Metrogyl®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METROGYL® (METROGYL®)

Composition:

active substance: metronidazole;

1 ml of solution contains 5 mg of metronidazole;

excipients: sodium chloride; citric acid, monohydrate; sodium hydrogen phosphate, anhydrous; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear solution, colorless to pale yellow.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Imidazole derivatives.

ATC code J01X D01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole is a stable compound capable of penetrating 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) values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), with breakpoints distinguishing 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

Typically susceptible strains

Anaerobes

Bacteroides fragilis

Clostridium difficile°

Clostridium perfringens°∆

Eubacterium

Fusobacterium spp. °

Peptoniphilus spp. °

Peptostreptococcus spp. °

Porphyromonas spp. °

Prevotella spp.

Veillonella spp. °

Other microorganisms

Entamoeba histolytica °

Gardnerella vaginalis °

Giardia lamblia °

Trichomonas vaginalis °

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 of these tables, no data were available. Probable standard reference values and therapeutic recommendations on susceptibility of 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 so far been only partially studied.

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

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

The prevalence of acquired resistance among individual strains may vary depending on region and time. Therefore, specific 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.

Since Metrogyl® is administered intravenously, its bioavailability is 100%.

Distribution

After administration, metronidazole is extensively distributed into body tissues. Metronidazole has been detected in most body tissues and 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 appears in breast milk at concentrations equivalent to serum levels. Protein binding is less than 20%; 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 an acidic oxidation product, a hydroxyl derivative, and a glucuronide conjugate. The main metabolite in serum is the hydroxylated metabolite, while the main urinary metabolite is the acidic one.

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 8 (6–10) hours.

Characteristics in special patient populations

Renal impairment only slightly delays elimination.

In severe hepatic disease, 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).

Treatment is effective in the following cases:

• infections of the central nervous system (CNS), 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 lesions of the abdominal or pelvic cavity;
• gynecological infections, including post-hysterectomy or post-cesarean endometritis, puerperal fever, septic abortion;
• infections of the ear, nose, throat (ENT) and oral cavity, including Vincent's angina (Plaut-Vincent angina);
• bone and joint infections, including osteomyelitis;
• gas gangrene;
• septicemia with thrombophlebitis.

In mixed aerobic and anaerobic infections, appropriate antibiotics for the treatment of aerobic infections should be administered 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 antimicrobial use should be taken into account.

Contraindications.

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

The drug should not be used in combination with disulfiram or alcohol.

Patients with Cockayne syndrome (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

Alcohol

During metronidazole therapy, consumption of alcoholic beverages and medicinal products containing alcohol should be avoided due to the risk of adverse reactions such as dizziness and nausea (disulfiram-like effect).

Amiodarone

Concomitant use of metronidazole and amiodarone has been associated with QT interval prolongation and torsade de pointes. 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.

Antibiotics and sulfonamides

The antimicrobial activity of Metrogyl® is enhanced when used in combination with antibiotics and sulfonamides.

Barbiturates

Phenobarbital may enhance the 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 this interaction has not been fully described. Due to the potential risk of severe toxicity and fatal outcomes associated with elevated busulfan plasma levels, concomitant use with 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 of the latter.

Contraceptives

Some antibiotics may in individual cases reduce the efficacy of oral contraceptives by affecting bacterial hydrolysis of steroid conjugates in the intestine, thereby reducing 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.

Oral anticoagulant therapy

Metronidazole enhances the effects of oral anticoagulants and increases the risk of hemorrhagic complications by slowing their hepatic metabolism. Monitoring of INR (International Normalized Ratio) should be performed more frequently. Dose adjustment of the oral anticoagulant is recommended during metronidazole therapy and for 8 days after its discontinuation.

Special concerns regarding INR

Many cases of increased oral anticoagulant activity have been observed in patients receiving antibiotic therapy. Risk factors may include infectious and inflammatory diseases and general health status. It is difficult to determine the exact role of infection and its treatment in the development of INR imbalance. However, certain types of antibacterial agents require special attention, including fluoroquinolones, macrolides, tetracyclines, clotrimazole, and some cephalosporins.

Cyclosporine

Concomitant treatment with cyclosporine and metronidazole carries a risk of increased serum cyclosporine concentrations. Frequent monitoring of cyclosporine and creatinine levels is required.

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 elevated serum lithium concentrations have been observed during metronidazole therapy. Lithium treatment should be discontinued or withheld prior to metronidazole administration. If patients are taking lithium simultaneously with metronidazole, serum concentrations of lithium, creatinine, and electrolytes should be monitored.

Mycophenolate mofetil

Agents 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 any reduction in the immunosuppressive effect of mycophenolic acid.

Phenytoin

Metronidazole inhibits the metabolism of phenytoin when used concomitantly, leading to decreased plasma concentrations of phenytoin. 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 likely 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 discontinuation of metronidazole therapy in patients stabilized on tacrolimus.

Effect on paraclinical tests

It should be noted that metronidazole may immobilize treponemes, potentially leading to false-positive Nelson test results.

Special precautions for use.

Metronidazole should be administered to patients with severe liver disease or impaired haematopoiesis (including granulocytopenia) only if the expected benefit outweighs the potential risk.

