Mistol®

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

Composition:

Active substance: metronidazole;

1 suppository contains 500 mg of metronidazole;

Excipient: hard fat.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical properties: suppositories from white to light yellow in color, torpedo-shaped.

Pharmacotherapeutic group.

Antimicrobial and antiseptic agents used in gynecology.

ATC code G01AF01.

Pharmacological properties.

Pharmacodynamics.

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

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 microbial strains: Propionibacterium, Actinomyces, Mobiluncus.

Pharmacokinetics.

After vaginal administration, systemic absorption is minimal.

The plasma half-life is 8–10 hours.

Plasma protein binding is low (less than 20%).

Rapid and extensive diffusion into lungs, kidneys, liver, bile, cerebrospinal fluid, skin, saliva, and vaginal secretions. Crosses the placental barrier and is excreted in breast milk.

Metabolism occurs primarily in the liver, forming two non-conjugated oxidized active metabolites (5–30% of the activity).

Excretion is mainly renal: 35–65% of the administered dose is eliminated in urine as metronidazole and its oxidized metabolites.

Clinical characteristics.

Indications.

Local treatment of trichomonal and nonspecific vaginitis.

Contraindications.

Hypersensitivity to metronidazole or to any other component of the medicinal product. Hypersensitivity to derivatives of imidazole.

Combination with disulfiram or alcohol (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Antabuse effect. There are several medicinal products that trigger an antabuse-type reaction to alcohol, and their concomitant use with alcohol is not recommended.

Combinations not recommended.

Disulfiram. Cases of acute transient encephalopathy (acute confusional state, disorientation) have been reported in patients receiving metronidazole and disulfiram concurrently.

Alcohol (in beverages or as an excipient). Alcoholic beverages and medicinal products containing alcohol should not be consumed during treatment and for at least one additional day after its completion due to the possible occurrence of a disulfiram-like reaction (Antabuse effect), including flushing, erythema, vomiting, tachycardia). The time required for complete elimination of the drug from the body should be taken into account, considering its half-life, before starting consumption of alcoholic beverages or administration of medicinal products containing alcohol.

Busulfan. Metronidazole may increase plasma levels of busulfan, which could lead to significant toxic effects of busulfan.

Combinations requiring precautions during use.

Oral anticoagulant therapy. Enhanced effects of oral anticoagulants and increased risk of hemorrhagic complications due to slowed metabolism in the liver. Prothrombin levels should be monitored more frequently, and monitoring of INR (International Normalized Ratio) should be performed. Dose adjustment of the oral anticoagulant is recommended during metronidazole administration and for 8 days after discontinuation.

Lithium. Increased blood concentrations of lithium, potentially reaching toxic levels, with signs of lithium overdose. Lithium blood levels should be monitored, and dosage adjustment of lithium-containing medications may be necessary.

Cyclosporine. Risk of increased cyclosporine levels in blood serum. If co-administration is necessary, serum levels of cyclosporine and creatinine should be closely monitored.

Rifampicin. Decreased plasma concentrations of metronidazole due to induction of its hepatic metabolism by rifampicin. Clinical monitoring should be performed during and after rifampicin treatment. Dose adjustment of metronidazole may be required.

Anticonvulsants that are enzyme inducers (carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone). Decreased plasma concentrations of metronidazole due to induction of its hepatic metabolism. Clinical monitoring should be performed during and after treatment with enzyme inducers. Dose adjustment of metronidazole may be necessary.

Combinations requiring special attention.

5-Fluorouracil (tegafur, capecitabine). Reduced clearance of 5-fluorouracil leads to increased toxicity.

Disturbance in INR (International Normalized Ratio) balance.

Numerous cases of enhanced activity of oral anticoagulants have been reported in patients receiving antibacterial therapy. Factors predisposing to this complication include presence of infection or significant inflammation, patient age, and general health status. Under these circumstances, it is difficult to determine to what extent the disturbance in INR balance is caused by the infection itself or by its treatment. However, certain classes of antibiotics play a more significant role, particularly: fluoroquinolones, macrolides, tetracyclines, co-trimoxazole, and some cephalosporins.

Laboratory test results. Metronidazole is capable of immobilizing treponemes, leading to a false-positive Nelson test result.

Special precautions for use.

In patients with severe, chronic or progressive diseases of the peripheral or central nervous system (CNS), there is a risk of worsening neurological status.

In patients with a history of hematological disorders or those receiving the drug in high doses and/or for a prolonged period, regular blood tests, especially leukocyte count determination, are necessary.

During prolonged treatment with the drug, patients should be monitored for the development of adverse reactions such as central or peripheral neuropathy (paresthesia, ataxia, dizziness, seizures).

Patients should be informed that metronidazole may darken the urine (due to the active metabolite).

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

If generalized erythema and pustular rash accompanied by fever occur at the beginning of treatment, acute generalized exanthematous pustulosis (AGEP) should be suspected (see section "Adverse reactions"); in case of such reaction, treatment with the drug must be stopped, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Acute skin reactions, including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), and acute generalized exanthematous pustulosis (AGEP), have been associated with metronidazole use. Patients should be informed about symptoms of such reactions, and careful skin monitoring should be performed.

If symptoms of Stevens-Johnson syndrome, Lyell's syndrome (e.g., progressive development of rash, skin blisters, or mucosal lesions), or generalized erythema with pustular rash accompanied by fever occur, treatment with the drug must be discontinued, and further use of metronidazole, either as monotherapy or in combination with other drugs, is contraindicated.

