Hainex® forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GYNEX® FORTE (GYNEX® FORTE)

Composition:

Active substances: metronidazole, miconazole nitrate;

1 suppository contains metronidazole 750 mg, miconazole nitrate 200 mg;

Excipient: hard fat.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical properties: suppositories from white to light yellow color, torpedo-shaped.

Pharmacotherapeutic group. Antimicrobial, antiprotozoal, antifungal agents.

ATC code G01AF20.

Pharmacological Properties

Pharmacodynamics

Gyneex® Forte is a combined antimicrobial agent, the action of which is due to metronidazole and miconazole contained in its composition.

Miconazole nitrate is a topical broad-spectrum antifungal and antibacterial agent of the imidazole group. Miconazole inhibits ergosterol biosynthesis and alters the lipid composition of the cell membrane, leading to fungal cell death. It exerts a fungicidal effect against dermatophytes (Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, Microsporum canis), yeasts and yeast-like fungi (Candida albicans, Candida glabrata, and other Candida species), as well as other pathogenic fungi (Malassezia furfur, Aspergillus niger, Penicillium crustaceum). Miconazole nitrate also exhibits antibacterial activity, particularly pronounced against gram-positive bacteria.

Metronidazole, a 5-nitroimidazole derivative, is an antibacterial and antiprotozoal agent. It is effective against infections caused by anaerobic bacteria and protozoa, including Trichomonas vaginalis, Gardnerella vaginalis, and anaerobic streptococci.

Miconazole nitrate and metronidazole do not exhibit synergistic or antagonistic effects.

In an open, multicenter, uncontrolled clinical study evaluating the efficacy and safety of suppositories containing metronidazole and miconazole, the clinical cure rates after 7 days of treatment in 104 patients with clinical/microbiological diagnosis of vaginitis 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 assessing the efficacy, safety, and tolerability of metronidazole and miconazole suppositories, the clinical and microbiological cure rates were 84% and 76%, respectively.

Pharmacokinetics

Absorption

Miconazole nitrate. Absorption of miconazole nitrate through the vaginal walls is minimal (approximately 1.4% of the dose). Miconazole nitrate is not detectable in blood plasma following intravaginal administration.

Metronidazole

The bioavailability of metronidazole following intravaginal administration is 20% compared to its oral bioavailability. The steady-state concentration of metronidazole in blood plasma ranges from 1.6 to 7.2 μg/mL after intravaginal administration of the daily dose of Gyneex® Forte.

Distribution

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

Metronidazole. It penetrates into tissues and body fluids, including bile, bones, milk, cerebral abscesses, cerebrospinal fluid, liver and hepatic abscesses, saliva, seminal fluid, and vaginal secretions, reaching concentrations similar to those in blood plasma. It crosses the placental barrier and rapidly penetrates into the fetal circulation. Plasma protein binding is less than 20%. The volume of distribution is 0.25–0.85 L/kg.

Metabolism

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

Metronidazole. It is metabolized in the liver via oxidation; the hydroxy metabolite is active. The main metabolites of metronidazole—hydroxy derivatives and acetic acid derivatives—are excreted in urine. The hydroxymetabolite exhibits 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%, mainly in unchanged form, is excreted in feces.

Metronidazole. The elimination half-life is 6–11 hours. Approximately 6–15% of the metronidazole dose is excreted in feces. About 60–80% of metronidazole is excreted in urine, both unchanged and as metabolites. Approximately 20% of metronidazole is excreted in urine unchanged.

Preclinical data

Results from standard preclinical studies on repeat-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk to humans.

In an in vitro microbiological study, no synergistic or antagonistic interaction between the active ingredients of the drug was observed against Candida albicans, Streptococcus (gram-positive Lancefield group), 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 a vaginal mucosa irritation study in female beagle dogs using the same drug combination, no irritation of the vaginal mucosa was observed, and no clinical, biochemical, or hematological abnormalities 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 medicinal product or to their derivatives.

− Consumption of alcoholic beverages during treatment or within 3 days after completion of treatment.

