ADALAT®OROS

PRODUCT INFORMATION

NAME OF THE MEDICINE

Nifedipine is dimethyl 1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-3,5-pyridinedicarboxylate,
C17H18N2O6, MW 346.3, CAS Registry No. [21829-25-4]. Its structural formula is shown
below.

Nifedipine is a yellow crystalline substance practically insoluble in water, and sparingly

soluble in absolute ethanol. It is sensitive to light.

DESCRIPTION
Adalat OROS tablets are a controlled release formulation (GITS, GastroIntestinal
Therapeutic System) containing nifedipine 20 mg, 30 mg or 60 mg. Besides the active
ingredient, Adalat OROS 20 mg, 30 mg and 60 mg tablets also contain the following inactive
ingredients: polyethylene oxide, magnesium stearate, sodium chloride, hypromellose, iron
oxide red (CI 77491), hydroxypropylcellulose, cellulose acetate, macrogol 3350, titanium
dioxide and propylene glycol.

Adalat OROS tablets are similar in appearance to conventional tablets. Each tablet consists
of a semipermeable membrane surrounding an osmotically active core. The core itself is
divided into two layers: an "active" layer containing nifedipine, and a "push" layer containing
pharmacologically inert but osmotically active components. As water from the
gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes"
against the nifedipine layer, releasing nifedipine through a precision laser-drilled tablet orifice
in the "active" layer. The coating of Adalat OROS remains intact during the gastrointestinal
passage and is eliminated in the faeces.

All strengths of Adalat OROS are round, biconvex shaped, rose-pink, film-coated tablets.
Tablet diameters are 8.4 mm (20 mg), 9 mm (30 mg) and 11 mm (60 mg). Adalat OROS 20
mg tablets are marked in black with the product name on one side (“Adalat 20”) and the
Adalat OROS 30 mg and 60 mg tablets are marked with the dose strength on one side (“30”
or “60”).

PHARMACOLOGY
Nifedipine is a calcium ion influx inhibitor (calcium channel blocker or calcium antagonist)
which inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth
muscle. The contractile processes of these tissues are dependent upon the movement of
extracellular calcium into the muscle cells through specific ion channels. Nifedipine
selectively inhibits the transmembrane influx of calcium through the slow channel without
affecting the transmembrane influx of sodium through the fast channel to any significant

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degree. This results in a reduction of free calcium ions available within the muscle cells and
an inhibition of the contractile process. Nifedipine does not affect total serum calcium. The
specific mechanisms by which nifedipine relieves angina and reduces blood pressure have
not been fully determined but are believed to be brought about largely by its vasodilatory
action.

Hypertension

The mechanisms by which nifedipine reduces arterial blood pressure involve peripheral
arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The
increased peripheral resistance that is an underlying cause of hypertension results from an
increase in active tension in the vascular smooth muscle. Studies have demonstrated that
the increase in acute tension reflects an increase in free calcium in the cytosol.

The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in

vascular smooth muscle results in an inhibition of calcium influx through these channels. The
reduction in calcium influx by nifedipine causes arterial vasodilatation and decreased peri-
pheral vascular resistance which results in reduced arterial blood pressure.

Angina

The precise mechanism by which inhibition of calcium influx relieves angina has not been
fully determined. Some of the possible mechanisms include vasodilatation and reduction of
oxygen utilisation.

Nifedipine dilates the main coronary arteries and coronary arterioles, both in normal and
ischaemic regions, resulting in an increase in blood flow and hence in myocardial oxygen
delivery in patients with coronary artery spasm.

Nifedipine reduces arterial blood pressure at rest and at a given level of exercise by dilating
peripheral arterioles and reducing the total peripheral vascular resistance (afterload) against
which the heart works. This unloading of the heart reduces myocardial energy consumption
and oxygen requirements, and probably accounts for the effectiveness of nifedipine in
chronic stable angina.

