Dimezine

Dimenhydrinate, cinnarizine.

Each tablet contains: Dimenhydrinate, BP 40 mg; Cinnarizine, BP 20 mg.

Antihistamine (Aminoalkyl ether)/Antivertigo.
Pharmacology: Pharmacodynamics: Dimenhydrinate, the chlorotheophylline salt of diphenhydramine, acts as antihistamine with anticholinergic (antimuscarinic) properties, exerting parasympatholytic and centrally-depressant effects. The substance exhibits antiemetic and antivertiginous effects through influencing the chemoreceptor trigger zone in the region of the 4th ventricle. Dimenhydrinate thus acts predominantly on the central vestibular system.
Due to its calcium antagonistic properties, cinnarizine acts mainly as a vestibular sedative through inhibition of the calcium influx into the vestibular sensory cells. Cinnarizine thus acts predominantly on the peripheral vestibular system.
Both cinnarizine and dimenhydrinate are known to be effective in the treatment of vertigo. The combination product is more effective than the individual compounds in the population studied. The product has not been evaluated in motion sickness.
Pharmacokinetics: Absorption and Distribution: Dimenhydrinate rapidly releases its diphenhydramine moiety after oral administration. Diphenhydramine and cinnarizine are rapidly absorbed from the gastro-intestinal tract. Maximum plasma concentrations (Cmax) of cinnarizine and diphenhydramine are reached in humans within 2-4 hours. The plasma elimination half-lives of both substances range from 4-5 hours, when given either alone or as the combination product.
Biotransformation: Cinnarizine and diphenhydramine are extensively metabolised in the liver. The metabolism of cinnarizine involves ring hydroxylation reactions that are in part catalysed by CYP2D6 and N-desalkylation reactions of low CYP-enzyme specificity. The main pathway in the diphenhydramine metabolism is the sequential N-demethylation of the tertiary amine. Studies in human liver microsomes in vitro indicate the involvement of various CYP-enzymes, including CYP2D6.
Elimination: Cinnarizine is mainly eliminated via the faeces (40-60%) and to a lower extent also in urine, mainly in the form of metabolites conjugated with glucuronic acid. The major route of elimination of diphenhydramine is in the urine, mainly in the form of metabolites, with the deaminated compound, diphenylmethoxy acetic acid, being the predominant metabolite (40-60%).

Treatment of vertigo symptoms of various origins.
Cinnarizine & Dimenhydrinate combination is indicated in adults.

Adults: 1 tablet three times daily.
Elderly: Dosage as for adults.
Renal impairment: Cinnarizine & Dimenhydrinate combination should be used with caution in patients with mild to moderate renal impairment. Cinnarizine & Dimenhydrinate combination should not be used by patients with a creatinine clearance of < 25mL/min (severe renal impairment).
Hepatic impairment: No studies in patients with hepatic impairment are available. Cinnarizine & Dimenhydrinate combination should not be used by patients with severe hepatic impairment.
Pediatric population: The safety and efficacy of Cinnarizine & Dimenhydrinate combination in children and adolescents under the age of 18 years has not been established. No data are available.
In general, the duration of treatment should not exceed four weeks. The physician shall decide whether longer treatment is required.
Method of administration: Cinnarizine & Dimenhydrinate combination tablets are to be taken unchewed, with some liquid after meals.

Symptoms of overdosage with Cinnarizine & Dimenhydrinate combination include drowsiness, dizziness and ataxia with anticholinergic effects such as dry mouth, flushing of the face, dilated pupils, tachycardia, pyrexia, headache and urinary retention. Convulsions, hallucinations, excitement, respiratory depression, hypertension, tremor and coma may occur, particularly in cases of massive overdosage.
Management of overdose: General supportive measures should be used to treat respiratory insufficiency or circulatory failure. Gastric lavage with isotonic sodium chloride solution is recommended. Body temperature should be closely monitored, since pyrexia may occur as a consequence of antihistamine intoxication, especially in children.
Cramp-like symptoms may be controlled by careful application of a short-acting barbiturate. In cases of marked central-anticholinergic effects, physostigmine (after physostigmine test) should be administered slowly intravenously (or, if necessary, intramuscularly): 0.03 mg/kg body weight (adults max. 2 mg, children max. 0.5 mg).
Dimenhydrinate is dialyzable, however treatment of overdosage by this measure is considered as unsatisfactory. Sufficient elimination can be achieved by means of haemoperfusion using activated charcoal. No data are available concerning the dialysability of cinnarizine.

Hypersensitivity to the active substances, diphenhydramine or other antihistamines of similar structure or to any of the excipients.
Diphenhydramine is completely excreted renally, and patients with severe renal impairment were excluded from the clinical development programme. Cinnarizine & Dimenhydrinate combination should not be used by patients with a creatinine clearance of ≤ 25 ml/min (severe renal impairment).
Since both active components of Cinnarizine & Dimenhydrinate combination are extensively metabolised by hepatic cytochrome P450 enzymes, the plasma concentrations of the unchanged drugs and their half-lives will increase in patients with severe hepatic impairment. This has been shown for diphenhydramine in patients with cirrhosis. Cinnarizine & Dimenhydrinate combination should therefore not be used by patients with severe hepatic impairment.
Cinnarizine & Dimenhydrinate combination should not be used in patients with angle-closure glaucoma, convulsions, suspicion of raised intracranial pressure, and alcohol abuse or urine retention due to urethroprostatic disorders.

