Metronidazole, miconazole nitrate.
Each vaginal suppository contains: Metronidazole, Ph. Eur 500 mg, Miconazole Nitrate, Ph. Eur 100 mg.
Pharmacology: Pharmacodynamics: Metronidazole + Miconazole nitrate (METINDAZ) contains miconazole nitrate for antifungal and metronidazole for antibacterial and antitrichomonal effects. Miconazole nitrate which is a synthetic imidazole derivative antifungal has a wide spectrum of activity and is particularly effective against pathogen fungi including Candida albicans. In addition, miconazole nitrate is effective against Gram-positive bacteria. Miconazole shows its effect by inhibiting ergosterol synthesis in the cytoplasmic membrane. Miconazole nitrate changes the permeability of the fungal cell of Candida species and inhibits glucose utilization in vitro.
Metronidazole, a 5-nitroimidazole derivative is an antiprotozoal and an antibacterial agent and is effective against several infections caused by anaerobic bacteria and protozoa, such as Trichomonas vaginalis, Gardnerella vaginalis and anaerobic bacteria including anaerobic streptococci.
Pharmacokinetics: Absorption: Metronidazole: Bioavailability of metronidazole by this route is 20% compared to the oral route. Steady state levels of metronidazole in plasma ranged from 1.1 to 5.0 μg/mL after daily intravaginal application of Metronidazole + Miconazole nitrate (METINDAZ).
Miconazole nitrate: Absorption of miconazole nitrate by the intravaginal route is very low (approximately 1.4% of dose). Following intravaginal application of Metronidazole + Miconazole nitrate (METINDAZ), miconazole nitrate was not detected in plasma.
Distribution: Metronidazole: It is widely distributed in body tissues and fluids including bile, bone, breastmilk, cerebral abscesses, cerebrospinal fluid, liver and liver abscesses, saliva, seminal fluids and vaginal secretion, and achieves concentrations similar to those in plasma. It crosses the placenta and rapidly enters the fetal circulation. No more than 20% is bound to plasma proteins. Distribution volume is 0.25-0.85 L/kg.
Miconazole nitrate: The protein binding is 90%-93%. Its distribution to cerebrospinal fluid is poor; however, it is widely distributed to other tissues. Distribution volume is 1400 L.
Biotransformation: Metronidazole: It is metabolized in the liver by oxidation. The hydroxy metabolite is active. Major metabolites of metronidazole, hydroxy and acetic acid metabolites, are excreted in urine. The hydroxy metabolite has a 30% of biological activity of metronidazole.
Miconazole nitrate: It is metabolized in liver. Two non-active metabolites are found (2,4-dichlorophenyl-1 H imidazole ethanol and 2,4-dichloromandelic acid).
Elimination: Metronidazole: Half-life is equal to 6-11 hours. About 6%-15% of metronidazole dose is excreted with faeces, 60%-80% is unchanged and excreted in urine as its metabolites. Approximately 20% of metronidazole is excreted in the urine as unchanged drug.
Miconazole nitrate: Half-life is equal to 24 hours. Less than 1% is excreted in the urine. Approximately 50%, usually unchanged, is excreted by feces.
Metronidazole + Miconazole nitrate (METINDAZ) is used in the treatment of candidal vulvovaginitis due to Candida albicans, in bacterial vaginosis due to anaerobic bacteria and Gardnerella vaginalis, in trichomonal vaginitis due to Trichomonas vaginalis and in mixed vaginal infections.
Vaginally, 1 vaginal suppository is administered at night and in the morning, in a supine position, for 7 days.
In case of recurrent vaginitis or vaginitis resistant to treatment, 1 vaginal suppository is administered once daily, in the evening, for 14 days. Or as prescribed by the physician.
Only for vaginal use. Metronidazole + Miconazole nitrate (METINDAZ) should be applied in a supine position. Insert the vaginal suppository in the vagina using disposable finger stalls provided in the package.
