Instructions for Arlevert tablets blister No. 50
Composition
active ingredients: cinnarizine; dimenhydrinate;
1 tablet contains cinnarizine 20 mg and dimenhydrinate 40 mg;
Excipients: microcrystalline cellulose, corn starch, talc, hypromellose, colloidal anhydrous silica, magnesium stearate, croscarmellose sodium.
Dosage form
Pills.
Main physicochemical properties: biconvex tablets from white to pale yellow in color with an embossed "A" on one side.
Pharmacotherapeutic group
Drugs that act on the nervous system. Combined preparation of cinnarizine.
ATX code N07C A52.
Pharmacological properties
Pharmacodynamics
Dimenhydrinate, the chlorotheophylline salt of diphenhydramine, acts as an antihistamine with anticholinergic (M-cholinoblocking) activity, which has parasympatholytic and CNS depressant effects. By acting on the chemoreceptor trigger zone in the 4th ventricle, dimenhydrinate suppresses the urge to vomit and dizziness. Thus, dimenhydrinate acts primarily on the central vestibular system.
Due to its ability to block calcium receptors, cinnarizine inhibits the influx of calcium into vestibular sensory cells, thereby acting as a vestibulolytic agent. Thus, cinnarizine affects mainly the peripheral vestibular system.
Both cinnarizine and dimenhydrinate are known agents for the treatment of vertigo. In trials, the combined agent has been shown to be more effective than either of its components alone. This drug has not been studied as an anti-vertigo agent.
Pharmacokinetics
Absorption and distribution. After oral administration of dimenhydrinate, diphenhydramine is rapidly released from it. Diphenhydramine and cinnarizine are rapidly absorbed from the gastrointestinal tract. In humans, maximum plasma concentrations (Cmax) of cinnarizine and diphenhydramine are reached within 2–4 hours. The plasma half-lives of both substances are 4 to 5 hours (regardless of whether they are used separately or as part of a combination product).
Metabolism. Cinnarizine and diphenhydramine are extensively metabolized in the liver. Cinnarizine is metabolized by hydroxylation reactions, which are partially catalyzed by the cytochrome isoenzyme CYP2D6, and by N-dealkylation reactions, for which cytochrome isoenzymes have low selectivity. The main metabolic pathway of diphenhydramine is sequential N-demethylation of the tertiary amine. In vitro studies on human liver microsomal fractions indicate that these reactions occur with the participation of various cytochrome isoenzymes, including the CYP2D6 isoenzyme.
Excretion. Cinnarizine is excreted mainly in the feces (40–60%) and partially in the urine (mainly as glucuronic acid-conjugated metabolites). Diphenhydramine is excreted mainly in the urine and mainly as metabolites; the main metabolite (40–60%) is the deaminated derivative, diphenylmethoxyacetic acid.
Preclinical safety data
Nonclinical studies revealed no special hazard for humans based on studies of repeated dose toxicity of the cinnarizine/dimenhydrinate combination, the effects of cinnarizine or dimenhydrinate on fertility, the effects of dimenhydrinate on embryo/fetal development, and the teratogenic effects of cinnarizine. In one study, rats treated with cinnarizine had reduced litter size, increased rates of embryo resorption, and reduced neonatal weights.
The genotoxic and carcinogenic effects of the cinnarizine/dimenhydrinate combination have not been evaluated.
Indication
Symptomatic treatment of dizziness of various genesis. Arlevert® is indicated for adult patients.
Contraindication
Allergic reactions to the active substances, diphenhydramine or other antihistamines of similar structure or to any of the excipients.
Diphenhydramine is excreted exclusively by the kidneys, therefore patients with severe renal insufficiency were excluded from the clinical development program. Arlevert® should not be used in patients with severe renal impairment (creatinine clearance ≤ 25 ml/min).
Since both active substances of Arlevert® are extensively metabolized by hepatic enzymes of the cytochrome P450 system, plasma concentrations of the active substances (in unchanged form) and their half-life increase in patients with severe hepatic impairment. This has been shown for diphenhydramine in patients with cirrhosis of the liver. Therefore, Arlevert® should not be used in patients with severe hepatic impairment.
Arlevert® should not be used in patients with angle-closure glaucoma, seizures, suspected increased intracranial pressure, as well as in patients with alcoholism, urinary retention caused by disorders of the urethra and prostate gland.
Interaction with other medicinal products and other types of interactions
Drug interaction studies have not been conducted.
Like other antihistamines, Arlevert® may enhance the sedative effects of central nervous system (CNS) depressants, including alcohol, barbiturates, narcotic analgesics, and tranquilizers. Patients should be advised not to consume alcoholic beverages. Arlevert® may enhance the effects of antihypertensives, ephedrine, and anticholinergics, including atropine and tricyclic antidepressants.
Arlevert® may mask the ototoxic effects of aminoglycoside antibiotics and skin reactions to skin allergy tests.
Concomitant use of drugs that prolong the QT interval on the ECG (class Ia and III antiarrhythmics) should be avoided.
There is insufficient information on the possible pharmacokinetic interaction of cinnarizine and diphenhydramine with other drugs. Diphenhydramine inhibits metabolic processes mediated by the cytochrome CYP2D6 isoenzyme, therefore caution is recommended when using Arlevert® in combination with substrates of this enzyme (especially those with a narrow therapeutic range).
