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

Composition:

Active substance: metronidazole;

100 ml of solution contain 0.5 g of metronidazole;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless or slightly yellowish liquid.

Theoretical osmolarity approximately 270 mOsmol/l.

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

Pharmacological properties.

Pharmacodynamics.

Metronidazole is an antibacterial and antiprotozoal active pharmaceutical ingredient belonging to the 5-nitroimidazole derivatives. Under anaerobic conditions, metronidazole forms nitro radicals via microbial pyruvate-ferredoxin-oxidoreductase through oxidation of ferredoxin and flavodoxin. The nitro radicals form adducts with DNA base pairs, leading to DNA strand breaks and bacterial cell death.

The minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish 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 data from the German National Reference Center for Surveillance of Antibiotic Resistance (December 2009):

Typically susceptible strains

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

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

Strains that may be resistant due to acquired resistance when using the drug:

Gram-negative aerobes: Helicobacter pylori

Strains with intrinsic resistance to the drug

All obligate aerobes.

Gram-positive microorganisms: Enterococcus spp., Staphylococcus spp., Streptococcus spp.
Gram-negative microorganisms: Enterobacteriaceae, Haemophilus spp.

Note

* - 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 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 nitroso radical does not occur.

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

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

The prevalence of acquired resistance in individual strains may vary depending on region and time. Therefore, it is necessary to use region-specific data, especially for effective treatment of severe infections. In cases of doubt 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 metronidazole is administered intravenously, its bioavailability is 100%.

Distribution.

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

Biological transformation.

Metronidazole is metabolized in the liver via hydroxylation, side-chain oxidation, and glucuronide formation (conjugation with glucuronic acid). Two non-conjugated oxidized active metabolites of metronidazole (5–30% of activity) are formed. The main metabolite, 2-hydroxymethylmetronidazole, exhibits some antiprotozoal activity in vitro.

Elimination.

Approximately 60–80% of the drug is excreted in urine, of which less than 10–20% is unchanged. A small amount is excreted via the intestine (6–15%).

The elimination half-life of metronidazole after a single intravenous dose is (7.3 ± 1) hours.

The elimination half-life of metronidazole after intravenous administration with normal liver function is 8 hours (range: 6–12 hours). Renal clearance is 10.2 mL/min.

Characteristics in special patient populations.

Renal impairment only slightly delays excretion.

In severe liver disease, reduced clearance and prolonged plasma half-life (up to 30 hours) are expected: in alcoholic liver disease, the half-life averages 18 hours (range: 10–29 hours).

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 (brain abscess, meningitis);
lung and pleural infections (including necrotizing pneumonia, aspiration pneumonia, lung abscess);
endocarditis;
gastrointestinal tract and abdominal cavity infections, including peritonitis, liver abscess, postoperative infections of the rectum and colon, purulent lesions of the abdominal or pelvic cavity;
gynecological infections (including post-hysterectomy or post-cesarean endometritis, puerperal sepsis, septic abortion);
infections of the ear, nose, throat, and oral cavity (including Simanovsky-Plaut-Vincent angina);
bone and joint infections (including osteomyelitis);
gas gangrene;
septicemia with thrombophlebitis.

In mixed aerobic and anaerobic infections, appropriate antibiotics should be administered in addition to metronidazole to treat aerobic infections.

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Alcohol

During metronidazole therapy, consumption of alcoholic beverages should be avoided due to the possibility of adverse reactions such as dizziness and nausea (disulfiram-like effect). Metronidazole inhibits alcohol dehydrogenase and other enzymes that oxidize ethanol.

Amiodarone

Co-administration of metronidazole and amiodarone has been associated with QT interval prolongation and bidirectional torsades de pointes ventricular tachycardia. 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 bidirectional torsades de pointes occur, such as dizziness, rapid heartbeat, or loss of consciousness.

Barbiturates

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

Busulfan

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

Carbamazepine

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

Cimetidine

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

Contraceptives

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

Anticoagulants

Warfarin and other coumarin derivatives. Concomitant administration of metronidazole, either orally or intravenously, may potentiate the anticoagulant effect of oral anticoagulants, increasing INR (International Normalized Ratio) due to prolonged prothrombin time, thereby increasing the risk of bleeding. This occurs due to inhibition of anticoagulant metabolism and displacement of coumarin anticoagulants from their chemical binding to albumin. Therefore, INR (prothrombin time) should be monitored and anticoagulant dosage adjusted during concomitant use of metronidazole and oral anticoagulants. Whenever possible, their combined use should be avoided. Adjustment of the oral anticoagulant dose is recommended during metronidazole therapy and for 8 days after its discontinuation.

