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

Composition:

Active ingredient: metronidazole;

100 ml of solution contain 500 mg of metronidazole;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or pale yellow solution.

Pharmacotherapeutic group.

Antibacterials 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 bases, leading to DNA strand breakage and cell death.

The minimum inhibitory concentration (MIC) has been defined by EUCAST (European Committee on Antimicrobial Susceptibility Testing). The breakpoints distinguishing susceptible organisms (S) from resistant ones (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 Antibiotic Resistance Testing, January 2011)

Typically susceptible strains

Anaerobes: Bacteroides fragilis, Clostridium difficile¹, Clostridium perfringens^1,2, Fusobacterium spp.¹, Peptoniphilus spp.¹, Peptostreptococcus spp.¹, Porphyromonas spp.¹, Prevotella spp., Veillonella spp.¹.

Other microorganisms: Entamoeba histolytica¹, Gardnerella vaginalis¹, Giardia lamblia¹, Trichomonas vaginalis¹.

Strains for which acquired resistance may be an issue

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.

¹ At the time of publication of this information, no data were available. Primary literature provides probable standard reference values and therapeutic recommendations regarding susceptibility of the respective strains.

² May be used only in patients with penicillin allergy.

Mechanisms of resistance to metronidazole

Mechanisms of resistance to metronidazole have so far been only partially elucidated.

Resistance of Helicobacter pylori to metronidazole 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 that 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. In case of doubts regarding metronidazole efficacy due to local resistance patterns, 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.

Absorption

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

Distribution

After administration, metronidazole is widely distributed into body tissues. Metronidazole has been detected in most tissues and body fluids, including bile, bone, cerebral 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.

Metabolism

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

Elimination

Approximately 80% of the substance 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.

Paediatric population

See section "Posology and method of administration".

Characteristics in special patient groups

Renal impairment only slightly delays 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 the following indications:

Central nervous system (CNS) 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, purulent infections of the abdominal or pelvic cavity);
Gynecological infections (including endometritis after hysterectomy or cesarean section, 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.

In mixed aerobic and anaerobic infections, appropriate antibiotics effective against aerobic organisms should be used in addition to metronidazole.

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

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

Contraindications.

Hypersensitivity to metronidazole, other drugs with similar chemical structure (nitroimidazoles), or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Amiodarone

Cases of QT interval prolongation and torsade de pointes have been reported during 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.

Barbiturates

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

Busulfan

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

Carbamazepine

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

Cimetidine

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

Contraceptives

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

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

Disulfiram

Concomitant use of disulfiram may cause confusion or even psychotic reactions. Combination of these drugs 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 metronidazole is used concomitantly with lithium salts, as increased 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 used concomitantly, leading to increased plasma phenytoin concentrations. Conversely, the efficacy of metronidazole may be reduced when used concomitantly with phenytoin.

Tacrolimus

Concomitant use of metronidazole may lead to increased blood concentrations of tacrolimus. This is likely due to 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 discontinuation of metronidazole in patients stabilized on tacrolimus therapy.

Alcohol

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

Special precautions for use.

Metronidazole should be administered to patients with severe liver impairment or hematopoietic disorders (including granulocytopenia) only if the expected benefit outweighs the potential risk.

Due to the risk of worsening of the condition, metronidazole should be used in patients with active or chronic severe disorders of the peripheral or central nervous system (CNS) only if the expected benefit significantly outweighs the potential risk.

Seizures and peripheral neuropathy characterized by numbness or paresthesia of extremities have been reported in patients receiving metronidazole therapy. The development of neurological disorders requires immediate reassessment of the benefit-risk ratio for continuing treatment (see section "Adverse reactions").

In case of severe hypersensitivity reactions (including anaphylactic shock) (see section "Adverse reactions"), metronidazole therapy must be discontinued immediately, and qualified medical personnel should initiate appropriate emergency treatment.

Severe persistent diarrhea occurring during or shortly after treatment may be a sign of pseudomembranous colitis (in many cases caused by Clostridium difficile) (see section "Adverse reactions"). This antibiotic-associated intestinal disorder may be life-threatening and requires immediate appropriate treatment. Medications that inhibit peristalsis must not be used.

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

Prolonged metronidazole therapy may be associated with bone marrow suppression, which can lead to hematopoietic disorders (see section "Adverse reactions"). Blood cell counts should be carefully monitored during long-term use.

Special warnings regarding certain excipients

This medicinal product contains 790 mg of sodium per dose. Caution is advised when administering to patients on a sodium-restricted diet.

Hepatotoxicity in patients with Cockayne syndrome

Cases of rapid development of severe hepatotoxicity/acute liver failure, including fatal outcomes, have been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medications.

