Gynocaps Biforte (Capsules) Instructions for Use

Marketing Authorization Holder

Minskintercaps Up (Republic Of Belarus)

ATC Code

G01AF20 (Imidazole derivative combinations)

Active Substances

Metronidazole (Rec.INN registered by WHO)

Miconazole (Rec.INN registered by WHO)

Dosage Form

Gynocaps Biforte

Vaginal capsules 750 mg+200 mg: 10 pcs.

Dosage Form, Packaging, and Composition

Vaginal capsules soft gelatin, egg-shaped with a pointed end, with a seam, elastic, opaque, almost white or light beige in color.

Excipients: yellow beeswax, medium-chain triglycerides (Miglyol 812 N).

Capsule shell composition: gelatin, glycerol, purified water, methylparahydroxybenzoate (E218), propylparahydroxybenzoate (E216), titanium dioxide (E171).

5 pcs. – contour cell packaging (2) – cardboard packs.

Clinical-Pharmacological Group

A drug with antibacterial, antiprotozoal, and antifungal action for topical use in gynecology

Pharmacotherapeutic Group

Antimicrobial agents and antiseptics used in gynecology; antimicrobial agents and antiseptics, except combinations with corticosteroids; imidazole derivatives

Pharmacological Action

Combined agent for intravaginal use.

Metronidazole is an antiprotozoal and antimicrobial drug, a nitro-5-imidazole derivative.

The mechanism of action involves the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa.

The reduced 5-nitro group of metronidazole interacts with the DNA of microbial cells, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria and protozoa.

Active against Trichomonas vaginalis, Entamoeba histolytica, Gardnerella vaginalis, Giardia lamblia, as well as obligate anaerobes Bacteroides spp. (including Bacteroides fragilis, Bacteroides ovatus, Bacteroides distasonis, Bacteroides thetaiotaomicron, Bacteroides vulgatus), Fusobacterium spp., Veillonella spp., Prevotella spp. (Prevotella bivia, Prevotella buccae, Prevotella disiens) and some gram-positive microorganisms (Eubacterium spp., Clostridium spp., Peptococcus spp., Peptostreptococcus spp.).

The MIC for these strains is 0.125-6.25 µg/ml.

Resistant to metronidazole are aerobic microorganisms and facultative anaerobes, but in the presence of mixed flora (aerobes and anaerobes), Metronidazole acts synergistically with antibiotics effective against aerobes.

Miconazole has an antifungal effect against dermatophytes, yeast fungi.

When used intravaginally, it is mainly active against Candida albicans.

Miconazole inhibits the biosynthesis of ergosterol in fungi and changes the composition of other lipid components in the membrane, which leads to the death of fungal cells.

Miconazole does not alter the composition of the normal microflora and vaginal pH.

Pharmacokinetics

When used intravaginally, Metronidazole is absorbed into the systemic circulation.

The C_max of metronidazole in the blood is determined after 6-12 hours and is approximately 50% of the C_max achieved (after 1-3 hours) after a single oral dose of an equivalent dose of metronidazole.

Metronidazole penetrates into breast milk and most tissues, crosses the BBB and the placental barrier.

Plasma protein binding is less than 20%.

It is metabolized in the liver by hydroxylation, oxidation, and glucuronidation.

The activity of the main metabolite (2-hydroxymetronidazole) is 30% of the activity of the parent compound.

It is excreted by the kidneys – 60-80% of the systemically administered drug dose (20% of this amount unchanged).

The metronidazole metabolite, 2-hydroxymetronidazole, colors the urine reddish-brown, due to the presence of a water-soluble pigment formed as a result of metronidazole metabolism.

The systemic absorption of miconazole after intravaginal use is low.

It is rapidly degraded in the liver.

It poorly crosses histohematic barriers.

8 hours after application of the drug, 90% of miconazole is still present in the vagina.

Unchanged Miconazole is not detected either in plasma or in urine.

Indications

For local treatment: vaginal candidiasis, bacterial vaginosis, trichomonal vaginitis, vaginitis caused by mixed infections.

