Neo-penotran® forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NEО-PENOTRAN® FORTE (NEO-PENOTRAN® FORTE)

Composition:

Active substances: metronidazole and miconazole nitrate;

1 suppository contains 750 mg of metronidazole and 200 mg of miconazole nitrate;

Excipient: Witepsol.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical characteristics: suppositories in the form of a flat body, white to yellowish in color.

Pharmacotherapeutic group. Antimicrobial, antiprotozoal, antifungal agents.

ATC code G01AF20.

Pharmacological Properties

Pharmacodynamics

Neo-Penotran® Forte contains miconazole nitrate with antifungal activity, and metronidazole with antibacterial and antitrichomonal activity. Miconazole nitrate, an antifungal agent and synthetic derivative of imidazole, has a broad spectrum of activity and is particularly effective against pathogenic fungi, including Candida albicans. In addition, miconazole nitrate is effective against Gram-positive bacteria. Miconazole exerts its action by inhibiting the synthesis of ergosterol in the fungal cytoplasmic membrane. Miconazole nitrate alters the permeability of Candida fungal cells and inhibits glucose utilization in vitro.

Metronidazole, a 5-nitroimidazole derivative, is an antiprotozoal and antibacterial agent; it 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 exhibit synergistic or antagonistic effects.

The clinical cure rates achieved in an open, multicenter, uncontrolled clinical study evaluating the efficacy and safety of Neo-Penotran® Forte in 104 patients with clinical/microbiological diagnosis of vaginitis treated for 7 days were 96.6% for candidal vulvovaginitis, 98.1% for bacterial vaginosis, 97.3% for trichomonal vaginitis, and 98.5% for mixed vaginal infections. The microbiological cure rates were 89.8%, 96.2%, 100%, and 91.7%, respectively, for each type of infection.

In a randomized, open, comparative study of efficacy, safety, and tolerability of Neo-Penotran® Forte, the clinical and microbiological cure rates were 84% and 76%, respectively.

Pharmacokinetics

Absorption.

Miconazole nitrate: Absorption of miconazole nitrate after intravaginal administration is very low (approximately 1.4% of the dose). After intravaginal administration of Neo-Penotran® Forte, miconazole nitrate was not detectable in plasma.

Metronidazole: The bioavailability of metronidazole via this route of administration is 20% compared to oral administration. Steady-state plasma levels of metronidazole ranged from 1.1 to 5 µg/mL after daily intravaginal administration of Neo-Penotran® Forte.

Distribution.

Miconazole nitrate: Plasma protein binding is 90–93%. Penetration into cerebrospinal fluid is low, but it is widely distributed in other tissues. The volume of distribution is 1400 L.

Metronidazole: Penetrates into tissues and body fluids, including bile, bones, mammary glands, breast milk, cerebral abscesses, cerebrospinal fluid, liver and hepatic abscesses, saliva, seminal fluid, and vaginal secretions, reaching concentrations similar to those in plasma. It crosses the placental barrier and rapidly enters the fetal circulation. Plasma protein binding is no more than 20%. The volume of distribution is 0.25–0.85 L/kg.

Biotransformation.

Miconazole nitrate: Metabolized in the liver. Two inactive metabolites are identified: 2,4-dichlorophenyl-1H-imidazole ethanol and 2,4-dichloromandelic acid.

Metronidazole: Metabolized in the liver via oxidation; the hydroxyl metabolite is active. The main metabolites of metronidazole, hydroxyl and acetic acid metabolites, are excreted in urine. The hydroxyl metabolite has 30% of the biological activity of metronidazole.

Elimination.

Miconazole nitrate: The elimination half-life is 24 hours. Less than 1% is excreted in urine. Approximately 50% is excreted in feces, usually in unchanged form.

Metronidazole: The elimination half-life is 6–11 hours. Approximately 6–15% of the metronidazole dose is excreted in feces, 60–80% is excreted unchanged in urine, along with its metabolites. Approximately 20% of metronidazole is excreted in urine as unchanged drug.

Preclinical data.

Results of standard preclinical studies on repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk for humans.

In vitro microbiological testing did not reveal synergistic or antagonistic interaction between the active substances of the drug against Candida albicans, Streptococcus (Gram B by Lancefield), Gardnerella vaginalis, and Trichomonas vaginalis.

Preclinical studies of the combination of 750 mg metronidazole and 200 mg miconazole nitrate showed no enhancement or synergy of lethal or toxic effects of either component in female rats.

In an irritation study of the vaginal mucosa in female Beagle dogs using the same drug combination, no vaginal mucosal irritation was observed, and no clinical, biochemical, or hematological disturbances were detected. No local or systemic toxic effects were observed in this study.

Clinical characteristics.

Indications.

For the treatment of candidal vulvovaginitis caused by Candida albicans, bacterial vaginosis caused by anaerobic bacteria and Gardnerella vaginalis, trichomonal vaginitis caused by Trichomonas vaginalis, and mixed vaginal infections.

Contraindications.

