GINOMAX CL Composition: Active ingredients: thiocanazole, tinidazole and lidocaine hydrochloride monohydrate; 1 vaginal suppository contains thiocanazole 0.2 g, tinidazole 0.3 g and lidocaine hydrochloride monohydrate 0.12326 g, equivalent to lidocaine 0.1 g; Excipient: hard fat. Pharmaceutical form. Vaginal suppositories. Main physicochemical properties: flat, white to yellowish suppository with a smooth surface. Pharmacotherapeutic group. Antimicrobial and antiseptic agents used in gynecology, excluding combinations with corticosteroids. Imidazole derivatives combination. ATC code G01AF20. Pharmacological properties. Pharmacodynamics. Thiocanazole is a synthetic antifungal agent with high in vitro activity against yeast-like fungi and other fungi (including dermatophytes). It is also effective against Trichomonas vaginalis, Gardnerella vaginalis, Bacteroides family bacteria and some Gram-positive bacteria (including Staphylococcus and Streptococcus species). Clinical studies have shown that thiocanazole is effective in treating infections caused by Candida albicans and other Candida species (e.g. Torulopsis glabrata) and vaginal infections caused by Trichomonas vaginalis. Thiocanazole acts by altering the permeability of the fungal cell membrane. Ergosterol is an essential component of the fungal cell membrane. Thiocanazole inhibits ergosterol synthesis by interacting with 14α-demethylase, a cytochrome P450 enzyme that converts lanosterol into ergosterol. Inhibition of ergosterol synthesis leads to increased cell membrane permeability and leakage of intracellular phosphorus and potassium compounds through the cell membranes. Tinidazole is effective against protozoa and anaerobic bacteria. Its antiprotozoal effect covers Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia. Tinidazole is effective against Gardnerella vaginalis and most anaerobic bacteria (Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides family, Clostridium family, Eubacterium family, Peptostreptococcus and Veillonella). The complete mechanism of action of tinidazole has not been fully elucidated. Reduction of the nitro group occurs via the ferredoxin system and due to the low redox potential created only by anaerobic bacteria. This may explain why tinidazole uptake is more pronounced in anaerobes than in aerobes, although tinidazole penetrates the cell membranes of both types of microorganisms. The reduction process creates an increased diffusion gradient, enhancing the uptake of tinidazole and reactive intermediate compounds. Lidocaine is a local anesthetic of the amide group. It stabilizes neuronal membranes by inhibiting ionic fluxes necessary for initiation and conduction of impulses, thereby providing local anesthetic action. Pharmacokinetics. Absorption Tinidazole After intravaginal administration, absorption of tinidazole is approximately 10%. The mean peak plasma concentration was 1.0 µg/mL; in 6 healthy volunteers, the time to reach this level (tmax) after administration of a vaginal suppository containing 500 mg tinidazole was 8.7 hours. Thiocanazole After intravaginal administration, thiocanazole is absorbed in low concentrations by the mucous membrane. The mean peak plasma concentration after a single 300 mg dose of thiocanazole administered as an ointment to women with candidal vulvovaginitis was 18 µg/mL. Lidocaine Lidocaine is absorbed in insignificant amounts through damaged skin and mucous membranes. Distribution Tinidazole Tinidazole is almost completely distributed in all body tissues and fluids and crosses the blood-brain barrier. The apparent volume of distribution is approximately 50 liters. Plasma protein binding is about 12%. Tinidazole crosses the placental barrier and is excreted in breast milk. Thiocanazole In most clinical studies, after a single intravaginal dose of 300 mg thiocanazole, concentrations in vaginal fluid were sufficient to inhibit the growth of Candida albicans for 2–3 days. It is unknown whether thiocanazole passes into breast milk. Lidocaine Plasma protein binding ranges from 60% to 80%. Lidocaine crosses the placenta and the blood-brain barrier via passive diffusion and is distributed into cerebrospinal fluid, highly perfused tissues (kidneys, liver, heart) and adipose tissue. The volume of distribution is 0.8–1.3 