Trichopol®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRICHOPOL® (TRICHOPOL®)

Composition:

active ingredient: metronidazol;

1 tablet contains 250 mg of metronidazole;

excipients: potato starch, gelatin, glucose solution, magnesium stearate.

Pharmaceutical form. Tablets.

Basic physico-chemical properties: white tablets with a yellowish tint, which turn yellow under the influence of light, round, flat, with a dividing line on one side.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Imidazole derivatives. ATC code J01X D01.

Pharmacological Properties

Pharmacodynamics

Metronidazole belongs to the nitro-5-imidazoles and has a broad spectrum of activity. The breakpoint concentrations that allow differentiation of susceptible strains (S) from those with intermediate susceptibility, and strains with intermediate susceptibility from resistant strains (R), are as follows: S ≤ 4 mg/L and R > 4 mg/L.

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

Organisms susceptible to the drug: 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). Maximum serum concentrations achieved after oral administration are similar to those achieved after intravenous infusion of equivalent doses.

The bioavailability after oral administration is 100%. It 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—no more than 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 penetrates into breast milk.

Biotransformation. Metronidazole is metabolized by hepatic oxidation. Two metabolites are formed:

• The main "alcohol" metabolite, which exhibits approximately 30% of the antibacterial activity of metronidazole against anaerobic bacteria; its elimination half-life is approximately 11 hours;
• The "acid" metabolite, present in smaller amounts and exhibiting approximately 5% of the antibacterial activity of metronidazole.

Excretion. Significant concentrations are found in the liver and bile; low concentrations in the colon; minimal fecal elimination. The drug is excreted via the kidneys by 35–65% (as unchanged 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; replacement of intravenous therapy for infections caused by anaerobic microorganisms sensitive to metronidazole.

Contraindications.

Hypersensitivity to metronidazole, imidazole derivatives, or to any other component of the drug.

First trimester of pregnancy.

Concomitant use of the drug with disulfiram or alcohol.

Children under 6 years of age (due to the pharmaceutical form).

Cockayne syndrome (see section "Adverse reactions").

Interaction with other medicinal products and other forms of interaction.

Alcohol. Metronidazole enhances the toxic effect of alcohol. Consumption of alcohol during metronidazole therapy may cause adverse reactions such as flushing, sweating, headache, nausea, vomiting, and abdominal pain. Alcohol intake should be avoided during metronidazole treatment and for at least 48 hours after completion of therapy due to the risk of developing a disulfiram-like (antabuse) reaction (flushing, erythema, vomiting, tachycardia).

Disulfiram. There is a risk of developing acute psychotic episodes or confusion in patients who have taken metronidazole and disulfiram concurrently. Metronidazole should not be administered within 2 weeks after discontinuation of disulfiram.

Busulfan. When high-dose busulfan is administered: doubling of busulfan concentrations has been observed in patients receiving metronidazole, which may lead to severe busulfan toxicity.

Combinations requiring caution.

Oral anticoagulant therapy. Enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications have been reported in patients undergoing antibacterial therapy, due to inhibition of their hepatic metabolism. Contributing 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 disturbance in INR (International Normalized Ratio) is caused by the infection itself or by its treatment. However, certain antibiotic groups are more frequently associated with this effect, particularly fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins. Prothrombin levels should be monitored more frequently, and INR should be closely observed. Dose adjustment of the oral anticoagulant is recommended during metronidazole therapy and for 8 days after its discontinuation.

Trichopol® does not interact with heparin.

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

Lithium. Increased serum lithium levels, potentially reaching toxic concentrations, with symptoms of lithium overdose. Serum lithium levels should be carefully monitored, and dose adjustments may be necessary. Cases of lithium retention associated with possible renal impairment have been reported in patients receiving concomitant lithium and metronidazole; lithium therapy should be discontinued or reduced prior to initiating metronidazole.

Cyclosporine. In patients receiving cyclosporine, there is a risk of increased cyclosporine serum levels. Monitoring of cyclosporine and creatinine plasma levels is recommended if concomitant use of cyclosporine and metronidazole is necessary.

Phenytoin and phenobarbital. Drugs that induce hepatic microsomal enzymes, such as phenytoin and phenobarbital, accelerate metronidazole elimination by reducing its elimination half-life to 3 hours, resulting in decreased serum concentrations of metronidazole.

Effect on paraclinical tests. It should be noted that metronidazole may immobilize treponemes, leading to a false-positive Nelson test result.

Cimetidine. Drugs that reduce hepatic enzyme activity (e.g., cimetidine) may prolong the elimination half-life of metronidazole.

Terfenadine and astemizole. Metronidazole may interact with terfenadine and astemizole and cause cardiovascular adverse reactions (prolongation of the QT interval on ECG, arrhythmias, etc.).

Enzyme-inducing anticonvulsants. Decreased plasma concentrations of metronidazole due to enhanced hepatic metabolism induced by enzyme inducers. This has been clinically observed, and dose adjustment of metronidazole may be required during and after treatment with enzyme inducers.