ICD codes

Dosage Regimen

Administer one vaginal capsule intravaginally, once daily, preferably at bedtime.

The standard treatment duration is 7 to 14 days, depending on the specific indication and clinical response.

For trichomonal vaginitis, treat for a full 14-day course and ensure simultaneous treatment of the sexual partner.

Continue treatment during menstruation; do not interrupt the course.

This intravaginal treatment can be used in combination with oral metronidazole therapy as directed by a physician.

Do not exceed the maximum treatment duration of 14 days with metronidazole-containing products.

Insert the capsule high into the vagina. Wash hands before and after administration.

Complete the full prescribed course of therapy, even if symptoms improve earlier.

Adverse Reactions

From the digestive system epigastric pain, nausea, vomiting, diarrhea, inflammation of the oral mucosa (glossitis, stomatitis), taste disorders (“metallic” taste in the mouth), decreased appetite, anorexia, dry oral mucosa, constipation, pancreatitis (reversible cases).

From the immune system angioedema, anaphylactic shock.

From the nervous system peripheral sensory neuropathy, headache, convulsions, dizziness, encephalopathy (e.g., confusion, vertigo) and subacute cerebellar syndrome (impaired coordination and synergy of movements, ataxia, dysarthria, gait disturbances, nystagmus and tremor), which are reversible after discontinuation of metronidazole, aseptic meningitis, vertigo.

Mental disorders psychotic disorders including confusion, hallucinations, depression, insomnia, irritability, increased excitability.

From the organ of vision transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, impaired color perception, optic neuropathy/neuritis.

From the organ of hearing and labyrinthine disorders hearing impairment/hearing loss (including sensorineural deafness), tinnitus.

From the cardiovascular system QT interval prolongation (especially when metronidazole is used simultaneously with drugs that can prolong the QT interval), T wave flattening on ECG.

From the blood and lymphatic system agranulocytosis, leukopenia, neutropenia and thrombocytopenia.

From the liver and biliary tract increased activity of liver enzymes (AST, ALT, ALP), development of cholestatic or mixed hepatitis and hepatocellular liver damage, sometimes accompanied by jaundice.

In patients treated with metronidazole in combination with other antibiotics, cases of liver failure requiring liver transplantation have been observed.

From the skin and subcutaneous tissues rash, skin itching, flushing, skin hyperemia, urticaria, pustular skin rash, acute generalized exanthematous pustulosis, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the kidneys and urinary tract: possible brownish-reddish discoloration of urine due to the presence of a water-soluble metabolite of metronidazole in the urine, dysuria, polyuria, cystitis, urinary incontinence, candidiasis.

Infectious and parasitic diseases after drug withdrawal, development of vaginal candidiasis is possible.

General disorders fever, nasal congestion, arthralgia, weakness.

Local reactions burning sensation or irritation of the partner’s penis, burning sensation or frequent urination, vulvitis (itching, burning pain or hyperemia of the mucous membrane in the external genital area).

Contraindications

Hypersensitivity to metronidazole, imidazoles, nitroimidazole derivatives, organic lesions of the CNS (including epilepsy), impaired coordination of movements, leukopenia (including history), hepatic insufficiency (in case of high-dose use), first trimester of pregnancy, breastfeeding period, children under 18 years of age.

With caution

Hepatic encephalopathy, acute and chronic diseases of the peripheral nervous system and CNS (risk of worsening neurological symptoms), renal failure.

Use in Pregnancy and Lactation

Use in the first trimester of pregnancy is contraindicated. Use of the drug in the second and third trimesters is possible only in cases where the potential benefit to the mother outweighs the risk to the fetus.

Metronidazole is excreted in breast milk. Use during breastfeeding is contraindicated. If use during lactation is necessary, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency (when prescribing the drug in high doses).

If liver function parameters are significantly exceeded during treatment, then the use of this agent should be discontinued.

Use in Renal Impairment

Use with caution in renal failure.

Pediatric Use

Use in children under 18 years of age is contraindicated.