Clinical Trials in Angina

The pivotal clinical studies were performed in patients with chronic stable angina. In these
studies, Adalat OROS at doses of 30 mg and 60 mg once daily improved exercise tolerance
test (ETT) parameters in reference to baseline. Adalat OROS 30 mg daily showed small but
sub-optimal benefit. When titrated to the dose of 60 mg once daily, Adalat OROS was as
effective as atenolol 100 mg once daily. In patients already on β-blocker therapy, Adalat
OROS improved ETT parameters and time to 1 mm ST depression, and at doses of up to
90 mg once daily, Adalat OROS was more effective than modified release nitrates
(isosorbide mononitrate 50 mg once daily, isosorbide dinitrate 20 – 40 mg twice daily).
However in this particular study, ETT performance was measured at 22 to 24 hours after the
last dose of Adalat OROS and isosorbide mononitrate, and about 15 hours after last dose of
isosorbide dinitrate. Therefore the higher efficacy observed for Adalat OROS may be
attributable to the difference in pharmacokinetics between Adalat OROS and nitrates. In
pivotal and supportive clinical studies, the duration of treatment with Adalat OROS was
limited to 2 to 12 weeks only, and the majority of patients in these studies were already on
background β-blocker therapy. Data in patients with unstable angina, asymptomatic
ischaemia, vasospastic angina and post-myocardial infarction are limited. Data on
monotherapy with Adalat OROS are limited and based on trials of short duration (≤ 4
weeks).

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Pharmacokinetics

Nifedipine is almost completely absorbed after oral administration. Plasma drug

concentrations rise at a gradual, controlled rate exhibiting zero-order absorption kinetics
after Adalat OROS administration and reach a plateau at approximately six hours after the
first dose. For subsequent doses, relatively constant plasma concentrations at this plateau
are maintained with minimal fluctuations over the 24 hour dosing interval. At steady state,
the bioavailability of Adalat OROS is 86% relative to an immediate release dosage form
which has a systemic availability of 45 – 68%. Administration of Adalat OROS in the
presence of food slightly alters the early rate of drug absorption, but does not influence the
extent of drug bioavailability. Markedly reduced gastrointestinal retention times over
prolonged periods (i.e., short bowel syndrome) may, however, influence the pharmacokinetic
profile of the medicine, which could result in lower plasma concentrations. Pharmacokinetics
of Adalat OROS are linear over the dose range of 30 to 180 mg in that plasma
concentrations are proportional to dose administered. There is no evidence of dose dumping
either in the presence or absence of food.

Nifedipine is about 95% bound to plasma protein (albumin).

The active substance nifedipine is almost completely metabolised in the liver, primarily by
oxidative processes: cytochrome P450 3A4 (CYP3A4). Some metabolic activity within the
gut wall may also contribute to the pre-systematic metabolism. These metabolites show no
pharmacodynamic activity. The main metabolite (95%) is the hydroxycarbolic acid derivative;
the remaining 5% is the corresponding lactone.

Nifedipine is excreted in the form of its metabolites predominantly via the kidneys (60 to
80%) and about 5 – 15% via the bile in the faeces. The unchanged substance is recovered
only in traces (below 0.1%) in the urine.

The terminal elimination half-life is 1.7 to 3.4 hours in an immediate release formulation. In
cases of impaired kidney function, no substantial changes have been detected in
comparison with healthy volunteers.

In cases of impaired liver function, the elimination half-life is distinctly prolonged and the total
clearance is reduced. A dose reduction may be necessary in severe cases.

Patients on haemodialysis or chronic ambulatory peritoneal dialysis have not reported

significantly altered pharmacokinetics of nifedipine.

Some published studies have reported slower elimination of nifedipine in different ethnic
groups (eg. Mexican, Japanese and South Asians). Currently, confirmatory studies only exist
for the South Asian population. In comparison to Caucasians, there were increases in AUC
due to a decrease in the activity of cytochrome P-450(IIIA), while increases in Cmax were less
pronounced. Elimination half lives of both nifedipine and its pyridine metabolite were
prolonged by approximately two-fold. Although haemodynamic responses in the South Asian
healthy volunteers were similar to those reported in Caucasians, lower doses of nifedipine
may be required in South Asian patients at the beginning of Adalat OROS therapy.

INDICATIONS
Adalat OROS is indicated for:

1. the treatment of mild to moderate hypertension

2. the prophylaxis of chronic stable angina pectoris

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CONTRAINDICATIONS
Adalat OROS is contraindicated in:

• patients with known hypersensitivity to nifedipine or related dihydropyridine calcium

channel blockers or to any of the excipients
• female patients throughout pregnancy
• breast feeding
• patients with cardiogenic shock
• patients with a Kock pouch (ileostomy after proctocolectomy)
• patients being administered rifampicin (see Interaction with Other Medicines)
• patients within the first 8 days of an acute episode of myocardial infarction

PRECAUTIONS
Excessive Hypotension

Caution should be exercised in patients with severe hypotension (systolic pressure

<90 mmHg) as there is a risk of further reduction in blood pressure.