Rifampicin. Decreased plasma concentrations of metronidazole due to enhanced hepatic metabolism by rifampicin. This has been clinically observed, and dose adjustment of metronidazole may be required during and after rifampicin therapy.

Metronidazole is an inhibitor of cytochrome P450 3A4 (CYP3A4); therefore, it may reduce the metabolism of drugs metabolized by this enzyme.

Metronidazole may interact with drugs that prolong the QT interval, such as: amiodarone, ciprofloxacin, levofloxacin, sparfloxacin, erythromycin, clarithromycin, mefloquine, ketoconazole, cisapride, tamoxifen, donepezil, haloperidol, pimozide, thioridazine, mesoridazine.

Special precautions for use.

Hypersensitivity / disorders of the skin and its derivatives. Allergic reactions, including anaphylactic shock, which may be life-threatening, can occur (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 (AGEP) should be suspected (see section "Adverse reactions"); in case of such a reaction, treatment with the drug must be stopped, and further use of metronidazole, either alone or in combination with other drugs, is contraindicated.

Severe skin reactions, some with fatal outcomes, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN or Lyell's syndrome), and acute generalized exanthematous pustulosis (AGEP), have been reported during metronidazole use. Patients should be informed about the signs and symptoms of these conditions, and any skin changes should be closely monitored.

Treatment must be discontinued immediately upon the appearance of any signs or symptoms of SJS, TEN (e.g., progressive skin rash, often with blistering or mucosal involvement), or AGEP (see section "Adverse reactions"), and any further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Disorders of the central nervous system. If symptoms characteristic of encephalopathy or cerebellar syndrome occur, the patient's treatment should be immediately reassessed and metronidazole discontinued.

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

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

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

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

Psychiatric disorders. Psychotic reactions, including self-destructive behavior (suicidal ideation or suicide attempts may occur in individual cases), may occur after the first dose of the drug, particularly in patients with a history of psychiatric disorders (see section "Adverse reactions"). If such events occur, metronidazole must be discontinued, the physician should be informed, and appropriate therapeutic measures should be initiated immediately.

Hematological effects.

Regular monitoring of leukocyte counts is recommended if the patient has a history of hematological disorders or if high doses of metronidazole are used and/or treatment is prolonged.

If leukopenia develops, careful consideration of the expected benefit versus potential risk of continuing treatment is essential. During long-term therapy, patients should be monitored for signs of adverse effects such as central and peripheral neuropathy (paresthesia, ataxia, dizziness, or convulsive seizures).

Patients who have shown blood parameter changes before or after metronidazole treatment should be under medical supervision if re-treatment with metronidazole is considered.

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

Interaction with other medicinal products. Concomitant use of metronidazole and alcohol is contraindicated due to the possibility of a disulfiram-like reaction (antabuse effect) (flushing, erythema, vomiting, tachycardia) (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 false-positive Nelson test results.

Metronidazole may alter certain laboratory parameters (alanine aminotransferase [ALT], aspartate aminotransferase [AST], lactate dehydrogenase, triglycerides, glucose).

There is a possibility of persistence of gonococcal infection after elimination of Trichomonas vaginalis.

In renal impairment, the elimination half-life of metronidazole is not altered. Therefore, dose reduction of metronidazole is not required. However, metabolites of metronidazole accumulate in these patients. The clinical significance of this phenomenon is currently unknown.

In patients undergoing hemodialysis, metronidazole and its metabolites are effectively removed from the bloodstream during an 8-hour dialysis session. Therefore, a supplemental dose of metronidazole should be administered immediately after completion of hemodialysis.

No dose adjustment is required for patients with renal impairment undergoing intermittent peritoneal dialysis or continuous ambulatory peritoneal dialysis.

Metronidazole is primarily metabolized by hepatic oxidation. In patients with severe hepatic impairment, a significant reduction in metronidazole clearance may occur. In patients with hepatic encephalopathy, significant accumulation of metronidazole may occur. High plasma concentrations resulting from such accumulation may partially contribute to encephalopathy symptoms. Therefore, Trichopol® should be used with caution in patients with hepatic encephalopathy. The daily dose should be reduced to one-third of the usual dose; this reduced dose may be administered once daily.

Metronidazole is considered not to pose any carcinogenic risk in humans, although carcinogenic effects have been observed in some strains of mice. However, this effect has not been observed in rats or hamsters.

Due to unclear mutagenicity risk, a careful assessment of the justification for long-term use of metronidazole is required.

Metronidazole should be prescribed with caution to patients who have taken corticosteroids and are prone to edema.

After metronidazole administration, candidiasis of the oral cavity, vagina, and gastrointestinal tract may develop, requiring appropriate treatment.

Patients should be warned that metronidazole may darken the urine (due to the presence of metronidazole metabolites).

