Metronidazole-pharmex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METRONIDAZOLE-PHARMEX (METRONIDAZOLE-PHARMEX)

Composition:

active substance: metronidazole;

1 suppository contains 500 mg of metronidazole;

excipient: hard fat.

Pharmaceutical form. Suppositories.

Main physico-chemical properties: smooth, white or almost white suppositories. On longitudinal section, absence of specks; presence of cup-shaped depression and air channel is acceptable.

Pharmacotherapeutic group.

Antimicrobial and antiseptic agents used in gynecology.

ATC code G01AF01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole belongs to the nitro-5-imidazoles and has a broad spectrum of activity. The susceptibility breakpoints that allow distinguishing susceptible strains (S) from strains with intermediate susceptibility, and strains with intermediate susceptibility from resistant strains (R), are as follows: S < 4 mg/L and R > 4 mg/L.

Organisms sensitive to the drug include: 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 sensitivity: Bifidobacterium spp., Eubacterium spp. Resistant microorganism strains: Propionibacterium, Actinomyces, Mobiluncus.

Pharmacokinetics.

After vaginal administration, systemic absorption is minimal.

The plasma elimination 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 is excreted in breast milk.

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

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

Clinical characteristics.

Indications.

Local treatment of trichomonal and nonspecific vaginitis.

Contraindications.

Hypersensitivity to metronidazole or to hard fat.

Hypersensitivity to imidazole derivatives.

Combination of metronidazole with disulfiram, alcoholic beverages, or medicinal products containing alcohol. (See section "Interaction with other medicinal products and other forms of interactions").

Interaction with other medicinal products and other forms of interactions.

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

Alcohol. Consumption of alcoholic beverages and medicinal products containing alcohol should be avoided due to the possible occurrence of a disulfiram-like (antabuse) 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 medicinal products containing alcohol.

Busulfan. When high-dose busulfan is used: doubling of busulfan concentrations in patients receiving metronidazole.

Combinations requiring precautions during use.

Oral anticoagulant therapy. Potentiation of the effects of oral anticoagulants and increased risk of hemorrhagic complications. Prothrombin levels and INR (International Normalized Ratio) should be monitored more frequently. Dose adjustment of the oral anticoagulant is recommended during metronidazole treatment and for 8 days after its discontinuation.

Enzyme-inducing anticonvulsants (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone). Decreased plasma concentrations of metronidazole due to stimulation of its hepatic metabolism by the inducer.

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

Rifampicin. Decreased plasma concentrations of metronidazole due to stimulation 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. Increased serum lithium concentrations, potentially reaching toxic levels, with signs of lithium overdose. Close monitoring of serum lithium concentrations is required, and dose adjustment of lithium may be necessary.

Cyclosporine. Risk of increased cyclosporine serum levels. If co-administration is necessary, serum levels of cyclosporine and creatinine should be carefully monitored.

Combinations requiring special attention.

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

INR (International Normalized Ratio) imbalance. 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. Under these circumstances, it is difficult to determine to what extent the INR imbalance is influenced by the infection itself or its treatment. However, certain classes of antibiotics play a greater role, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins.

Laboratory test results. Metronidazole may immobilize treponemes, leading to a false-positive Nelson test result.

Special precautions.

In patients with severe, chronic or progressive diseases of the peripheral or central nervous system, there is a risk of exacerbation of neurological status.

Patients with a history of hematological disorders or those receiving the drug in high doses and/or for a prolonged period should have regular blood tests, especially leukocyte count determination.

During prolonged treatment with the drug, 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 the presence of an active metabolite).

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

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

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

Acute skin reactions, including Stevens-Johnson syndrome, Lyell's syndrome, and acute generalized exanthematous pustulosis, have been associated with metronidazole administration. Patients should be informed about symptoms of such reactions, and careful skin monitoring should be performed.

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 rash accompanied by fever, treatment with the drug must be stopped, 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 reviewed 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 localized in the cerebellum (especially in the dentate nucleus) and the corpus callosum. In most cases, encephalopathy and MRI changes 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 disease, benefit-risk ratio should be reassessed.

Peripheral nervous system disorders. Patients should be monitored for possible signs of peripheral neuropathy, especially during long-term 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 treatment should be discontinued, the physician should be notified, and appropriate therapeutic measures should be initiated immediately.