Since metronidazole is primarily metabolized by hepatic oxidation, its clearance may be reduced in patients with impaired liver function. Significant accumulation of metronidazole may occur in patients with hepatic encephalopathy. Due to increased plasma concentrations of metronidazole, symptoms of encephalopathy may worsen. If necessary, the daily dose may be reduced to one-third and administered once daily.

In patients with renal impairment, the elimination half-life of metronidazole remains unchanged; therefore, dose adjustment is not required. However, metabolites of metronidazole may accumulate in such patients. The clinical significance of this is unknown.

Metronidazole should be used with caution in patients with bone marrow disorders or central nervous system (CNS) diseases, as well as in elderly patients.

If there is a history of haematological disorders or when high-dose metronidazole therapy and/or prolonged treatment is required, regular monitoring of white blood cell count is recommended. If leucopenia develops, careful assessment of the expected benefit versus potential risk of continuing treatment is essential.

During prolonged therapy, vigilance is required for the development of adverse effects such as central and peripheral neuropathy (paresthesia, ataxia, dizziness, or seizure).

Metronidazole is not recommended for patients with porphyria.

Treatment with the drug must be discontinued if ataxia, dizziness, or confusion occurs.

It is important to consider the potential risk of worsening neurological status in patients with severe, chronic, or active disorders of the central or peripheral nervous system.

Metronidazole is ineffective against aerobic and facultative anaerobic microorganisms.

During prolonged treatment (more than 10 days), blood counts and liver function tests should be performed.

After treatment for Trichomonas vaginalis, the possibility of gonococcal infection remains.

Metronidazole and its metabolites are removed by haemodialysis within 8 hours. Therefore, patients undergoing haemodialysis should receive an immediate repeat dose of metronidazole after dialysis.

Metronidazole may cause falsely low serum aspartate aminotransferase (AST) levels.

Because of reported carcinogenicity of metronidazole, long-term use of the drug is not recommended.

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

Severe persistent diarrhoea occurring during or shortly after treatment may indicate pseudomembranous colitis (often caused by Clostridium difficile), see section "Adverse reactions". This antibiotic-associated intestinal disorder can be life-threatening and requires immediate appropriate treatment. Medications that inhibit 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 and when clinically necessary may the treatment period be extended, under appropriate clinical and laboratory monitoring. Repeated therapy should be limited to individual cases. These limitations must be strictly observed, as mutagenic activity of metronidazole cannot be excluded, and 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 reported during systemic administration of metronidazole-containing drugs. Metronidazole should not be used in patients in this group, except when the benefit is considered to outweigh the risk and no alternative therapy is available. Liver function should be monitored immediately before starting treatment, during treatment, and after discontinuation until liver function values return to normal or baseline levels. 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 be associated with bone marrow suppression, which may lead to impaired haematopoiesis. Manifestations are described in the section "Adverse reactions". Complete blood counts should be closely monitored during prolonged therapy.

This medicinal product contains 325.9 mg of sodium per 100 ml. Caution is advised when administering the drug to patients on a sodium-restricted diet.

Effect on laboratory tests

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

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

Drug administration may cause immobilization of Treponema, potentially leading to a false-positive Nelson test.

For single use only. Any unused portion should be discarded.

Metrogyl® infusion solution may be diluted with 0.9% sodium chloride solution or 5% glucose solution. Standard aseptic techniques should be followed during dilution.

The solution should be used only if it is clear and the container or packaging shows no visible signs of damage.

The inner container should not be removed from its outer wrapping until immediately before use. The outer wrapping protects the product from moisture. The inner container ensures sterility. After removing the outer wrapping, the container should be gently pressed to check for any leakage. If leakage is detected, the container must be replaced.

Immediately before administration, the vial should be warmed to room temperature or preferably to 37°C.

As soon as possible, intravenous administration should be switched to oral administration (200–400 mg three times daily).

Use during pregnancy or breastfeeding

Pregnancy

The use of this drug is contraindicated during pregnancy.

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

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.

Dosage and Administration

The dose 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 children aged 12 years and older

The usual dose is 500 mg every 8 hours. At the beginning of treatment, a loading dose of 15 mg/kg body weight may be administered when medically indicated.

Children aged 2 to 12 years

7–10 mg metronidazole/kg body weight every 8 hours, corresponding to a daily dose of 20–30 mg metronidazole/kg body weight.

Patients with renal impairment

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

Patients with hepatic impairment

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

Duration of treatment

The duration of treatment depends on its efficacy. In most cases, a 7-day course is sufficient. Treatment may be extended if clinically indicated (see also section "Special Warnings and Precautions for Use").

Pre- and postoperative infection prophylaxis

Adults and children aged 11 years and older

500 mg, administered to be completed approximately 1 hour before surgery. The dose should be repeated at 8 and 16 hours.

Children aged 2 to 11 years

15 mg/kg body weight, administered to be completed approximately 1 hour before surgery, followed by 7.5 mg/kg body weight at 8 and 16 hours.

Method of administration

Administer by intravenous infusion.

