Metronidazole

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

Composition:

Active substance: metronidazole;

1 ml of solution contains 5 mg of metronidazole;

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

Pharmaceutical form. Infusion solution.

Main physico-chemical characteristics: clear, colorless or slightly yellowish liquid.

Pharmacotherapeutic group. Antimicrobial 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 oxidation of ferredoxin and flavodoxin by microbial pyruvate-ferredoxin oxidoreductase. Nitro radicals form adducts with DNA base pairs, leading to DNA strand breaks and cell death.

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible (S) from resistant (R) organisms, 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 data from the German National Reference Center for Monitoring of Antibiotic Resistance, December 2009)

Susceptible microorganisms

Anaerobes:
Bacteroides fragilis, Clostridium difficile 0, Clostridium perfringens 0***⌂***, Fusobacterium spp. 0, Peptoniphilus spp. 0, Peptostreptococcus spp. 0, Porphyromonas spp. 0, Prevotella spp., Veillonella spp. 0

Other microorganisms:
Entamoeba histolytica 0, Gardnerella vaginalis 0, Giardia lamblia 0, Trichomonas vaginalis 0.

Strains capable of developing resistance

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.

0At the time of publication of this list, no standardized susceptibility data were available. Probable reference standards and therapeutic recommendations for the respective strains are provided in primary literature.

⌂ May be used only in patients with penicillin allergy.

Mechanisms of resistance to metronidazole

Mechanisms of resistance to metronidazole are currently only partially understood. Resistance to metronidazole in H. pylori is caused by mutations in genes encoding NADPH-nitroreductase. These mutations lead to amino acid substitutions resulting in enzyme inactivation. Thus, the activation step of metronidazole into an active nitro radical does not occur.

Bacteroides strains resistant to metronidazole possess genes encoding nitroimidazole reductases, which convert nitroimidazoles into aminoimidazoles, thereby inhibiting the formation of antibacterial active nitro radicals. There is complete cross-resistance 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 used, especially for effective treatment of severe infections. If there is any doubt regarding metronidazole efficacy, expert advice should be sought. Microbiological diagnosis, including identification of microbial strains and 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 approach those in plasma. 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.

Metabolism

Metronidazole is metabolized in the liver via side-chain oxidation and glucuronide formation. Its metabolites include the acid oxidation product, hydroxylated derivative, and glucuronide. 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 by the liver. The elimination half-life is 6–10 hours.

Characteristics in special patient populations

Renal impairment causes only slight delay in elimination.

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

Clinical characteristics.

Indications.

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

Metronidazole is active against a broad spectrum of pathogenic microorganisms, particularly species of Bacteroides, Fusobacteria, Clostridia, Eubacteria, anaerobic cocci, and Gardnerella vaginalis.

Metronidazole is indicated in adults and children for:

• prophylaxis of postoperative infections caused by anaerobic bacteria, particularly species of Bacteroides and anaerobic species of Streptococci;
• treatment of sepsis, bacteremia, peritonitis, brain abscess, necrotic pneumonia, osteomyelitis, postpartum sepsis, intra-abdominal pelvic abscess, pelvic cellulitis, and postoperative wound infection – when pathogenic anaerobes have been isolated.

When using metronidazole, national and international guidelines on appropriate use of antimicrobial agents should be taken into account.

Contraindications.

• Hypersensitivity to metronidazole, other nitroimidazole derivatives, or any of the excipients;
• organic disorders of the central nervous system (CNS);
• blood disorders;
• hepatic impairment (if high doses of the drug are required).

The use of the drug in combination with disulfiram or alcohol is not recommended.

Interaction with other medicinal products and other forms of interaction.

Disulfiram

Concomitant administration of disulfiram and metronidazole may cause confusion and psychotic reactions. Metronidazole should not be administered to patients who have taken disulfiran within the last two weeks.

Alcohol

Alcoholic beverages and medicinal products containing alcohol should be avoided. Patients should be advised not to consume alcohol during metronidazole therapy and for at least 72 hours after completion of treatment due to the possibility of a disulfiram-like reaction (antabuse effect) (flushing, vomiting, tachycardia).

