Metronidazole

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

Composition:

Active ingredient: metronidazole;

100 ml of solution contains metronidazole — 0.5 g;

Excipients: sodium chloride, disodium edetate, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly greenish-yellow liquid; theoretical osmolarity — 303 mosmol/L; pH 4.5–6.0.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Imidazole derivatives. ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole is a stable compound capable of penetrating into microorganisms. Under anaerobic conditions, metronidazole forms nitro radicals via microbial pyruvate-ferredoxin-oxidoreductase through oxidation of ferredoxin and flavodoxin. Nitro radicals form adducts with DNA base pairs, leading to DNA strand breaks and cell death.

The minimal inhibitory concentration (MIC) has been established by EUCAST (European Committee on Antimicrobial Susceptibility Testing). The breakpoints distinguishing susceptible organisms (S) from resistant organisms (R) are as follows:

Gram-positive anaerobes (S: ≤ 4 mg/L, R: > 4 mg/L);

Gram-negative anaerobes (S: ≤ 4 mg/L, R: > 4 mg/L).

List of susceptible and resistant microorganisms.

(According to the German Central Committee for the Evaluation of Resistance Data for Systemic Antibiotics, January 2011)

Typically susceptible strains

Anaerobes: Bacteroides fragilis, Clostridium difficile °, Clostridium perfringens °^, Fusobacterium spp. °, Peptoniphilus spp. °, Peptostreptococcus spp. °, Porphyromonas spp. °, Prevotella spp., Veillonella spp. °.

Other microorganisms: Entamoeba histolytica °, Gardnerella vaginalis °, Giardia lamblia °, Trichomonas vaginalis °.

Strains for which acquired resistance may be a concern

Gram-negative aerobes: Helicobacter pylori.

Naturally resistant microorganisms

All obligate aerobes.

Gram-positive microorganisms: Enterococcus spp., Staphylococcus spp., Streptococcus spp.

Gram-negative microorganisms: Enterobacteriaceae, Haemophilus spp.

° At the time of publication, no clinical data were available. Probable standard reference values and therapeutic recommendations regarding susceptibility of the respective strains are provided in the primary literature.

^ May be used only in patients with penicillin allergy.

Mechanisms of resistance to metronidazole

Mechanisms of resistance to metronidazole have been only partially elucidated.

Resistance to metronidazole in Helicobacter pylori is caused by mutations in genes encoding NADPH-nitroreductase. These mutations lead to amino acid substitutions, resulting in enzyme inactivity. Thus, the activation step of metronidazole into the active nitro radical does not occur.

Bacteroides strains are resistant to metronidazole due to genes encoding nitroimidazole reductases, which convert nitroimidazoles into aminoimidazoles, thereby inhibiting the formation of antibacterial active nitro radicals.

Complete cross-resistance exists between metronidazole and other nitroimidazole derivatives (tinidazole, ornidazole, nimorazole).

The prevalence of acquired resistance in individual strains may vary depending on region and time. Therefore, local data should be consulted, especially for effective treatment of severe infections. In cases of uncertainty regarding metronidazole efficacy due to local resistance patterns, expert advice should be sought. A microbiological diagnosis, including identification of microbial strains and determination of their susceptibility to metronidazole, should be established, particularly in cases of severe infection or treatment failure.

Pharmacokinetics.

Since metronidazole is administered intravenously, its bioavailability is 100%.

Distribution

After administration, metronidazole is extensively distributed into body tissues. Metronidazole has been detected in most tissues and body fluids, including bile, bone, brain abscess, cerebrospinal fluid, liver, saliva, seminal fluid, and vaginal secretions, where concentrations close to those in plasma are achieved. It also crosses the placenta and is excreted into breast milk at concentrations equivalent to those in blood serum. Protein binding is less than 20%, and the apparent volume of distribution is 36 liters.

Biological transformation

Metronidazole is metabolized in the liver by side-chain oxidation and glucuronide formation. Its metabolites include an acidic oxidation product, a hydroxylated derivative, and a glucuronide conjugate. The main metabolite in serum is the hydroxylated metabolite, while the main metabolite in urine is the acidic metabolite.

Elimination

Approximately 80% of the administered dose is excreted in urine, of which less than 10% is unchanged. A small amount is excreted via the liver. The elimination half-life is approximately 8 (6–10) hours.

Characteristics in special patient populations

Renal impairment causes only a slight delay in elimination.

In severe liver disease, a reduced plasma clearance and prolonged elimination half-life from serum (up to 30 hours) can be expected.

Clinical Characteristics.

Indications.

Treatment and prevention of infections caused by microorganisms sensitive to metronidazole (mainly anaerobic bacteria).