No interaction has been reported with heparin-type anticoagulants. However, anticoagulant activity should be continuously monitored.

Cyclosporine

Concomitant treatment with cyclosporine and metronidazole carries a risk of increased serum cyclosporine concentrations. 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. Metronidazole should not be administered to patients who have taken disulfiram within the preceding two weeks.

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 co-administered with lithium salts, as increased serum lithium concentrations have been observed during metronidazole therapy.

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 effects of mycophenolic acid.

Phenytoin

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

Primidone

Accelerates the metabolism of metronidazole, resulting in reduced plasma concentrations.

Tacrolimus

Concomitant administration 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 frequently monitored, and dosage adjusted accordingly, especially after initiating or discontinuing metronidazole therapy in patients stabilized on tacrolimus.

Effect on paraclinical tests.

Metronidazole may immobilize treponemes, leading to false-positive Nelson test results.

Special precautions for use

Metronidazole should be prescribed with caution to patients with epilepsy or CNS disorders associated with a lowered seizure threshold.

Metronidazole should be administered to patients with severe hepatic impairment or impaired hematopoiesis (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 only if the expected benefit substantially outweighs the potential risk. Convulsive seizures and peripheral neuropathy, characterized by numbness or paresthesia of the extremities, have been reported in patients receiving metronidazole therapy. The appearance of abnormal neurological signs requires immediate reassessment of the benefit-risk ratio for continuing treatment.

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

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

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

Prolonged metronidazole therapy may be associated with bone marrow suppression leading to impaired hematopoiesis. Manifestations are described in the section "Adverse reactions". Blood counts should be monitored during prolonged therapy. If leukopenia develops, treatment should be continued only if the expected benefit substantially outweighs the potential risk.

During prolonged treatment, patients should be monitored for signs of adverse effects such as central and peripheral neuropathy (paresthesia, ataxia, dizziness, or convulsive episodes).

This medicinal product contains 275 mg of sodium per 100 ml, which should be taken into account for patients on a controlled sodium diet.

Effect on laboratory parameters

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

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

Metronidazole 0.5% infusion solution is intended for single use only. Any unused portions remaining in the container must be immediately discarded.

The solution may be diluted with 0.9% sodium chloride solution or 5% glucose solution. Standard antiseptic precautions should be observed during the dilution procedure.

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

Patients should refrain from consuming alcohol and ethanol-containing medicinal products for at least 48 hours after discontinuation of metronidazole therapy, as a disulfiram-like (antabuse-like) reaction may occur, characterized by hypotension, facial flushing, headache, nausea, vomiting, abdominal cramps, and sweating.

Metronidazole should be used with caution in patients with porphyria. High doses of metronidazole may mask symptoms of syphilis.

In patients undergoing hemodialysis, metronidazole and its metabolites are effectively removed during an eight-hour dialysis session. Therefore, metronidazole should be re-administered immediately after hemodialysis. Metronidazole is primarily metabolized by hepatic oxidation. Thus, dose adjustment of metronidazole is not required in patients with renal insufficiency undergoing intermittent dialysis (IHD) or continuous ambulatory peritoneal dialysis (CAPD). However, significant dose reduction of metronidazole may be necessary in cases of progressive hepatic insufficiency. In patients with hepatic encephalopathy, accumulation of metronidazole may occur, and high plasma concentrations may exacerbate encephalopathy symptoms. Therefore, metronidazole should be administered with caution in 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

In patients with Cockayne syndrome, severe hepatotoxicity and acute liver failure, including fatal cases with rapid progression, have been reported following systemic administration of metronidazole-containing medicinal products. Therefore, metronidazole should not be used in this patient group, except when the benefit is considered to outweigh the risk and no alternative treatment is available. In such cases, liver function tests should be performed immediately before initiation of therapy, during treatment, and after its completion—until liver function parameters return to normal or baseline values. If liver function parameters increase significantly during treatment, the drug should be discontinued. Patients with Cockayne syndrome should be advised to discontinue metronidazole immediately and contact their physician if any symptoms suggestive of potential liver injury occur (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Pregnancy

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

Metronidazole is contraindicated during the first trimester of pregnancy, as it crosses the placental barrier and appears in the fetal circulation.

During the second and third trimesters, metronidazole may be used for the treatment of trichomoniasis if local metronidazole therapy is ineffective.

In life-threatening situations, the benefit-risk ratio of using the medicinal product must be evaluated; however, short-term regimens with high-dose administration should not be used in these cases.

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 the end of therapy, due to the prolonged elimination half-life of metronidazole.

Ability to influence 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. Therefore, patients should refrain from driving or operating machinery during treatment.

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 metronidazole/kg body weight may be administered when clinically indicated.

