New Zealand Datasheet
1 PRODUCT NAME
Duolin® 100 mcg / 20 mcg metered dose aerosol inhaler
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Salbutamol 100 mcg / Ipratropium bromide 20 mcg per inhalation.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Duolin Inhaler consists of a white homogenous suspension of micronised substances in a
CFC-free (HFA-227) propellant mixture filled in an aluminium canister with a metering valve.
Each metered dose contains salbutamol 100 mcg (equivalent to 120 mcg salbutamol
sulphate), and ipratropium bromide 20 mcg (equivalent to 21 mcg of ipratropium bromide
monohydrate). Duolin Inhaler uses a metered dose inhaler that has a grey actuator and
mouthpiece with a light blue cap. Each inhaler contains 200 doses.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Duolin Inhaler is indicated for the treatment of reversible bronchospasm associated with
obstructive airway diseases in patients who require more than a single bronchodilator.
4.2 Dose and method of administration
Adults (including elderly patients): Two inhalations four times daily. The dose may be
increased as required up to a maximum of 12 inhalations in 24 hours.
Children: There has been no experience with the use of Duolin Inhaler in children below the
age of 12 years.
Duolin Inhaler has not been studied in patients with hepatic or renal insufficiency. It should
be used with caution in those patient populations.
In asthma, concomitant anti-inflammatory therapy should be considered.
In patients who find coordination of a pressurised metered-dose inhaler difficult, a spacer
device may be used with Duolin Inhaler. Please follow the instruction for use provided with
the spacer.
Patients should be advised to consult a doctor or the nearest hospital immediately in the
case of acute or rapidly worsening dyspnoea (difficulty in breathing) if additional inhalations
do not produce an adequate improvement.
4.3 Contraindications
Duolin Inhaler is contraindicated in patients with a history of hypersensitivity to atropine or its
derivatives, or to any other component of the product and in patients with hypertrophic
obstructive cardiomyopathy and tachyarrhythmia.
4.4 Special warnings and precautions for use
In the case of acute, rapidly worsening dyspnoea, a doctor should be consulted immediately.
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Immediate hypersensitivity reactions may occur after administration of Duolin Inhaler as
demonstrated by rare cases of angioedema, bronchospasm, oropharyngeal oedema, rash
and urticaria.
There have been isolated reports of ocular complications (e.g. mydriasis, increased
intraocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium
bromide either alone or in combination with an adrenergic beta2-agonist containing
ipratropium bromide have escaped into the eyes.
Eye pain or discomfort, blurred vision, visual halos or coloured images in association with
red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-
angle glaucoma. Should any combination of these symptoms develop, treatment with miotic
drops should be initiated and specialist advice sought immediately. Patients should be
instructed in the correct administration of Duolin Inhaler and care must be taken to prevent
Duolin from entering the eye. Patients who may be predisposed to glaucoma should be
warned specifically to protect their eyes.
In the following situations Duolin Inhaler should only be used after careful risk / benefit
assessment, especially when doses higher than recommended are used: Insufficiently
controlled diabetes mellitus, recent myocardial infarction, severe organic heart or vascular
disorders, hyperthyroidism, phaeochromocytoma, risk of narrow-angle glaucoma, prostatic
hypertrophy or bladder-neck obstruction.
Cardiovascular effects may be seen with sympathomimetic drugs, including Duolin Inhaler.
There is some evidence from post-marketing data and published literature of rare
occurrences of myocardial ischaemia associated with salbutamol. Patients with underlying
severe heart disease (e.g. ischaemic heart disease, tachyarrhythmia or severe heart failure)
who are receiving salbutamol for respiratory disease, should be warned to seek medical
advice if they experience chest pain or other symptoms of worsening heart disease.
Attention should be paid to assessment of symptoms (e.g. dyspnoea and chest pain), as
they may be of either respiratory or cardiac origin.
Potentially serious hypokalaemia may result from prolonged and / or high dose beta2-
agonist therapy. Additionally, hypoxia may aggravate the effects of hypokalaemia on cardiac
rhythm.
Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.
If higher than recommended doses of Duolin Inhaler are required to control symptoms, the
patient's therapy plan should be reviewed by a doctor.
The use of Duolin Inhaler may lead to positive results with regards to salbutamol in tests for
nonclinical substance abuse e.g. in the context of athletic performance enhancement
(doping).
Duolin Inhaler contains a very small amount of lactose (less than 0.04 mcg per actuation).
For people that are intolerant to lactose, this small amount does not normally cause
problems. Caution should be taken for those with severe milk protein allergies.
4.5 Interaction with other medicines and other forms of interaction
The concurrent administration of other beta-mimetics, systemically absorbed anticholinergics
and xanthine derivatives may increase the side effects.