Metronidazole is indicated in adults and children for:

• central nervous system infections (including brain abscess, meningitis);
• lung and pleural infections (including necrotizing pneumonia, aspiration pneumonia, lung abscess);
• endocarditis;
• gastrointestinal and intra-abdominal infections (including peritonitis, liver abscess, postoperative infections following surgery on the colon or rectum, suppurative abdominal or pelvic infections);
• gynecological infections (including post-hysterectomy or post-cesarean endometritis, puerperal fever, septic abortion);
• infections of the ear, nose, throat and oral cavity (including Vincent's angina);
• bone and joint infections (including osteomyelitis);
• gas gangrene;
• septicemia with thrombophlebitis.

When treating mixed aerobic and anaerobic infections, appropriate additional antibiotics should be administered to cover aerobic pathogens.

Prophylactic use is always indicated prior to surgeries with a high risk of anaerobic infection (e.g., gynecological and intra-abdominal surgeries).

Official guidelines on appropriate use of antimicrobial agents should be taken into account.

Contraindications.

Hypersensitivity to metronidazole, other nitroimidazole derivatives, or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Amiodarone. Cases of QT interval prolongation and ventricular tachycardia have been reported during concomitant use of metronidazole and amiodarone. Monitoring of the QT interval on electrocardiogram (ECG) may be advisable when amiodarone is used in combination with metronidazole. Outpatients should be advised to seek medical attention if symptoms suggestive of ventricular tachycardia occur, such as dizziness, palpitations, or loss of consciousness.

Barbiturates. Phenobarbital may enhance hepatic metabolism of metronidazole, reducing its plasma half-life to 3 hours.

Busulfan. Concomitant administration of metronidazole may significantly increase busulfan plasma concentrations. The mechanism of interaction is not fully described. Due to the potential risk of severe toxicity and fatal outcomes associated with elevated busulfan plasma levels, concomitant use of busulfan and metronidazole should be avoided.

Carbamazepine. Metronidazole may inhibit the metabolism of carbamazepine, thereby increasing its plasma concentrations.

Cimetidine. Concomitant use of cimetidine may in some cases reduce the elimination of metronidazole, leading to increased serum concentrations.

Contraceptives. Some antibiotics may in individual cases reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the intestine, thereby decreasing reabsorption of unconjugated steroids and lowering plasma levels of active steroids. This unusual interaction may occur in women with high biliary excretion of steroid conjugates. Cases of oral contraceptive failure have been reported with various antibiotics, including ampicillin, amoxicillin, tetracyclines, and metronidazole.

Coumarin derivatives. Concomitant use of metronidazole may potentiate the anticoagulant effect of coumarin derivatives and increase the risk of bleeding due to reduced hepatic degradation. Dose adjustment of anticoagulants may be required.

Cyclosporine. Concurrent treatment with cyclosporine and metronidazole may increase serum cyclosporine concentrations. Frequent monitoring of cyclosporine levels and creatinine is necessary.

Disulfiram. Concomitant use of disulfiram may cause confusion or even psychotic reactions. Combination of these agents should be avoided.

Fluorouracil. Metronidazole inhibits the metabolism of fluorouracil when administered concomitantly, resulting in increased plasma concentrations of fluorouracil.

Lithium. Caution should be exercised when administering metronidazole with lithium salts, as elevated serum lithium concentrations have been observed during metronidazole therapy.

Mycophenolate mofetil. Agents that alter gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid. Close clinical and laboratory monitoring is recommended during anti-infective therapy to detect any reduction in the immunosuppressive effect of mycophenolic acid.

Phenytoin. Metronidazole inhibits the metabolism of phenytoin when administered concomitantly, leading to increased plasma phenytoin concentrations. Conversely, the efficacy of metronidazole may be reduced when used with phenytoin.

Tacrolimus. Concomitant use of metronidazole may lead to increased blood concentrations of tacrolimus. The probable mechanism involves inhibition of hepatic metabolism of tacrolimus via CYP3A4. Blood levels of tacrolimus and renal function should be monitored frequently, and dosage adjusted accordingly, especially after initiation or discontinuation of metronidazole therapy in patients stabilized on tacrolimus.

Alcohol. Consumption of alcoholic beverages should be avoided during metronidazole therapy due to the risk of adverse reactions such as dizziness and nausea (disulfiram-like effect).

Special precautions for use.

Metronidazole should be administered to patients with severe hepatic impairment or impaired haemopoiesis (including granulocytopenia) only if the expected benefit outweighs the potential risk.

Due to the risk of worsening of the condition, metronidazole should be administered to patients with active or chronic severe disorders of the peripheral or central nervous system only if the expected benefit clearly outweighs the potential risk.

Seizures and peripheral neuropathy, characterized by numbness or paresthesia of the extremities, have been reported in patients receiving metronidazole therapy. The emergence of neurological pathology requires immediate reassessment of the benefit-risk ratio for continuing therapy.