Hematological effects. Patients with a history of blood system disorders and those receiving the drug in high doses and/or for a prolonged period should undergo regular blood tests, especially leukocyte count monitoring.

Continuation of treatment in patients with leukopenia depends on the severity of the underlying infection.

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

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

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

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.

In patients with Cockayne syndrome, cases of rapid development of acute liver failure, including fatal outcomes, have been observed during systemic administration of metronidazole-containing drugs. Metronidazole should not be used in these patients, except when benefit outweighs risk and no alternative therapy is available.

Liver function tests should be performed immediately before starting the drug, during its administration, and after completion of 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 suggestive of impaired liver function 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 conducted studies on two species. Clinical data have not demonstrated any specific teratogenic or fetotoxic effects associated with metronidazole administration during pregnancy. However, absence of such risk can only be confirmed by epidemiological studies. Therefore, the drug should be used only as prescribed by a physician.

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

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the risk of dizziness, confusion, hallucinations, seizures, and visual disturbances. If such symptoms occur, patients should not drive or operate machinery.

Dosage and Administration.

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

Metronidazole-Farmeks, suppositories, are generally used in combination with metronidazole tablets.

Trichomonal vaginitis. Administer 1 suppository once daily for 10 days. Insert the suppository deeply into the vagina. Treatment should be conducted concurrently with oral administration of metronidazole tablets.

Non-specific vaginitis. Insert 1 suppository deeply into the vagina once daily for 7 days. If necessary, oral metronidazole tablets may be prescribed. Simultaneous 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-Farmeks should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

Children.

The drug is contraindicated for use in pediatric patients.

Overdose.

Cases of single-dose intake up to 12 g have been reported during suicide attempts and accidental overdoses. Ataxia, vomiting, and mild disorientation may occur. Since a specific antidote for metronidazole is not known, symptomatic therapy is recommended.

Adverse reactions.

Gastrointestinal system:

− mild gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea);

− glossitis with dryness of the mouth, stomatitis, taste disturbances, anorexia;

− cases of pancreatitis, which are reversible;

− changes in color or appearance of the tongue (fungal infection).

Skin and appendages:

− flushing with hyperemia, pruritus, rash, which may be accompanied by sweating;

− urticaria, angioneurotic edema, anaphylactic shock (see section "Special precautions");

− very rare cases of acute generalized exanthematous pustulosis (see section "Special precautions");

− toxic epidermal necrolysis;

− fixed drug eruption;

− Lyell’s syndrome;

− Stevens-Johnson syndrome.

Nervous system:

− peripheral sensory neuropathy;

− headache, dizziness, confusion, seizures;

− aseptic meningitis (see section "Special precautions");

− encephalopathy, which may be associated with changes on MRI, usually reversible. Very rare fatal cases have been reported (see section "Special precautions");

− subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, nystagmus, tremor) (see section "Special precautions").

Psychiatric disorders:

− hallucinations;

− psychotic reactions with paranoia and/or delirium, which in isolated cases may be accompanied by suicidal ideation or suicide attempts (see section "Special precautions");

− depressive mood.

Eye disorders:

− transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, changes in color perception;

− optic neuropathy/neuritis.

Blood disorders:

− agranulocytosis, neutropenia, thrombocytopenia.

Hepatobiliary disorders:

− increased levels of liver enzymes (AST, ALT, alkaline phosphatase); very rarely, cases of acute cholestatic or mixed hepatitis and hepatocellular liver injury have been reported, sometimes with jaundice. Isolated cases of hepatocellular failure have been reported, which may necessitate liver transplantation.

Ear and labyrinth disorders:

− hearing impairment/hearing loss (including sensorineural);

− tinnitus.

Other:

− red-brown discoloration of urine due to water-soluble pigments formed during the metabolism of this medicinal product.

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

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report all suspected adverse reactions through 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 the reach of children.

Packaging.

5 tablets in a blister, 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. LLC "FARMEX GROUP".

Manufacturer's address and location of operations.

100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine.

All cases of adverse reactions should be reported to the manufacturer:

LLC "FARMEX GROUP", 100 Shevchenka Street, Boryspil, Kyiv Oblast, 08301, Ukraine,
Phone: +38(044)391-19-19, Fax: +38(044)391-19-18, or via the form on the website: http://www.pharmex.com.ua/kontakty/forma-137-o/