• Hypersensitivity to any of the active substances of the drug or to their derivatives.
• Consumption of alcoholic beverages during treatment or within 3 days after completion of treatment.
• Use of disulfiram during treatment or within 2 weeks after treatment.
• Porphyria.
• Epilepsy.
• Severe impairment of liver function.

Interaction with other medicinal products and other forms of interaction.

Due to the absorption of metronidazole, drug interaction reactions may occur when used concomitantly with certain substances and medicinal products:

Alcohol: interaction between metronidazole and alcohol may cause a reaction similar to that of disulfiram. Alcohol must not be consumed during therapy and for 3 days after completion of the course;

Amiodarone: increased risk of cardiotoxicity (QT interval prolongation, ventricular fibrillation, cardiac arrest);

Astemizole and terfenadine: metronidazole inhibits the metabolism of these drugs and increases their plasma concentration;

Carbamazepine: increased blood concentration of carbamazepine;

Cimetidine: increased blood level of metronidazole and risk of neurological adverse effects;

Cyclosporine: increased risk of cyclosporine toxicity;

Disulfiram: central nervous system effects (e.g., psychotic reactions);

Lithium: increased blood level and lithium toxicity;

Phenytoin: increased blood level of phenytoin, decreased blood level of metronidazole;

Phenobarbital: decreased blood level of metronidazole;

Fluorouracil: increased blood level and fluorouracil toxicity;

Oral anticoagulants: enhanced anticoagulant effect.

During metronidazole treatment, effects on blood levels of liver enzymes, glucose (hexokinase method), theophylline, and procainamide have been observed.

Due to specific absorption characteristics of miconazole nitrate, the following reactions may occur when the following medicinal products are used concomitantly:

Acenocoumarol, anisindione, dicumarol, phenidione, phenprocoumon, warfarin: increased risk of bleeding;

Astemizole, cisapride, and terfenadine: miconazole inhibits the metabolism of these drugs and increases their plasma concentration;

Carbamazepine: decreased metabolism of carbamazepine;

Cyclosporine: increased risk of cyclosporine toxicity (renal dysfunction, cholestasis, paresthesia);

Fentanyl: increased or prolonged opioid effect (central nervous system depression, sedation, respiratory depression);

Phenytoin and fosphenytoin: increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor);

Glimepiride: enhanced hypoglycemic effect;

Oxybutynin: increased plasma concentration or effect of oxybutynin;

Oxycodone: increased plasma concentration of oxycodone and reduced elimination;

Pimozide: increased risk of cardiotoxicity (QT interval prolongation, ventricular fibrillation, cardiac arrest);

Solifenacin: increased bioavailability of solifenacin in individuals with impaired cytochrome P450 2D6 activity;

Trimethoprim-sulfamethoxazole: increased trimethoprim-sulfamethoxazole toxicity (bone marrow suppression, renal and hepatic dysfunction, and ulcer formation in the stomach and intestine).

Special precautions for use

Patients should be warned not to consume alcohol during therapy and for 3 days after completion of the treatment course due to the possibility of central nervous system reactions similar to those caused by disulfiram.

High doses and prolonged use of the drug may cause peripheral neuropathy and seizures.

The suppository base may adversely interact with rubber or latex, from which contraceptive diaphragms and condoms are made; therefore, their simultaneous use with suppositories is not recommended.

Sexual partners of patients with trichomoniasial vaginitis should also undergo treatment.

In patients with renal impairment, the dose of metronidazole should be reduced.

In severe hepatic insufficiency, metronidazole clearance may be altered. Metronidazole may worsen symptoms of encephalopathy due to its increased plasma levels. Therefore, metronidazole should be used with caution in patients with hepatic encephalopathy. The daily dose for such patients should be reduced to one-third of the standard dose.

For elderly patients (aged 65 years and older): the same recommendations apply as for other patients.

The drug is not recommended for use in virgins.

Suppositories must not be swallowed or administered by any other route.

Metronidazole may increase plasma levels of busulfan, potentially leading to significant busulfan toxicity. Prothrombin time and INR (international normalized ratio) should be monitored more frequently when oral anticoagulants are used concomitantly with metronidazole, both during treatment and for 8 days after discontinuation.

Suppositories should not be used with contraceptive diaphragms and condoms, as the suppository base may adversely interact with rubber.

Other intravaginal products (e.g., tampons, douching, or spermicides) should not be used simultaneously with this treatment.

Sexual partners in whom Trichomonas vaginalis has been identified should undergo treatment concurrently with the patient.

Use during pregnancy or breastfeeding

Pregnancy category C.

Since the effects of the active ingredients of NEО-PENOTRAN® FORTE on the fetus and neonatal development have not been fully studied, women who need to use this drug should avoid pregnancy using an effective contraceptive method.

Data from preclinical animal studies regarding pregnancy, embryonic development, fetal development, perinatal and/or postnatal development are insufficient. The potential risk to humans is unknown.

NEO-PENOTRAN® FORTE should not be used during the first trimester of pregnancy. In the second and third trimesters, the drug may be used only if necessary, when the physician determines that the benefit outweighs the potential risk.

There is no evidence of harmful effects on fertility in humans or animals with administration of metronidazole or miconazole nitrate alone.