Cinnarizine & Dimenhydrinate combination does not reduce blood pressure significantly, however, it should be used with caution in hypotensive patients.
Cinnarizine & Dimenhydrinate combination should be taken after meals to minimise any gastric irritation.
Cinnarizine & Dimenhydrinate combination should be used with caution in patients with conditions that might be aggravated by anticholinergic therapy, e.g. raised intra-ocular pressure, pyloro-duodenal obstruction, prostatic hypertrophy, hypertension, hyperthyroidism or severe coronary heart disease.
Caution should be exercised when administering Cinnarizine & Dimenhydrinate combination to patients with Parkinson's disease.
Effects on Ability to Drive and Use Machine: Cinnarizine and Dimenhydrinate combination may have minor influence on the ability to drive and use machines.
Cinnarizine and Dimenhydrinate combination may cause drowsiness, especially at the start of treatment. Patients affected in this way should not drive or operate machinery.

Pregnancy: The safety of Cinnarizine & Dimenhydrinate combination in human pregnancy has not been established. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development and postnatal development.
The teratogenic risk of the single actives dimenhydrinate/diphenhydramine and cinnarizine is low. No teratogenic effects were observed in animal studies. There are no data from the use of Cinnarizine & Dimenhydrinate combination in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. Based on human experience dimenhydrinate is suspected to have an oxytoxic effect and may shorten labour. Cinnarizine & Dimenhydrinate combination is not recommended during pregnancy.
Breast-feeding: Dimenhydrinate and cinnarizine are excreted in human breast milk. Cinnarizine & Dimenhydrinate combination should not be used during breast-feeding.

The most frequently occurring ADRs are somnolence (including drowsiness, tiredness, fatigue, daze) occurring in about 8% of patients and dry mouth occurring in about 5% of patients in clinical trials. These reactions are usually mild and disappear within a few days even if treatment is continued. The frequency of ADRs associated with Cinnarizine & Dimenhydrinate combination in clinical trials and following spontaneous reports are as follows (Common ≥1/100 to <1/10, Uncommon ≥1/1,000 to <1/100, Rare ≥1/10,000 to <1/1,000 and Very Rare ≥1/10,000).
Blood and Lymphatic System Disorders: Very Rare: Leucopenia, Thrombopenia, Aplastic Anemia.
Immune System Disorders: Rare: Hypersensitivity Reactions (e.g., cutaneous reactions).
Nervous System Disorders: Common: Somnolence, Headache.
Uncommon: Paraesthesia, Amnesia, Tinnitus, Tremor, Nervousness, Convulsions.
Eye Disorders: Rare: Visual Disorders.
Gastrointestinal Disorders: Common: Dry Mouth, Abdominal Pain.
Uncommon: Dyspepsia, Nausea, Diarrhea.
Skin and Subcutaneous Tissue Disorders: Uncommon: Perspiration, Rash.
Rare: Photosensitivity.
Renal and Urinary Disorders: Rare: Urinary Hesitancy.
In addition the following adverse reactions are associated with dimenhydrinate and cinnarizine (frequency cannot be estimated from the available data): Dimenhydrinate: Paradoxical excitability (especially in children), worsening of an existing angle-closure glaucoma, reversible agranulocytosis.
Cinnarizine: Constipation, weight gain, tightness of the chest, cholestatic jaundice, extrapyramidal symptoms, lupus-like skin reactions, lichen planus.

No interaction studies have been performed.
The anticholinergic and sedative effects of Cinnarizine & Dimenhydrinate combination may be potentiated by monoamine oxidase inhibitors. Procarbazine may enhance the effect of Cinnarizine & Dimenhydrinate combination.
In common with other antihistamines, Cinnarizine & Dimenhydrinate combination may potentiate the sedative effects of CNS depressants including alcohol, barbiturates, narcotic analgesics and tranquillisers. Patients should be advised to avoid alcoholic drinks. Cinnarizine & Dimenhydrinate combination may also enhance the effects of antihypertensives, ephedrine and anticholinergics such as atropine and tricyclic antidepressants.
Cinnarizine & Dimenhydrinate combination may mask ototoxic symptoms associated with aminoglycosidic antibiotics and mask the response of the skin to allergic skin tests.
The concomitant administration of medicines that prolong the QT interval of the ECG (such as Class Ia and Class III anti-arrhythmics) should be avoided.
The information about potential pharmacokinetic interactions with cinnarizine and diphenhydramine and other medicinal products is limited. Diphenhydramine inhibits CYP2D6 mediated metabolism and caution is advised if Cinnarizine & Dimenhydrinate combination is combined with substrates of this enzyme, especially those with narrow therapeutic range.

Store at temperatures not exceeding 30°C.

Antivertigo Drugs

N07CA52 - cinnarizine, combinations ; Belongs to the class of antivertigo preparations.

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