Adalat OROS may be used in combination with beta-blocking medicines and other
antihypertensive agents, but the possibility of potentiation of existing antihypertensive
therapy should be noted.

Increased Angina and/or Myocardial Infarction

Rare cases of increased frequency, duration and/or severity of angina or acute myocardial
infarction on starting nifedipine or at the time of dosage increase have been reported. These
well-documented cases are mainly in those patients who have severe obstructive coronary
artery disease. The mechanism of this effect is not established.

Chest Pain

There have been a small number of reports of chest pain not associated with myocardial
infarction (in certain circumstances, angina pectoris-like symptoms) occurring soon after
administration of a single dose. In this case, Adalat OROS should be withdrawn if a causal
relationship is suspected.

Beta Blocker Withdrawal

When nifedipine is administered simultaneously with beta-blockers the patient should be

carefully monitored, since deterioration of heart failure may develop in isolated cases.

Adalat OROS has no inherent anti-arrhythmic action and therefore gives no protection
against any arrhythmias which may result from abrupt withdrawal of beta-blockers. Any such
withdrawal of beta-blockers should be achieved gradually over a period of several days.

Congestive Heart Failure

The onset of heart failure has occasionally been observed during clinical use. Care should
be observed with patients whose cardiac reserve is poor, or who are receiving large doses of
beta-blockers.

Peripheral Oedema

Mild to moderate peripheral oedema occurs in a dose-dependent manner with an incidence

ranging from approximately 10% on 30 mg to about 33% on Adalat OROS 120 mg daily.

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This is due to arteriolar vasodilatation and is not due to heart failure. With patients whose
hypertension is complicated by congestive heart failure, care should be taken to differentiate
this peripheral oedema from the effects of increasing left ventricular dysfunction.

Hypotension/Heart Rate

Because Adalat OROS (nifedipine) is an arterial and arteriolar vasodilator, hypotension and
a compensatory increase in heart rate may occur. Thus, blood pressure and heart rate
should be monitored carefully during nifedipine therapy. Close monitoring is especially
recommended for patients who are prone to develop hypotension, those with a history of
cerebrovascular insufficiency and those who are taking medications that are known to lower
blood pressure.

Acute Treatment of Angina Pectoris

Adalat OROS is not suitable for the acute treatment of angina pectoris due to delayed
absorption of the medicine from the modified release dosage formulation.

Aortic Stenosis

Patients with severe aortic stenosis are at risk of developing heart failure or hypotension
because of the vasodilating effects of Adalat OROS.

Severe Gastrointestinal Narrowing

As with any other non-deformable material, caution should be used when administering
Adalat OROS to patients with a previous history of severe gastrointestinal narrowing or
obstruction. Bezoars can occur in very rare cases and may require surgical intervention.

There have been rare reports of bowel obstruction requiring surgery in patients with known
oesophageal stricture, small bowel stenosis, and after gastroplexy, due to the
non-deformable nature of Adalat OROS. In single cases obstructive symptoms have been
described without known history of gastrointestinal disorders.

Shortened Transit Times

The sustained release of Adalat OROS may be impaired in chronic diarrhoea (e.g., Crohn's
disease, ulcerative colitis) or short bowel syndrome, when the gastrointestinal transit time is
less than 18 – 22 hours. Monitoring of trough blood pressure (24-hour) is advised in these
patients. If control of trough blood pressure is not satisfactory, then conventional Adalat
tablets taken twice daily should be used.

Other Nifedipine Formulations

Adalat OROS modified release tablets are not bioequivalent to immediate release nifedipine
capsules and tablets and patients should be carefully monitored if it is decided to switch
between immediate release and modified release nifedipine or vice versa. Adalat OROS may
not be bioequivalent to modified-release nifedipine preparations available overseas.

Effects on Fertility

In isolated cases of in vitro fertilisation, calcium channel blockers like nifedipine have been
associated with reversible biochemical changes in the head section of the spermatozoa that
may result in impaired sperm function. In those men who are repeatedly unsuccessful in
fathering a child by in vitro fertilisation, and where no other explanation can be found, the

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use of calcium channel blockers such as nifedipine should be considered as possible
causes.

