FORMULATION

Each Tablet contains :

Cinnarizine… 20mg
Dimenhydrinate…40mg

INDICATION

Treatment of vertigo symptoms of various origins.

CONTRAINDICATIONS

The fix dose combination of Cinnarizine and Dimenhydrinate is contraindicate in patients with known hypersensitivity to the active substances, diphenhydramine (the metabolite of dimenhydrinate) or other antihistamines of similar structure, severe renal impairment (creatinine clearance of < 25 mL/min), severe hepatic impairment, pregnancy and lactation. The fixed dose combination of Cinnarizine and Dimenhydrinate should not be used in patients with angle-closure glaucoma, convolsions, suspicion of raised intracranial pressure, and alcohol abuse or urine retention due to urethroprostatic disorders.

DOSAGE AND ADMINISTRATION

In general, the duration of treatment should not exceed four weeks. The physician shall decide whether longer treatment is required.

Adults & Elderly

One tablet containing 20mg Cinnarizine plus 40mg Dimenhydrinate three times daily, to be taken with some liquid after meals. Or as prescribed by the physician.

Children and adolescents under the age of 18 years

The fixed dose combination of Cinnarizine and Dimenhydrinate is not recommended in children and adolescents under the age of 18 years because there is no data available on its use in this age group.

Renal Impairment

Diphenhydramine is completely excreted renally. The fixed dose combination of Cinnarizine plus Dimenhydrinate should be used with caution in patients with mild to moderate renal impairment. The fixed dose combination of Cinnarizine plus Dimenhydrinate is contraindicated in patients with a creatinine clearance of < 25mL/min (severe renal impairment).

Hepatic Impairment

Studies in patients with hepatic impairement have not been conducted. Since both active components of the fixed dose combination of Cinnarizine and Dimenhydrinate are extensively metabolized 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  for diphenydramine in patients with cirrhosis. The fixed dose combination of Cinnarizine and Dimenhydrinate should therefore not be used by patients with severe hepatic impairment.

CLINICAL PHARMACOLOGY

Mechanism of Action

Dimenhydrinate, the chlorotheophylline salt of diphenhydramine, acts as an antihistamine with anticholinergic (antimuscarinic) properties, exerting parasympatholytic and centrally-depressant effects. The substance exhibits anti-emetic 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.

PHARMACOKINETICS

Absorption

Dimenhydrinate rapidly releases its diphenhydramine moiety after oral administration. Cinnarizine and Diphenhydramine are rapidly absorbed from the gastrointestinal 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 to 5 hours, when given either alone or as the combination product.

Metabolism

Cinnarizine and diphenhydramine are extensively metabolized in the liver. The metabolism of Cinnarizine involves ring hydroxylation reactions that are in part catalyzed by CPY2D6 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

The plasma elimination half-lives of both substances range from  4 to 5 hours, when given either alone or as the combination product. Cinnarizine is mainly eliminated via the feces (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 urine, mainly in the form of metabolites, with the deaminated compound, diphenyl- methoxy acetic acid, being the predominant metabolite (40-60%).

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

The fixed dose combination of Cinnarizine plus Dimenhydrinate does not reduce blood pressure significantly; however, it should be used with caution in hypotensive patients. The fixed dose combination of Cinnarizine plus Dimenhydrinate should be taken after meals to minimize any gastric irritation. The fixed dose combination of Cannirizine and Dimenhydrinate should be used with caution in patients with conditions that might be aggravated by anti-cholinergic therapy, e.g. raised intra-ocular pressure, pyloro-doudenal obstruction, prostatic hypertrophy, hypertension, hyperthyroidism or severe  coronary heart disease. Caution should be exercised when administering  the fixed dose combination of Cinnarizine plus Dimenhydrinate to patients with Parkinson’s disease.

DRUG INTERACTIONS

The anticholinergic and sedative effects of the fixed dose combination of Cinnarizine plus Dimenhydrinate may be potentiated by monoamine oxidase inhibitors. Procarbazine may enhance the effect of the fixed dose combination of Cinnarizine plus Dimenhydrinate. In common with antihistamines, the fixed dose combination of Cinnarizine plus Dimenhydrinate may potentiate the sedative effects of CNS depressants including alcohol, barbiturates, narcotic analgesics and tranquillizers.

Patients should be advised to avoid alcoholic drinks.

The fixed dose combination of Cinnarizine plus Dimenhydrinate may also enhance the effects of antihypertensives, ephedrine and anticholinergics such as atropine and tricyclic antidepressants.

The fixed dose combination of Cinnarizine plus Dimenhydrinate may mask ototoxic symptoms associated with amino glycosidic 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 the fixed dose combination of Cannarizine plus Dimenhydrinate is combined with substrates of this enzyme, especially those with narrow therapeutic range.

ADVERSE EFFECTS

The most frequently occurring adverse reactions 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 adverse reactions associated with the fixed dose combination of Cinnarizine plus Dimenhydrinate in clinical trials and following spontaneous reports are as follows  (Common  >1/1000,  <1/10,  Uncommon >1/1,000, <1/100, Rare >1/10,000, < 1/1,000, 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 Cinnarizine and Dimenhydrinate

Dimenhydrinate: paradoxical excitability (especially in children), worsening of existing angle-closure glaucoma, reversible agranulocytosis. Cinnarizine: constipation, weight gain, tightness of the chest, cholestatic jaundice, extrapyramidal symptoms, lupus-like skin reactions, lichen planus.

USE IN PREGNANCY AND LACTATION

The safety of the fixed dose combination of Cinnarizine plus Dimenhydrinate in human pregnancy has not been established. Dimenhydrinate and Cinnarizine are excreted in human breast milk. The fixed dose combination of Dimenhydrinate and Cinnarizine should not be taken by women who are pregnant or breast feeding.

CAUTION

Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

STORE AT TEMPERATURES NOT EXCEEDING 30ºC. PROTECT FROM LIGHT.

AVAILABILITY

Alu-alu blister pack of 10’s box 30 tablets