Not to be swallowed or applied by other routes.
For vaginal use only.
Additional Information on Special Populations: Renal/Liver failure: In renal failure, the half-life of metronidazole is not changed. Therefore, dose reduction is not necessary, but in serious impaired renal function in which hemodialysis is required, dose adjustment should be done.
In serious liver function failures, metronidazole clearance may be impaired. Metronidazole may increase encephalopathy symptoms due to increased plasma levels and therefore should be used carefully in hepatic encephalopathy patients. The daily dose of metronidazole must be reduced to 1/3 in patients with hepatic encephalopathy.
Pediatric population: Not to be used in children under 18 years of age.
Geriatric population: Same dose as for adults is administered in elderly over 65 years.
Or as prescribed by the physician.
No cases of overdose are known with the medicinal product Metronidazole + Miconazole nitrate (METINDAZ).
When excessive amount of ovule is applied, systemic effects may occur due to metronidazole, but intravaginal metronidazole is not expected to cause life-threatening symptoms.
Symptomatic and supportive treatment should be instituted. There is no specific antidote for metronidazole. Cure can be provided in individuals who ingested a dose of 12 g of metronidazole.
Symptoms of metronidazole overdose are nausea, vomiting, abdominal pain, diarrhea, itching, metallic taste, ataxia, dizziness, paresthesia, convulsion, leucopoenia, darkening of urine. Symptoms of miconazole nitrate overdose are sore mouth and throat, anorexia, nausea, vomiting, headache, diarrhea.
Metronidazole + Miconazole nitrate (METINDAZ) should not be used in the following situations: Hypersensitivity to other medicinal product's components (including other nitroimidazole derivatives).
Epilepsy.
Porphyria.
Severe liver function impairment.
1st trimester of pregnancy.
Breastfeeding period.
Age under 18 years (virgins).
Metronidazole + Miconazole nitrate (METINDAZ) should be used cautiously in patients with alteration of hematopoietic function, with central and peripheral nervous system disorders.
It is recommended to avoid sexual contacts during the treatment. Administration of the suppositories can reduce the efficacy of local contraception (preservatives, vaginal diaphragms) due to interactions of the suppository base with the latex.
As a prophylaxis for reinfection, simultaneous treatment of sexual partner is recommended and in the case of trichomonadal vaginitis - administration of systemic medicinal products, for example, metronidazole orally.
Patients should be advised not to take alcohol during the therapy and for 3 days after the end of the treatment, because of the possibility of a disulfiram-like reaction.
During the treatment, there may be a change in the values of transaminases and glycemia.
Effects on Ability to Drive and Use Machines: Systemic administration of metronidazole may affect driving and using machines. In comparison with systemic use, topical metronidazole is absorbed in vagina in low concentrations.
Metronidazole + Miconazole nitrate (METINDAZ) may cause dizziness, ataxia, fatigue and weakness, therefore may affect driving or operating machinery.
General advice: Pregnancy category is C.
Women of Childbearing Potential/Birth Control (Contraception): Since the effects of active ingredients in Metronidazole + Miconazole nitrate (METINDAZ) for fetus and newborn growth are not clearly known, women who must use this product should avoid pregnancy with a proper birth control method.
Pregnancy: The medicinal product is contraindicated in the first trimester of pregnancy. In the second and third trimester of pregnancy, the use of the medicinal product may be possible only when the benefits for the mother are greater than the possible risks for the baby.
Lactation: Breastfeeding should be discontinued since metronidazole appears in milk. Breastfeeding can be started again 24-48 hours after the end of treatment.
If the use of the medicinal product is mandatory during the breastfeeding period, the breastfeeding needs to be interrupted, being reinitiated 24-48 hours after the treatment.
Reproduction/Fertility: There is no evidence regarding hazardous effect on human and animal fertility when metronidazole or miconazole nitrate is administered alone.