Special Precautions

Since simultaneous use of the drug with alcohol (ethanol) can have an effect similar to that of disulfiram (skin flushing, flushing, vomiting, tachycardia), patients should be warned that during treatment and for at least one day after the end of use of this agent, they should not consume alcoholic beverages or medications containing ethanol.

Indications for long-term use of this agent should be carefully weighed and, in the absence of strict indications, its long-term use should be avoided.

If, in the presence of strict indications, this agent is used for longer than is usually recommended, then treatment should be carried out under the control of hematological parameters (especially leukocytes) and adverse reactions such as peripheral or central neuropathy, manifested by paresthesias, ataxia, dizziness, vertigo, convulsions, upon the appearance of which treatment should be discontinued.

When treating trichomonal vaginitis in women, the patient should refrain from sexual intercourse. Simultaneous treatment of sexual partners is mandatory.

Treatment should not be interrupted during menstruation.

After therapy for trichomoniasis, control tests should be performed over 3 consecutive cycles before and after menstruation.

Metronidazole should be used with caution in patients with hepatic encephalopathy, as well as in patients with acute or chronic diseases of the central or peripheral nervous system due to the possible risk of neurological deterioration.

Severe hepatotoxicity/acute liver failure (including fatal cases that developed very rapidly after initiation of treatment) has been reported in patients with Cockayne syndrome treated with systemic metronidazole.

In this category of patients, Metronidazole should be prescribed only after careful assessment of the benefit-risk ratio and only in the absence of alternative treatment.

Liver function tests should be performed before starting treatment, during therapy and after its completion until liver function parameters reach normal values, or until baseline values of these parameters are reached.

Patients with Cockayne syndrome should be advised to immediately report any symptoms of potential liver damage to their doctor and discontinue metronidazole.

Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis or acute generalized exanthematous pustulosis, have been reported after the use of metronidazole.

If symptoms or signs of these diseases develop, treatment should be discontinued immediately.

Patients should be advised to discontinue treatment and immediately consult their physician if psychiatric disorders occur during treatment with this agent.

Long-term use of metronidazole must be carefully justified due to possible mutagenicity and carcinogenicity.

It must be taken into account that Metronidazole can immobilize treponemes, which leads to a false-positive Nelson test.

Metronidazole may distort the results of some blood tests (determination of ALT, AST, LDH, triglycerides, glucose).

Drug Interactions

Psychotic reactions have been reported in patients receiving Metronidazole and disulfiram simultaneously (the interval between the use of these two drugs should be at least 2 weeks).

When used concomitantly with ethanol, disulfiram-like reactions may occur (skin flushing, flushing, vomiting, tachycardia).

Enhancement of the anticoagulant effect and an increased risk of bleeding associated with reduced hepatic metabolism of indirect anticoagulants is possible, which may lead to prolongation of prothrombin time.

In case of simultaneous use of metronidazole and indirect anticoagulants, more frequent monitoring of prothrombin time and, if necessary, adjustment of anticoagulant doses is required.

When metronidazole is used concomitantly with lithium preparations, an increase in the plasma concentration of the latter is possible.

During concomitant use, plasma concentrations of lithium, creatinine and electrolytes should be monitored.

When metronidazole is used concomitantly with cyclosporine, the concentration of cyclosporine in the blood serum may increase.

If simultaneous use of metronidazole and cyclosporine is necessary, serum concentrations of cyclosporine and creatinine should be monitored.

Cimetidine inhibits the metabolism of metronidazole, which may lead to an increase in its serum concentration and an increased risk of adverse events.

Concomitant use of metronidazole with drugs that induce microsomal oxidation isoenzymes in the liver (phenobarbital, phenytoin) may accelerate the elimination of metronidazole, resulting in a decrease in its plasma concentration.

Metronidazole reduces the clearance of fluorouracil, leading to increased toxicity.

Metronidazole increases the plasma concentration of busulfan, which may lead to the development of severe toxic effects of busulfan.

Not recommended for use with non-depolarizing muscle relaxants (vecuronium bromide).

Sulfonamides enhance the antimicrobial effect of metronidazole.

QT interval prolongation has been reported, especially when metronidazole is used simultaneously with drugs that can prolong the QT interval.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.