Metronidazole-novopharm

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

Composition:

Active substance: metronidazole;

1 ml of solution contains 5 mg of metronidazole;

Excipients: sodium chloride; sodium dihydrogen phosphate dihydrate; citric acid monohydrate; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellowish-green solution.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Imidazole derivatives. ATC code J01XD01.

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 breakage and cell death.

The minimal inhibitory concentration (MIC) has been established by the European Committee on Antimicrobial Susceptibility Testing. The 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
(According to data from the German National Reference Center for Surveillance of Antibiotic Resistance, December 2009)

Anaerobes: Bacteroides fragilis, Clostridium difficile*0*, Clostridium perfringens*0* Δ, 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 with potential acquired resistance issues:

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.

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

Δ Can only be used in patients with penicillin allergy.

Mechanisms of resistance to metronidazole

Mechanisms of resistance to metronidazole are currently only partially understood. 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 inactivity. Consequently, the activation step of metronidazole into the 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 susceptibility of individual strains may vary depending on region and over time. Therefore, region-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. 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 widely distributed and metabolized in 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 blood 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%. The apparent volume of distribution is 36 liters.

Biotransformation

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

Elimination

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

Characteristics in special patient groups

Renal impairment only slightly delays elimination.

In severe liver disease, a reduction in plasma clearance and prolongation of the serum elimination half-life (up to 30 hours) should 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:

• 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, purulent abdominal or pelvic infections;
• Gynecological infections (including endometritis after hysterectomy or cesarean section, puerperal fever, septic abortion);
• Otorhinolaryngological and oral infections (including Simanovsky-Plaut-Vincent angina);
• Bone and joint infections (including osteomyelitis);
• Gas gangrene;
• Sepsis associated with thrombophlebitis.

In mixed aerobic and anaerobic infections, appropriate additional antibiotics should be administered to treat aerobic infections.

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

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

Interaction with other medicinal products and other forms of interaction.

Patients should be advised to avoid alcohol during metronidazole treatment and for at least 48 hours after completion of therapy due to the risk of a disulfiram-like reaction (antabuse effect). Psychotic reactions have been reported in patients receiving metronidazole and disulfiram concurrently.

Antibiotics and sulfonamides. The antimicrobial activity of Metronidazole-NovoFarm is enhanced when used in combination with antibiotics and sulfonamides.

Oral anticoagulant therapy. Enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications due to slowed 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 discontinuation.

Specific issues regarding INR (International Normalized Ratio).

Numerous cases of increased activity of oral anticoagulants have been observed in patients undergoing antibiotic therapy. Risk factors may include infectious and inflammatory diseases and general health status. It is difficult to determine the role of infectious pathology and its treatment on INR fluctuations. However, certain antibacterial agents require particular attention, including fluoroquinolones, macrolides, tetracyclines, clotrimazole, and some cephalosporins.

Prothrombin level monitoring is necessary. There is no interaction with heparin.

In patients receiving lithium and metronidazole concurrently, lithium retention has been observed, accompanied by signs of possible renal damage. Lithium therapy should be limited or discontinued before initiating metronidazole. For patients on lithium therapy, monitoring of plasma lithium concentrations, creatinine, and electrolytes is necessary during metronidazole treatment.

Phenytoin and phenobarbital: when phenobarbital or phenytoin is administered, metronidazole metabolism is significantly accelerated, resulting in a shortened elimination half-life of approximately 3 hours.

Metronidazole reduces the clearance of 5-fluorouracil and may consequently increase 5-fluorouracil toxicity.

Patients receiving cyclosporine are at risk of elevated plasma cyclosporine levels. If combination therapy is necessary, careful monitoring of cyclosporine and serum creatinine levels is required.

Metronidazole may increase plasma levels of busulfan, potentially leading to severe busulfan toxicity.

Amiodarone

When metronidazole is used concomitantly with amiodarone, QT interval prolongation and torsade de pointes have been reported. ECG monitoring of the QT interval 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.

Carbamazepine

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

Cimetidine

Concomitant use of cimetidine may in individual cases reduce metronidazole elimination and consequently lead to increased serum concentrations of metronidazole.

Contraceptives

Some antibiotics may in rare 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 oral contraceptive failure have been reported with various antibiotics, including ampicillin, amoxicillin, tetracyclines, and metronidazole.

Mycophenolate mofetil

Agents that alter gastrointestinal flora (e.g., antibiotics) may reduce the oral bioavailability of mycophenolic acid formulations. During anti-infective therapy, careful clinical and laboratory monitoring is recommended to detect a potential reduction in the immunosuppressive effect of mycophenolic acid.

Tacrolimus

Concomitant use of metronidazole 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 discontinuation of metronidazole in patients stabilized on tacrolimus therapy.

Effect on serological tests

It should be remembered that metronidazole can immobilize treponemes, potentially leading to a false-positive Nelson test.

Special precautions for use

Metronidazole should be prescribed with caution to patients with epilepsy or central nervous system (CNS) disorders associated with a lowered seizure threshold.

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

Alcohol consumption should be avoided during treatment, as it may provoke a disulfiram-like reaction: spastic abdominal pain, nausea, vomiting, headache, and flushing.

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

If there is a history of haematological disorders, or when high-dose metronidazole therapy is used and/or prolonged treatment is required, regular monitoring of white blood cell count is recommended.