Central nervous system disorders. If symptoms characteristic of encephalopathy or cerebellar syndrome occur (see section "Adverse reactions"), treatment should be immediately re-evaluated 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 localized 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. Very rare cases with fatal outcomes have been reported.

Patients should be monitored for possible signs of encephalopathy or for worsening of symptoms in case of pre-existing CNS disorders.

If aseptic meningitis develops during treatment with the drug, re-administration of metronidazole is not recommended; for patients with serious infectious diseases, a re-evaluation of the benefit-risk ratio is required.

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

Psychiatric disorders. Psychotic reactions, including self-harming behavior, may occur after the first dose of the drug, particularly in patients with a history of psychiatric disorders (see section "Adverse reactions"). In such cases, metronidazole treatment should be discontinued, the physician should be notified, and appropriate therapeutic measures should be taken immediately.

Hematological effects. In patients with a history of blood system disorders or those receiving the drug in high doses and/or for a prolonged period, regular blood tests, especially leukocyte count monitoring, are necessary.

Continuation of treatment with the drug in patients with leukopenia depends on the severity of the infectious disease.

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").

Other types of interactions. The maximum duration of metronidazole treatment should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

Use of suppositories may increase the risk of latex condom or diaphragm rupture.

Hepatotoxicity in patients with Cockayne syndrome

In patients with Cockayne syndrome, cases of rapidly developing acute liver failure, including fatal outcomes, have been observed during systemic administration of metronidazole-containing drugs. Metronidazole should not be used in these patients except when the benefit outweighs the risk and only if no alternative treatment is available.

Liver function tests should be performed immediately before starting treatment, during treatment, and after treatment completion until liver function parameters return to normal or baseline levels. If liver function tests show markedly elevated values during treatment, 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 liver dysfunction occur (see section "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy.

Animal studies have not demonstrated teratogenic effects. Since no teratogenic effect is observed in animals, malformations in humans are not expected. Clinical data from numerous studies do not indicate specific teratogenic or fetotoxic effects associated with metronidazole. However, absence of such risk can only be confirmed by epidemiological studies. Therefore, metronidazole should be prescribed during pregnancy only if clearly necessary.

Breastfeeding.

Metronidazole is excreted in breast milk. Therefore, use of this medicinal product during breastfeeding should be avoided.

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned about the risk of dizziness, confusion, hallucinations, seizures, and visual disturbances. If such symptoms occur, patients should refrain from driving vehicles or operating machinery.

Method of administration and dosage.

The medication is permitted for use in the treatment of adult female patients only.

The vaginal suppository should be inserted deeply into the vagina.

It is absolutely essential to treat the sexual partner of the female patient simultaneously, even if he has no symptoms of infection.

The maximum duration of treatment with Mistol*®* should not exceed 10 days, and the number of treatment courses should not exceed 2–3 per year.

Children.

The drug is contraindicated for use in the treatment of children.

Overdose.

Oral intake of metronidazole in doses up to 12 g has been reported in suicide attempts and accidental overdoses. Leukopenia, neuropathy, ataxia, vomiting, and mild disorientation may occur.

Treatment. Since there is no specific antidote for metronidazole, symptomatic therapy is recommended.

Adverse Reactions

Gastrointestinal system: Mild gastrointestinal disturbances (epigastric pain, nausea, vomiting, diarrhea), inflammation of the oral mucosa, glossitis with dry mouth, stomatitis, taste disturbances (metallic taste), anorexia, changes in the color or appearance of the tongue (fungal infection), coated tongue, reversible pancreatitis.

Skin and appendages: Flushing with hyperemia, pruritus, rashes which may be 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 (Lyell’s syndrome), fixed drug eruption, Stevens–Johnson syndrome, and erythema multiforme.

Nervous system: Peripheral sensory neuropathy; headache, dizziness, confusion, seizures, ataxia, somnolence; encephalopathy*, subacute cerebellar syndrome**, aseptic meningitis (see section "Special precautions").

Psychiatric disorders: Hallucinations; psychotic reactions with paranoia and/or delirium, which in isolated cases may be associated with suicidal ideation or suicide attempts (see section "Special precautions"); depressive mood.

Eye disorders: Transient visual disturbances (e.g., diplopia, myopia, blurred vision, decreased visual acuity, color vision changes); optic neuropathy/neuritis.

Hematological disorders: Agranulocytosis, neutropenia, thrombocytopenia, pancytopenia, and leukopenia.

Hepatobiliary disorders: Elevated liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase); acute cholestatic or mixed hepatitis; hepatocellular liver injury (sometimes with jaundice); hepatocellular failure (may lead to complications requiring liver transplantation).

Ear and labyrinth disorders: Hearing disturbances, hearing loss (including sensorineural type); tinnitus.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Other adverse reactions: Increased body temperature, reddish-brown discoloration of urine (due to pigments resulting from metronidazole metabolism).

* Clinical manifestations of encephalopathy (confusion, fever, photophobia, nystagmus, hallucinations, paralysis, visual and motor disturbances) may be accompanied by reversible changes on MRI and resolve after discontinuation of the drug. Very rare fatal cases have been reported (see section "Special precautions").

** Clinical manifestations of subacute cerebellar syndrome (ataxia, dysarthria, gait disturbance, nystagmus, tremor) may resolve after discontinuation of the drug (see section "Special precautions").

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 "Special precautions").

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua

Shelf life.

3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

5 suppositories per strip. 2 strips per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD
Kusum Healthcare PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial Area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India /
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.