− Intake of disulfiram during treatment or within 2 weeks after completion of treatment.

− First trimester of pregnancy.

− Porphyria.

− Epilepsy.

− Severe impairment of liver function.

Interaction with other medicinal products and other forms of interaction.

Related to metronidazole (due to its absorption).

Alcohol: interaction between metronidazole and alcohol may cause a reaction similar to that with disulfiram. Alcohol must not be consumed during therapy and for 3 days after completion of the course (see section "Special precautions for use").

Amiodarone: increased risk of cardiotoxicity (prolongation of QT interval, 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: effects on the central nervous system (e.g., psychotic reactions).

Lithium: increased lithium toxicity.

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

Phenobarbital: decreased blood level of metronidazole.

Fluorouracil: increased blood level and toxicity of fluorouracil.

Oral anticoagulants: enhanced anticoagulant effect, increased risk of bleeding (see section "Special precautions for use").

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

Related to miconazole nitrate (due to peculiarities of its absorption).

Acenocoumarol, anisindione, dicoumarol, 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 effect of opioids (central nervous system depression, 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 (dry mouth, constipation, headache).

Oxycodone: increased plasma concentration of oxycodone and reduced elimination.

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

Solifenacin: increased bioavailability of solifenacin in individuals with cytochrome P450 2D6 deficiency.

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

Special precautions for use.

Alcohol

Patients should be warned not to consume alcohol during therapy and for 3 days after completion of treatment, as reactions affecting the central nervous system similar to those of disulfiram may occur (see section "Interaction with other medicinal products and other forms of interaction").

Prolonged use

High doses and prolonged duration of treatment may cause peripheral neuropathy and seizures.

Concomitant treatment of sexual partners

Sexual partners of patients with trichomonal vaginitis should also undergo treatment. Sexual partners in whom Trichomonas vaginalis has been identified must be treated simultaneously with the patient.

Renal and hepatic impairment

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

In severe hepatic impairment, metronidazole clearance may be altered. Metronidazole may exacerbate symptoms of encephalopathy due to 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.

Use in patients of different age groups

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

The product is not recommended for use in virgins and young patients who have not reached sexual maturity.

Concomitant use with oral anticoagulants

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 and for 8 days after discontinuation of metronidazole.

Other special precautions for use

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

The suppository base may adversely interact with rubber or latex used in the manufacture of contraceptive diaphragms and condoms; therefore, concomitant use of these products with suppositories is not recommended.

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

If severe vaginal irritation (burning, itching) occurs, treatment with Gynex® Forte should be discontinued (see section "Adverse reactions").

Hepatotoxicity in patients with Cockayne syndrome

Cases of rapid development of acute liver failure, including fatal outcomes, have been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medicinal products. Metronidazole should not be used in patients with Cockayne syndrome except when the benefit is considered to outweigh the risk and only if no alternative treatment is available.

Liver function tests should be performed immediately before starting treatment, during treatment, and after completion of treatment with the medicinal product until liver function parameters return to normal or baseline levels. If liver function tests show markedly elevated values during treatment, the medicinal product should be discontinued.

Patients with Cockayne syndrome should be advised to immediately inform their physician and discontinue metronidazole if any symptoms suggestive of liver dysfunction occur (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Pregnancy

Pregnancy category C.

Due to insufficient data on the absence of negative effects on the fetus and neonatal development following intravaginal administration of suppositories containing metronidazole and miconazole nitrate, women of reproductive age should avoid pregnancy during treatment with Gynex® Forte.

Use of Gynex® Forte during the first trimester of pregnancy is contraindicated.

During the second and third trimesters of pregnancy, the product should be used only as prescribed by a physician when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

Breastfeeding should be discontinued during treatment, as metronidazole is excreted in breast milk. Breastfeeding may be resumed 1–2 days after completion of treatment.

Fertility

There is no evidence of harmful effects on fertility with the use of metronidazole or miconazole nitrate alone.

