- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Benylin Dry Coughs Night Syrup
This medicine contains diphenhydramine hydrochloride 14 mg, L-menthol 2 mg and dextromethorphan hydrobromide 6.5 mg in each 5 ml.
Clear red syrup
This product is indicated as an antitussive, for the night time relief of persistent, dry, irritating cough, and aiding restful sleep.
Adults and children aged 12 years and over:
Patients may start with two 5 ml spoonfuls at bedtime followed by two 5 ml spoonfuls every 6 hours.
Or two 5 ml spoonfuls four times a day.
Do not take more than 4 doses (1 dose = two 5 ml spoonfuls) in 24 hours.
Children under 12 years:
This product is contraindicated in children under the age of 12 years (see section 4.3).
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.
This medicine is contraindicated in individuals with known hypersensitivity to the product or any of its components.
This medicine 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.
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).
Cases of dextromethorphan abuse have been reported. Caution is particularly recommended for adolescents and young adults as well as in patients with a history of drug abuse or psychoactive substances.
Dextromethorphan is metabolised by hepatic cytochrome P450 2D6. The activity of this enzyme is genetically determined. About 10% of the general population are poor metabolisers of CYP2D6. Poor metabolisers and patients with concomitant use of CYP2D6 inhibitors may experience exaggerated and/or prolonged effects of dextromethorphan. Caution should therefore be exercised in patients who are slow metabolizers of CYP2D6 or use CYP2D6 inhibitors (see also section 4.5).
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.]
Dextromethorphan is metabolized by CYP2D6 and has an extensive first-pass metabolism. Concomitant use of potent CYP2D6 enzyme inhibitors can increase the dextromethorphan concentrations in the body to levels multifold higher than normal. This increases the patient's risk for toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhoea and respiratory depression) and development of serotonin syndrome. Potent CYP2D6 enzyme inhibitors include fluoxetine, paroxetine, quinidine and terbinafine. In concomitant use with quinidine, plasma concentrations of dextromethorphan have increased up to 20-fold, which has increased the CNS adverse effects of the agent. Amiodarone, flecainide and propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be monitored and the dextromethorphan dose may need to be reduced.
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.
This medicine 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.
This product may cause drowsiness; if affected, individuals should not drive or operate machinery.
This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:
• The medicine is likely to affect your ability to drive
• Do not drive until you know how the medicine affects you
• It is an offence to drive while under the influence of this medicine
• However, you would not be committing an offence (called 'statutory defence') if:
o The medicine has been taken to treat a medical or dental problem and
o You have taken it according to the information provided with the medicine and
o It was not affecting your ability to drive safely.
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law
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 this medicine this product are not anticipated.
Symptoms and signs
The effects of acute toxicity of this medicine 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 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.
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 possesses antitussive, antihistaminic, 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.
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 Cmax varied from < 1 μg/l to 8 μg/l, occurring within 2.5 hrs of administration.
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.
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 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 undergoes rapid and extensive first-pass metabolism in the liver after oral administration. Genetically controlled O-demethylation (CYD2D6) 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. In some individuals metabolism proceeds more slowly and unchanged dextromethorphan predominates in the blood and urine.
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 this medicine 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 this medicine 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 this medicine or dextromethorphan in the elderly.
The active ingredients of this medicine 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.
Citric acid monohydrate
Raspberry flavour 503.850/T
Ponceau 4R (E124)
Do not store above 30°C. Store in the original 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
McNeil Products Limited
Berkshire SL6 3UG
McNeil Products Ltd
Foundation Park, Roxborough Way, Maidenhead, Berks, SL6 3UG