In case of severe hypersensitivity reactions (including anaphylactic shock), metronidazole treatment must be discontinued immediately and appropriate emergency therapy initiated.

Severe persistent diarrhea occurring during or within weeks after treatment may be a sign of pseudomembranous colitis (often caused by Clostridium difficile), see section "Adverse reactions". This antibiotic-associated intestinal disease can be life-threatening and requires immediate appropriate treatment. Medications that suppress intestinal motility must not be used.

The duration of treatment with metronidazole or other nitroimidazole-containing agents should not exceed 10 days. Only in exceptional cases, when urgently necessary, may the treatment period be extended under appropriate clinical and laboratory monitoring. Repeated therapy should be strictly limited to individual cases. These limitations must be strictly observed, as mutagenic activity of metronidazole cannot be excluded due to increased incidence of certain tumours observed in animal studies.

In patients with Cockayne syndrome, cases of rapid onset of severe hepatotoxicity/acute liver failure, including fatal outcomes, have been observed during systemic administration of metronidazole-containing drugs. Metronidazole should not be used in patients of this group, except when the benefit is considered to outweigh the risk and no alternative treatment is available. Liver function should be monitored immediately before starting treatment, during treatment, and after treatment completion until liver function parameters return to normal or baseline values. If liver function tests during treatment show markedly elevated values, 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").

Prolonged metronidazole therapy may lead to impaired haemopoiesis due to bone marrow suppression. Manifestations are described in the section "Adverse reactions". Complete blood count should be carefully monitored during prolonged therapy.

This medicinal product contains 13.74 mmol (or 315.94 mg) of sodium per 100 ml. Caution is advised when administering to patients on a sodium-restricted diet.

Effect on laboratory parameters

Metronidazole affects the results of enzymatic spectrophotometric assays for aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase, reducing their values (possibly to zero).

Metronidazole has high absorbance at the wavelength used for measuring nicotinamide adenine dinucleotide (NADH). Therefore, in continuous flow assays based on measuring the endpoint reduction of reduced NADH, metronidazole may mask elevated concentrations of liver enzymes. Unusually low concentrations of liver enzymes, including zero values, may be observed.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of metronidazole use during pregnancy has not been fully established. Reports on its use are conflicting. Some studies have reported an increased incidence of congenital malformations. Animal studies have not shown teratogenic effects of metronidazole.

During the first trimester, metronidazole should be used only for the treatment of severe, life-threatening infections when no safer alternative is available. During the second and third trimesters, metronidazole may also be used for the treatment of other infections if the expected benefit clearly outweighs the potential risk.

Breastfeeding period

Since metronidazole is excreted in breast milk, breastfeeding should be discontinued during treatment. Breastfeeding may be resumed no earlier than 2–3 days after completion of therapy due to the prolonged elimination half-life of metronidazole.

Ability to affect reaction speed when driving or operating machinery.

Even when used according to the recommended regimen, metronidazole may affect reaction speed and thus impair the ability to drive or operate machinery. This effect usually occurs at the beginning of treatment or when combined with alcohol.

Dosage and Administration

Adjust the dose according to the individual patient's response to treatment, age, body weight, and the type and severity of the disease. The following dosage guidelines should be observed:

Adults and Adolescents

Treatment of Anaerobic Infections

The usual single dose is 1500 mg (300 ml) on the first day of treatment; in subsequent days, administer a single dose of 1000 mg (200 ml).

Alternative regimen: 500 mg (100 ml) every 8 hours. If medically indicated, a loading dose of 15 mg/kg body weight may be administered at the beginning of treatment. The duration of treatment depends on its effectiveness. In most cases, a 7-day course is sufficient. Treatment may be extended if clinically indicated.

Prophylaxis of Postoperative Infection Caused by Anaerobic Bacteria

500 mg, administered intravenously to be completed approximately 1 hour before surgery. Repeat the dose at 8 and 16 hours.

Children

Treatment of Anaerobic Infections

• Children aged 8 weeks to 12 years: usual daily dose is 20–30 mg/kg/day as a single dose or 7.5 mg/kg every 8 hours. The daily dose may be increased up to 40 mg/kg depending on the severity of infection.
• Children under 8 weeks of age: 15 mg/kg once daily or 7.5 mg/kg every 12 hours.

In neonates with a gestational age of up to 40 weeks, metronidazole may accumulate during the first week of life; therefore, monitoring of serum metronidazole concentration is advisable after several days of treatment.

The usual duration of treatment is 7 days.

Prophylaxis of Postoperative Infection Caused by Anaerobic Bacteria

• Children under 12 years: 20–30 mg/kg body weight as a single dose 1–2 hours before surgery.
• Neonates with a gestational age of up to 40 weeks: 10 mg/kg as a single dose before surgery.

