4MP) be approved for the proposed indication of:
‘Antizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol
poisoning either alone or in combination with haemodialysis (see Dosage and administration).’

15. References
Baum, et al. ‘Experience and reason: Fomepizole treatment of ethylene glycol poisoning in an
infant.’Pediatrics Vol. 106 No. 6 December 1, 2000 pp. 1489 -1491
Bien Dang vua, et al. Analytical and Pharmacokinetic Study of 4-Methylpyrazole, a New Antidote
for the Treatment of Ethylene Glycol Intoxication: Ann. Fais. Exp. Chim., ~(906), 99-110 (May
1992).
Hovda et al. ‘Studies on ethylene glycol poisoning: One patient – 154 admissions. ‘ Clinical
Toxicology (2011), 49, 478–484
Jacobsen D, et al. 4-Methylpyrazole: A controlled study of safety in healthy human subjects after
single, ascending doses. Alcoholism: Clinical and experimental research. Vol.12,No.4. 1988.
Jacobsen D, et al. Kinetic interactions between 4-Methylpyrazole and Ethanol in Healthy
Humans. Alcoholism: Clinical and experimental research. Vol.20,No.5. 1996.

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Jacobsen D, et al. Effects of 4-Methylpyrazole, Methanol/ Ethylene Glycol Antidote in healthy

humans. The Journal of Emergency Medicine, Vol. 8. pp. 455-461, 1990
McMartin KE, et al. Kinetics and metabolism of fomepizole in healthy humans. Clinical
Toxicology (2012), 50, 375–383.
Maraffa J, et al. Oral administration of fomepizole produces similar blood levels as identical
intravenous dose. Clinical Toxicology (2008) 46, 181–186.
Wacker, et al. ‘Treatment of ethylene glycol poisoning with ethyl alcohol.’ JAMA Dec 13, 1965.
Vol. 194, No. 11.
Weintraub, M, Standish R. 4-Methy1pyrazole: an antidote for ethylene glycol and methanol
intoxication. Hosp Formul 1988; 23:960-969

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