Combinations requiring precautions during use

Oral anticoagulants (warfarin)

There have been reports of some potentiation of anticoagulant effect when metronidazole is used concomitantly with warfarin and other oral anticoagulants, and of increased risk of hemorrhagic complications due to slowed hepatic metabolism. Prothrombin time (PT) and international normalized ratio (INR) should be monitored more frequently. Patients should be monitored for signs and symptoms of bleeding. Dose adjustment of the oral anticoagulant is recommended during metronidazole therapy and for 8 days after its discontinuation. No interaction occurs with heparin.

Numerous cases of increased activity of oral anticoagulants have been observed in patients receiving antibiotics concurrently. Risk factors may include infectious and inflammatory diseases, advanced age, and poor general health. It is difficult to determine whether the prolonged PT is due to the infectious disease itself or its treatment. However, use of certain antibacterial agents requires special attention. These include fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and certain cephalosporins.

Vecuronium

Metronidazole may enhance the effect of vecuronium (a non-depolarizing curare-like neuromuscular blocker).

Combinations with warnings

Fluorouracil

Metronidazole reduces the clearance of 5-fluorouracil and may therefore lead to increased toxicity of 5-fluorouracil.

Lithium

In patients receiving lithium and metronidazole concurrently, lithium retention has been observed, accompanied by signs of renal impairment. Lithium therapy should be restricted or discontinued prior to initiating metronidazole. In patients receiving both lithium and metronidazole, monitoring of lithium, creatinine, and electrolyte concentrations in serum is required.

Cholestyramine

Cholestyramine may delay or reduce absorption of metronidazole.

Phenytoin and barbiturates (phenobarbital)

With concomitant use of drugs that stimulate hepatic microsomal enzyme activity, such as phenobarbital or phenytoin, the metabolism of metronidazole is significantly accelerated, thus reducing its half-life to approximately 3 hours and consequently decreasing metronidazole efficacy.

Cimetidine

Concomitant use of drugs that reduce hepatic microsomal enzyme activity, such as cimetidine, may in individual cases reduce metronidazole elimination and thereby lead to increased metronidazole serum concentrations, which in turn may increase metronidazole toxicity.

CYP3A4 substrates

When metronidazole is used concomitantly with CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, quinidine), increased plasma levels of the respective CYP3A4 substrates may occur. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.

Amiodarone

Cases of QT interval prolongation and development of paroxysmal torsade de pointes ventricular tachycardia have been reported with concomitant use of metronidazole and amiodarone. Monitoring of the QT interval on ECG may be advisable when amiodarone is used in combination with metronidazole. Outpatients should be advised to seek medical attention if symptoms suggestive of torsade de pointes occur, such as dizziness, rapid heartbeat, or loss of consciousness.

Tacrolimus

Concomitant use of metronidazole and tacrolimus may lead to increased blood concentrations of tacrolimus. The likely mechanism is 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.

Cyclosporine

Patients receiving cyclosporine in combination with metronidazole are at risk of increased serum cyclosporine levels. If combination therapy is necessary, careful monitoring of cyclosporine and serum creatinine levels is required.

Carbamazepine

Metronidazole may inhibit the metabolism of carbamazepine and thereby increase its plasma concentrations.

Busulfan

Metronidazole may increase plasma levels of busulfan, potentially leading to severe busulfan toxicity, which may manifest as sinusoidal obstruction syndrome (veno-occlusive liver disease) and gastrointestinal mucositis.

Contraceptives

Some antibiotics may in individual cases reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the gut, thereby reducing reabsorption of unconjugated steroids and leading to decreased plasma levels of active steroids. This unusual interaction may occur in women with high biliary excretion of steroid conjugates. Cases of failure of oral contraceptives have been associated with use of various antibiotics, including ampicillin, amoxicillin, tetracyclines, and also metronidazole.