Each tablet contains 6.6 g of glucose. Use with caution in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of metronidazole during pregnancy are limited. Metronidazole crosses the placental barrier. Use during the first trimester of pregnancy is contraindicated. The drug may be prescribed during the second and third trimesters only if clearly necessary, when the benefit outweighs the potential risk.

Breastfeeding.

Metronidazole is excreted in breast milk. Trichopol® should not be used during breastfeeding.

Ability to affect the speed of reactions while driving or operating machinery.

Individuals operating vehicles or machinery should be aware of the possible occurrence of confusion, dizziness, hallucinations, or seizures during treatment with this drug and should refrain from driving or operating machinery during therapy.

Administration and Dosage.

For amoebiasis, take Trichopol® for 7 days. Adults: 1.5 g per day (in 3 divided doses); children (with body weight ≥ 20 kg): 30–40 mg/kg per day, divided into 3 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 750–1000 mg of Trichopol® per day; children aged 10–15 years – 500 mg per day in two divided doses.

For trichomoniasis in women (urethritis and vaginitis caused by trichomonads), Trichopol® should be administered for a 10-day treatment course, combining 1 tablet twice daily with 1 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), Trichopol® should be administered for a 10-day treatment course: 1 tablet twice daily.

In exceptional cases, it may be necessary to increase the daily dose to 0.750 g or 1 g.

For non-specific vaginitis, administer 500 mg of Trichopol® twice daily for 7 days. The partner should be treated simultaneously.

For the treatment of anaerobic infections (first-line therapy or substitute treatment), administer to adults 1.0–1.5 g of Trichopol® per day; for children aged 6 years and older (with body weight ≥ 16 kg) – 20–30 mg/kg per day.

Children.

The 250 mg tablet formulation of the drug can be used in children aged 6 years and older.

Overdose.

The lethal dose of metronidazole in humans is unknown. In isolated cases, symptoms of neurotoxicity have been observed after oral administration of metronidazole at doses of 6–10.4 g per day over 5–7 days, including seizures and peripheral neuropathy.

Cases of single-dose ingestion of up to 15 g during suicide attempts and accidental overdoses have been reported. Symptoms included vomiting, ataxia, and mild disorientation.

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

Adverse Reactions.

Gastrointestinal disorders:

• Epigastric pain, nausea, vomiting, diarrhea;
• Inflammation of the oral mucosa with a sensation of dryness, stomatitis, taste disturbances, metallic taste in the mouth, anorexia;
  • Cases of pancreatitis, which are reversible;
• Changes in color or appearance of the tongue (fungal infection).

Skin and subcutaneous tissue disorders:

• Prolonged hyperemia, skin itching, flushing, rash (in isolated cases – pustular rash); sometimes febrile reactions;
• Urticaria, angioneurotic edema, rare cases of anaphylactic shock (see section "Special Warnings and Precautions for Use");
• Very rare cases of acute generalized exanthematous pustulosis (see section "Special Warnings and Precautions for Use");
• Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, fixed drug eruption.

Nervous system disorders:

• Peripheral sensory neuropathy;
• Headache;
• Dizziness;
• Confusion;
• Seizures;
• Transient epileptic seizures;
• Ataxia, fever, drowsiness;
• Subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, nystagmus, tremor), which may resolve after discontinuation of the drug (see section "Special Warnings and Precautions for Use");
  • Encephalopathy (e.g., elevated body temperature, headache, photophobia, nuchal rigidity, hallucinations, paralysis, visual and motor disturbances), which may be associated with MRI changes that usually resolve after discontinuation of treatment. Very rare cases of fatal outcomes have been reported (see section "Special Warnings and Precautions for Use");
• Aseptic meningitis (see section "Special Warnings and Precautions for Use").

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 ideation or suicide attempts (see section "Special Warnings and Precautions for Use");
• Depressed mood.

Blood and lymphatic system disorders:

• In isolated cases – agranulocytosis, neutropenia, thrombocytopenia, pancytopenia, leukopenia.

Hepatobiliary disorders:

• Increased liver enzyme activity (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, hepatocellular liver injury, sometimes with jaundice;
• Cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole in combination with other antibiotics;
• Cases of severe hepatotoxicity / acute liver failure, including fatal outcomes, have been reported shortly after initiation of systemic treatment with metronidazole-containing products in patients with Cockayne syndrome (see section "Contraindications").

Musculoskeletal and connective tissue disorders:

• Arthralgia, myalgia.

Reproductive system disorders:

• Vaginal discomfort, candidiasis.

Other:

During treatment, urine may turn reddish-brown due to the presence of water-soluble pigments, which are metabolites of metronidazole.

Shelf life: 3 years.

Storage conditions: Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging: 10 tablets in a blister; 2 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer:

Pharmaceutical Works "Polpharma" S.A., Poland.

Manufacturer's address:

19 Pelplinska Street, 83-200 Starogard Gdanski, Poland.