L/kg. Biotransformation Tinidazole Tinidazole is partially metabolized via oxidation, hydroxylation and conjugation. Tinidazole is mainly biotransformed by cytochrome CYP3A4. Thiocanazole The main metabolite of thiocanazole is a glucuronide conjugate. Thiocanazole is not metabolized in vaginal fluid, but a portion of the drug absorbed systemically after intravaginal administration undergoes metabolism. One registered metabolite is formed via N-glucuronidation of the nitrogen on the imidazole ring, another via O-deethylation of the chlorothienyl group, hydration to alcohol and glucuronidation. Lidocaine Lidocaine is metabolized in the liver. Its active metabolites are monoethylglycinexylidide and glycinexylidide. Elimination Tinidazole The elimination half-life of tinidazole from plasma is approximately 12–14 hours. Tinidazole is eliminated via the liver and kidneys. It is excreted predominantly unchanged in urine (about 20–25% of the administered dose). Approximately 12% of the drug is excreted in feces. Thiocanazole After intravaginal administration, thiocanazole is eliminated from plasma typically within 72 hours. After oral administration, 25–27% of the dose is excreted in urine as metabolites, and 59% of the dose is excreted in feces (mainly unchanged). Lidocaine After intravenous administration, 90% of the absorbed dose is excreted as metabolites and less than 10% unchanged in urine. Linear/non-linear characteristics Data unavailable. Clinical characteristics. Indications. For the treatment of candidal vulvovaginitis caused by Candida albicans, bacterial vaginosis caused by Gardnerella vaginalis and anaerobic bacteria, trichomonal vaginitis caused by Trichomonas vaginalis, and vaginitis caused by mixed infections. Contraindications. - Hypersensitivity to the active ingredients or their derivatives.
- Alcohol consumption during treatment and for 3 days after treatment.
- Disulfiram intake during treatment and for 2 weeks after treatment.
- Porphyria.
- Epilepsy.
- Severe hepatic impairment.
- First trimester of pregnancy.
- Lactation period.
- Organic diseases of the nervous system.
- Hematopoietic disorders, including in medical history.
Interaction with other medicinal products and other forms of interaction. Due to the absorption of tinidazole, the following interactions with other drugs may occur: Acenocoumarol, anisindione, dicoumarol, phenindione, phenprocoumon, warfarin: increased risk of bleeding. Cholestyramine: reduced efficacy of tinidazole. Cimetidine: increased plasma concentration of tinidazole. Cyclosporine: increased cyclosporine levels. Disulfiram: adverse effects on the central nervous system (e.g. psychotic reactions). Fluorouracil: increased blood concentration of fluorouracil and signs of possible intoxication (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting). Fosphenytoin: increased fosphenytoin toxicity and/or decreased blood concentration of tinidazole. Ketoconazole: increased plasma concentration of tinidazole. Lithium preparations: increased blood concentration of lithium and signs of lithium intoxication (weakness, tremor, polydipsia, confusion). Phenobarbital: decreased blood concentration of tinidazole. Phenytoin: increased risk of phenytoin intoxication and/or decreased blood concentration of tinidazole. Rifampicin: decreased blood concentration of tinidazole. Tacrolimus: increased tacrolimus levels. Inducers/inhibitors of CYP3A4: reduced efficacy of tinidazole or increased risk of adverse reactions (CYP3A4 inhibitors such as cimetidine and ketoconazole may prolong the elimination half-life, reduce tinidazole clearance and increase plasma concentration of tinidazole). Due to the absorption of thiocanazole, the following interactions with other drugs may occur: Oxycodone: concomitant use of tinidazole and oxycodone may increase oxycodone plasma concentration and reduce its clearance. Due to the absorption of lidocaine, the following interactions with other drugs may occur: Propranolol: reduced plasma clearance of lidocaine. Cimetidine: reduced plasma clearance of lidocaine. Antiarrhythmics: increased toxicity of lidocaine. Phenytoin or barbiturates: decreased plasma concentration of lidocaine. Additional information regarding special patient groups Interaction studies involving special patient groups