Mycophenolate mofetil

Substances that alter gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid preparations. During anti-infective therapy, careful clinical and laboratory monitoring is recommended to detect reduced immunosuppressive effect of mycophenolic acid.

Effect on paraclinical tests

It should be remembered that metronidazole may immobilize treponemes, which may cause a false-positive Nelson test result.

Special precautions for use.

Hepatic impairment

Metronidazole should be used with caution in patients with severe hepatic impairment and only if the expected benefit outweighs the potential risk.

Metronidazole is generally metabolized by hepatic oxidation. A significant reduction in metronidazole clearance may occur in patients with severe hepatic impairment. The benefit-risk ratio of metronidazole use for the treatment of trichomoniasis in such patients should be carefully evaluated (for dose adjustment, see section "Posology and method of administration"). Plasma metronidazole levels should be closely monitored.

In patients with severe hepatic encephalopathy, metronidazole plasma concentrations may increase, potentially exacerbating encephalopathy symptoms. Therefore, metronidazole should be administered with caution in patients with hepatic encephalopathy. If necessary, the daily dose should be reduced to ⅓ and administered once daily.

Cockayne syndrome

Rapid onset of severe hepatotoxicity / acute liver failure, including fatal cases, has been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medicinal products. Metronidazole should be used in this patient group only when the expected benefit outweighs the potential risk and no alternative treatment is available.

Liver function should be monitored immediately before initiating treatment, during treatment, and after treatment completion until liver function parameters return to normal or baseline values. If liver function tests show markedly elevated values during metronidazole therapy, 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 "Undesirable effects").

Neurological disorders

Metronidazole should be used with caution in patients with epilepsy or active or chronic severe disorders of the peripheral or central nervous system (CNS) with reduced seizure threshold due to the risk of neurological exacerbation.

Serious neurological disorders (seizures, peripheral and optic neuropathies) have been reported in patients receiving metronidazole. If abnormal neurological symptoms such as ataxia, dizziness, confusion, or other CNS symptoms occur, metronidazole therapy should be discontinued.

The risk of worsening neurological status should be considered in patients with persistent or progressive paresthesia, epilepsy, or CNS disorders in an acute phase, except for brain abscess.

Cases of encephalopathy due to toxic effects of metronidazole on the cerebellum have been reported, with characteristic symptoms (ataxia, dizziness, dysarthria) and corresponding changes on magnetic resonance imaging (MRI). In most cases, encephalopathy and MRI changes resolved within several days or weeks after discontinuation of metronidazole.

Aseptic meningitis may develop during metronidazole therapy. Symptoms may appear within several hours after metronidazole administration and usually resolve after discontinuation of the drug (see section "Undesirable effects").

Severe bullous skin reactions

Cases of severe bullous skin reactions, sometimes fatal, such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or acute generalized exanthematous pustulosis (AGEP), have been reported with metronidazole use (see section "Undesirable effects"). SJS typically occurred within 7 weeks of starting metronidazole therapy. Patients should be informed about the signs and symptoms of severe bullous skin reactions and closely monitored for skin manifestations. If symptoms of SJS, TEN, or AGEP (e.g., influenza-like symptoms, progressive skin rashes, often with blisters or mucosal lesions) are present, treatment should be immediately discontinued.

Clostridium difficile-associated disease

Severe persistent diarrhea occurring during or within weeks after treatment may be due to pseudomembranous colitis (often caused by Clostridium difficile) – see section "Undesirable effects". This antibiotic-associated intestinal disorder may be life-threatening and requires immediate appropriate treatment. Antiperistaltic agents should not be used.

Porphyria

Metronidazole is not recommended for patients with porphyria.

Hematopoietic disorders

Metronidazole should be used with caution in patients with impaired hematopoiesis and only if the expected benefit outweighs the potential risk, as cases of agranulocytosis, leukopenia (including granulocytopenia), and neutropenia have been observed after metronidazole administration.

Renal impairment

In patients with renal impairment, the elimination half-life of metronidazole remains unchanged; therefore, dose reduction is not necessary. However, such patients retain metronidazole metabolites. The clinical significance of this is currently unknown.

