Stugeron^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Contact Information

GEDEON RICHTER JSC (Hungary)

ATC Code

N07CA02 (Cinnarizine)

Active Substance

Cinnarizine (Rec.INN registered by WHO)

Dosage Form

Stugeron®

Tablets 25 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, round, flat, disc-shaped, with a beveled edge, practically odorless, with the engraving “STUGERON•” on one side and a score line on the other.

Excipients: colloidal silicon dioxide, potato starch, magnesium stearate, povidone K30, talc, corn starch, lactose monohydrate.

25 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Calcium channel blocker with a predominant effect on cerebral vessels

Pharmacotherapeutic Group

BMCC (Bone Mineral Crystal Complex)

Pharmacological Action

Cinnarizine inhibits the contraction of vascular smooth muscle cells by blocking calcium channels. In addition to direct calcium antagonism, Cinnarizine reduces the vasoconstrictive effects of vasoactive substances such as norepinephrine and serotonin by blocking receptor-operated calcium channels. The blockade of calcium entry into the cell is tissue-selective and, as a result, prevents vasoconstriction without affecting blood pressure and heart rate.

Cinnarizine may further improve microcirculation by increasing the deformability of erythrocytes and reducing blood viscosity. It increases cell resistance to hypoxia.

Cinnarizine inhibits stimulation of the vestibular apparatus, which results in the suppression of nystagmus and other autonomic disorders. Cinnarizine prevents the occurrence or reduces the severity of acute episodes of vertigo.

Pharmacokinetics

Absorption

C_max of cinnarizine in blood plasma is reached 1-3 hours after oral administration.

Distribution

The binding of cinnarizine to blood plasma proteins is 91%.

Metabolism

Cinnarizine is actively metabolized, mainly via the CYP2D6 isoenzyme.

Excretion

The known T_1/2 of cinnarizine ranges from 4 to 24 hours. About 1/3 of metabolites are excreted by the kidneys and 2/3 through the intestines.

Preclinical safety data

The single lethal dose LD50 values in various animal models show a large safety margin when calculated in mg/kg compared to the maximum recommended human dose (MRHD) of 225 mg/day or 4.5 mg/kg of human body weight (calculated for a 50 kg person). LD50 values were >1000 mg/kg body weight in mice after oral, subcutaneous and intraperitoneal administration. Similarly, LD50 values in rats and dogs were >640 mg/kg body weight and 160 mg/kg body weight respectively for all 3 routes of administration. The LD50 level after intravenous administration in mice and rats was 22 mg/kg body weight and 24 mg/kg body weight, respectively. The LD50 in guinea pigs was >40 mg/kg body weight after oral and subcutaneous administration. Results of acute oral, subcutaneous and peritoneal toxicity in mice and rats with cinnarizine dihydrochloride were similar to those of the parent compound.

Repeated oral dose toxicity studies (administered in the diet) in rats showed some reduction in food intake and changes in serum chemistry (decreased inorganic phosphorus content, increased calcium/phosphorus ratio), organ weights (decreased spleen and heart, increased liver, kidneys and brain) and histopathological changes (pancreas and chronic centrilobular degeneration). These observations were generally in the high-dose group (320 mg/kg body weight or about 72×MRHD) and were more pronounced after 18 months of treatment. After 3 or 12 months of oral cinnarizine administration in dogs, all observations were similar to controls, except for some reduction in body weight (after 3 months at 80 mg/kg or about 18×MRHD). Some limited histopathological findings (focal nuclear vacuolization and satellitosis in the CNS, liver edema, pancreatic changes, lymphoid tissue depletion, inhibition of spermatogenesis and atrophy of the female genital tract) were also identified after 12 months at a high dose of 20 mg/kg (~5×MRHD).

In reproductive toxicity studies in rats, rabbits and dogs, no effects on fertility and teratogenicity were found. At very high doses (from 80 to 320 mg/kg, about 18-72×MRHD) in rats, toxic effects on the maternal organism led to a reduction in litter size, an increase in the percentage of resorption and a decrease in fetal birth weight.

An in vitro mutagenicity study with Salmonella typhimurium showed that the parent compound was not mutagenic up to 10 µmol/plate. However, after interaction with nitrite and the formation of nitroso compounds, weak mutagenic activity was observed. Carcinogenicity was not specifically assessed. However, during chronic 18-month oral administration in rats, no preneoplastic changes were observed up to a dose approximately 72 times the maximum recommended human dose.

