Metronidazole

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

Composition:

Active substance: metronidazole;

One tablet contains metronidazole equivalent to 100% content of metronidazole 250 mg;

Excipients: potato starch, calcium stearate, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose, povidone.

Pharmaceutical form. Tablets.

Main physicochemical properties: intact, regular, round cylindrical tablets with flat upper and lower surfaces, beveled edges, scored, white or white with yellowish or greenish tint.

Pharmacotherapeutic group.

Antibacterials for systemic use. Antiprotozoal agents. Imidazole derivatives. ATC code J01X D01.

Agents for treatment of amoebiasis and other protozoal diseases. Antiprotozoal agents. ATC code P01A B01.

Pharmacological properties.

Pharmacodynamics.

Metronidazole belongs to nitro-5-imidazoles and has a broad spectrum of activity. The serum concentration breakpoints that allow differentiation of susceptible strains (S) from strains with moderate susceptibility, and strains with moderate susceptibility from resistant strains (R), are as follows: S < 4 mg/L and R > 4 mg/L.

The prevalence of acquired resistance among certain microorganisms may vary depending on geographical location and time. Therefore, information on local resistance patterns is useful, especially when treating severe infections. These data are general guidelines only, indicating the likelihood that a particular bacterial strain is susceptible to this antibiotic.

Organisms susceptible to the drug include: Peptostreptococcus spp., Clostridium spp., Bacteroides spp., Fusobacterium spp., Porphyromonas, Bilophila, Helicobacter pylori, Prevotella spp., Veilonella. Metronidazole inhibits the growth of protozoa – Trichomonas vaginalis, Giardia intestinalis (Lamblia intestinalis), Entamoeba histolytica. Organisms with variable susceptibility: Bifidobacterium spp., Eubacterium spp. Resistant microorganism strains: Propionibacterium, Actinomyces, Mobiluncus.

Pharmacokinetics.

Absorption. After oral administration, metronidazole is rapidly and almost completely absorbed (at least 80% within one hour). The maximum serum concentration achieved after oral administration is similar to that achieved after intravenous administration of equivalent doses.

The oral bioavailability is 100% and is not significantly reduced by concomitant food intake.

Distribution. Approximately 1 hour after a single 500 mg dose, the mean peak plasma concentration is 10 µg/mL. After 3 hours, the mean plasma concentration is 13.5 µg/mL.

The elimination half-life is 8–10 hours; plasma protein binding is low, not exceeding 20%. The volume of distribution is high (approximately 40 L, i.e., 0.65 L/kg).

Distribution is rapid and extensive, achieving concentrations close to plasma levels in the lungs, kidneys, liver, skin, bile, cerebrospinal fluid, saliva, seminal fluid, and vaginal secretions.

Metronidazole crosses the placental barrier and is excreted in breast milk.

Biotransformation. Metronidazole is metabolized by oxidation in the liver, producing two metabolites:

• The main alcohol metabolite, which accounts for approximately 30% of metronidazole's antibacterial activity against anaerobic bacteria, with an elimination half-life of approximately 11 hours;
• The acid metabolite, present in smaller amounts and accounting for approximately 5% of metronidazole's antibacterial activity.

Elimination. High concentrations are found in the liver and bile; low concentrations in the colon; minimal excretion in feces. The drug is eliminated via the kidneys by 35–65% (as metronidazole and oxidized metabolites).

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the drug: amoebiasis; urogenital trichomoniasis; nonspecific vaginitis; giardiasis; surgical infections caused by anaerobic microorganisms sensitive to metronidazole. As a substitute for intravenous treatment of infections caused by anaerobic microorganisms sensitive to metronidazole.

Contraindications.

Hypersensitivity to metronidazole or to imidazole group drugs, as well as to other components of the drug. - Cockayne syndrome (see section "Adverse reactions"). Age under 6 years (due to the pharmaceutical form) (see section "Special instructions").

Interaction with other medicinal products and other types of interactions.

Antabuse reaction

There are many medicinal products that trigger an antabuse reaction to alcohol, and their concomitant use with alcohol is not recommended.

Combinations not recommended.

Alcohol (as a beverage or as an excipient in medicinal products). Antabuse effect (flushing, erythema, vomiting, tachycardia). Alcohol-containing beverages and medicinal products containing alcohol must be avoided.

Disulfiram. Risk of developing acute psychotic episodes or confusion, which are reversible after discontinuation of the drug.