Clinical or laboratory monitoring (especially white blood cell count) is recommended. If metronidazole administration continues for more than 10 days, monitoring becomes mandatory. Particular attention should be paid to adverse reactions such as peripheral or central neuropathy (symptoms include paraesthesia, ataxia, dizziness, and seizures).

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

In case of severe hypersensitivity reactions (including anaphylactic shock), metronidazole therapy must be discontinued immediately and appropriate emergency treatment 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 may be life-threatening and requires immediate appropriate treatment. Medications that inhibit peristalsis must not be used.

Metronidazole should be used with caution in patients with active or chronic severe disorders of the peripheral or central nervous system due to the risk of neurological exacerbation.

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

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

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

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

Metronidazole is primarily metabolized via hepatic oxidation. A significant reduction in metronidazole clearance may occur in the presence of hepatic insufficiency. In patients with hepatic encephalopathy, plasma concentrations of metronidazole may increase.

Therefore, metronidazole should be administered with caution to patients with hepatic encephalopathy.

The daily dose should be reduced to one-third of the standard dose and administered once daily.

Hepatotoxicity in patients with Cockayne syndrome

Cases of rapid onset of severe hepatotoxicity / acute liver failure, including fatal outcomes, have been observed in patients with Cockayne syndrome receiving systemic metronidazole-containing medicinal products. Metronidazole should not be used in these patients unless 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 until liver function tests 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 "Adverse reactions").

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

Metronidazole should be used with caution in elderly patients.

Metronidazole is not recommended for patients with porphyria.

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

Metronidazole interferes with enzymatic spectrophotometric assays of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, triglycerides, and glucose-hexokinase, resulting in falsely reduced values (possibly down to zero).

Patients should be informed that metronidazole may cause darkening of the urine.

The medicinal product may be diluted in 0.9% sodium chloride solution or 5% glucose solution.

Due to the potential mutagenicity in humans, the long-term use of metronidazole beyond the usual duration should be carefully considered.

This medicinal product contains 14 mmol (or 322 mg) of sodium per 100 ml of solution, which should be taken into account for patients on a controlled sodium diet.

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 frequency 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

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 influence the speed of reactions 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 guidelines 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 if 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 plasma half-life of metronidazole 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 effectiveness. In most cases, a 7-day course is sufficient. If clinically indicated, treatment may be prolonged (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.

Administration method

Administer as an intravenous infusion.

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

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

Antibiotics administered concomitantly should be given separately.

Children

Metronidazole may be used in children aged 2 years and older, when indicated.

Overdose

There have been reports of single oral doses of metronidazole up to 12 g taken in suicide attempts and accidental overdoses. Symptoms were limited to vomiting, ataxia, and mild disorientation. There is no specific antidote for metronidazole overdose. In case of 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.

The following frequency categories are used to describe adverse effects: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000; unknown: frequency cannot be determined from available data.

Infections and infestations

Rare: genital superinfections caused by Candida.

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

Blood and lymphatic system disorders

Very rare: agranulocytosis, neutropenia, thrombocytopenia, pancytopenia.

Unknown: agranulocytosis, aplastic anemia.

Regular monitoring of blood counts is mandatory during prolonged use.

Immune system disorders

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

Very rare: severe systemic hypersensitivity reactions: anaphylaxis up to anaphylactic shock; severe skin reactions.

Unknown: Quincke's edema, urticaria, exanthema.

Metabolism and nutrition disorders

Unknown: anorexia.

Psychiatric disorders

Uncommon: irritability.

Very rare: psychotic disorders, including confusion and hallucinations.

Unknown: depressive state.

Nervous system disorders

Very 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, and tremor), which may resolve after discontinuation of the drug; somnolence, dizziness, seizures, headache.

Unknown: 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; aseptic meningitis.

Eye disorders

Very rare: visual disturbances such as diplopia and myopia, which are mostly transient.

Unknown: optic neuropathy/neuritis.

Cardiac disorders

Very rare: ECG changes resembling T-wave flattening.

Gastrointestinal disorders

Uncommon: vomiting, nausea, diarrhea, glossitis, and stomatitis, bitter taste on burping.

Unknown: taste disturbances, oral mucositis, coated tongue, nausea, vomiting, gastrointestinal disorders such as epigastric pain and diarrhea.

Hepatobiliary disorders

Very rare: elevated liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, hepatocellular liver injury, jaundice, and pancreatitis, which are reversible upon discontinuation of the drug; 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.

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, skin rashes, pustular eruptions, pruritus, erythema.

Unknown: polymorphic erythema.

Musculoskeletal and connective tissue disorders

Very rare: myalgia, joint pain.

Renal and urinary disorders

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

General disorders and administration site conditions

Common: pain, prolonged hyperemia, hyperemia or swelling at injection site, venous irritation (up to thrombophlebitis) following intravenous administration, sinusitis, pharyngitis, pustular rash.

Rare: weakness.

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

Shelf life. 3 years.

Storage conditions. Store in a light-protected place at a temperature not exceeding +25°C. Keep out of reach of children.

Incompatibility.

This medicinal product must not be mixed with cefamandole nafate, cefoxime sodium, 10% dextrose IV, in combination with sodium lactate injection, or penicillin G potassium.

Packaging.

100 ml or 200 ml in glass bottles.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Novopharm-Biosynthesis".

Manufacturer's address and location of business activity.

38 Zhytomyrska St., city of Zviahel, Zviahel district, Zhytomyr region, 11700, Ukraine.