In patients undergoing hemodialysis, metronidazole and its metabolites are effectively removed during an 8-hour dialysis session. Therefore, metronidazole should be immediately re-administered after hemodialysis.

For patients with renal impairment undergoing intermittent peritoneal dialysis (IPD) or continuous ambulatory peritoneal dialysis (CAPD), no dose adjustment of metronidazole is required.

Patients with renal impairment, including those undergoing peritoneal dialysis, should be monitored for signs of toxicity due to potential accumulation of toxic metronidazole metabolites.

Microbial susceptibility

Metronidazole has no direct activity against aerobic or facultative anaerobic bacteria.

There is a possibility that gonococcal infection may persist after eradication of Trichomonas vaginalis.

Hypersensitivity reactions

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

Alcohol

Patients should be advised to avoid alcohol-containing beverages or products before, during, and for at least 72 hours after metronidazole administration due to the possibility of a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headache, flushing, and tachycardia) (see section "Interaction with other medicinal products and other forms of interaction").

Intensive or prolonged metronidazole therapy

The duration of intravenous metronidazole therapy or other nitroimidazole derivatives should not exceed 10 days. Due to the risk of mutagenicity in humans, the appropriateness of metronidazole use for longer than usual periods must be carefully evaluated. Only in exceptional cases, when urgently needed and after benefit-risk assessment, may the treatment period be extended under medical supervision with 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 (e.g., damage to human germ cells) cannot be excluded, and due to increased incidence of certain tumors observed in animal studies.

If prolonged therapy is necessary, the physician should pay special attention to the development of adverse reactions such as peripheral or central neuropathy (symptoms include paresthesia, ataxia, dizziness, seizures) or leukopenia. Peripheral neuropathy and leukopenia are usually reversible. Leukopenia treatment may be continued only if the expected benefit clearly outweighs the potential risk.

High-dose metronidazole has been associated with transient epileptic seizures.

Monitoring

Due to increased risk of adverse reactions, regular clinical and laboratory monitoring (including complete blood count, particularly leukocyte count) is recommended in the following cases: high-dose or prolonged metronidazole therapy, history of hematopoietic disorders, severe infectious disease, and severe hepatic impairment. Monitoring is mandatory if metronidazole administration continues beyond 10 days.

Elderly patients

Metronidazole should be used with caution in elderly patients.

Effect on laboratory test results

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

Metronidazole interferes with enzymatic spectrophotometric determination of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, triglycerides, and glucose-hexokinase, reducing their measured values (possibly to zero).

Other special considerations

Patients should be informed that metronidazole may cause darkening of urine (due to a metronidazole metabolite).

Excipients

This medicinal product contains 12 mmol (or 276.61 mg) of sodium per 100 ml of solution, which should be taken into account when prescribing to patients on a controlled sodium diet.

Compatibility

Metronidazole medicinal product can be diluted in 0.9% sodium chloride solution or 5% glucose solution.

Use during pregnancy or breastfeeding.

Pregnancy

Metronidazole crosses the placental barrier.

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 or fetotoxic effects of metronidazole. However, unrestricted administration of nitroimidazoles to the mother may be associated with carcinogenic or mutagenic risk to the fetus or newborn.

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 infections (e.g., trichomoniasis) if the expected benefit to the mother clearly outweighs the potential risk to the fetus; however, short-course, high-dose regimens should not be used in these cases.

Lactation

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

Ability to influence reaction speed while driving or operating machinery.

Patients should be warned about the possible occurrence of somnolence, dizziness, confusion, hallucinations, seizures, or transient visual disturbances, which may impair the ability to drive or operate machinery. These adverse reactions usually occur at the beginning of treatment.

Method of Administration and Dosage

Metronidazole should be administered intravenously at a rate of 5 ml/min.

Pre- and postoperative infection prophylaxis: primarily in abdominal (especially colorectal) and gynecological surgery.

Adults: 500 mg administered immediately before surgery, with infusion completed approximately 1 hour prior to surgery. Repeat the dose every 8 hours.