Patients with Renal Impairment

Dose reduction is not required (see section "Pharmacological Properties").

For patients undergoing hemodialysis, the usual dose of metronidazole should be administered on dialysis day after the procedure to prevent removal of metronidazole during hemodialysis.

Patients with Hepatic Impairment

Since in severe hepatic impairment the plasma half-life of metronidazole is prolonged and plasma clearance is reduced, lower doses are required for such patients (see section "Pharmacological Properties").

Administration Method

Administer intravenously. The contents of 1 vial should be administered intravenously slowly—maximum rate of 100 ml over at least 20 minutes, usually over 1 hour. Metronidazole may be diluted in 0.9% sodium chloride solution or 5% glucose solution. Concomitantly administered antibiotics should be given separately.

Children. May be used in children from the first days of life.

Overdose.

Symptoms: In case of overdose, adverse effects described in the section "Side Effects" may occur.

Treatment: There is no specific treatment or antidote available for severe metronidazole overdose. If necessary, metronidazole can be effectively removed by hemodialysis.

Adverse Reactions

Adverse effects are mainly associated with prolonged use or administration of high doses. The most commonly observed side effects are nausea, taste disturbances, and risk of neuropathy with long-term use.

The frequency of adverse effects is defined as follows: very common: ≥1/10; common: ≥1/100 to <1/10; uncommon: ≥1/1,000 to <1/100; rare: ≥1/10,000 to <1/1,000; very rare: <1/10,000; frequency not known: cannot be estimated.

Infections and infestations. Common: superinfections caused by Candida (e.g., genital infections). Rare: pseudomembranous colitis, which may occur during or after therapy and presents as severe persistent diarrhea. Detailed emergency management is described in the section "Special Instructions".

Blood and lymphatic system disorders. Very rare: during metronidazole therapy, decreased counts of leukocytes and platelets (granulocytopenia, agranulocytosis, pancytopenia, and thrombocytopenia). Frequency not known: leukopenia, aplastic anemia. Regular blood count monitoring is mandatory during prolonged treatment.

Immune system disorders. Rare: severe hypersensitivity reactions including anaphylaxis up to anaphylactic shock; severe skin reactions (see below, "Skin and subcutaneous tissue disorders"). Severe reactions require immediate treatment. Frequency not known: mild to moderate hypersensitivity reactions, including skin reactions, angioneurotic edema.

Metabolism and nutrition disorders. Frequency not known: anorexia.

Psychiatric disorders. Very rare: psychotic disorders, confusion, hallucinations. Frequency not known: depression.

Nervous system disorders. Very rare: encephalopathy, headache, excitement, drowsiness, dizziness, visual and motor disturbances, vertigo, ataxia, dysarthria, seizures. Frequency not known: drowsiness or insomnia, myoclonus, convulsive seizures, peripheral neuropathy presenting as paresthesia, pain, heaviness, and tingling in the extremities, aseptic meningitis. If seizures or signs of peripheral neuropathy occur, a physician should be notified immediately.

Eye disorders. Very rare: visual disturbances, diplopia, myopia. Frequency not known: oculogyric crisis, optic neuropathy/neuritis (isolated cases).

Cardiac disorders. Rare: ECG changes such as flattening of the T wave.

Gastrointestinal disorders. Frequency not known: vomiting, nausea, diarrhea, glossitis and stomatitis, bitter eructation, epigastric pain and discomfort, metallic taste in the mouth, coated tongue. Dysphagia (caused by central nervous action of metronidazole).

Hepatobiliary disorders. Very rare: abnormal liver enzyme and bilirubin levels, hepatitis, jaundice, pancreatitis. Frequency not known: in patients with Cockayne syndrome, cases of severe irreversible hepatotoxicity or acute liver failure, including fatal cases with rapid progression after systemic administration of metronidazole, have been observed (see section "Special Instructions").

Skin and subcutaneous tissue disorders. Very rare: allergic skin reactions including pruritus, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis (isolated reports). The last two reactions require immediate treatment. Frequency not known: erythema multiforme.

Musculoskeletal and connective tissue disorders. Very rare: arthralgia, myalgia.

Renal and urinary disorders. Uncommon: dark urine color (due to excretion of metronidazole metabolite).

General disorders and administration site conditions. Frequency not known: venous irritation (up to thrombophlebitis) after intravenous administration, general weakness, fever.

The frequency, type, and severity of adverse reactions in children are the same as in adults.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C, in a place inaccessible to children.

Incompatibilities. This medicinal product must not be mixed with other medicinal products except those specified in the sections "Dosage and Administration" and "Special Instructions".

Packaging. 100 ml of solution in bottles.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of business operations.
84A Nemirovskoye Shose St., Vinnytski Khotory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.