Klion^®-D 100 (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Or

Gedeon Richter-Rus, JSC (Russia)

Packaging and Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER-RUS, JSC (Russia)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

G01AF20 (Imidazole derivative combinations)

Active Substances

Metronidazole (Rec.INN registered by WHO)

Miconazole (Rec.INN registered by WHO)

Dosage Form

Klion®-D 100

Vaginal tablets 100 mg+100 mg: 10 pcs.

Dosage Form, Packaging, and Composition

Vaginal tablets almost white in color, biconvex, oval in shape with a pointed end, engraved with “100” on one side.

Excipients: sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate, povidone-K30, sodium bicarbonate, tartaric acid, sodium carboxymethyl starch (type A), crospovidone, hypromellose 2910, lactose monohydrate.

10 pcs. – aluminum strips (1) – cardboard packs.

Clinical-Pharmacological Group

A drug with antibacterial, antiprotozoal, and antifungal action for topical use in gynecology

Pharmacotherapeutic Group

Antimicrobial agents and antiseptics used in gynecology; antimicrobial agents and antiseptics, except combinations with corticosteroids; imidazole derivatives

Pharmacological Action

A combined drug for intravaginal use, containing Metronidazole and miconazole.

Metronidazole is an antiprotozoal and antimicrobial drug, a nitro-5-imidazole derivative. The mechanism of action involves the biochemical reduction of the 5-nitro group of metronidazole by intracellular transport proteins of anaerobic microorganisms and protozoa. The reduced 5-nitro group of metronidazole interacts with the DNA of the microorganism’s cell, inhibiting the synthesis of their nucleic acids, which leads to the death of bacteria and protozoa.

Active against Trichomonas vaginalis, Entamoeba histolytica, Gardnerella vaginalis, Giardia lamblia, as well as obligate anaerobes Bacteroides spp. (including Bacteroides fragilis, Bacteroides ovatus, Bacteroides distasonis, Bacteroides thetaiotaomicron, Bacteroides vulgatus), Fusobacterium spp., Veillonella spp., Prevotella spp. (Prevotella bivia, Prevotella buccae, Prevotella disiens) and some gram-positive microorganisms (Eubacterium spp., Clostridium spp., Peptococcus spp., Peptostreptococcus spp.). The MIC for these strains is 0.125-6.25 µg/ml.

Resistant to metronidazole are aerobic microorganisms and facultative anaerobes, but in the presence of mixed flora (aerobes and anaerobes), Metronidazole acts synergistically with antibiotics effective against aerobes.

Miconazole has an antifungal effect against dermatophytes, yeast fungi. When used intravaginally, it is mainly active against Candida albicans. Miconazole inhibits the biosynthesis of ergosterol in fungi and alters the composition of other lipid components in the membrane, leading to the death of fungal cells. Miconazole does not alter the composition of the normal flora and vaginal pH.

Preclinical safety data

The toxicity of metronidazole upon long-term administration varies among different mouse strains and different animal species. Neurological disturbances observed in dogs were not detected in other animal species.

The drug, when administered orally at high doses, caused a decrease in body weight and testicular atrophy in one strain of mice and rats, whereas intravenous administration of Metronidazole did not affect body weight gain in rats and did not lead to any significant changes in blood pressure or hematological and biochemical parameters. In marmosets receiving the drug at high doses, histological changes in the liver parenchyma were detected in the absence of concomitant deviations in liver enzyme activity.

In mice administered the drug at doses up to 1 mg/kg/day for 5 weeks, no significant lethal effect was noted. In one laboratory study, an increased prevalence of lung tumors and malignant lymphomas was observed in Swiss mice; however, this effect was not determined in Sprague-Dawley rats or hamsters in other research centers. A mutagenic effect of metronidazole was established in a number of in vitro test systems, but in vivo studies in mammals failed to demonstrate the possibility of genetic damage.

Studies of acute and chronic toxicity of the drug in mice, rats, guinea pigs, and dogs yielded positive results that cannot be ignored even with the topical use of vaginal tablets containing Metronidazole and Miconazole nitrate, i.e., with the topical use of metronidazole.

In teratogenesis studies, it was found that 80-160 mg of the drug mixed with 100 grams of food did not have a teratogenic effect on pregnant animals. The pregnancy rate did not differ compared to control animals, the implantation rate and fetal weight were normal, and no congenital developmental anomalies were noted.

In female marmosets vaginally administered 5 mg/kg/day of the drug, no deviations in hematological or biochemical parameters, or histopathological changes were noted.

Pharmacokinetics

Absorption

Metronidazole. When used intravaginally, Metronidazole is absorbed into the systemic circulation. The C_max of metronidazole in the blood is determined after 6-12 hours and is approximately 50% of the C_max achieved (after 1-3 hours) after a single oral administration of an equivalent dose of metronidazole.

Miconazole. Systemic absorption of miconazole after intravaginal application is low. Eight hours after application of the drug, 90% of miconazole is still present in the vagina.

Distribution

Metronidazole. Plasma protein binding is less than 20%. Metronidazole penetrates into breast milk and most tissues, crosses the blood-brain barrier and the placental barrier.

Miconazole. Poorly crosses histohematic barriers.

