Azalon

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZALON (AZALON)

Composition:

Active substances: cinnarizine, dimenhydrinate;

One tablet contains cinnarizine 20 mg and dimenhydrinate 40 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, corn starch, hypromellose 2910/5, colloidal anhydrous silicon dioxide, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white to almost white, round, biconvex tablets, 8 mm in diameter.

Pharmacotherapeutic group. Agents acting on the nervous system. Combined cinnarizine preparation. ATC code N07C A52.

Pharmacological properties.

Pharmacodynamics.

Dramamine, chlorotheophyllinate salt of diphenhydramine, acts as an antihistamine with anticholinergic (M-cholinoblocking) activity, exerting a parasympatholytic effect and a depressant effect on the central nervous system (CNS). By acting on the chemoreceptor trigger zone in the area of the fourth ventricle, dimenhydrinate suppresses the urge to vomit and relieves dizziness. Thus, dimenhydrinate primarily affects the central vestibular system.

By blocking calcium receptors, cinnarizine inhibits calcium influx into vestibular sensory cells, thereby acting as a vestibular suppressant. Cinnarizine primarily affects the peripheral vestibular system.

Both cinnarizine and dimenhydrinate are well-known agents used in the treatment of vertigo. Clinical studies have shown that the combined preparation is more effective than either component administered separately. This medication has not been studied for the prevention of motion sickness.

Pharmacokinetics.

Absorption and distribution. After oral administration, dimenhydrinate rapidly releases diphenhydramine. Both diphenhydramine and cinnarizine are quickly absorbed from the gastrointestinal tract. In humans, maximum plasma concentrations (C_max) of cinnarizine and diphenhydramine are reached within 2–4 hours. The elimination half-life of both substances from plasma is 4 to 5 hours, regardless of whether they are administered separately or in combination.

Metabolism. Cinnarizine and diphenhydramine are extensively metabolized in the liver. Cinnarizine undergoes hydroxylation reactions, partially catalyzed by the CYP2D6 isoenzyme of cytochrome P450, and N-dealkylation reactions, for which cytochrome isoenzymes show low specificity. The primary metabolic pathway of diphenhydramine is sequential N-demethylation of the tertiary amine. In vitro studies using human liver microsomal fractions indicate that these reactions are mediated by various cytochrome P450 isoenzymes, including CYP2D6.

Excretion. Cinnarizine is primarily excreted in feces (40–60%) and partially in urine (mainly as metabolites conjugated with glucuronic acid). Diphenhydramine is mainly excreted in urine, predominantly as metabolites; the primary metabolite (40–60%) is the deaminated derivative—diphenylmethoxyacetic acid.

Preclinical safety data

Preclinical studies revealed no particular hazard to humans in repeated-dose toxicity studies of the cinnarizine/dimenhydrinate combination, or in studies of the effects of cinnarizine or dimenhydrinate on fertility, the effect of dimenhydrinate on embryonic/fetal development, or the teratogenic potential of cinnarizine. However, in one study in rats treated with cinnarizine, a reduced number of offspring, increased frequency of embryonic resorption, and reduced birth weight were observed.

The genotoxic and carcinogenic potential of the cinnarizine/dimenhydrinate combination has not been evaluated.

Clinical characteristics.

Indications.

Symptomatic treatment of dizziness of various origins. The medicinal product Azalon is indicated for adult patients.

Contraindications.

Hypersensitivity to the active substances, diphenhydramine or other antihistamines of similar structure, or to any excipient.

Diphenhydramine is exclusively eliminated by the kidneys; therefore, patients with severe renal impairment were excluded from the clinical development program. Azalon must not be used in patients with severe renal function impairment (creatinine clearance ≤ 25 ml/min).

Since both active substances of Azalon are extensively metabolized by hepatic enzymes of the cytochrome P450 system, in patients with severe hepatic impairment, plasma concentrations of the active substances (in unchanged form) and their elimination half-life are increased. This has been demonstrated for diphenhydramine in patients with liver cirrhosis. Therefore, this medicinal product must not be used in patients with severe hepatic impairment. Azalon must not be used in patients with closed-angle glaucoma, seizures, suspected increased intracranial pressure, as well as in patients with alcoholism, urinary retention caused by urinary tract or prostate disorders.

Interaction with other medicinal products and other forms of interaction.

Studies on drug interactions have not been conducted.

The anticholinergic and sedative effects of Azalon may be enhanced when used concomitantly with monoamine oxidase inhibitors. The effect of the drug may be enhanced by procarbazine.

Like other antihistamines, Azalon may enhance the CNS depressant effects of other agents, including alcohol, barbiturates, narcotic analgesics, and tranquilizers. Patients should be warned not to consume alcoholic beverages. Azalon may enhance the effects of antihypertensive agents, ephedrine, and anticholinergic drugs, including atropine and tricyclic antidepressants.

Azalon may mask the ototoxic effects of aminoglycoside antibiotics and skin reactions in skin allergy tests.

Concomitant use of drugs that prolong the QT interval on ECG (antiarrhythmic agents of class Ia and III) should be avoided.

