Benylin Dry Coughs (Original) (McNeil Products Ltd)

1. Name Of The Medicinal Product

Benylin Dry Coughs (Original)

2. Qualitative And Quantitative Composition

Benylin Dry Coughs (Original) contains diphenhydramine hydrochloride 14 mg, L-menthol 2 mg and dextromethorphan hydrobromide 6.5 mg in each 5 ml.

3. Pharmaceutical Form

Clear red syrup

4. Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Posology And Method Of Administration

Adults and children aged 12 years and over:

Oral. 10 ml syrup 4 times a day.

Children under 12 years:

Benylin Dry Coughs (Original) is contraindicated in children under the age of 12 years (see section 4.3).

The Elderly:

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

Do not exceed the stated dose.

Keep out of the reach and sight of children.

4.3 Contraindications

Benylin Dry Coughs (Original) is contraindicated in individuals with known hypersensitivity to the product or any of its components.

Benylin Dry Coughs (Original) is contraindicated in individuals who are taking, or have taken, monoamine oxidase inhibitors 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.

Not to be used in children under the age of 12 years.

4.4 Special Warnings And Precautions For Use

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

Diphenhydramine should not be taken by individuals with narrow-angle glaucoma or symptomatic prostatic hypertrophy. Subjects with moderate to severe renal or hepatic dysfunction should exercise caution when using this product (see pharmacokinetics).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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. [See Contraindications.]

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.

4.6 Pregnancy And Lactation

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 (Original) should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing foetus or suckling infant.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

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

Dextromethorphan: dizziness, nausea, vomiting, or gastro-intestinal disturbance may occur.

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

4.9 Overdose

Symptoms and signs

The effects of acute toxicity of Benylin Dry Coughs (Original) may include drowsiness, hyperpyrexia, anticholinergic effects, lethargy, nystagmus, ataxia, respiratory depression, nausea, vomiting, and hyperactivity. With higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse 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. Convulsions may be controlled with diazepam and thiopental sodium.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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.

5.2 Pharmacokinetic 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 < 1 μg/l to 8 μg/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 (Original) 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 (Original) 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 (Original) or dextromethorphan in the elderly.

5.3 Preclinical Safety Data

The active ingredients of Benylin Dry Coughs (Original) are well-known constituents of medicinal products and their safety profiles are well documented. The results of pre-clinical studies do not add anything of relevance for therapeutic purposes.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Liquid glucose

Sucrose

Ethanol (96%)

Glycerol

Sodium citrate

Saccharin sodium

Citric acid monohydrate

Sodium benzoate

Caramel T12

Raspberry flavour 503.850/T

Carbomer

Ponceau 4R (E124)

Purified water

6.2 Incompatibilities

None known

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 30°C. Store in the original container.

6.5 Nature And Contents Of Container

125 or 150 ml amber glass bottles with a 2 piece or a 3 piece plastic child resistant, tamper evident closure fitted with a polyterephtalate ethylene faced aluminium/expanded polyethylene laminated wad

6.6 Special Precautions For Disposal And Other Handling

None applicable.

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0053

9. Date Of First Authorisation/Renewal Of The Authorisation

26/02/2009

10. Date Of Revision Of The Text

05 March 2010