Neo-Penotran Forte

Slightly white or yellowish, ellipsoid pessary.
1 vaginal ovule contains Metronidazole 750 mg, Miconazole nitrate 200 mg.
Excipients/Inactive Ingredients: Hard Fat (Witepsol S55).

Pharmacotherapeutic Group: Antibacterial, antiprotozoal, antifungal. ATC Code: G01AF20.
Pharmacology: Pharmacodynamics: NEO-PENOTRAN FORTE PESSARY 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 ergosterol synthesis in the cytoplasmic membrane. Miconazole nitrate changes permeability of the mycotic 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.
Miconazole nitrate and metronidazole do not have synergic or antagonistic effects.
The clinical cure rates achieved in an open, multicentre, uncontrolled clinical study to assess the efficacy and safety of NEO-PENOTRAN FORTE PESSARY for 7 days in 104 patients with clinical/microbiological diagnosis of vaginitis are 96.6% candidal vulvovaginitis, 98.1% for bacterial vaginosis, 97.3% for trichomonal vaginitis and 98% for mixed vaginal infections. Microbiological cure rates are 89.8%, 96.2%, 100%, 91.7% for each infection respectively.
In a randomized, open, comparative study with NEO-PENOTRAN FORTE PESSARY to assess the efficacy, safety and tolerability, clinical and microbiological cure rates are found to be 84% and 76%, respectively.
Pharmacokinetics: General Properties: Absorption: Miconazole nitrate: Absorption of miconazole nitrate by the intravaginal route is very low (approximately 1.4% of dose). Following intravaginal application of NEO-PENOTRAN FORTE PESSARY, miconazole nitrate was not detected in plasma.
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 NEO-PENOTRAN FORTE PESSARY.
Distribution: 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.
Metronidazole: It is widely distributed in body tissues and fluids including bile, bone, breast, milk, 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 to fetal circulation. No more than 20% is bound to plasma proteins. Distribution volume is 0.25-0.85 L/kg.
Biotransformation: 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).
Metronidazole: It is metabolized in the liver by oxidation, 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.
Elimination: Miconazole nitrate: Half-life is 24 hours. Less than 1% is excreted in the urine. Approximately 50%, usually unchanged, excreted by feces.
Metronidazole: Half-life is 6-11 hours. About 6%-15% of metronidazole dose is excreted with feces, 60%-80% is unchanged and excreted in urine as its metabolites. Approximately 20% of metronidazole is excreted in the urine as unchanged drug.
Toxicology: Preclinical safety data: Preclinical data pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, reproduction toxicity studies reveal no special hazard for humans.
In microbiological in vitro study, there is no synergic or antagonistic interactions against Candida albicans, Streptococcus (Gram B of Lancefield), Gardnerella vaginalis and Trichomonas vaginalis between active substances of the combination.
A preclinical study carried out with the combination of 750 mg metronidazole and 200 mg miconazole nitrate indicated no potentiation or synergism with regards to lethal or toxic effects of the ingredients in female rats.
In a vaginal mucous irritation study in female Beagle dogs with the same combination, it was concluded that it does not cause vaginal mucous irritation as well as nor clinical, biochemical and haematological alterations. In the same study, local and systemic toxic effects are not detected.

It is used in the treatment of candidal vulvovaginitis due to Candida albicans, in bacterial vaginosis, in trichomonal vaginitis due to Trichomonas vaginalis and in mixed vaginal infections.

Posology/Frequency and duration of administration: One ovule should be inserted high into the vagina at night for 7 days.
In recurrent cases, application of one ovule at night for 14 days is recommended.
It is not recommended that the administration of NEO-PENOTRAN FORTE PESSARY in the menstrual period because of the impaired efficacy of the product or facing some difficulties during administration.
Method of Administration: Only for intravaginal use. NEO-PENOTRAN FORTE PESSARY should be applied in lying position, high into the vagina using.
Not to be swallowed or applied by other routes.
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 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.
Paediatric population: Not to be used in children under 18.
Geriatric population: No data.

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, leukopenia, darkening of urine; symptoms of miconazole nitrate overdose are sore mouth and throat, anorexia, nausea, vomiting, headache, diarrhea.

NEO-PENOTRAN FORTE PESSARY should not be used: In patients known to be hypersensitive to the active ingredients or their derivatives; In patients using alcohol during the treatment or within 3 days after the treatment; In patients using disulfiram during the treatment or within 2 weeks; During the first trimester of pregnancy; In pregnant women who have trichomanal vaginitis in the first trimester; In cases of porphyria, epilepsy, serious liver function disorders.