Children aged 2 to 12 years

Metronidazole should be administered every 8 hours at a dose of 7–10 mg metronidazole/kg body weight, 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 the elimination half-life of metronidazole is prolonged and its clearance reduced in patients with severe hepatic impairment, 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 seven-day course is sufficient. Treatment may be extended if clinically indicated (see also section "Special Warnings and Precautions for Use").

Perioperative infection prophylaxis

Adults and adolescents

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

Children (aged 2 to 11 years)

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

Administration method

Administer as an intravenous infusion.

The contents of 1 container should be administered intravenously slowly, i.e., at least 20 minutes for a maximum of 100 mL, but usually over 1 hour.

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

Antibiotics administered concomitantly should be given separately.

Children

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

Overdose

Symptoms

In overdose, nausea, vomiting, diarrhea, anorexia, metallic taste in the mouth, headache, dizziness, and occasionally insomnia and drowsiness may occur.

The incidence and severity of adverse effects described above may increase.

Treatment

There is no specific antidote; treatment is symptomatic. Hemodialysis is effective.

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 and oral superinfections caused by Candida; pseudomembranous colitis, which may occur during or after therapy and presents as severe persistent diarrhea. Detailed description of emergency management is provided in the section "Special Instructions".

Blood and lymphatic system disorders

During metronidazole therapy, reduced counts of leukocytes and platelets (leukopenia, granulocytopenia, and thrombocytopenia), agranulocytosis, and aplastic anemia have been reported. Regular monitoring of blood counts is mandatory during prolonged treatment.

Metronidazole therapy may lead to bone marrow suppression, such as aplastic anemia, agranulocytosis, neutropenia, leukopenia, thrombocytopenia, and pancytopenia, which in most cases are reversible and resolve after discontinuation of the drug.

Immune system disorders

Hypersensitivity reactions ranging from mild to moderate, including skin reactions (see “Skin and subcutaneous tissue disorders” below), angioneurotic edema, 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.

Psychiatric disorders

Psychotic disorders, including disorientation and hallucinations; depressed mood, decreased libido.

Nervous system disorders

Irritability, depression, headache, dizziness, somnolence or insomnia, seizures, peripheral neuropathy manifested as paresthesia, pain, heaviness, and tingling in the extremities, encephalopathy (e.g., confusion), epileptiform seizures, subacute cerebellar syndrome (e.g., ataxia, dysarthria, gait disturbance, nystagmus, tremor), aseptic meningitis. If seizures or signs of peripheral neuropathy occur, medical advice should be sought immediately.

Eye disorders

Visual disturbances (diplopia (double vision), myopia (nearsightedness), optic neuropathy (neuritis), oculogyric crisis (isolated cases).

Cardiac disorders

ECG changes resembling T-wave flattening.

Gastrointestinal disorders

Vomiting, nausea, diarrhea, glossitis and stomatitis, oral mucositis, bitter belching, epigastric fullness and pain, loss of appetite, metallic taste in the mouth, coated tongue, pancreatitis (isolated cases), abdominal cramps; constipation.

Hepatobiliary disorders

Abnormal liver enzymes and bilirubin levels, liver function test abnormalities, which are reversible, cholestatic hepatitis, jaundice. These manifestations are reversible and usually resolve after completion or discontinuation of treatment. Cases of liver failure requiring liver transplantation have been reported in patients receiving metronidazole in combination with other antibiotics.

Severe irreversible hepatotoxicity / acute liver failure, including fatal rapidly progressing cases, have occurred in patients with Cockayne syndrome during systemic metronidazole use (see section "Special Instructions").

Respiratory system disorders

Sinusitis, pharyngitis.

Skin and subcutaneous tissue disorders

Allergic skin reactions, including pruritus, urticaria, erythema multiforme; pustular rash, Stevens-Johnson syndrome (isolated reports), toxic epidermal necrolysis (isolated reports). The last two reactions require immediate therapeutic intervention.

Musculoskeletal and connective tissue disorders

Arthralgia, myalgia.

Renal and urinary system disorders

Dark urine color due to excretion of a metronidazole metabolite; dysuria, cystitis, urinary incontinence.

Reproductive system and breast disorders

Dysmenorrhea.

Administration site reactions

Pain, hyperemia, or swelling at the injection site, venous irritation (up to thrombophlebitis) following intravenous administration, weakness.

Storage conditions. Store in a place protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

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

Packaging. 100 ml in containers.

Prescription status.

Prescription only.

Manufacturer. State Enterprise "Farmatreyd".

Manufacturer's address and place of business.

85 Sambirska Street, Drohobych, Lviv Oblast, Ukraine, 82111.