Metronidazole should not be used in patients of this group, except when the benefit is considered to outweigh the risk and only if no alternative treatment is available.

Liver function should be monitored immediately before starting treatment, during treatment, and after completion of therapy until liver function parameters return to normal or baseline values. 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").

Effect on laboratory parameters

Metronidazole interferes with enzymatic spectrophotometric assays for aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides, and glucose-hexokinase, leading to decreased values (possibly down to zero).

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

Use during pregnancy or breastfeeding.

Contraception in men and women

See section "Interaction with other medicinal products and other forms of interaction".

Pregnancy

The safety of metronidazole use during pregnancy has not been fully established. In particular, reports on its use during early pregnancy are conflicting. Some studies have reported an increased frequency of congenital malformations. Animal studies have not shown teratogenic effects of metronidazole.

During the first trimester of pregnancy, 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 if the expected benefit to the mother clearly outweighs the potential risk to the fetus.

Breastfeeding period

Since metronidazole is excreted in breast milk, breastfeeding should be discontinued during treatment. Breastfeeding should not be resumed earlier than 2–3 days after completion of therapy, due to the prolonged elimination half-life of metronidazole.

Fertility

Preclinical studies indicate a potential negative effect of metronidazole on the male reproductive system only when high doses, significantly exceeding the maximum recommended human dose, are administered.

Ability to affect reaction speed when driving or operating machinery.

Even when following the recommended dosing regimen, metronidazole may affect reaction speed and thus impair the ability to drive or operate machinery. This effect is most commonly observed at the beginning of treatment or when alcohol is consumed concurrently.

Administration and Dosage.

The dosage of the medicinal product should be adjusted according to the individual patient's response to treatment, age, body weight, and the type and severity of the disease.

The following dosage recommendations 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 approximately 1 hour before surgery. Repeat the dose after 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 less than 40 weeks, accumulation of metronidazole may occur during the first week of life; therefore, monitoring of metronidazole serum 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 gestational age under 40 weeks: 10 mg/kg as a single dose before surgery.

Patients with renal impairment

Dosage 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 elimination half-life of metronidazole in serum 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, i.e., at least 20 minutes for 100 ml, usually over 1 hour. Metronidazole may be diluted in 0.9% sodium chloride solution or 5% glucose solution. Antibiotics administered concomitantly should be given separately.

Children.

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

Overdose.

Symptoms: adverse reactions described in the section "Adverse reactions" may occur in case of overdose.

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

Side effects.

Side effects are mainly associated with prolonged use of the medicinal product or administration of high doses. The most commonly observed adverse effects are nausea, taste disturbances, and risk of neuropathy with long-term use.

The frequency of adverse reactions 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 from available data).

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. A detailed description of emergency management is provided in the section "Special precautions for use".

Blood and lymphatic system disorders. Very rare: during treatment with metronidazole, decreased counts of leukocytes and platelets (granulocytopenia, agranulocytosis, pancytopenia, and thrombocytopenia) (see section "Special precautions for use"). Frequency not known: leukopenia, aplastic anemia.

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 and moderate hypersensitivity reactions, including skin reactions (see below "Skin and subcutaneous tissue disorders"), angioedema.

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, excitation, drowsiness, dizziness, visual and motor disturbances, vertigo, ataxia, dysarthria, seizures. Frequency not known: drowsiness or insomnia, myoclonus, seizure attacks, peripheral neuropathy manifesting as paresthesia, pain, heaviness, and tingling sensations in the extremities, aseptic meningitis. In case of seizures or signs of peripheral neuropathy, immediate medical attention is required (see section "Special precautions for use").

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

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

Gastrointestinal disorders. Frequency not known: vomiting, nausea, diarrhea, glossitis and stomatitis, bitter regurgitation, 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.

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

Skin and subcutaneous tissue disorders. Very rare: allergic skin reactions including pruritus, urticaria, Stevens-Johnson syndrome. Frequency not known: toxic epidermal necrolysis. 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) following intravenous administration, general weakness, fever.

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions occurring after marketing authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Unused medicinal product and waste material should be disposed of properly.

Incompatibilities.

Metronidazole for intravenous infusion is not recommended to be mixed with other medicinal products except those specified in the section "Method of administration and dosage".

Packaging. 100 ml of solution in containers. 1 container in a pouch inside a carton.

Prescription status. Prescription only.

Manufacturer. EuroLife Healthcare Pvt. Ltd.

Manufacturer's address.

Plot No. 520, Bhagwanpur, Roorkee, Haridwar, Uttarakhand, India.

Marketing Authorization Holder. Ananta Medikare Ltd.

Address of Marketing Authorization Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.