Ability to affect reaction speed 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 still occur. If such symptoms occur, driving or operating machinery is not recommended.

Method of Administration and Dosage.

For adults: apply intravaginally once daily in the evening before bedtime, 1 suppository per night for 7 days.

In cases of recurrent infections or vaginitis resistant to other treatments, the drug should be used in the evening before bedtime, 1 suppository per night for 14 days.

It is not recommended to use Gynex® Forte during menstruation due to reduced drug efficacy and possible complications associated with insertion.

Vaginal suppositories should be inserted while lying down, deeply into the vagina. If possible, avoid assuming an upright position for at least half an hour after insertion. Do not use double doses to compensate for a missed dose.

Children.

The drug is not recommended for use in children.

Overdose.

The drug is intended exclusively for vaginal use. There are no data on metronidazole overdose following vaginal administration. When administered intravaginally, metronidazole may be absorbed in amounts sufficient to cause systemic effects. Systemic effects related to metronidazole may occur after excessive use of suppositories; however, intravaginal administration of metronidazole is not expected to cause life-threatening symptoms.

If a large amount of the drug is accidentally ingested, appropriate gastric lavage should be performed if necessary. Treatment should be considered when 12 g of metronidazole has been ingested.

There is no specific antidote; symptomatic treatment is recommended. Symptoms of metronidazole overdose include: nausea, vomiting, abdominal pain, diarrhea, itching, metallic taste in the mouth, ataxia, vertigo, paresthesia, seizures, leukopenia, and darkening of urine. Symptoms of overdose with miconazole nitrate include: nausea, vomiting, inflammation of the throat and oral cavity, anorexia, headache, and diarrhea.

Metronidazole and its metabolites are effectively eliminated by hemodialysis.

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 ≥1/10000 to <1/1/1000); very rare (<1/10000); unknown (cannot be estimated from available data).

The incidence of systemic adverse effects is low due to the very low plasma levels of metronidazole achieved with vaginal administration of the drug (2–12% of the levels reached after oral administration of metronidazole). The other active ingredient of the drug, miconazole nitrate, may cause vaginal irritation (burning, itching), as do all other imidazole derivative antifungal agents administered intravaginally (2–6%). In cases of vaginitis, use of the drug may provoke inflammation of the vaginal mucosa. Therefore, burning and itching in the vagina may occur from the beginning of treatment up to the third day of therapy. These symptoms significantly decrease during the course of treatment. In case of severe irritation or other allergic reactions (rash, angioedema in the area of the face, lips, tongue, larynx, and bronchospasm), treatment must be discontinued.

Local adverse reactions due to the active ingredients of Gynex® Forte.

Metronidazole: hypersensitivity reactions (including skin rash), abdominal pain, headache, itching, burning, and vaginal irritation.

Miconazole nitrate: vaginal irritation (burning, itching).

Systemic adverse reactions due to the active ingredients of Gynex® Forte.

Blood and lymphatic system disorders

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia.

Unknown: leukopenia.

Immune system disorders

Rare: anaphylactic shock.

Unknown: hypersensitivity reactions, allergic reactions, angioedema, urticaria, fever.

Psychiatric disorders

Very rare: disturbances of consciousness, 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).

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: elevated liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase), cholestatic or mixed hepatitis, and 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 rash, including rashes that may be accompanied by chills, flushing, hyperemia, itching.

Unknown: polymorphic erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, contact dermatitis.

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: anorexia, taste disturbances, oral mucosal inflammation, metallic taste in the mouth, coated tongue, stomatitis, glossitis, nausea, vomiting, constipation, epigastric pain, 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 sensation in the vagina, itching, irritation.

Unknown: local irritation and hypersensitivity, flushing, increased body temperature.

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

* These may resolve after discontinuation of the drug.

Cases of severe irreversible hepatotoxicity/acute liver failure, including fatal cases with rapid progression after initiation of systemic metronidazole therapy, have been reported in patients with Cockayne syndrome (see section "Special precautions").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

7 suppositories per strip. 1 strip per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business activity.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.