have not been conducted. Special precautions for use. For intravaginal use only. Do not swallow or administer elsewhere. As with other drugs of similar structure, tinidazole should not be used in patients with hematopoietic disorders, including in medical history. Transient leukopenia and neutropenia may develop. No persistent hematological abnormalities were observed in preclinical and clinical studies. Patients should abstain from alcohol consumption during treatment and for at least 3 days after completion of therapy due to the increased risk of disulfiram-like reactions. Should not be used in virgins. The drug should be used with caution in patients with cardiovascular disorders. Suppositories should not be used with contraceptive devices – diaphragm and condoms – as the suppository may adversely interact with rubber. Lidocaine may cause cardiac arrhythmias, respiratory depression, coma and even death if applied to large skin surfaces or under occlusion. Other intravaginal products (e.g. tampons, douching or spermicides) should not be used simultaneously with GINOMAX CL. When treating patients with trichomonal vaginitis, simultaneous treatment of the sexual partner is necessary. Use during pregnancy or breastfeeding. Since the effects of the active ingredients of GINOMAX CL on the fetus and newborn are unknown, women using this drug should avoid pregnancy by using effective contraceptive methods. Pregnancy Tinidazole crosses the placental barrier. Data from animal studies on the effects of the drug on pregnancy, embryonal/fetal development, delivery and postnatal development are insufficient. The potential risk for humans is unknown. There is insufficient data on the use of GINOMAX CL during the first trimester of pregnancy. Therefore, the drug is contraindicated in the first trimester of pregnancy. The possibility of prescribing the drug during the second and third trimesters should be evaluated by a physician, considering the benefit-risk ratio. The drug should not be used during pregnancy unless clearly necessary. Period of breastfeeding Breastfeeding should be discontinued during treatment, as the active ingredients of GINOMAX CL pass into breast milk. Breastfeeding may be resumed 72 hours after completion of treatment. Reproductive function / fertility In a 60-day reproductive toxicity study, tinidazole at a dose of 600 mg/kg/day reduced fertility levels and promoted histopathological changes in the testes of male animals. Doses of 300 and 600 mg/kg/day caused spermatogenic effects. The maximum dose of the drug that did not cause observed adverse effects in the testes and sperm was 100 mg/kg/day. These effects are characteristic of 5-nitroimidazole class drugs. In male animals, oral administration of thiocanazole at doses up to 150 mg/kg/day did not show effects on fertility. However, data indicate preimplantation losses in female rats after oral administration of the drug at doses above 35 mg/kg/day. There are no data on harmful effects of lidocaine on fertility in animals or humans. Ability to influence reaction speed when driving or operating machinery. It is unknown whether GINOMAX CL affects the ability to drive or operate machinery. Method of administration and dosage. Do not use without a physician's prescription. Unless otherwise prescribed by a physician, insert 1 suppository deeply into the vagina at bedtime for 3 consecutive days. Do not use twice daily without prescription. Use of GINOMAX CL during menstruation is not recommended due to reduced efficacy and application difficulties. For intravaginal use only. GINOMAX CL should be inserted deeply into the vagina while lying down. Do not swallow or administer elsewhere. Additional information regarding special patient groups Renal/hepatic impairment In patients with severe renal insufficiency (CrCL < 22 mL/min), no significant changes in pharmacokinetic parameters of tinidazole were observed. Therefore, dose adjustment is not required in these patients. Tinidazole clearance is significantly increased during hemodialysis, and the elimination half-life is reduced from 12 hours to 4.9 hours. During a 6-hour dialysis procedure, 43% of available tinidazole was eliminated. If tinidazole is administered before hemodialysis, administration of half the recommended dose after hemodialysis