Breastfeeding should be discontinued during treatment with NEO-PENOTRAN® FORTE, as metronidazole, one of the active components, is excreted in breast milk. Breastfeeding may be resumed 1–2 days after completion of treatment.

Ability to affect reaction rate when driving or operating machinery

Systemic administration of metronidazole may affect the ability to drive or operate machinery. Compared to systemic administration, vaginal administration results in significantly lower absorption of metronidazole. However, dizziness, ataxia, and psychoemotional disturbances may occur. If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage

One vaginal suppository should be inserted deeply into the vagina at night for 7 days.

In cases of recurrent infections or vaginitis resistant to other treatments, the drug Neo-Penotran® Forte should be used for 14 days.

Neo-Penotran® Forte is not recommended during menstruation due to reduced drug efficacy and possible complications associated with insertion.

Children.

The drug is not recommended for use in children.

Overdose.

There are no data on metronidazole overdose following vaginal administration. However, when administered vaginally, metronidazole may be absorbed in amounts sufficient to cause systemic effects.

If a large amount of the drug is accidentally ingested, appropriate gastric lavage should be considered if necessary. Treatment should be considered when 12 g of metronidazole have been ingested. There is no specific antidote; symptomatic treatment is recommended. Symptoms observed in metronidazole overdose include: nausea, vomiting, abdominal pain, diarrhea, itching, metallic taste in the mouth, ataxia, vertigo, paresthesia, seizures, leukopenia, and darkening of urine.

In overdose of miconazole nitrate, the following symptoms may occur: nausea, vomiting, inflammation of the throat and oral cavity, anorexia, headache, diarrhea.

Side effects.

The frequency of the adverse reactions listed below is defined as follows:

Very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1000); very rare (<1/10,000); unknown (cannot be estimated from available data).

In individual cases, the following adverse effects may occur: hypersensitivity reactions (including skin rash), abdominal pain, headache, itching, burning, and irritation of the vagina. The incidence of systemic adverse effects is very low due to the very low plasma levels of metronidazole achieved after vaginal administration of the drug (2–12% of the levels reached with oral metronidazole). The other active ingredient of the drug, miconazole nitrate, may cause vaginal irritation (burning, itching), as may all other imidazole-derived antifungal agents administered vaginally (2–6%). In case of severe irritation, treatment should be discontinued.

Adverse effects due to systemic action of the active ingredients of Neo-Penotran® Forte are listed below.

Blood and lymphatic system disorders:

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia
Unknown: leukopenia

Immune system disorders:

Rare: anaphylactic shock
Unknown: hypersensitivity reactions, allergic reactions, angioneurotic edema, urticaria, fever

Metabolism and nutritional disorders:
Unknown: anorexia

Psychiatric disorders:

Very rare: disturbances of consciousness, including confusion and hallucinations
Unknown: depression

Nervous system disorders:

Common: dizziness, headache
Very rare: encephalopathy (e.g. confusion, fever, photophobia, torticollis, hallucinations, paralysis, visual and motor disturbances) and subacute cerebellar syndrome (e.g. ataxia, dysarthria, gait disturbances, nystagmus, tremor), which may resolve after discontinuation of the drug
Unknown: increased fatigue or weakness, seizures, peripheral neuropathy due to intensive and/or prolonged metronidazole therapy, aseptic meningitis

Eye disorders:

Very rare: transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color perception
Unknown: optic neuropathy/neuritis

Hepatobiliary disorders:

Very rare: increased levels of liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, hepatocellular damage (hepatocytes), sometimes with jaundice; cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole and other antibiotics

Skin and subcutaneous tissue disorders:

Very rare: skin rashes, pustular rashes, flushing with hyperemia, pruritus
Unknown: polymorphic erythema, Stevens-Johnson syndrome, or toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders:

Very rare: myalgia, arthralgia

Renal and urinary disorders:
Very rare: darkening of urine (due to metronidazole metabolism)

Gastrointestinal disorders:

Unknown: taste disturbances, inflammation of the oral mucosa, metallic taste, coated tongue, nausea, vomiting, constipation, gastrointestinal disorders such as epigastric pain and diarrhea, dry mouth, decreased appetite, abdominal pain and cramps

General disorders and administration site conditions:

Very common: vaginal discharge
Common: vaginitis, vulvovaginal irritation, pelvic discomfort
Uncommon: sensation of thirst
Rare: burning in the vagina, itching, irritation, stomach pain, rash
Unknown: local irritation and hypersensitivity, contact dermatitis

The above-mentioned side effects are rarely observed, as the concentration of metronidazole in the blood after intravaginal administration is low.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25°C, in places inaccessible to children. The product may be stored in the refrigerator at 2–8°C. Do not freeze.

Packaging.

One package contains 7 vaginal suppositories.

Prescription category.

Prescription only.

Manufacturer.

Embil Pharmaceutical Co. Ltd

Manufacturer's address and place of business.

Tekirdag province, Cerkezkoy district, Cerkezkoy Organize Sanayi Bolgesi, Gaziosmanpasa Mah., Fatih Bulvari, № 19/2, Turkey