Busulfan. When high-dose busulfan is administered: doubling of busulfan concentrations in patients receiving metronidazole.

Combinations requiring precautions during use.

Enzyme-inducing anticonvulsants. Decreased plasma concentrations of metronidazole due to enhanced hepatic metabolism induced by enzyme inducers. Clinical monitoring is indicated; dose adjustment of metronidazole may also be required during and after treatment with the inducer.

Rifampicin. Decreased plasma concentrations of metronidazole due to enhanced hepatic metabolism by rifampicin. Clinical monitoring is indicated; dose adjustment of metronidazole may also be required during and after treatment with rifampicin.

Lithium. Increased blood levels of lithium, potentially reaching toxic levels, with signs of lithium overdose. Close monitoring of blood lithium levels is required; dose adjustment may be necessary.

Combinations requiring special attention.

Fluorouracil (and, by extrapolation, tegafur and capecitabine). Increased toxicity of fluorouracil due to slowed clearance.

Special issues regarding INR (International Normalized Ratio).

Numerous cases of enhanced activity of oral anticoagulants have been reported in patients receiving antibacterial therapy. Risk factors include severity of infection or inflammation, patient age, and general health status. Under these circumstances, it is difficult to determine to what extent the imbalance in INR is influenced by the infection itself or by its treatment. However, certain groups of antibiotics are more commonly associated with this effect, particularly fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Special precautions for use.

Hypersensitivity/skin and appendage disorders. Allergic reactions may occur, including anaphylactic shock, which can be life-threatening (see section "Adverse reactions"). In such cases, metronidazole therapy must be discontinued and appropriate treatment initiated.

If generalized erythema and pustular eruptions accompanied by fever develop at the beginning of treatment, acute generalized exanthematous pustulosis should be suspected (see section "Adverse reactions"); if such a reaction occurs, treatment with the drug must be stopped, and subsequent use of metronidazole, either alone or in combination with other drugs, is contraindicated.

Nervous system disorders. If symptoms characteristic of encephalopathy or cerebellar syndrome occur, the patient's treatment must be immediately reassessed and metronidazole discontinued.

Cases of encephalopathy have been reported during post-marketing surveillance. In addition, MRI changes associated with encephalopathy have been observed (see section "Adverse reactions"). Lesions are most commonly localized in the cerebellum (particularly in the dentate nucleus) and the corpus callosum. In most cases, encephalopathy and MRI abnormalities resolved after discontinuation of the drug. Fatal outcomes have been reported very rarely.

Patients should be monitored for possible signs of encephalopathy or for worsening of symptoms in those with pre-existing central nervous system disorders.

If aseptic meningitis develops during treatment with the drug, re-administration of metronidazole is not recommended; in patients with serious infectious diseases, a benefit-risk assessment must be performed.

Peripheral nervous system disorders. Patients should be monitored for possible signs of peripheral neuropathy, particularly during prolonged treatment or in the presence of severe, chronic, or progressive peripheral neurological disorders.

Psychiatric disorders. Psychotic reactions that may endanger patient safety can occur after the first dose of the drug, especially in patients with a history of psychiatric disorders. If this occurs, metronidazole must be discontinued, the physician should be informed, and appropriate therapeutic measures initiated immediately.

Hematological effects. Blood counts, particularly white blood cell counts, should be monitored regularly in patients with a history of hematological disorders or those receiving high doses and/or prolonged treatment.

In patients with leukopenia, the decision on continuing treatment depends on the severity of the infection.

Hepatotoxicity in patients with Cockayne syndrome.

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

Pediatric patients. The use of tablets is contraindicated in children under 6 years of age due to the risk of developing laryngospasm. Other metronidazole formulations are available for younger children.

Interaction with other medicinal products. Concomitant use of metronidazole and alcohol is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and busulfan is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of metronidazole and disulfiram is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Effect on laboratory test results. Metronidazole may immobilize treponemes, thereby causing a false-positive Nelson test result.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies have not demonstrated teratogenic effects. Since teratogenic effects are not observed in animals, malformations in humans are not expected. According to available data, substances causing developmental abnormalities in humans produce teratogenic effects in animals during adequately conducted studies in two species. From a clinical standpoint, no fetotoxic effects on pregnancy have been observed after analysis.

However, further epidemiological studies are needed to confirm the absence of risk. Therefore, metronidazole should be prescribed during pregnancy only if clearly needed, when the benefit of treatment outweighs the potential risk.