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.
High doses and long term metronidazole may cause peripheral neuropathy and convulsion due to systemic usage.
Should not be used in virgins and in young people (girls) who are not sexually mature.
The ovules must not be used with contraceptive diaphragms and preservatives since the ovule base may react with the rubber.
Other vaginal products (e.g. tampon, douche or spermicide) should not be used concurrently during the treatment.
Sexual partners with Trichomonas vaginalis should be treated at the same time.
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.
NEO-PENOTRAN FORTE PESSARY may cause dizziness, ataxia, fatigue and weakness, therefore may affect driving or operating machinery.

General Advice: Pregnancy category is C.
Women of child bearing potential/Birth Control (Contraception): Since the effects of active ingredients in NEO-PENOTRAN FORTE PESSARY 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: Preclinical studies on animals regarding the pregnancy, embryonal/fetal growth, perinatal and/or postnatal growth are insufficient. Potential risk for human is not known.
There is insufficient data regarding the use of NEO-PENOTRAN FORTE PESSARY in the first trimester of pregnancy. Therefore, NEO-PENOTRAN FORTE PESSARY should not be used in the first trimester of pregnancy. In the second and third trimesters, benefit/risk ratio should be evaluated by a physician, should not be used unless it is necessary.
Lactation: Breastfeeding should be discontinued, since metronidazole appears in milk. Breastfeeding can be started again 24-48 hours after the end of treatment.
Reproduction/Fertility: There is no evidence regarding hazardous effect on human and animal fertility when metronidazole or miconazole nitrate is administered alone.

The frequency of adverse events listed as follows is defined using the following convention: 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), not known (cannot be estimated from the available data).
The frequency of systemic side/adverse effects is very rare since after intravaginal administration of metronidazole, very low plasma levels are observed (2%-12% compared to oral route). Miconazole nitrate can cause vaginal irritation (burning, itching) as all other imidazole derivative antifungal drugs applied intravaginally (2-6%). In vaginitis, vaginal mucosa could be inflamed, therefore vaginal burning and itching may be seen after the first ovule is applied or toward to the third day of the treatment. These symptoms are fastly reduced while the treatment continues. If there is a severe irritation symptoms, the treatment should be stopped.
Undesirable effects regarding systemic use of active substances of NEO-PENOTRAN FORTE PESSARY are listed as follows: Blood and lymphatic system disorders: Not known: Leukopenia.
Immune system disorders: Not known: Hypersensitivity reactions, allergic reactions (anaphylaxis may occur in severe cases).
Psychiatric disorders: Uncommon: Depression.
Very rare: Mental alterations.
Nervous system disorders: Common: Dizziness, headache.
Not known: Tiredness or weakness, ataxia, convulsion, peripheral neuropathy due to intensive and/or prolonged metronidazole therapy.
Gastrointestinal disorders: Not known: Taste changes, metallic taste, nausea, vomiting, constipation, dry mouth, diarrhea, lack of appetite, abdominal pain or cramp.
General disorders and administration site conditions: Very common: Vaginal discharge.
Common: Vaginitis, vulvovaginal irritation, pelvic discomfort.
Uncommon: Feeling of thirst.
Rare: Vaginal burning, itching, irritation, stomachache, rash.
Not known: Local irritation and hypersensitivity, contact dermatitis.
These adverse effects are observed rarely since blood concentration of metronidazole is much lower when administered via intravaginal route.

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.
Carbamazepine: Increase in blood concentration of carbamazepine.
Cimetidine: Increase in blood levels of metronidazole and the risk of neurologic side effects.
Cyclosporine: Increase in cyclosporine toxicity risk.
Disulfiram: Central nervous system related effects (e.g. psychotic reactions).
Lithium: Increase in blood levels and lithium toxicity.
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.
Oral anticoagulants: Increase in anticoagulant effect.
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.
Carbamazepine: Decrease in carbamazepine metabolism.
Cyclosporine: Increase in cyclosporine risk toxicity (renal dysfunction, cholestasis, paresthesias).
Fentanyl: Increase or prolonged effects of opioid (CNS depression, respiratory depression).
Phenytoin and Fosphenytoin: Increase in phenytoin toxicity risk (ataxy, hyperlexia, nystagmus, tremor).
Glimepiride: Increase of hypoglycemic action.
Oxybutynin: Increase in plasma concentration or exposure to oxybutynin.
Oxycodone: Increase in oxycodone plasma concentration and reduction in clearance.
Pimozide: Increase in cardiotoxicity risk (QT prolongation, torsades de pointes, cardiac arrest).
Tolterodine: Increase in tolterodine bioavalaibility in individuals with deficient cyctocrome 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.
Paediatric population: No interaction study has been conducted on children.

Incompatibilities: There is not any known incompatibility.

Store at room temperature below 30°C.
Shelf life: 36 months.

Preparations for Vaginal Conditions

G01AF20 - combinations of imidazole derivatives ; Belongs to the class of imidazole derivative antiinfectives. Used in the treatment of gynecological infections.

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