Use in Pregnancy

Category C: Nifedipine is contraindicated throughout pregnancy. Medicines in this class

carry the potential to produce fetal hypoxia, caesarean deliveries, prematurity and
intrauterine growth retardation, which may be associated with maternal hypotension.
Nifedipine was shown to produce teratogenic findings in rats, mice and rabbits, including
digital anomalies, malformation of the extremities, cleft palates, cleft sternum and
malformation of the ribs. Digital anomalies are possibly a result of compromised uterine
blood flow. Nifedipine administration has been associated with a variety of embryotoxic,
placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small
placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats,
mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in
other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic
effects in animals were maternally toxic and several times the recommended maximum dose
for humans. There are no adequate and well controlled studies in pregnant women.

Use in Lactation

Nifedipine passes into the breast milk. So far, insufficient evidence is available to determine
whether nifedipine has an effect on breast-fed infants. Breastfeeding should be stopped first
if nifedipine treatment becomes necessary during the breastfeeding period.

Paediatric use

The safety and efficacy of Adalat OROS in children below 18 years has not been
established.

Use in Patients with Liver Impairment

ADALAT OROS should be used with caution in patients with mild, moderate or severe
impaired liver function (see PHARMACOLOGY). A dose reduction may be required (see
DOSAGE AND ADMINISTRATION). Close monitoring of response and metabolic effect
should apply. The pharmacokinetics of nifedipine has not been investigated in patients with
severe hepatic impairment. Therefore, nifedipine should be used with caution in patients with
severe hepatic impairment.

Use in the Elderly

Caution should be exercised in the use of Adalat OROS in elderly patients, especially those
with a history of hypotension or cerebral vascular insufficiency. Lower doses may be
required in patients with reduced drug clearance.

Use in Diabetes

Treatment with nifedipine can theoretically impair glucose metabolism, which may be of
clinical relevance in some cases.

Carcinogenicity/Mutagenicity

Nifedipine was administered orally to rats for two years and was not shown to be
carcinogenic. In vitro and in vivo mutagenicity studies were negative.

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INTERACTION WITH OTHER MEDICINES

Nifedipine is metabolised via CYP3A4, located in the intestinal mucosa and the liver.
Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first pass or
the clearance of nifedipine.

Drugs, which are inhibitors of CYP3A4 and therefore may lead to increased plasma
concentrations of nifedipine, are, e.g.:

• macrolide antibiotics (e.g. erythromycin),

• anti-HIV protease inhibitors (e.g. ritonavir),
• azole antimycotics (e.g. ketoconazole),
• the antidepressants nefazodone and fluoxetine,
• quinupristin/dalfopristin,
• valproic acid,
• cimetidine.

Upon co-administration with these drugs, the blood pressure should be monitored and, if
necessary, a reduction of the nifedipine dose should be considered.

Drugs that affect nifedipine

Nifedipine is metabolised via CYP3A4, located in the intestinal mucosa and the liver.
Medicines that are known to inhibit or induce CYP3A4 may therefore alter the first pass or
the clearance of nifedipine.

The extent as well as the duration of interactions should be taken into account when
administering nifedipine together with the following drugs:

Rifampicin
Rifampicin strongly induces CYP3A4. Upon co-administration with rifampicin, the
bioavailability of nifedipine is distinctly reduced and thus its efficacy is also reduced. The use
of nifedipine in combination with rifampicin is therefore contraindicated.

Upon co-administration of the following weak to moderate inhibitors of CYP3A4 the

blood pressure should be monitored and, if necessary, a reduction in the nifedipine
dose considered (see DOSAGE AND ADMINISTRATION).
Macrolide antibiotics (e.g. erythromycin)
No interaction studies have been carried out between nifedipine and macrolide antibiotics.
Certain macrolide antibiotics are known to inhibit CYP3A4 mediated metabolism of other
medicines, and could increase plasma concentrations of nifedipine if administered
concomitantly.

Azithromycin, although structurally related to the class of macrolide antibiotics does not
inhibit CYP3A4.

Anti-HIV Protease Inhibitors

A clinical study investigating the potential interaction between nifedipine and certain anti-HIV
protease inhibitors has not yet been performed. Medicines of this class are known to inhibit
CYP3A4. In addition, drugs of this class have been shown to inhibit in vitro the CYP3A4
mediated metabolism of nifedipine. When administered together with nifedipine, a

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substantial increase in plasma concentrations of nifedipine due to a decreased first-pass
metabolism and decreased elimination cannot be excluded.

Azole anti-mycotics (e.g. ketoconazole)

A formal interaction study investigating the potential of a drug interaction between nifedipine
and certain azole anti-mycotics has not yet been performed. These medicines are known to
inhibit CYP3A4. When administered orally with nifedipine, a substantial increase in systemic
bioavailability of nifedipinedue to a decreased first pass metabolism cannot be excluded.

