McNeil Healthcare (Ireland) Ltd

Benylin Dry Coughs Syrup

Each 5 mls contains diphenhydramine hydrochloride 14 mg, levomenthol 2 mg and dextromethorphan hydrobromide 6.5 mg .

Excipients: Each 5ml contains liquid glucose 3.49g, sucrose 1g and Ponceau 4R (E124) 250 micrograms.

For a full list of excipients, see 6.1

Syrup

A clear red syrup having a menthol-raspberry flavour

Benylin Dry Coughs is indicated as an antitussive, for the relief of persistent, dry, irritating cough.

Adults and children 12 years and over:

Oral. 10 ml syrup 3 to 4 times a day.

Maximum daily dose: 40 ml syrup

Children under 12 years:

Benylin Dry Coughs is not recommended. [See section 4.3]

The Elderly:

Normal adult dosage is appropriate, [See Pharmacokinetics in the Elderly].

Hepatic Dysfunction:

Due to the extensive hepatic metabolism of dextromethorphan, caution should be exercised in the presence of moderate to severe hepatic impairment, [See Phamacokinetics].

Renal Dysfunction

It may be prudent to increase the dosage interval in subjects with moderate to severe renal failure, [See Pharmacokinetics in Renal Impairment].

Benylin Dry Coughs is contra-indicated in individuals with known hypersensitivity to the product or any of its components.

Benylin Dry Coughs is contra-indicated in individuals who are taking, or have taken, monoamine oxidase inhibitors (including the antibacterial agent furazolidone) within the preceding two weeks. The concomitant use of a dextromethorphan-containing product and monoamine oxidase inhibitors, can occasionally result in symptoms such as hyperpyrexia, hallucinations, gross excitation or coma.

Dextromethorphan, in common with other centrally acting antitussive agents, should not be given to subjects in, or at risk of developing respiratory failure.

Benylin Dry Coughs is contraindicated for use in children under 12 years of age.

This product may cause drowsiness, if affected; individuals should not drive or operate machinery.

Caution should be exercised if moderate to severe renal and/or hepatic impairment is present, [See Pharmacokinetics].

This product contains diphenhydramine and therefore should not be taken by individuals with narrow-angle glaucoma or symptomatic prostatic hypertrophy.

This product may act as a cerebral stimulant in children and occasionally in adults.

Benylin Dry Coughs should only be used under medical supervisions for persistent or chronic cough such as occurs with smoking, asthma or emphysema, or where cough is accompanied by excessive secretions.

If symptoms persist, please consult your doctor.

Patients who are taking other medication and / or under the care of a physician, should consult their doctor / pharmacist before taking this product.

Do not exceed the recommended dose schedule

The concomitant use of a dextromethorphan-containing product and monoamine oxidase inhibitors (including the antibacterial agent furazolidone), can occasionally result in symptoms such as hyperpyrexia, hallucinations, gross excitation or coma,. [See Contra-indications]

This product contains diphenhydramine and therefore may potentiate the effects of alcohol and other CNS depressants.

As diphenhydramine possess some anticholinergic activity, the effects of anticholinergics (e.g. some psychotrophic drugs and atropine) may be potentiated by this product. This may result in tachycardia, mouth dryness, gastrointestinal disturbances (e.g. colic), urinary retention and headache.

Both diphenhydramine and dextromethorphan have been in widespread use for many years without apparent ill consequence. However, there is insufficient information on the effects of the administration of dextromethorphan during human pregnancy. In addition, it is not known whether dextromethorphan or its metabolites are excreted in breast milk. Diphenhydramine is known to cross the placenta and has also been detected in breast milk.

Benylin Dry Coughs should not be used during pregnancy unless considered essential by the physician.

This product may cause drowsiness, if affected, individuals should not drive or operate machinery.

Side effects associated with the use of Benylin Dry Coughs are uncommon.

Diphenhydramine may cause: drowsiness; dizziness; gastrointestinal disturbance; dry mouth, nose and throat; difficulty in urination or blurred vision. Rarely, a rash may occur.

Side-effects attributed to dextromethorphan are uncommon; occasionally dizziness, confusion, excitation, nausea, vomiting, or gastro-intestinal disturbance, bronoconstriction and dyspnoea may occur.

There have been a few reports of abuse of dextromethorphan, but there is no evidence of drug dependence at therapeutic dosages.

Adverse reactions to menthol at the low concentration present in Benylin Dry Coughs are not anticipated.

Symptoms and signs

The effects of acute toxicity from of Benylin Dry Coughs may include drowsiness, hyperpyrexia, anticholinergic effects, lethargy, nystagmus, ataxia, respiratory depression, nausea, vomiting, hyperactivity, nervousness, tremors. With higher doses, and particularly in children, symptoms of cardiovascular collapse and CNS excitation including hallucinations and epileptiform convulsions may appear; large doses of antihistamines may precipitate attacks in epilepsy with massive doses, coma may follow.

Treatment

Treatment of overdose should be symptomatic and supportive. Measures to promote rapid gastric emptying (with syrup of ipecac-induced emesis or gastric lavage) and, in cases of acute poisoning, the use of activated charcoal, may be useful. The intravenous use of physostigmine may be efficacious in antagonising severe anticholinergic symptoms. Naloxone has been used successfully as a specific antagonist to dextromethorphan toxicity in children.