is recommended. There are no data on the pharmacokinetics of tinidazole in patients with hepatic insufficiency. The recommended dose of tinidazole should be administered cautiously in patients with hepatic insufficiency. In patients with hepatic insufficiency, the elimination half-life of lidocaine may be doubled or more. Renal insufficiency does not affect the pharmacokinetics of lidocaine, but may increase metabolite accumulation. These characteristics should be considered in patients with hepatic and/or renal insufficiency receiving GINOMAX XL. Elderly patients Patients over 65 years of age should receive the same dose as adults. Children. Not to be used in children. Overdose. Systemic adverse effects may occur after accidental ingestion of a large amount of the drug, but life-threatening symptoms are not expected with intravaginal administration. There is no specific antidote for tinidazole. In case of overdose, symptomatic and supportive therapy should be initiated. Gastric lavage may be performed. Adverse effects in overdose are unknown. Overdose with topical application of thiocanazole is unlikely due to its low systemic absorption. With topical application of high doses of lidocaine, cardiac arrhythmias, respiratory depression, coma and even death may occur. Adverse reactions. The frequency of the following adverse events is defined according to the following classification: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). GINOMAX CL is well tolerated at the site of application. Adverse reactions typical of systemic administration of the active ingredients of GINOMAX CL are listed below, although they have not been reported during vaginal administration. Since blood concentrations of tinidazole are much lower with intravaginal administration, effects are expected to be less pronounced. Blood and lymphatic system disorders Frequency not known: leukopenia (transient), neutropenia (transient). Immune system disorders Frequency not known: allergic reactions (anaphylactic shock possible in particularly severe cases). Nervous system disorders Common: weakness, increased fatigue, malaise, headache, dizziness. Frequency not known: ataxia, coma (rare), confusion (rare), depression (rare), loss of sensation, lethargy, insomnia, sleep disturbances, anxiety, psychosis, syncope, speech disorders, fear sensations, vertigo, peripheral neuropathy, convulsions, restlessness, disorientation, euphoria, hallucinations, hyperesthesia, hypoesthesia, lethargy. Cardiovascular system disorders Frequency not known: arrhythmia, bradycardia, arterial spasm, cardiovascular collapse, increased defibrillator threshold, edema, hyperemia, heart block, hypotension, sinus node suppression. Gastrointestinal disorders Common: metallic/bitter taste in mouth, nausea, anorexia, loss of appetite, flatulence, dyspepsia, abdominal cramps, epigastric discomfort, vomiting, constipation. Frequency not known: stomach pain, diarrhea, coated tongue, stomatitis, tongue discoloration, dry mouth, pseudomembranous colitis. Skin and subcutaneous tissue disorders Frequency not known: pruritus, urticaria, angioneurotic edema, skin rash. Urinary system disorders Common: dark urine color. General disorders and administration site conditions Frequency not known: burning at site of administration, dysuria, local swelling and irritation, pruritus, vaginal discharge, dyspareunia, nocturia, vaginal pain. Reporting suspected adverse reactions After marketing authorization of a medicinal product, it is very important to report suspected adverse reactions. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any adverse reactions via the national reporting system. In case of adverse events, adverse reactions or lack of therapeutic effect, please report to ZENTIVA UKRAINE LLC, 5I Brovarskyi Avenue, Kyiv, 02002, Ukraine, tel./fax: +38 044 517-75-00, e-mail: [email protected]. Shelf life. 3 years. Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children. Packaging. 3 vaginal suppositories in a strip; 1 strip in a cardboard box. Prescription status. Prescription only. Manufacturer. EXELTIS ILAC SANAYI VE TICARET ANONIM SIRKETI Manufacturer's address and place of business. Cerkezkoy Organized Industrial Zone, Gazi Osmanpasa Mah. Fatih Boulevard No. 19/2, Cerkezkoy, 59500 Tekirdag, Turkey. |