Fluoxetine

A clinical study investigating the potential of a drug interaction between nifedipine and
fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the
CYP3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma
concentrations upon co-administration of both medicines cannot be excluded (see
PRECAUTIONS).

Nefazodone
A clinical study investigating the potential of a drug interaction between nifedipine and
nefazodone has not yet been performed. Nefazodone is known to inhibit CYP3A4 mediated
metabolism of other medicines. Therefore an increase of nifedipine plasma concentrations
upon co-administration of both medicines cannot be excluded.

Quinupristin/Dalfopristin

Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased

plasma concentrations of nifedipine, with the effect varying markedly between individuals.

Valproic acid
No formal studies have been performed to investigate the interaction of nifedipine with
valproic acid, but it has been shown to increase the plasma concentrations of another
dihydropyridine calcium channel blocker (nimodipine) through enzyme inhibition. Therefore
an increase in the plasma concentrations of nifedipine is possible which may mean that an
adjustment in the dosage of nifedipine may be required.

Cimetidine
Elevation of plasma nifedipine levels during cimetidine administration has been reported. It is
suggested that patients taking both nifedipine and cimetidine should be carefully monitored.
In case of hypotension, the dosage of nifedipine should be reduced or the patient should be
treated with ranitidine, as the interaction with this medicine and nifedipine is less
pronounced.

Diltiazem
Diltiazem decreases the clearance of nifedipine and, hence, increases plasma nifedipine
levels. Therefore caution should be exercised when the two medicines are used
concomitantly and a reduction in the dose of nifedipine may be necessary.

Further studies
Cisapride
Simultaneous administration of cisapride and nifedipine may lead to increased plasma
concentrations of nifedipine.

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CYP3A4-inducing anti-epileptic drugs such as phenytoin, carbamazepine and
phenobarbitone

Phenytoin induces CYP3A4. Co-administration of phenytoin with nifedipine reduces the

bioavailability of nifedipine. When both medicines are concomitantly administered, the
clinical response to nifedipine should be monitored and an increase in the nifedipine dose
considered, if necessary. If the dose of nifedipine is increased during co-administration of
both medicines, a reduction of the nifedipine dose should be considered when phenytoin is
discontinued. No formal studies have been performed to investigate the potential interaction
between nifedipine and carbamazepine or phenobarbitone. As both drugs have been shown
to reduce the plasma concentrations of the structurally similar calcium channel blocker,
nimodipine, through enzyme induction, a decrease in nifedipine plasma concentrations and
hence a decrease in efficacy cannot be excluded.

Effects of nifedipine on other drugs

Blood pressure lowering drugs

Nifedipine may increase the blood pressure lowering effect of concomitant applied
antihypertensives, such as:

• diuretics,
• β-blockers,
• ACE-inhibitors,
• angiotensin I (ATI) receptor – antagonists,
• other calcium antagonists,
• α-adrenergic blocking agents,
• PDE5 inhibitors,
• α -methyldopa.

When nifedipine is used in conjunction with β-receptor blockers, patients should be carefully
monitored since deterioration of heart failure is also known to develop in isolated cases.

Digoxin
Simultaneous administration of nifedipine and digoxin can lead to reduced digoxin clearance
and hence an increase in the plasma digoxin level. It is recommended that digoxin levels be
monitored when initiating, adjusting and discontinuing nifedipine and, if necessary, the dose
of digoxin adjusted.

Quinidine
Quinidine levels have been observed to decrease upon introduction of nifedipine and
increase upon its withdrawal. For this reason, it is recommended that when nifedipine is
either added to quinidine therapy or withdrawn from it, quinidine concentrations are
monitored and the dose adjusted accordingly. Some authors reported increased plasma
levels of nifedipine upon co-administration of both medicines, while others did not observe
an alteration in the pharmacokinetics of nifedipine. Therefore, if quinidine is added to existing
nifedipine therapy, blood pressure should be monitored, and if necessary the dose of
nifedipine should be reduced.

Tacrolimus
Tacrolimus is metabolised by CYP3A4. Published data indicate that the dose of nifedipine
administered simultaneously with tacrolimus may be reduced in individual cases. Upon co-

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administration of both medicines, the tacrolimus plasma concentrations should be monitored
and, if necessary, a reduction in the tacrolimus dose should be considered.

Coumarin Anticoagulants
There have been rare reports of increased prothrombin time when nifedipine was
administered to patients taking coumarin anticoagulants. However, the relationship to
nifedipine therapy is uncertain.