Dextromethorphan

Dextromethorphan is a non-opioid antitussive drug. It exerts its antitussive activity by acting on the cough centre in the medulla oblongata, raising the threshold for the cough reflex. A single oral dose of 10-20 mg dextromethorphan produces its antitussive action within 1 hour and lasts for at least 4 hours.

Diphenhydramine

Diphenhydramine possesses antitussive, antihistaminic, and anticholinergic properties. Experiments have shown that the antitussive effect (resulting from an action on the brainstem) is discrete from its antihistaminic effect. The duration of activity of diphenhydramine is between 4 and 8 hours.

Menthol has mild local anaesthetic and decongestant properties.

Absorption

Diphenhydramine, dextromethorphan and menthol are well absorbed from the gut following oral administration. Peak serum levels of diphenhydramine following a 50 mg oral dose are reached at between 2 and 2.5 hrs after an oral dose. Due to individual differences in the metabolism of dextromethorphan [See Metabolism & Elimination], pharmacokinetic values are highly variable. After the administration of a 20 mg dose of dextromethorphan to healthy volunteers, the C_max varied from < 1μg/l to 8μg/l, occurring within 2.5 hrs of administration.

Distribution

Diphenhydramine

Diphenhydramine is widely distributed throughout the body, including the CNS. Following a 50 mg oral dose of diphenhydramine, the volume of distribution is in the range 3.3 - 6.8 L/kg, and it is some 78% bound to plasma proteins.

Dextromethorphan

Due to extensive pre-systemic metabolism by the liver, detailed analysis of the distribution of orally administered dextromethorphan is not possible.

Metabolism and elimination

Diphenhydramine

Diphenhydramine undergoes extensive first pass metabolism. Two successive N-demethylations occur, with the resultant amine being oxidised to a carboxylic acid. Values for plasma clearance of a 50 mg oral dose of diphenhydramine lie in the range 600 - 1300 ml/min and the terminal elimination half-life lies in the range 3.4 - 9.3 hours. Little unchanged drug is excreted in the urine.

Dextromethorphan

Dextromethorphan undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation is the main determinant of dextromethorphan pharmacokinetics in human volunteers. It appears that there are distinct phenotypes for this oxidation process resulting in highly variable pharmacokinetics between subjects. Unmetabolised dextromethorphan, together with the three demethylated morphinan metabolites; dextrorphan (also known as 3-hydroxy-N-methylmorphinan), 3-hydroxymorphinan and 3-methoxymorphinan have been identified as conjugated products in the urine. Dextrorphan, which also has antitussive action, is the main metabolite.

Menthol

Menthol is hydroxylated in the liver by microsomal enzymes to p-methane -3,8 diol. This is then conjugated with glucuronide and excreted both in urine and bile as the glucuronide.

Pharmacokinetics in Renal Impairment

The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on the glomerular filtration rate (GFR).

There have been no specific studies of BENYLIN Dry Coughs or dextromethorphan in renal impairment.

Pharmacokinetics in Hepatic Impairment

After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease. However, the mean plasma clearance and apparent volume of distribution were not significantly affected.

There have been no specific studies of BENYLIN Dry Coughs or dextromethorphan in hepatic impairment.

Pharmacokinetics in the Elderly

Pharmacokinetic studies indicate no major differences in distribution or elimination of diphenhydramine compared to younger adults.

There have been no specific studies of BENYLIN Dry Coughs or dextromethorphan in the elderly.

Mutagenicity

The results of a range of tests suggest that neither diphenhydramine or menthol have mutagenic potential. There is insufficient information to determine whether dextromethorphan has mutagenic potential.

Carcinogenicity

There is insufficient information to determine the carcinogenic potential of diphenhydramine, dextromethorphan or menthol, although such effects have not been associated with these drugs in animal studies.

Teratogenicity

The results of a number of studies suggest that the administration of either diphenhydramine or menthol does not produce any statistically significant teratogenic effects in rats, rabbits and mice. There is insufficient information to determine whether dextromethorphan has teratogenic potential.

Fertility

There is insufficient information to determine whether diphenhydramine or dextromethorphan has the potential to impair fertility, although a diminished fertility rate with diphenhydramine has been observed in mice in one study.

Glucose syrup

Sucrose

Ethanol (96%)

Glycerol

Sodium citrate

Saccharin sodium

Citric acid monohydrate

Sodium benzoate

Caramel T12

Raspberry flavour 503.850/T

Ponceau 4R (E124)

Carbomer

Purified water

None known

3 years.

Do not store above 30^oC.

Keep bottle tightly closed.

Amber glass bottle with ROPP aluminium cap or a 3 piece child resistant tamper evident closure fitted with a PE-Alu-PET or polyethylene expanded/polyethylene laminated wad or with a HDPE plastic cap fitted with a PE-Alu-PET wad.

Pack size: 125 ml

None

McNeil Healthcare (Ireland) Limited

Airton Road

Tallaght

Dublin 24

Ireland

PA 823/14/1

June 2009