Children

Children < 12 years: single dose of 20–30 mg/kg, with infusion completed approximately 1 hour before surgery.

Neonates with gestational age <40 weeks: single dose of 10 mg/kg body weight before surgery.

Anaerobic infections

Duration of treatment depends on its effectiveness. In most cases, a 7-day course is sufficient. Treatment may be extended in the presence of clinical indications (e.g., eradication of infection from organs inaccessible to drainage, risk of endogenous contamination by aerobic pathogens from the intestine, oropharynx, or genital tract).

Treatment of established anaerobic infections

Adults: 500 mg every 8 hours.

Children

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. Treatment duration is usually 7 days.

Children aged < 8 weeks: 15 mg/kg/day as a single dose or 7.5 mg/kg every 12 hours.

In neonates with gestational age < 40 weeks, metronidazole accumulation may occur during the first week of life; therefore, monitoring of serum metronidazole concentrations is advisable after several days of treatment.

Bacterial vaginosis

Adolescents: 400 mg twice daily for 5–7 days or a single dose of 2000 mg.

Urogenital trichomoniasis

Adults and adolescents: 2000 mg as a single dose, or 200 mg three times daily for 7 days, or 400 mg twice daily for 5–7 days.

Children aged < 10 years: 40 mg/kg as a single dose or 15–30 mg/kg/day divided into 2–3 doses for 7 days; do not exceed 2000 mg per dose.

Giardiasis

Patients aged > 10 years: 2000 mg once daily for 3 days, or 400 mg three times daily for 5 days, or 500 mg twice daily for 7–10 days.

Children aged 7 to 10 years: 1000 mg once daily for 3 days.

Children aged 3 to 7 years: 600–800 mg once daily for 3 days.

Children aged 1 to 3 years: 500 mg once daily for 3 days.

Alternatively, administer 15–40 mg/kg/day divided into 2–3 doses.

Amebiasis

Patients aged > 10 years: 400–800 mg three times daily for 5–10 days.

Children aged 7 to 10 years: 200–400 mg three times daily for 5–10 days.

Children aged 3 to 7 years: 100–200 mg four times daily for 5–10 days.

Children aged 1 to 3 years: 100–200 mg three times daily for 5–10 days.

Alternatively, administer 35–50 mg/kg/day divided into 3 doses for 5–10 days, not exceeding 2400 mg/day.

Helicobacter pylori eradication in pediatric patients

Use as part of combination therapy at 20 mg/kg/day, not exceeding a maximum daily dose of 1000 mg, divided into two doses for 7–14 days. Official guidelines should be consulted before initiating treatment.

Elderly patients

Caution is recommended in elderly patients, especially when high doses are used.

Children

May be used from the first days of life.

Overdose

Cases of single oral doses of metronidazole up to 12 g have been reported in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia, and mild disorientation. There is no specific antidote for metronidazole overdose. In suspected overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

Unwanted effects are mainly associated with prolonged use of high doses.

When planning long-term treatment, the benefit should be weighed against the risk of developing peripheral neuropathy.

Adverse reactions are classified by organ systems according to MedDRA terminology. The following criteria are used to describe the frequency of adverse effects: very common: ≥ 1/10; common: ≥ 1/100 – < 1/10; uncommon: ≥ 1/1000 – < 1/100; rare: ≥ 1/10,000 – < 1/1000; very rare: < 1/10,000; frequency not known: cannot be estimated based on available data.

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

Infections and infestations

Rare: genital superinfections caused by Candida species.

Very rare: pseudomembranous colitis, which may occur during or after therapy and manifest as severe persistent diarrhea.

Blood and lymphatic system disorders

Uncommon: leukopenia.

Rare: agranulocytosis, pancytopenia, neutropenia, thrombocytopenia.

Frequency not known: eosinophilia, aplastic anemia.

Immune system disorders

Uncommon: mild to moderate hypersensitivity reactions, including skin reactions (see below "Skin and subcutaneous tissue disorders"), angioedema, and drug fever.