Application features
Arlevert® does not cause a significant decrease in blood pressure, but it should be used with caution in patients with low blood pressure.
To minimize stomach irritation, Arlevert® should be taken after meals.
Arlevert® should be used with caution in patients with diseases or conditions that may be exacerbated by anticholinergic agents, such as patients with increased intraocular pressure, pyloric obstruction, prostatic hypertrophy, arterial hypertension, hyperthyroidism, or severe ischemic heart disease.
Arlevert® should be used with caution in patients with Parkinson's disease.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug Arlevert® may slightly affect the reaction speed when driving vehicles or using other mechanisms.
Arlevert® may cause drowsiness, especially at the beginning of treatment. In such cases, patients should not drive or operate machinery.
Use during pregnancy or breastfeeding
Pregnancy: The safety of Arlevert® for pregnant women has not been established.
Animal studies alone are insufficient to assess the effects of Arlevert® on pregnancy, embryonal and foetal development, and postnatal development (see section 5.3). The risk of teratogenic effects of each of the individual components (dimenhydrinate/diphenhydramine and cinnarizine) is low. Animal studies have not shown any teratogenic effects.
There are no data on the use of Arlevert® in pregnant women.
Dimenhydrinate may have a stimulating effect on the uterine muscles and shorten the duration of labor, therefore Arlevert® should not be used during pregnancy.
Breastfeeding. Dimenhydrinate and cinnarizine pass into breast milk, therefore Arlevert® should not be used in women who are breastfeeding.
Fertility: Unknown.
Method of administration and doses
Adults: 1 tablet 3 times a day after meals, do not chew, drink with a small amount of liquid.
Elderly patients: No dose adjustment is required.
Renal impairment: Arlevert® should be used with caution in patients with mild to moderate renal impairment. Arlevert® should not be used in patients with creatinine clearance ≤ 25 mL/min (severe renal impairment).
Hepatic impairment. Studies of the use of the drug in patients with hepatic impairment have not been conducted. Arlevert® should not be used in patients with severe hepatic insufficiency.
The duration of use of the drug should not exceed 4 weeks. The decision on longer treatment should be made by a doctor.
Children
The safety and efficacy of Arlevert® in children and adolescents (under 18 years of age) have not been established. Data are not available.
Overdose
Symptoms of Arlevert® overdose. Symptoms of Arlevert® overdose include drowsiness, dizziness and ataxia in combination with anticholinergic effects such as dry mouth, flushing, mydriasis, tachycardia, fever, headache and urinary retention. Complications such as convulsions, hallucinations, agitation, respiratory depression, hypertension, tremor and coma (especially in severe overdose) may also occur.
For cramp-like pain, short-acting barbiturates can be prescribed, but they should be used with caution. In the case of pronounced anticholinergic effects on the CNS, a trial with physostigmine should be performed, and then physostigmine should be administered by slow intravenous infusion (or, if necessary, by intramuscular injection) at a dose of 0.03 mg/kg body weight (maximum dose for adults is 2 mg, maximum dose for children is 0.5 mg).
Dimenhydrinate can be removed from the blood by hemodialysis, but this method of treatment for overdose is considered unacceptable. The required amount of the drug can be removed from the blood by hemoperfusion with the use of activated charcoal. Data on the removal of cinnarizine by hemodialysis are not available.
Adverse reactions
The most common adverse reactions observed during clinical trials were confusion (including drowsiness, fatigue, tiredness, dizziness), which occurred in 8% of patients in clinical trials, and dry mouth, which occurred in 5% of patients in clinical trials. These reactions are usually mild and resolve within a few days, even with prolonged use.
Adverse reactions that occurred with the use of Arlevert®, according to clinical trials and subsequent spontaneous reports, are presented in the table below.
| Organs and organ systems | Frequency | | | |
Often
>1/100 - <1/10 | Infrequently
>1/1000 - <1/100 | Rarely
>1/10000 - <1/1000 | Very rare
<1/10000 | |
| Blood and lymphatic system disorders | | | | Leukopenia Thrombocytopenia Aplastic anemia |
| On the part of the immune system | | | Allergic reactions (e.g. skin reactions) | |
| From the nervous system | Drowsiness Headache | Paresthesia Amnesia Tinnitus Tremor Nervousness Convulsions | | |
| From the organs of vision | | | Vision impairment | |
| From the digestive system | Dry mouth Abdominal pain | Dyspepsia Nausea Diarrhea | | |
| Skin and subcutaneous fat | | Sweating Rash | Photosensitization | |
| Renal and urinary disorders | | | Difficulty starting urination | |
In addition, the following adverse reactions have been associated with the use of dimenhydrinate and cinnarizine (frequency cannot be estimated from the available data):
Dimenhydrinate: paradoxical excitability (especially in children), exacerbation of pre-existing angle-closure glaucoma, reversible agranulocytosis.
Cinnarizine: constipation, weight gain, chest tightness, cholestatic jaundice, extrapyramidal disorders, skin reactions resembling systemic lupus erythematosus, lichen planus.
Reporting possible adverse reactions
Reporting of possible adverse reactions after the registration of a medicinal product plays an important role. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
No special storage conditions are required. Keep out of the reach of children.
Packaging
25 tablets in a blister; 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Hennig Artzneimittel GmbH & Co. KG.
Location of the manufacturer and its business address
Liebigstrasse 1-2, 65439 Florsheim am Main, Germany.