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Beta-agonist induced hypokalaemia may be increased by concomitant treatment with
xanthine derivatives, glucocorticosteroids and diuretics. This should be taken into account
particularly in patients with severe airway obstruction.
Hypokalaemia may result in an increased susceptibility to arrhythmias in patients receiving
digoxin. It is recommended that serum potassium levels be monitored in such situations.
A potentially serious reduction in bronchodilator effect may occur during concurrent
administration of beta-blockers.
Beta-adrenergic agonists should be administered with caution to patients being treated with
monoamine oxidase inhibitors or tricyclic antidepressants, since the action of beta-
adrenergic agonists may be enhanced.
Inhalation of halogenated hydrocarbon anaesthetics such as halothane, trichloroethylene
and enflurane may increase the susceptibility to the cardiovascular effects of beta-agonists.
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of Duolin Inhaler during human pregnancy is not established. The usual
precautions regarding the use of drugs in pregnancy, especially during the first trimester,
should be observed. The inhibitory effect of Duolin Inhaler on uterine contraction should be
taken into account.
Duolin Inhaler during a confirmed or suspected pregnancy must be weighed against possible
hazards to the unborn child.
For ipratropium bromide, preclinical studies have shown no embryotoxic or teratogenic
effects following inhalation or intranasal application at doses considerably higher than those
recommended in man. For salbutamol sulphate, non-inhalation preclinical studies did not
indicate direct or indirect harmful effects unless the inhalation Maximum Recommended
Human Daily Dose (MRHDD) was exceeded (please refer to section Toxicology).
No studies on the effect on human fertility have been conducted for Duolin Inhaler.
Preclinical studies performed with ipratropium bromide and salbutamol showed no adverse
effect on fertility (please refer to section Toxicology).
Breast feeding
It is not known whether salbutamol sulphate and ipratropium bromide are excreted in breast
milk. Although lipid-insoluble quaternary cations pass into breast milk, it is considered
unlikely that ipratropium bromide would reach the infant to an important extent when
administered by inhalation. However, because many drugs are excreted in breast milk,
caution should be exercised when Duolin Inhaler is administered to nursing mothers.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
However, patients should be advised that they may experience undesirable effects such as
dizziness, accommodation disorder, mydriasis and blurred vision during treatment with
Duolin Inhaler. Therefore, caution should be recommended when driving a car or operating
machinery. If patients experience the above-mentioned side effects, they should avoid
potentially hazardous tasks such as driving or operating machinery.
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4.8 Undesirable effects
Many of the listed undesirable effects can be assigned to the anticholinergic and beta2-
sympathomimetic properties of Duolin Inhaler. As with all inhalation therapy, Duolin Inhaler
may show symptoms of local irritation. Adverse drug reactions were identified from data
obtained in clinical trials and pharmacovigilance during post approval use of the drug.
The most frequent side effects reported in clinical trials were headache, throat irritation,
cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhoea and
vomiting), nausea, and dizziness.
Immune system disorders:
Anaphylactic reaction
Hypersensitivity
Metabolism and nutrition disorders:
Hypokalaemia
Psychiatric disorders:
Mental disorder
Nervousness
Nervous system disorders:
Dizziness
Headache
Tremor
Eye disorders:
Glaucoma
Eye pain
Intraocular pressure increased
Mydriasis
Vision blurred
Accommodation disorder
Corneal oedema
Conjunctival hyperaemia
Halo vision
Cardiac disorders:
Arrhythmia
Atrial fibrillation
Myocardial ischaemia
Palpitations
Tachycardia
Supraventricular tachycardia
Respiratory, thoracic and mediastinal disorders:
Bronchospasm
Bronchospasm paradoxical
Laryngospasm
Pharyngeal oedema
Cough
Dysphonia
Dry throat
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Gastrointestinal disorders:
Oedema mouth
Dry mouth
Throat irritation
Diarrhoea
Gastrointestinal motility disorder
Constipation
Nausea
Vomiting
Stomatitis
Skin and subcutaneous tissue disorders:
Skin reactions such as:
Rash
Pruritus
Urticaria
Angioedema
Hyperhidrosis
Musculoskeletal and connective tissue disorders:
Muscle spasms
Muscular weakness
Myalgia
Renal and urinary disorders:
Urinary retention
General disorders and administration site conditions:
Asthenia
Investigations:
Blood pressure diastolic decreased
Blood pressure systolic increased
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare
professionals are asked to report any suspected adverse reactions
https://nzphvc.otago.ac.nz/reporting/.