Breastfeeding. Metronidazole passes into breast milk. Metronidazole should not be used during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients should be aware of the possible occurrence of confusion, dizziness, hallucinations, seizures, or visual disturbances during treatment and should refrain from driving or operating machinery during therapy.

Dosage and Administration

For amoebiasis: Metronidazole should be taken continuously for 7 days. Adults: 1.5 g per day, i.e., 500 mg (2 tablets) three times daily.

Children aged 6 years and older: 30–40 mg/kg body weight per day, divided into three doses.

In cases of hepatic abscess due to amoebiasis, drainage or aspiration of pus should be performed concurrently with metronidazole therapy.

For giardiasis: treatment lasts 5 days. Adults should be administered 750 mg–1 g of metronidazole per day. Children aged 6–10 years: 375 mg/day; children aged 10–15 years: 500 mg/day. To achieve the prescribed dosage, metronidazole in an appropriate dosage strength or other pharmaceutical forms should be used.

For trichomoniasis in women (urethritis and vaginitis caused by trichomonads), metronidazole is prescribed for a 10-day treatment course, combining 250 mg (1 tablet) twice daily with one vaginal suppository (500 mg) daily. The sexual partner must be treated simultaneously, regardless of the presence or absence of clinical signs of trichomoniasis, even if laboratory test results are negative.

For trichomoniasis in men (urethritis caused by trichomonads), metronidazole is prescribed for a 10-day treatment course: 250 mg (1 tablet) twice daily.

In exceptional cases, it may be necessary to increase the daily dose to 750 mg or 1 g.

For non-specific vaginitis, administer 500 mg (2 tablets) of the drug twice daily for 7 days. The sexual partner should be treated simultaneously.

For the treatment of anaerobic infections (first-line therapy or substitute treatment), adults should be administered 1–1.5 g (4–6 tablets) of metronidazole per day; children aged 6 years and older: 20–30 mg/kg body weight per day, divided into two doses.

Children

The 250 mg tablet formulation of the drug may be administered to children aged 6 years and older.

Overdose

Single doses of up to 12 g have been reported in suicide attempts and accidental overdoses.

Symptoms included vomiting, ataxia, and mild disorientation.

Treatment: There is no specific antidote. In cases of significant overdose, symptomatic therapy should be administered.

Adverse Reactions

Adverse reactions reported during metronidazole use

Gastrointestinal system:

• Mild gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea);
• Glossitis with dry mouth, stomatitis, taste disturbances, anorexia;
• Pancreatitis, which is reversible upon discontinuation of the drug;
  • Changes in color or appearance of the tongue (fungal infection).

Skin and appendages:

• Flushing, pruritus, skin rash, sometimes accompanied by fever;
• Urticaria, angioneurotic edema, anaphylactic shock (see section "Special precautions");
• Very rare cases of acute generalized exanthematous pustulosis (see section "Special precautions");
  • Toxic epidermal necrolysis;
  • Fixed drug eruption;
  • Stevens−Johnson syndrome.

Nervous system:

• Peripheral sensory neuropathy;
• Headache;
• Dizziness;
• Seizures;
• Encephalopathy and subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, nystagmus, tremor), which may be associated with MRI abnormalities that usually resolve after discontinuation of the drug. Very rare fatal cases have been reported (see section "Special precautions");
• Aseptic meningitis (see section "Special precautions").

Eye disorders:

• Transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, color vision changes;
• Optic neuropathy/optic neuritis.

Psychiatric disorders:

• Hallucinations;
• Psychotic reactions with paranoia and/or delirium, which in some cases may be associated with suicidal thoughts or suicide attempts (see section "Special precautions");
• Depressed mood.

Blood and lymphatic system disorders:

− Neutropenia, agranulocytosis, thrombocytopenia.

Hepatobiliary system:

• Increased levels of liver enzymes (AST, ALT, alkaline phosphatase). Very rare cases of acute cholestatic or mixed hepatitis and hepatocellular liver injury, sometimes with jaundice, have been reported. Isolated cases of hepatocellular failure requiring liver transplantation have also been reported.

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

Auditory system:

• Hearing impairment and hearing loss (including sensorineural);
• Tinnitus.

Other:

• Reddish-brown discoloration of urine due to water-soluble pigments formed during drug metabolism.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in blisters.

10 tablets per blister; 2 or 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Lubnipharm".

Manufacturer's address and location of business activity.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.