Drug-food interactions
Grapefruit
Grapefruit juice inhibits CYP3A4. Administration of nifedipine together with grapefruit juice
thus results in elevated plasma concentrations of nifedipine due to a decreased first pass
metabolism. As a consequence, the blood pressure lowering effect may be increased. After
regular intake of grapefruit juice this effect may last for at least 3 days after the last ingestion
of grapefruit juice.

Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine.

Interactions shown not to exist
In drug interaction studies, aspirin, omeprazole, pantoprazole, and ranitidine did not have
clinically significant effects on the pharmacokinetics of nifedipine. Nifedipine did not have a
clinically significant effect on the effect of 100 mg aspirin on platelet aggregation and
bleeding time.

Candesartan cilexetil, Irbesartan, Doxazosin

The blood pressure lowering effect of these agents may be potentiated by co-administration
with nifedipine, so caution should be used in initiating combination therapy. Concomitant
administration of irbesartan or doxazosin and nifedipine has no effect on the
pharmacokinetics of nifedipine, and concomitant administration of candesartan cilexetil and
nifedipine has no effect on the pharmacokinetics of either medicine.

Other Forms of Interactions

Barium Contrast X-Ray

Adalat OROS may cause false positive findings (e.g. filling defects interpreted as polyp)
when barium contrast x-ray is undertaken.

Spectrophotometric test for Vanillylmandelic Acid

Nifedipine may falsely increase spectrophotometric assay values of urinary vanillylmandelic
acid. However, measurement with HPLC is unaffected.

Effect on Ability to Drive and Use Machines

Reactions to the medicine, which vary in intensity from individual to individual, can impair the
ability to drive or to operate machinery. This applies particularly at the start of treatment, on
changing doses, and in combination with alcohol.

Effect on Laboratory Tests

Rare, usually transient, but occasionally significant elevations of enzymes such as AP, CPK,
LDH, AST (SGOT) and ALT (SGPT) have been noted. The relationship to nifedipine therapy

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is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely
been associated with clinical symptoms, however cholestasis with or without jaundice has
been reported. Rare instances of allergic hepatitis have been reported.

Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. A
limited number of clinical studies have demonstrated a moderate but statistically significant
decrease in platelet aggregation and increase in bleeding time in nifedipine-treated patients.
This is thought to be a function of inhibition of calcium transport across the platelet
membrane. No clinical significance for these findings has been demonstrated.

ADVERSE EFFECTS
Adverse Drug Reactions (ADRs) listed under “common” were observed with a frequency
below 3 % with the exception of oedema (9.9 %) and headache (3.9 %). ADR is defined as a
response to a medicinal product which is noxious and unintended and which occurs at doses
normally used in man. Response in this context means that a causal relationship between a
medicinal product and an adverse event is at least a reasonable possibility. Adverse drug
reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III
categories of frequency (clinical trial database: nifedipine n = 6,486; placebo n = 5,326) are
listed below. The frequencies are defined as:

Common ≥ 1/100 to < 1/10

Uncommon ≥ 1/1000 to < 1/100
Rare ≥ 1/10000 to < 1/1000

Table 1. ADRs reported based on clinical trial data

System Organ Class Common Uncommon Rare

Immune system Allergic reaction Urticaria
disorders
Allergic
oedema/angioedema
(including larynx oedema*)
Psychiatric disorders Anxiety reactions
Sleep disorders
Nervous system Headache Paraesthesia Hypaesthesia
disorders
Dizziness Somnolence Dysaethesia
Tremor
Vertigo
Migraine
Eye disorders Visual disturbances
Cardiac disorders Palpitation Chest pain Chest pain
substernal
Angina pectoris
Tachycardia Cardiovascular
disorder
Vascular disorders Oedema Syncope
Vasodilatation Hypotension
Respiratory, thoracic, Dyspnoea
and mediastinal
Nosebleed
disorders
Nasal congestion

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 System Organ Class Common Uncommon Rare
Gastrointestinal Constipation Gastrointestinal and Gingival
disorders abdominal pain hyperplasia
Nausea Anorexia
Dry mouth Eructation
Dyspepsia Gastrointestinal
Vomiting disorder

Flatulence GGT increased

Diarrhoea Gingivitis
Hepatobiliary disorders Increase in transaminases
Skin and cutaneous Pruritus Sweating
tissue disorders
Rash Macupapular rash
Erythema Pustular rash
Vesiculobullous
rash
Musculoskeletal and Muscle cramps Arthralgia
connective tissue
Joint swelling Myalgia
disorders
Leg cramps Joint disorder

Renal and urinary Polyuria Urinary frequency

disorders increased
Dysuria

General disorders and Feeling unwell Unspecific pain Fever

administration site
Asthenia Chills
conditions
Leg pain

Reproductive system Erectile dysfunction

and breast disorders

* = may result in life-threatening outcome.