Rare: anaphylactic shock, Jarisch-Herxheimer reaction.

Very rare: severe systemic hypersensitivity reactions: anaphylaxis, severe skin reactions.

Frequency not known: Quincke's edema, urticaria, fever.

Metabolism and nutrition disorders

Frequency not known: decreased appetite, anorexia.

Psychiatric disorders

Uncommon: irritability.

Rare: hallucinations.

Very rare: psychotic disorders, including confusion.

Frequency not known: depression, decreased libido.

Nervous system disorders

Common: dysgeusia.

Uncommon: headache.

Rare: encephalopathy (e.g., confusion, fever, headache, hallucinations, paralysis, photophobia, visual and motor disturbances, torticollis) and subacute cerebellar syndrome (e.g., ataxia, dysarthria, gait disturbances, nystagmus, tremor), which may resolve after discontinuation of the drug; drowsiness or insomnia; dizziness; seizures; peripheral neuropathy manifesting as paresthesia, pain, heaviness, and tingling in the extremities; aseptic meningitis.

Frequency not known: paresthesia, hypoesthesia, peripheral sensory neuropathy, transient epileptiform seizures during intensive and/or prolonged metronidazole therapy. In most cases, neuropathy resolved after discontinuation of treatment or dose reduction.

Eye disorders

Rare: optic neuropathy; visual disturbances such as diplopia and myopia, which are mostly transient.

Frequency not known: optic neuritis.

Ear and labyrinth disorders

Frequency not known: vertigo, hearing disturbances / hearing loss (including sensorineural), tinnitus.

Cardiac disorders

Very rare: ECG changes resembling T-wave flattening.

Frequency not known: tachycardia, palpitations.

Respiratory, thoracic and mediastinal disorders

Common: sinusitis, pharyngitis.

Frequency not known: dyspnea, suffocation.

Gastrointestinal disorders

Common: glossitis, stomatitis, dry mouth.

Uncommon: bitter eructation.

Rare: vomiting, nausea, diarrhea; epigastric pain; pancreatitis, which is reversible upon discontinuation of the drug.

Frequency not known: taste disturbances, oral mucositis, coated tongue, tongue discoloration, constipation.

Hepatobiliary disorders

Rare: cholestatic jaundice.

Very rare: elevated liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase), cholestatic or mixed hepatitis, and hepatocellular liver damage. Cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole in combination with other antibacterial agents.

Skin and subcutaneous tissue disorders

Uncommon: allergic skin reactions.

Rare: SJS, TEN, polymorphic erythema.

Very rare: skin rashes, pustular eruptions, pruritus, erythema, AGEP.

Frequency not known: hyperhidrosis.

Musculoskeletal and connective tissue disorders

Common: myalgia.

Very rare: joint pain.

Frequency not known: muscle spasms.

Renal and urinary disorders

Rare: chromaturia.

Very rare: dysuria, cystitis, urinary incontinence, darkening of urine (due to metronidazole metabolite).

Reproductive system and breast disorders

Common: dysmenorrhea.

General disorders and administration site conditions

Uncommon: asthenia.

Common: reactions at the administration site, including venous irritation (up to thrombophlebitis) after intravenous administration, pustular rash.

Rare: weakness, mucosal inflammation, pyrexia.

Frequency not known: malaise, peripheral edema, chest pain, chills.

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 administration, have been reported in patients with Cockayne syndrome (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

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

Incompatibilities.

The medicinal product Metronidazole must not be mixed with cefamandole nafate, cefoxime sodium, 10% dextrose IV, in combination with sodium lactate injection, or penicillin G potassium (brand name Pfizerpen).

Packaging.

100 ml in glass bottles.

100 ml in polymer bottles.

Prescription status. Prescription only.

Manufacturer.

TOV "Yuria-Farm".

Manufacturer's address and location of business activity.

108, Kobzarska Street, Cherkasy, Cherkasy region, 18030, Ukraine. Tel.: (044) 281-01-01.