4.9 Overdose
Symptoms
The effects of overdosage are expected to be primarily related to salbutamol. The expected
symptoms with overdosage are those of excessive beta-adrenergic-stimulation, the most
prominent being tachycardia, palpitation, tremor, hypertension, hypotension, widening of the
pulse pressure, anginal pain, arrhythmias, and flushing.
Expected symptoms of overdosage with ipratropium bromide (such as dry mouth, visual
accommodation disorders) are mild and transient in nature in view of the wide therapeutic
range and topical administration.
Treatment
Administration of sedatives, tranquillisers, in severe cases intensive therapy.
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Beta-receptor blockers, preferably beta1-selective, are suitable as specific antidotes;
however, a possible increase in bronchial obstruction must be taken into account and the
dose should be adjusted carefully in patients suffering from bronchial asthma.
Contact the Poisons Information Centre (phone: 0800 764 766) for advice on management
of overdosage.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive
airway diseases, ATC code: R03AL02
Duolin Inhaler contains two active bronchodilating substances, salbutamol sulphate and
ipratropium bromide.
Salbutamol sulphate is a beta2-adrenergic agonist which acts on airway smooth muscle
resulting in muscle relaxation. Salbutamol relaxes all smooth muscle from the trachea to the
terminal bronchioles and aids to prevent bronchoconstriction when challenged.
Ipratropium bromide is a quaternary ammonium compound with anticholinergic
(parasympatholytic) properties. In preclinical studies, it appears to inhibit vagally mediated
reflexes by antagonising the action of acetylcholine, the transmitter agent released from the
vagus nerve. Anticholinergics prevent the increase of intracellular concentration of Ca++
which is caused by interaction of acetylcholine with muscarinic receptors on bronchial
smooth muscle. Ca++ release is mediated by the second messenger system consisting of
IP3 (inositol triphosphate) and DAG (diacylglycerol). The bronchodilation following inhalation
of ipratropium bromide is primarily local and site specific to the lung and not systemic in
nature.
Duolin Inhaler provides the simultaneous release of ipratropium bromide and salbutamol
allowing the synergistic efficacy on the muscarinic and beta2-adrenergic receptors in the
lung resulting in a bronchodilation which is superior to that provided by each single agent.
Controlled studies in patients with reversible bronchospasm have demonstrated that Duolin
Inhaler has a greater bronchodilator effect than either of its components and there was no
potentiation of adverse events.
5.2 Pharmacokinetic properties
From a pharmacokinetic perspective, the efficacy observed in the Inhalation Aerosol
pulmonary clinical trials is due to a local effect on the lung following inhalation.
Following inhalation, 10% to 39% of a dose is generally deposited in lungs, depending on
the formulation, inhalation technique and device, while the remainder of the delivered dose is
deposited in the mouthpiece, mouth and the upper part of the respiratory tract (oropharynx).
The portion of the dose deposited in the lungs reaches the circulation rapidly (within
minutes). The amount of the active substance deposited in the oropharynx is slowly
swallowed and passes the gastrointestinal tract. Therefore, the systemic exposure is a
function of both oral and lung bioavailability.
Ipratropium
Cumulative renal excretion (0-24 hrs) of ipratropium (parent compound) is approximated to
46% of an intravenously administered dose, below 1% of an oral dose and approximately 3-
4% of an inhaled dose. Based on this data, the total systemic bioavailability of oral and
inhaled doses of ipratropium bromide is estimated at 2% and 7-9% respectively. Taking this
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into account, swallowed dose portions of ipratropium bromide do not relevantly contribute to
systemic exposure.
Kinetic parameters describing the disposition of ipratropium were calculated from plasma
concentrations after i.v. administration. A rapid biphasic decline in plasma concentrations is
observed. The apparent volume of distribution at steady-state (Vdss) is approximately 176 L
(≈ 2.4 L/kg). The drug is minimally (less than 20%) bound to plasma proteins. Preclinical
studies with rats and dogs revealed that the quarternary amine ipratropium does not cross
the blood-brain barrier.
The half-life of the terminal elimination phase is approximately 1.6 hours. Ipratropium has a
total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous
administration, approximately 60% of a dose is metabolised probably mainly in the liver by
oxidation.
In an excretion balance study, cumulative renal excretion (6 days) of drug-related
radioactivity (including parent compound and all metabolites) accounted for 72.1% after
intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total
radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5%
following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related
radioactivity after intravenous administration, the main excretion occurs via the kidneys. The
half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6
hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be
regarded as ineffective.