The contents of 1 vial should be administered intravenously slowly, i.e., at a rate of no more than 100 mL in at least 20 minutes, but usually over 1 hour.

The drug may also be diluted prior to administration by adding other drugs or diluent solutions such as 0.9% sodium chloride solution for infusion or 5% glucose solution for infusion.

Antibiotics administered concurrently should be given separately.

Children

The drug may be used in children aged 2 years and older when indicated.

Overdose

Symptoms

Overdose may result in adverse effects described in the section "Adverse Reactions", such as nausea, vomiting, dizziness, ataxia, paresthesia, and seizures.

Treatment: symptomatic therapy. There is no specific antidote. Metronidazole is eliminated from the body by hemodialysis.

Adverse Reactions

Unwanted effects are mainly associated with prolonged use of high doses. The most commonly observed are nausea, altered taste sensations, and risk of neuropathy with long-term use.

Infections and infestations: Genital superinfections caused by Candida; pseudomembranous colitis, which may occur during or after therapy and manifest as severe persistent diarrhea. See also section "Special Warnings and Precautions for Use".

Blood and lymphatic system disorders: Granulocytopenia, agranulocytosis, pancytopenia, thrombocytopenia, neutropenia, leukopenia, aplastic anemia.

Regular blood count monitoring is mandatory during prolonged treatment.

Immune system disorders: Hypersensitivity reactions ranging from mild to moderate, including skin reactions (see "Skin and subcutaneous tissue disorders"), nasal congestion, angioedema, and drug fever. Severe systemic hypersensitivity reactions: anaphylaxis up to anaphylactic shock; severe skin reactions (see "Skin and subcutaneous tissue disorders").

Severe reactions require immediate therapeutic intervention.

Metabolism and nutrition disorders: Anorexia.

Psychiatric disorders: Confusional state, irritability, increased excitability, depression, psychotic disorders including hallucinations, decreased libido.

Nervous system disorders: Headache, dizziness, sleep disturbances, somnolence, insomnia, seizures, peripheral neuropathy manifested as paresthesia, pain, heaviness and tingling sensations in the extremities, encephalopathy (confusion, fever, hallucinations, paralysis, photosensitivity, visual and motor disturbances, nuchal rigidity), development of subacute cerebellar syndrome (symptoms include ataxia, dysarthria, gait disturbances, nystagmus, tremor), coordination disorders, aseptic meningitis, transient epileptic seizures.

If adverse effects affecting the CNS or signs of peripheral neuropathy occur, the drug should be discontinued immediately and a physician should be informed.

Eye disorders: Visual disturbances, diplopia, myopia, oculogyric crisis, optic neuropathy.

Cardiac disorders: ECG changes resembling flattening of the T wave.

Gastrointestinal disorders: Vomiting, nausea, diarrhea, constipation, glossitis, stomatitis, bitter eructation, epigastric fullness, epigastric pain, loss of appetite, metallic taste in the mouth, dry mouth, coated tongue, black hairy tongue (e.g., due to excessive fungal flora growth), dysphagia (caused by metronidazole’s effect on the CNS).

Hepatobiliary disorders: Abnormal liver enzyme and bilirubin levels, hepatitis, jaundice, hepatocellular injury, cases of liver failure requiring liver transplantation in patients treated with metronidazole in combination with other antibiotics. Frequency unknown: severe irreversible hepatotoxicity or acute liver failure, including fatal rapidly progressing cases, have been observed in patients with Cockayne syndrome following systemic administration of metronidazole (see section "Special Warnings and Precautions for Use").

Skin and subcutaneous tissue disorders: Allergic skin reactions including pruritus, rash, skin hyperemia, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

The last two reactions require immediate therapeutic intervention.

Musculoskeletal and connective tissue disorders: Arthralgia, myalgia.

Renal and urinary disorders: Dark urine color (due to excretion of metronidazole metabolite), dysuria, cystitis, burning sensation in the urethra, polyuria, enuresis, urinary incontinence, increased risk of vaginal fungal flora (candidiasis).

Endocrine disorders: Dysmenorrhea.

Respiratory, thoracic and mediastinal disorders: Sinusitis, pharyngitis.

General disorders and administration site conditions: Pain, hyperemia or swelling at injection site, venous irritation (up to thrombophlebitis) following intravenous administration, pustular rash, weakness.

Shelf Life.

Shelf life of the medicinal product – 3 years in the original packaging.

Unused contents of the container should be discarded and must not be stored for future use.

Storage Conditions.

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

Keep out of the reach and sight of children.

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the sections "Special Warnings and Precautions for Use" and "Method of Administration and Dosage".

Packaging.

100 ml in single-use plastic bottles, packed in cellophane pouches.

1 bottle per cardboard box.

Prescription Status.

Prescription only.

Manufacturer.

"Unique Pharmaceutical Laboratories" (a division of "J. B. Chemicals & Pharmaceuticals Ltd.") / Unique Pharmaceutical Laboratories (a division of J. B. Chemicals & Pharmaceuticals Ltd.).

Manufacturer's Address and Place of Business.

Plot No. 4, Phase-IV, G.I.D.C. Industrial Estate, City: Panoli – 394 116, Dist: Bharuch, India.