Indications

Adults

• Supportive therapy for symptoms of Ménière’s disease of labyrinthine origin, including vertigo, nausea, vomiting, tinnitus and nystagmus;
• Prevention of motion sickness (“travel sickness” – seasickness and airsickness);
• Prevention of migraine attacks;
• Supportive therapy for symptoms of cerebrovascular origin, including vertigo, tinnitus, headache, irritability, withdrawal, memory and concentration impairment;
• Supportive therapy for symptoms of peripheral circulatory disorders, including Raynaud’s disease, acrocyanosis, intermittent claudication, microcirculation disorders, trophic venous ulcers, paresthesia, night cramps, cold extremities.

Children

• Prevention of motion sickness (“travel sickness” – seasickness and airsickness) in children from 5 years of age.

ICD codes

Dosage Regimen

The drug is taken orally, after meals.

Adults

Supportive therapy for symptoms of Ménière’s disease of labyrinthine origin 1 tab. 3 times/day (75 mg/day).

Prevention of motion sickness 1 tab. (25 mg) at least half an hour before the trip; the dose can be repeated every 6 hours.

Prevention of migraine attacks 1 tab. 3 times/day (75 mg/day).

Supportive therapy for symptoms of cerebrovascular origin 1 tab. 3 times/day (75 mg/day).

Supportive therapy for symptoms of peripheral circulatory disorders 2-3 tab. 3 times/day (150-225 mg/day).

The maximum recommended dose should not exceed 225 mg/day (9 tab.).

Patients with renal and/or hepatic impairment, elderly patients (over 65 years) no data.

Children and adolescents under 18 years of age

Prevention of motion sickness:adolescents aged 13 years and older – 1 tab. (25 mg) at least half an hour before the trip; the dose can be repeated every 6 hours; children aged 5 to 12 years are recommended to take half the adult dose.

Adverse Reactions

The use of cinnarizine has been associated with drowsiness, nausea and increased body weight (≥1%). Also, with the use of cinnarizine, increased drowsiness, lethargy, stomach discomfort, vomiting, upper abdominal pain, dyspepsia, hyperhidrosis, fatigue (<1%) have been observed.

During post-marketing use of cinnarizine, the following adverse events have been reported (frequency – very rare (<1/10000)).

Nervous system disorders dyskinesia, extrapyramidal disorders, parkinsonism, tremor.

Skin and subcutaneous tissue disorders lichenoid keratosis, lichen planus, subacute cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders muscle rigidity.

Contraindications

• Hypersensitivity to cinnarizine and other components of the drug;
• Pregnancy;
• Breastfeeding period;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• Age under 5 years (efficacy and safety not established).

With caution in Parkinson’s disease.

Use in Pregnancy and Lactation

The use of the drug during pregnancy is contraindicated.

There are no data on the penetration of cinnarizine into breast milk, therefore, breastfeeding should be discontinued during the drug intake.

Use in Hepatic Impairment

There are no data on the use of the drug in patients with hepatic impairment.

Use in Renal Impairment

There are no data on the use of the drug in patients with renal impairment.

Pediatric Use

The use of the drug is contraindicated in children under 5 years of age.

Geriatric Use

There are no data on the use of the drug in elderly patients (over 65 years).

Special Precautions

Taking Stugeron^®, like taking other antihistamines, may cause discomfort in the upper abdomen; taking the drug after meals may reduce stomach irritation.

Stugeron^® should be prescribed to patients with Parkinson’s disease only if the benefits of its use outweigh the possible risk of worsening the condition.

Stugeron^® may cause drowsiness, especially at the beginning of treatment, so caution should be exercised when taking it concomitantly with alcohol, CNS depressants, or tricyclic antidepressants.

In case of lactose intolerance, it should be taken into account that each Stugeron^® tablet contains 175 mg of lactose monohydrate. The drug should not be taken by patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Effect on ability to drive vehicles and operate machinery

Since taking the drug may cause drowsiness, especially at the beginning of treatment, one should refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms

Cases of acute cinnarizine overdose have been reported with doses ranging from 90 to 2250 mg. The most frequently reported signs and symptoms due to cinnarizine overdose include altered consciousness from drowsiness to stupor and coma, vomiting, extrapyramidal symptoms and hypotension. A small number of young children developed seizures. In most cases, the clinical consequences were not severe, however, fatal acute overdose has been reported (such cases have been noted both with cinnarizine alone and with cinnarizine in combination with multiple other drugs).

Treatment

There is no specific antidote. For any overdose, symptomatic and supportive treatment is prescribed. If appropriate, activated charcoal can be administered.

Drug Interactions

Alcohol, CNS depressants, and tricyclic antidepressants when taken concomitantly may potentiate the sedative effects of Stugeron^®.

Diagnostic interventions. Due to the antihistamine effect, taking Stugeron^® less than 4 days before skin diagnostic tests may interfere with the detection of reactions that are positive in the absence of the drug.

Storage Conditions

The drug should be stored in the original packaging (blister in a carton to protect from light), in a place inaccessible to children, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.