Disorders of Gastrointestinal Tract: pain or abdominal spasms, metallic taste, xerostomia, constipation, diarrhea, loss of appetite, nausea, vomiting.
Disorders of the Nervous System: headache, motor abnormalities (ataxia), vertigo, psycho-emotional disorders, peripheral neuropathy (on long-term use), cramps.
Disorders of Hematopoietic System: leucopenia.
Disorders of Urogenital System: dark-brown coloration of urine, due to the presence of hydrosoluble pigment resulting from metronidazole metabolism.
Allergic Reactions: urticaria, prurigo of teguments, eruption.
Local Reactions: itching, burning, pain and irritation of vaginal mucosa, especially at the initiation of the treatment, which do not require the interruption of the treatment and is determined by the influence of the medicinal product on inflamed vaginal mucosa. If severe irritation occur, treatment should be discontinued.
Due to metronidazole absorption, the following interactions can be seen if used concomitantly with the drugs as follows: Alcohol: Alcohol intolerance (disulfiram - like reaction).
Amiodarone: Increase in risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest).
Astemizole and terfenadine: Metronidazole inhibits the metabolism of these drugs and increases their plasma concentrations.
Disulfiram: Central nervous system related effects (e.g. psychotic reactions).
Phenytoin: Increase in blood levels of phenytoin, decrease in blood levels of metronidazole.
Phenobarbital: Decrease in blood levels of metronidazole.
Fluorouracil: Increase in blood levels and toxicity of fluorouracil.
Carbamazepine: Increase in blood concentration of carbamazepine.
Lithium: Increase in blood levels and lithium toxicity.
Oral anticoagulants: Increase in anticoagulant effect.
Cyclosporine: Increase in cyclosporine toxicity risk.
Cimetidine: Increase in blood levels of metronidazole and the risk of neurologic side effects.
Interference with blood levels of liver enzymes, glucose (hexokinase method), theophylline and procainamide have been observed during the treatment with metronidazole.
Due to miconazole nitrate absorption, the following interactions can be seen if used concomitantly with the drugs as follows: Acenocoumarol, Anisindione, Dicumarol, Phenindione, Phenprocoumon, Warfarin: Increase in bleeding risk.
Astemizole, Cisapride and terfenadine: Miconazole inhibits the metabolism of these drugs and increases their plasma concentrations.
Phenytoin and Fosphenytoin: Increase in phenytoin toxicity risk (ataxy, hyperlexia, nystagmus, tremor).
Fentanyl: Increased or prolonged effects of opioid (CNS depression, respiratory depression).
Glimepiride: Increase of hypoglycemic action.
Carbamazepine: Decrease in carbamazepine metabolism.
Oxybutinin: Increase in plasma concentration or exposure to oxybutinin.
Oxycodone: Increase in oxycodone plasma concentration and reduction in clearance.
Pimozide: Increase in cardiotoxicity risk (QT prolongation, torsades de pointes, cardiac arrest).
Cyclosporine: Increase in cyclosporine risk toxicity (renal dysfunction, cholestasis, parasthesias).
Tolterodine: Increase in tolterodine bioavailability in individuals with deficient cytochrome P450 2D6 activity.
Trimetrexate: Increase in trimetrexate toxicity (bone marrow suppression, renal and hepatic dysfunction and gastrointestinal ulceration).
Additional information on special populations: No interaction study has been conducted on special populations.
Pediatric population: No interaction study has been conducted on children.
Special Precautions for Disposal: Empty blisters may be disposed of in household waste. Return unused drug to the pharmacy for disposal. Do not dispose of unused drug in household waste or flush it down the toilet.
Store at temperatures not exceeding 30 °C. Do not freeze.
Store in original package to protect from light and moisture.
G01AF20 - combinations of imidazole derivatives ; Belongs to the class of imidazole derivative antiinfectives. Used in the treatment of gynecological infections.
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