In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood
pressure can occur as a result of vasodilation.

The most common adverse effect reported was oedema which was dose-related and ranged
in frequency from approximately 10% on 30 mg to 30% at the highest dose studied
(180 mg). In clinical trials of 20 mg the frequency of peripheral oedema ranged from 0% to
4%.

There have been a small number of reports of chest pain not associated with myocardial
infarction occurring soon after administration of a single dose. In such an event, the
medicine must be discontinued if a causal relationship is suspected.

Aggravation of cardiac insufficiency has occasionally been reported in patients with

compromised cardiac function or when nifedipine is given in combination with beta blockers.

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A small (5.4%) increase in mean AP has been noted in patients treated with controlled-
release nifedipine tablets. These cases are rare and not associated with clinical symptoms
and they rarely result in values outside the normal range.

In controlled studies, controlled release nifedipine tablets did not adversely affect serum uric
acid, glucose or cholesterol. Serum potassium was unchanged in patients receiving
controlled-release nifedipine tablets in the absence of concomitant diuretic therapy, and
slightly decreased in patients receiving concomitant diuretics.

Nifedipine, like other calcium channel blockers, decreases platelet aggregation in vitro. A
limited number of clinical studies have demonstrated a moderate but statistically significant
decrease in platelet aggregation in some nifedipine patients. This is thought to be a function
of inhibition of calcium transport across the platelet membrane. No clinical significance for
this finding has been demonstrated.

In a double-blind comparison of Adalat OROS and Adalat tablets, the incidence of

vasodilator reactions did not differ.

Post Marketing Experience

A small number of events identified during ongoing post-marketing surveillance associated
with nifedipine for which a frequency could not be estimated are listed in the table below.

Table 2. ADRs reported based on post-marketing experience

System Organ Class Not known

(MedDRA)
Blood and lymphatic system disorders Agranulocytosis
Leukopenia
Immune system disorders Anaphylactic/ anaphylactoid reactions
Metabolism and nutrition disorders Hyperglycaemia
Nervous system disorders Hypoaesthesia
Somnolence
Eye disorders Eye pain
Blurred vision
Cardiac disorders Chest pain (Angina pectoris)
Respiratory, thoracic, and mediastinal disorders Dyspnoea
Gastrointestinal disorders Vomiting
Gastro-oesophageal sphincter insufficiency
Gum hyperplasia
Bezoar
Dysphagia
Intestinal obstruction
Intestinal ulcer
Oesophagitis
Gum disorder
Hepatobiliary disorders Jaundice

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 System Organ Class Not known
(MedDRA)
Skin and subcutaneous tissue disorders Toxic Epidermal Necrolysis (exfoliative
dermatitis)
Erythromelalgia
Photosensitivity allergic reaction
Palpable purpura
Gynaecomastia
Musculoskeletal and connective tissue disorders Arthralgia
Myalgia
Muscle cramps
Investigations Weight loss
ALT increased

DOSAGE AND ADMINISTRATION

As far as possible the treatment must be tailored to the needs of the individual and
depending on the clinical picture in each case, the basic dose must be introduced gradually.
In patients with impaired liver function, careful monitoring is advised and, in severe cases, a
dose reduction may be necessary.

The tablets are swallowed whole without chewing or being broken up with a little liquid.
They may be taken with or without food, however grapefruit juice is to be avoided.

Hypertension - In general Adalat OROS therapy should be initiated with 30 mg once daily.
A starting dose of 20 mg may be considered when medically indicated. Monitoring of trough
blood pressure should be done initially to ensure blood pressure control lasts over the dosing
interval. Depending on the severity of the disease and the patient’s response, the dose can
be decreased to 20 mg or increased in stages to 120 mg daily. In general, titration should
proceed over a 7 – 14 day period so that the physician can fully assess the response to each
dose level and monitor the blood pressure before proceeding to higher doses. Since steady
state levels are achieved on the second day of dosing, titration may proceed more rapidly if
symptoms so warrant, provided the patient is assessed frequently. Titration to doses above
120 mg per day is not recommended.