There is insufficient information on possible pharmacokinetic interactions of cinnarizine and diphenhydramine with other medicinal products. Diphenhydramine inhibits metabolic processes mediated by the CYP2D6 isoenzyme of cytochrome P450; therefore, caution is recommended when using Azalon in combination with substrates of this enzyme (especially those with a narrow therapeutic index).

Special precautions for use

The medicinal product Azalon does not cause a significant reduction in blood pressure; however, it should be used with caution in patients with low arterial pressure.

To minimize gastric irritation, Azalon should be administered after food intake.

Azalon should be used with caution in patients with diseases or conditions that may be exacerbated by anticholinergic agents, for example, patients with increased intraocular pressure, gastric or duodenal outlet obstruction (pyloric stenosis), prostatic hypertrophy, arterial hypertension, hyperthyroidism, or severe ischemic heart disease.

Azalon should be used with caution in patients with Parkinson's disease.

The medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is practically "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. The safety of Azalon in pregnant women has not been established.

Animal studies alone are insufficient to assess the effects of Azalon on pregnancy, embryonic and fetal development, and postnatal development (see section "Preclinical safety data"). The teratogenic risk of each individual component (dimenhydrinate/diphenhydramine and cinnarizine) is considered low. Animal studies have not revealed teratogenic effects. However, data on the use of Azalon in pregnant women are lacking.

Dimenhydrinate may have a stimulatory effect on uterine musculature and may prolong the duration of labour; therefore, Azalon should not be used during pregnancy.

Breastfeeding period. Dimenhydrinate and cinnarizine pass into breast milk; therefore, Azalon should not be used in women who are breastfeeding.

Fertility. Unknown.

Ability to influence reaction speed when driving or operating machinery.

Azalon may have a minor influence on the ability to react when driving or operating machinery.

Azalon may cause drowsiness, especially at the beginning of treatment. In such cases, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage.

Adults. 1 tablet 3 times daily after meals. Do not chew; swallow whole with a small amount of liquid.

Elderly patients. Dose adjustment is not required.

Renal impairment. Alazon should be used with caution in patients with mild to moderate renal impairment. Alazon is contraindicated in patients with creatinine clearance ≤ 25 ml/min (severe renal insufficiency).

Hepatic impairment. Studies on the use of Alazon in patients with hepatic impairment have not been conducted. Alazon should not be used in patients with severe hepatic insufficiency.

The duration of treatment should not exceed 4 weeks. Any decision regarding longer-term therapy must be made by a physician.

Children.

The safety and efficacy of Alazon in children and adolescents (under 18 years of age) have not been established. Data are lacking.

Overdose.

Symptoms of Alazon overdose. Symptoms of Alazon overdose include drowsiness, dizziness, and ataxia in combination with anticholinergic effects such as dry mouth, facial flushing, pupillary dilation, tachycardia, fever, headache, and urinary retention. Severe complications may include seizures, hallucinations, agitation, respiratory depression, arterial hypertension, tremor, and coma (particularly in cases of severe overdose).

Treatment. In cases of respiratory depression or acute circulatory failure, supportive therapy should be administered. Gastric lavage with isotonic sodium chloride solution is recommended. Body temperature should be closely monitored, as intoxication with antihistamines may cause hyperthermia (especially in children).

In the case of colicky pain, short-acting barbiturates may be administered, but with caution. In cases of pronounced anticholinergic CNS effects, a physostigmine test should be performed, followed by administration of physostigmine via slow intravenous infusion (or, if necessary, by intramuscular injection) at a dose of 0.03 mg/kg body weight (maximum dose for adults – 2 mg; maximum dose for children – 0.5 mg).

Diphenhydramine can be removed from the blood by hemodialysis, but this method is considered unsuitable for treating overdose. Required amounts of the drug can be removed via hemoperfusion using activated charcoal. Data on the removal of cinnarizine by hemodialysis are lacking.

Adverse Reactions

The most commonly observed adverse reactions during clinical trials were confusion (including drowsiness, fatigue, tiredness, and lethargy), reported in 8% of patients participating in clinical trials, and dry mouth, reported in 5% of patients participating in clinical trials. These reactions are usually mild in severity and resolve within a few days, even with continued treatment.

Adverse reactions reported during clinical trials and post-marketing spontaneous reports with the use of the drug Azalon are listed in the table below.

In addition, the following adverse reactions are associated with the use of dimenhydrinate and cinnarizine (frequency cannot be estimated from available data):

Dimenhydrinate: paradoxical excitation (especially in children), worsening of pre-existing closed-angle glaucoma, reversible agranulocytosis.

Cinnarizine: constipation, weight gain, chest tightness, cholestatic jaundice, extrapyramidal disorders, skin reactions resembling systemic lupus erythematosus, lichen planus.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging. 10 tablets per blister; 3, 5, or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Medocem Limited / Medochemie Limited
2. Medocem Limited / Medochemie Limited

Manufacturer's address and place of business.

1. Konstantinoupoleos 1-10, Limassol, 3011, Cyprus / Konstantinoupoleos 1-10, Limassol, 3011, Cyprus
2. Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus