METRONIDAZOLE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METRONIDAZOLE (METRONIDAZOLE)

Composition:

Active ingredient: metronidazole;

1 suppository contains metronidazole 0.1 g (100 mg);

Excipient: hard fat.

Pharmaceutical form. Vaginal suppositories.

Main physico-chemical properties: white or white with a slightly yellowish tint suppositories.

Pharmacotherapeutic group. Antimicrobial and antiseptic agents used in gynecology. Imidazole derivatives. ATC code G01AF01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole belongs to nitro-5-imidazoles and has a broad spectrum of activity. The minimum inhibitory concentrations that allow differentiation of susceptible strains (S) from strains with moderate susceptibility, and strains with moderate susceptibility from resistant strains (R), are as follows: S ≤ 4 mg/L and R > 4 mg/L.

Organisms susceptible to the drug: Peptostreptococcus spp., Clostridium spp., Bacteroides spp., Fusobacterium spp., Porphyromonas, Bilophila, Helicobacter pylori, Prevotella spp., Veilonella. Metronidazole inhibits the growth of protozoa – Trichomonas vaginalis, Giardia intestinalis (Lamblia intestinalis), Entamoeba histolytica.

Organisms with variable susceptibility to the drug: Bifidobacterium spp., Eubacterium spp.

Resistant microbial strains: Propionibacterium, Actinomyces, Mobiluncus.

Pharmacokinetics.

After vaginal administration, systemic absorption is minimal.

The plasma half-life is 8–10 hours.

Plasma protein binding is low (less than 20%).

Rapid and pronounced diffusion into lungs, kidneys, liver, bile, cerebrospinal fluid, skin, saliva, and vaginal secretions. Crosses the placental barrier and enters breast milk.

Metabolism occurs primarily in the liver: two non-conjugated oxidized active metabolites are formed (5–30% of the parent compound's activity).

Excretion is primarily renal: 35–65% of the administered dose is excreted in urine as metronidazole and its oxidized metabolites.

Clinical characteristics.

Indications.

Local treatment of trichomonas and nonspecific vaginitis.

Contraindications.

Hypersensitivity to metronidazole or to any other component of the medicinal product. Hypersensitivity to imidazole derivatives.

This medicinal product is not recommended for use in combination with disulfiram or alcohol (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Disulfiram: cases of acute transient encephalopathy (acute confusional state, disorientation) have been reported in patients receiving metronidazole and disulfiram concurrently.

Alcohol: alcoholic beverages and medicinal products containing alcohol should not be consumed during treatment and for at least one additional day after its completion due to the possibility of a disulfiram-like reaction (flushing, erythema, vomiting, tachycardia). The time required for complete elimination of the drug from the body should be taken into account, considering its half-life, before starting consumption of alcoholic beverages or administration of alcohol-containing medicinal products.

Oral anticoagulant therapy (warfarin-like): enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications due to inhibition of their hepatic metabolism. Prothrombin levels and monitoring of the International Normalized Ratio (INR) should be performed more frequently. Dose adjustment of the oral anticoagulant is recommended during metronidazole therapy and for 8 days after discontinuation.

Rifampicin: decreased plasma concentrations of metronidazole due to induction of its hepatic metabolism by rifampicin.

Clinical monitoring should be performed during and after treatment with rifampicin. Dose adjustment of metronidazole may be necessary.

Lithium: plasma lithium levels may increase during concomitant administration with metronidazole. Plasma concentrations of lithium, creatinine, and electrolytes should be monitored in patients receiving both lithium and metronidazole.

Cyclosporine: there is a risk of increased serum levels of cyclosporine. If co-administration is necessary, serum levels of cyclosporine and creatinine should be closely monitored.

Anticonvulsants that are enzyme inducers (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone): cause decreased plasma levels of metronidazole due to induction of its hepatic metabolism.

Fluorouracil (as well as tegafur and capecitabine): reduced clearance of fluorouracil leads to increased toxicity.

Busulfan: metronidazole may increase plasma concentrations of busulfan, potentially leading to significant busulfan toxicity.

Changes in INR: numerous cases of enhanced activity of oral anticoagulants have been reported in patients receiving antibacterial therapy. Risk factors predisposing to this complication include presence of infection or marked inflammation, patient age, and overall health status. In such circumstances, it is difficult to determine to what extent the disturbance in INR balance is due to the infection itself or its treatment. However, certain classes of antibiotics play a more significant role, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins.

Laboratory test results: metronidazole may immobilize treponemes, leading to a false-positive Nelson test.

Special precautions for use.

Therapy should preferably be initiated at the beginning of the menstrual cycle. Postmenopausal women may start treatment at any time. Douching should be avoided.

During treatment of trichomonal vaginitis, sexual abstinence is recommended. Simultaneous treatment of the sexual partner with oral metronidazole is advisable.

Metronidazole has no direct activity against aerobic or facultative anaerobic bacteria. Metronidazole should not be prescribed for longer than 10 days or more frequently than 2–3 times per year.

Alcohol consumption must be avoided during metronidazole therapy (disulfiram-like reaction (see section "Interaction with other medicinal products and other forms of interaction")). Gonococcal infection may persist after elimination of trichomonal infection.

In patients undergoing hemodialysis, metronidazole and its metabolites are eliminated during 8 hours of hemodialysis; therefore, metronidazole should be administered immediately after hemodialysis.

Dosage adjustment is not required in patients with renal insufficiency undergoing peritoneal dialysis.

The drug should be discontinued if the patient develops ataxia, dizziness, or confusion.

In patients with severe, chronic, or progressive diseases of the peripheral or central nervous system, the risk of neurological deterioration should be considered.

In patients with a history of hematological disorders or those receiving high doses and/or prolonged treatment, regular blood tests, especially leukocyte counts, should be performed.

Metronidazole should be used with caution in patients with hepatic encephalopathy. In patients with hepatic encephalopathy, the daily dose should be reduced by one-third and may be administered once daily.

In patients with leukopenia, the possibility of continuing treatment will depend on the severity of the infectious disease.

During prolonged treatment, patients should be monitored for the development of adverse reactions such as central or peripheral neuropathy (paresthesia, ataxia, dizziness, seizures).

Patients should be informed that metronidazole may darken the urine (due to an active metabolite).

The use of vaginal suppositories together with latex condoms or diaphragms may increase the risk of latex rupture.

Hypersensitivity/skin and appendage disorders. Allergic reactions, including life-threatening anaphylactic shock, may occur (see section "Adverse reactions"). In such cases, metronidazole therapy must be discontinued and appropriate treatment initiated.

If generalized erythema and pustular eruptions accompanied by fever occur at the beginning of treatment, acute generalized exanthematous pustulosis (AGEP) should be suspected (see section "Adverse reactions"); if such a reaction develops, treatment with the drug must be stopped, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Metronidazole has been associated with severe skin reactions, including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), and acute generalized exanthematous pustulosis. Patients should be informed about the symptoms of these reactions, and careful skin monitoring is required.

If a patient develops symptoms of Stevens-Johnson syndrome, Lyell's syndrome (e.g., progressive rash, skin blisters, or mucosal lesions), or generalized erythema with pustular eruptions accompanied by fever, treatment with the drug must be discontinued, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Central nervous system disorders. If symptoms characteristic of encephalopathy or cerebellar syndrome occur, the patient's treatment should be immediately reassessed and metronidazole therapy discontinued.

Cases of encephalopathy have been reported during post-marketing surveillance. Additionally, MRI changes associated with encephalopathy have been observed (see section "Adverse reactions"). Lesions are most commonly located in the cerebellum (particularly in the dentate nucleus) and the corpus callosum. In most cases, encephalopathy and MRI abnormalities resolve after discontinuation of the drug. Fatal outcomes have been reported very rarely.

Patients should be monitored for possible signs of encephalopathy or worsening of symptoms in case of pre-existing CNS disorders.

If aseptic meningitis develops during treatment with the drug, re-administration of metronidazole is not recommended. In patients with serious infectious diseases, a re-evaluation of the benefit-risk ratio is required.

Peripheral nervous system disorders. Patients should be monitored for possible signs of peripheral neuropathy, especially during prolonged treatment or in the presence of severe, chronic, or progressive peripheral neuropathy.

Psychiatric disorders. Psychotic reactions, including self-harming behavior, may occur after the first dose of the drug, particularly in patients with a history of psychiatric disorders (see section "Adverse reactions"). In such cases, metronidazole therapy should be discontinued, the physician should be informed, and appropriate therapeutic measures should be initiated immediately.

Hematological effects. In patients with a history of blood disorders or those receiving high doses and/or prolonged treatment, regular blood tests, especially leukocyte counts, should be performed.

Continuation of treatment in patients with leukopenia depends on the severity of the infectious disease.

Interaction with other medicinal products. Concomitant use of metronidazole and alcoholic beverages or medicinal products containing alcohol is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and busulfan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and disulfiram is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Other interactions. The maximum duration of metronidazole treatment should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

The use of suppositories together with condoms or diaphragms increases the risk of latex rupture.

Hepatotoxicity in patients with Cockayne syndrome

In patients with Cockayne syndrome, cases of rapidly developing acute liver failure, including fatal outcomes, have been observed during systemic administration of metronidazole-containing drugs. Metronidazole should not be used in this patient group, except when the benefit is considered to outweigh the risk and no alternative treatment is available.

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

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

Use during pregnancy or breastfeeding

Pregnancy. Animal studies have not demonstrated teratogenic effects. Since teratogenic effects are not observed in animals, developmental abnormalities in humans are not expected. According to available data, substances causing developmental abnormalities in humans also show teratogenic effects in animals during adequately performed studies in two species. Clinical data have not demonstrated any specific teratogenic or fetotoxic effects associated with metronidazole. However, the absence of such risk can only be confirmed by epidemiological studies. Therefore, metronidazole should be used during pregnancy only if clearly necessary.

Breastfeeding. Metronidazole is excreted in breast milk. Therefore, use of this medicinal product during breastfeeding should be avoided.

Ability to influence reaction speed when driving or operating machinery

If dizziness, confusion, hallucinations, seizures, or temporary visual disturbances occur during treatment, patients should refrain from driving vehicles or operating machinery.

Method of Administration and Dosage

The drug is permitted for use in the treatment of adult patients only.

Trichomonas vaginitis. Administer 2 vaginal suppositories twice daily for 10 days. Insert the suppository deeply into the vagina. Treatment should be accompanied by simultaneous oral administration of Metronidazole tablets.

Non-specific vaginitis. Insert 2 vaginal suppositories deeply into the vagina twice daily for 7 days. If necessary, oral Metronidazole tablets may be prescribed. Concurrent treatment of the patient's sexual partner is absolutely essential, even in the absence of infection symptoms in the partner.

The maximum duration of treatment with Metronidazole should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

Children

The drug is contraindicated in children.

Overdose

Leukopenia, neuropathy, ataxia, vomiting, and mild disorientation may occur. As there is no specific antidote for metronidazole, symptomatic therapy is recommended.

Adverse reactions.

Blood and lymphatic system disorders: very rare – agranulocytosis, neutropenia, thrombocytopenia, pancytopenia, and leukopenia.

Hypersensitivity reactions: skin rashes with hyperemia, pruritus, erythema, urticaria, erythema multiforme; flushing, hot flushes, angioneurotic edema, rare cases of anaphylactic shock, isolated cases of pustular rash, toxic epidermal necrolysis, fixed drug eruption, Lyell’s syndrome, Stevens-Johnson syndrome.

Central and peripheral nervous system disorders: peripheral sensory neuropathy, headache, seizures, dizziness, ataxia, somnolence, aseptic meningitis; encephalopathy (e.g., confusion, fever, photophobia, nuchal rigidity, hallucinations, paralysis, visual and motor disturbances), and subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, tremor, nystagmus), which may resolve after discontinuation of the drug.

Psychiatric disorders: psychiatric disorders including confusion, hallucinations,
psychotic reactions with paranoia and/or delirium, which in rare cases may be associated with suicidal ideation or suicide attempts (see section "Special precautions"); depressed mood.

Eye disorders: transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, color vision changes; optic neuropathy/neuritis.

Hepatobiliary disorders: elevated liver enzyme levels (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis and hepatocellular injury (hepatocyte damage), sometimes with jaundice; cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole and other antibiotics.

Renal and urinary disorders: possible discoloration of urine to brown-red due to pigments related to metronidazole metabolism; with prolonged treatment, overgrowth of vaginal fungal flora (candidiasis) may occur, requiring antifungal therapy.

Gastrointestinal disorders: mild gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea); oral mucositis, taste disturbances (metallic taste in the mouth), glossitis with dry mouth, stomatitis, coated tongue, changes in tongue color or appearance (mucosis), anorexia, reversible pancreatitis.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

Ear and labyrinth disorders: hearing impairment/hearing loss (including sensorineural); tinnitus.

Other adverse reactions: increased body temperature.

Adverse reactions reported with metronidazole use

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 of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report all suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 2 years.

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

Keep out of reach and sight of children.

Packaging. 5 suppositories in a strip. 2 strips in a carton.

Prescription status. Prescription only.

Manufacturer. JSC "Monfarm".

Manufacturer's address and site of operations.
8, Zavodska Street, Avramivka village, Uman district, Cherkasy region, 19161, Ukraine.