Salbutamol
Salbutamol is rapidly and completely absorbed following administration either by the inhaled
or gastric route and has an oral bioavailability of approximately 50%. Mean peak plasma
salbutamol concentrations of 492 pg/ml occur within three hours after inhalation of Duolin
Inhaler. Following this single inhaled administration, approximately 27% of the estimated
mouthpiece dose is excreted unchanged in the 24-hour urine. Kinetic parameters were
calculated from plasma concentrations after i.v. administration. The apparent volume of
distribution (Vz) is approximately 156 L (≈ 2.5 L/kg). Only 8% of the drug is bound to plasma
proteins. Salbutamol will cross the blood brain barrier reaching concentrations amounting to
about 5% of the plasma concentrations. The mean terminal half-life is approximately 4 hours
with a mean total clearance of 480 mL/min and a mean renal clearance of 291 mL/min.
Salbutamol is conjugatively metabolised to salbutamol 4'-O-sulphate. The R(-)-enantiomer of
salbutamol (levosalbutamol) is preferentially metabolised and is therefore cleared from the
body more rapidly than the S(+)-enantiomer. Following intravenous administration, urinary
excretion was complete after approximately 24 hours. The majority of the dose was excreted
as parent compound (64.2%) and 12.0% was excreted as sulphate conjugate. After oral
administration, urinary excretion of unchanged drug and sulphate conjugate were 31.8% and
48.2% of the dose, respectively.
Co-administration of ipratropium bromide and salbutamol sulphate does not potentiate the
systemic absorption of either component and therefore the additive activity of Duolin Inhaler
is due to the combined local effect on the lung following inhalation.
5.3 Preclinical safety data
None stated
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6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate, propellant HFA-227.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Shelf life is 24 months (2 years) from manufacture. The expiry date is the last day of the
expiry month.
6.4 Special precautions for storage
Store below 25ºC. Do not freeze. Do not expose the aerosol canister to high temperatures.
Do not force open even when empty.
6.5 Nature and contents of container
Aerosol, aluminium aerosol can with metered dose valve and actuator – 200 doses.
6.6 Special precautions for handling and disposal
Instructions for Use/Handling
Testing your inhaler:
Before first use, the Duolin Inhaler should be shaken and the mouthpiece cover removed
and the canister depressed twice to release two actuations into the air. If the inhaler has not
been used for more than one week the canister should be depressed twice to re-prime the
inhaler.
Using your inhaler:
The correct operation of the inhaler is essential for successful therapy.
1. Remove the mouthpiece cover.
Shake the inhaler well before each use. If the inhaler has not been used for more
than one week depress the canister twice to prime the inhaler.
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2. Breathe out deeply through your mouth.
Hold the inhaler, with the inhaler upright and your thumb on the base and either one
or two fingers on top of the canister and place the mouthpiece of the inhaler in your
mouth and close lips over the mouthpiece (do not bite it).
3. Start breathing in as deeply as possible. As you breathe in, depress the canister to
release one dose, while continuing to breathe in steadily and deeply.
4. Hold your breath for 10 seconds, or for as long as it is comfortable. Then remove the
mouthpiece from your mouth and breathe out slowly.
5. If another dose is required, it is recommended that you wait for at least one minute
and then repeat steps 2 to 4.
6. After use, replace the mouthpiece cover.
IMPORTANT: Do no rush steps 3 to 4. It is important that you start to breathe in slowly just
before releasing the dose.
Practice in front of a mirror for the first few times. If you see “mist” coming from the top of
your inhaler or the sides of your mouth you should start again from stage 2. This escaping
“mist” indicates incorrect technique.
Cleaning
Note: The mouthpiece should always be kept clean to maintain the proper functioning of the
inhaler. Clean your inhaler at least once per week as follows:
1. Gently pull the metal canister out of the plastic body of the inhaler. Remove the
mouthpiece cover.
2. Immerse the plastic body and the mouthpiece cover in warm water.
3. Rinse the plastic body and mouthpiece cover under running tap water.
4. Shake well to remove excess water. Leave to dry in a warm place.
5. Replace the canister and mouthpiece cover correctly.
DO NOT PUT THE METAL CANISTER INTO WATER.
Note: If soap or detergent is used, the mouthpiece should be thoroughly rinsed in clear
water. When cleaning the inhaler always make sure that you have a spare inhaler ready to
use.
7 MEDICINE SCHEDULE
Prescription Medicine.
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8 SPONSOR
REX Medical Ltd
PO Box 18-119
Glen Innes 1743
AUCKLAND
admin@rexmed.co.nz
Ph (09) 574 6060
Fax (09) 574 6070
9 DATE OF FIRST APPROVAL
18 November 2010
10 DATE OF REVISION OF THE TEXT
15 February 2019
V6 © REX Medical Ltd
Duolin® is a registered trademark of REX Medical Ltd.
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Summary table of changes:
Section changed Summary of new information
All Format update
4.4 Caution regarding lactose content.
6.6 Updated graphics
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