Chronic Stable Angina - Adalat OROS should be initiated with 30 mg once daily. If
necessary, the dosage can be increased in stages to a maximum of 90 mg once daily.
Experience with doses greater than 90 mg per day in patients with angina is limited.

The initiation of Adalat OROS therapy in South Asians who have not previously taken
nifedipine should start at low doses (see PHARMACOKINETICS).

Co-administration with CYP3A4 inhibitors or inducers may require nifedipine dose

adjustment or for nifedipine not to be used at all (see Interaction with Other Medicines).

OVERDOSAGE

Symptoms

The following symptoms are observed in cases of severe nifedipine intoxication:

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Disturbances of consciousness to the point of coma, severe hypotension,
tachycardiac/bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis,
hypoxia, cardiogenic shock with pulmonary oedema.

Management of Overdose

As far as treatment is concerned, elimination of the active substance and restoration of

stable cardiovascular conditions have priority.

After oral ingestion of a potentially dangerous amount, thorough gastric lavage is indicated
particularly in cases of intoxication with controlled release products like Adalat OROS.
Elimination must be as complete as possible, including the irrigation of the small intestine, to
prevent the subsequent absorption of the active substance. Symptoms and signs of
overdose may be delayed due to the controlled release properties of these products, so
patients should be kept under observation for at least 24 hours.

Haemodialysis is ineffective in removing nifedipine in the body because nifedipine is not

dialysable (high plasma protein binding, relatively low volume of distribution), but
plasmapheresis may be considered.

Bradycardiac heart rhythm disturbances may be treated symptomatically with

beta-sympathomimetics and, in life-threatening situations, temporary pacemaker therapy
may be advisable.

Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with
calcium (10 – 20 mL of a 10% calcium gluconate solution administered slowly intravenously
and repeated if necessary). As a result, the serum calcium can reach the upper normal
range to slightly elevated levels. If the effects are inadequate, the treatment can be
continued with ECG monitoring, with the addition of a beta-sympathomimetic medicine (eg,
Isoprenaline 0.2 mg slowly intravenously, repeated if necessary as a continuous infusion at
5 µg/min). If this is still insufficient to return the blood pressure to normal, vasoconstricting
sympathomimetics such as dopamine or noradrenaline may be additionally administered.
The dosage of these medicines is determined solely by the effect obtained.

Additional liquid or volume must be administered with caution because of the danger of
overloading the heart.

PRESENTATION AND STORAGE CONDITIONS

Adalat OROS tablets are round, biconvex, rose-pink, film-coated tablets, supplied in packs of
10 or 30 tablets. Adalat OROS 20 mg tablets are marked in black with the product name on
one side (“Adalat 20”) and the Adalat OROS 30 mg and 60 mg tablets are marked with the
dose strength on one side (“30” or “60”).

Not all pack sizes may be marketed.

The drug release mechanism of Adalat OROS is triggered by moisture. Contact of the
tablets with moisture may not be apparent but loss of contents may have already occurred.
To prevent this, the tablet must be kept in its original blister-foil packaging until immediately
before use.
Container types and Storage Conditions for Adalat Oros 20 mg:
Blister Pack (PA/Al/PVC/Al) – Store below 30 °C.
Blister Pack (PVC/PVDC/Al) – Store below 30 °C.

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Container types and Storage Conditions for Adalat Oros 30 mg:
Blister Pack (PA/Al/PVC/Al) – Store below 30 °C.
Blister Pack (PVC/PE/PCTFE/Al) – Store below 30 °C
Blister Pack (PVC/PVDC/Al) – Store below 25 °C.
Container types and Storage Conditions for Adalat Oros 60 mg:
Blister Pack (PA/Al/PVC/Al) – Store below 30 °C.
Blister Pack (PVC/PVDC/Al) – Store below 25 °C.
Blister Pack (PP/Al) – Store below 25 °C. Protect from light.
Blister Pack (PVC/PE/PCTFE/Al) – Store below 30 °C.

Not all packaging material types may be marketed. Refer to medicine carton for storage
instructions.

NAME AND ADDRESS OF THE SPONSOR

BAYER AUSTRALIA LTD

ABN 22 000 138 714
875 Pacific Highway
PYMBLE NSW 2073

POISON SCHEDULE OF THE MEDICINE

PRESCRIPTION ONLY MEDICINE

DATE OF FIRST INCLUSION IN THE ARTG: 23 July 1997

DATE OF MOST RECENT AMENDMENT: 3 May 2016

®
Registered Trademark of Bayer AG

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