CNS Depressants: This product contains diphenhydramine and therefore may potentiate the effects of alcohol and other central nervous system depressants including opiod analgesics, anticonvulsants, antidepressants, antihistamines, antiemetics, antipsychotics, antixiolytic sedatives and hypnotics..

Antimuscarinic drugs: As diphenhydramine possesses some anti-cholinergic activity, the effects of anti-cholinergics (e.g. some psychotropic drugs and atropine) may be potentiated by this product giving rise to tachycardia, mouth dryness, gastrointestinal disturbances (e.g. colic), urinary retention and headache.

MAOIs: Not to be used in patients taking MAOIs or within 14 days of stopping treatment as there is a risk of serotonin syndrome.

Section 4.6 Fertility, Pregnancy and lactation

Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has also been detected in breast milk. Menthol is also excreted in breast milk.  Benylin Cough Medicine should not be used during pregnancy or lactation unless considered essential by a doctor.

Section 4.8 Undesirable effects

Side effects associated with the use of Benylin Cough Medicine are uncommon.

Diphenhydramine may cause drowsiness; dizziness; gastrointestinal disturbance; dry mouth, nose and throat; difficulty in urination, headache or rash.

Diphenhydramine

Data from several clinical trials are available with a total population of 936 people treated with diphenhydramine where adverse events were assessed. Additionally, adverse events reported in post-marketing are included.

Post-marketing Data:

* Frequency category based on clinical trials with single-ingredient diphenhydramine.

§ Adverse drug reaction only reported in one clinical trial.

Menthol

Adverse reactions to menthol at the low concentration present are not anticipated.

Section 4.9 Overdose

Diphenhydramine

Symptoms and signs

Mild to Moderate Symptoms Drowsiness, anticholinergic syndrome (hyperpyrexia, mydriasis, flushing, fever, tachycardia, dry mouth, urinary retention, decreased bowel sounds, agitation confusion and hallucinations), mild hypertension, nausea and vomiting are common after overdose.

Severe Symptoms: Effects may include delirium, psychosis, seizures, coma, hypotension, QRS widening, and ventricular dysrhythmias (including torsades de pointe), but are generally only reported in adults after large ingestions. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma, or seizures. Death may occur as a result of respiratory failure or circulatory collapse.With higher doses, and particularly in children, symptoms of CNS excitation including insomnia, nervousness, tremors and epileptiform convulsions may appear; with massive doses, coma or cardiovascular collapse may follow.

Menthol

Excessive use of menthol may lead to abdominal pain, vomiting, flushed face, dizziness, weakness, tachycardia, stupor, and ataxia.

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.

Section 5.1 Pharmacodynamic properties

Diphenhydramine HCl

ATC Code: R06AA52 Pharmacotherapeutic Group: Antihistamines for systemic use, Aminoalkyl ethers

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.

Diphenhydramine is a potent antihistamine and antitussive with concurrent anticholinergic and sedative properties. Experiments have shown that the antitussive action is discrete from H1-rececptor blockade and is located in the brain stem. The duration of activity of diphenhydramine is between 4 and 8 hours. The sedative mechanism for diphenhydramine is thought to result from antagonism of central histamine and cholinergic receptors. The time course for sedation following a 50 mg oral dose was associated with higher plasma concentrations, and was significantly different from placebo during the first three hours following administration. The pharmacodynamics of sedation was correlated with peak concentrations of drug occurring during absorption and the alpha distribution phase.

Menthol

Menthol has mild local anaesthetic and decongestant properties. The mechanism by which menthol may act as an antitussive may be related to a strong stimulant effect on cold receptors in the larynx in the absence of cold air. It has been noted that substances which produce a hot sensation in the airway may stimulate the cough reflex, while menthol, which produces a cold sensation, has the opposite effect.

Section 5.2 Pharmacokinetic properties

Diphenhydramine

Absorption

Diphenhydramine is well absorbed from the gastrointestinal tract, reaching peak plasma concentrations from 47-153 ng/mL between 1.5 and 4 hours after a single 50-mg dose in adults. After multiple oral doses of 50 mg diphenhydramine HCl four times during each day to four subjects, minimum diphenhydramine plasma concentrations at steady state on the third day ranged from 57-150 ng/mL. Diphenhydramine 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 hours.

Distribution

Diphenhydramine is widely distributed throughout the body, including the CNS. The pharmacokinetics of diphenhydramine follows a two-compartment model in which the distribution or alpha phase is apparent over the first eight to ten hours. The volume of distribution adjusted by body weight is large for diphenhydramine at 14.0 L/kg (38%) for adults, 16.0 (32%) for adolescents, and 19.5 (28%) for children. Diphenhydramine is highly protein bound, with free drug concentrations of 24.0 ± 1.9% ng/mL and 14.8 ± 1.5% ng/mL measured in Asian and Caucasian plasma. In adults with liver disease, protein binding is lower, although the volume of distribution is comparable to healthy adults 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.

Metabolism and elimination

Diphenhydramine undergoes extensive first pass metabolism with an absolute bioavailability of 72% ± 8%. It is extensively metabolized in the liver by demethylation to N-demethyl diphenhydramine (DMDP), and the extent of DMDP measured in plasma is highly correlated with the clearance of diphenhydramine. DMDP is subsequently demethylated to N,Ndidemethyl diphenhydramine. Because only the latter, minor metabolic pathway of N,N-didemethylation appears to be mediated by cytochrome P450 2D6, diphenhydramine disposition in humans is not determined by CYP2D6 activity. Rather, clinical pharmacokinetics data suggest that diphenhydramine may be an inhibitor of CYP2D6 without being extensively metabolized by this cytochrome P450 isozyme. N,Ndidemethyl diphenhydramine is further metabolized by oxidative deamination to diphenylmethoxyacetic acid..  Two successive N-dimethylations 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.  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.

Elimination

Mean beta elimination half-life from 8.5 and 11.5 hours in adults have been reported in studies in which blood is sampled up to 24 to 72 hours. The half-life is increased to 13.6 ± 4.2 h in the elderly and to 15.2 ± 1.5 h in adults with liver cirrhosis. Little unchanged drug is excreted in the urine.

Mean oral clearances for adults after a 25- and 50-mg dose are 1041 and 1029 mL/min, respectively, having coefficients of variation of 40% and 35%. Oral clearance is about 50% lower in elderly adults. Oral clearance is 691 mL/min (32%) for children ages 2 to 11 years, and is 1251 mL/min (43%) for adolescents’ ages 12 to 17 years.

The elderly

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

Renal dysfunction

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 glomerular filtration rate (GFR).

Hepatic dysfunction

After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged shelf-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.

Menthol

Absorption

Menthol is highly lipid soluble and, when taken orally, is rapidly absorbed from the small intestine.

Distribution

There is insufficient data on the distribution of menthol.

Metabolism

In humans, menthol is partially metabolized to menthol glucuronide by rapid conjugation. Animal studies in rats have demonstrated that menthol then undergoes extensive enterohepatic recirculation after being cleaved from the glucuronide conjugate and reabsorbed in the small intestine . The reabsorbed menthol is then subsequently metabolized by oxidative processes in the liver. There is support for this model in humans as well because menthol has been shown to be oxidized by CYP2A6 in human liver microsomes.

Elimination

A study in humans has demonstrated that approximately 50% of a menthol dose is excreted in the urine as menthol glucuronide. Other studies in rats have shown that menthol glucuronide is excreted in both the bile and the urine, but with the bile containing the majority of menthol glucuronide and with the urine also containing various oxidation products.

Section 6.6 Instructions for Use/Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product properties

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.