Metabolism

Metronidazole. Metabolized in the liver by hydroxylation, oxidation, and glucuronidation. The activity of the main metabolite (2-hydroxymetronidazole) is 30% of the activity of the parent compound.

Miconazole. Rapidly degraded in the liver.

Excretion

Metronidazole. Excreted by the kidneys – 60-80% of the systemically administered drug dose (20% of this amount unchanged). The metronidazole metabolite, 2-hydroxymetronidazole, colors the urine reddish-brown due to the presence of a water-soluble pigment formed as a result of metronidazole metabolism. Excreted through the intestines – 6-15% of the systemically administered drug dose.

Miconazole. Unchanged miconazole is not detected either in plasma or in urine.

Indications

For adults aged 18 years and over

• Local treatment of vaginitis of mixed etiology caused simultaneously by Trichomonas spp. and Candida spp.

ICD codes

Dosage Regimen

Intravaginally.

The vaginal tablet (after slightly moistening with water) is inserted deep into the vagina in the evening before bedtime.

For trichomoniasis, 1 vaginal tablet once/day (in the evening, before bedtime) for 10 days in combination with oral administration of Metronidazole tablets.

To prevent reinfection, simultaneous treatment of the sexual partner with Metronidazole in the form of oral tablets is necessary.

In case of treatment failure: the 10-day course of treatment can be repeated.

For fungal infection, 1 vaginal tablet once/day (in the evening, before bedtime) for 10 days.

Children

The safety and efficacy of the drug Klion^®-D 100 in children and adolescents aged 0 to 18 years have not been established. No data available.

Adverse Reactions

Cases of irritation with the local use of the drug Klion^®-D 100 vaginal tablets have been reported. In rare cases, local hypersensitivity reactions may occur.

Undesirable reactions of metronidazole, which may occur when used in combination with oral metronidazole tablets, are presented in accordance with the MedDRA system organ classification, as well as according to the frequency of occurrence: very common (≥1/10), common (≥ 1/100, but < 1/10), uncommon (≥ 1/1000, but < 1/100), rare (≥ 1/10000, but < 1/1000), very rare (< 1/10000), frequency unknown (cannot be estimated from the available data).

* Darkening of urine is due to a metabolite of metronidazole and has no clinical significance.

Description of selected adverse reactions

Peripheral neuropathy (numbness of extremities), headache, convulsions, drowsiness, dizziness, impaired coordination, and state of confusion have been observed in rare cases with long-term use of high doses of the drug. After dose reduction or discontinuation of therapy, all the symptoms listed in the table above resolved spontaneously.

Cases of severe irreversible hepatotoxicity/acute liver failure, including fatal cases, which occurred very rapidly after the initiation of systemic use of metronidazole, have been reported in patients with Cockayne syndrome (see the “Special Precautions” section).

Adverse reactions due to the presence of miconazole nitrate in the composition of the drug Klion^®-D 100 vaginal tablets

Adverse reactions occur rarely and are mild in severity. The occurrence of irritation and burning with local use has been reported.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to metronidazole, to other nitroimidazole derivatives, to miconazole, to imidazoles and/or to any of the excipients included in the drug;
• Organic lesions of the CNS (including epilepsy);
• Leukopenia (including history);
• Hepatic insufficiency (in case of prescription of high doses);
• First trimester of pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

Klion^®-D 100 is contraindicated for use in the first trimester of pregnancy. The use of the drug in the second and third trimesters is possible only in cases where the potential benefit to the mother outweighs the risk to the fetus.

Breastfeeding period

Metronidazole is excreted in breast milk. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated in hepatic insufficiency.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Since the simultaneous use of metronidazole with alcohol (ethanol) can have an effect similar to that of disulfiram (skin hyperemia, flushing, vomiting, tachycardia), the patient should be warned not to consume alcoholic beverages or medicines containing ethanol during treatment and for at least one day after the end of the drug use.

Indications for long-term use of the drug (more than 10 days) should be carefully weighed, and in the absence of strict indications, its long-term use should be avoided. If, in the presence of strict indications (after carefully weighing the ratio between the expected effect and the potential risk of complications), the drug is used for longer than is usually recommended, then treatment should be carried out under the control of hematological parameters (especially leukocytes) and adverse reactions such as peripheral or central neuropathy, manifested by paresthesia, ataxia, dizziness, convulsions, upon the appearance of which treatment should be discontinued.

When treating trichomonal vaginitis in women and trichomonal urethritis in men, it is necessary to refrain from sexual intercourse. Simultaneous treatment of sexual partners is mandatory. Treatment is not interrupted during menstruation. After therapy for trichomoniasis, control tests should be performed during 3 subsequent cycles before and after menstruation.

In case of treatment failure, replacement with another systemic trichomonacidal and/or antifungal drug is recommended.

In case of hypersensitivity, irritation of the vaginal mucosa, treatment with this drug should be discontinued.

The development of severe hepatotoxicity/acute liver failure (including fatal cases) has been reported in patients with Cockayne syndrome. Metronidazole should be used with caution and only in the absence of alternative treatment in this category of patients.

Cases of severe hepatotoxicity/acute liver failure, including fatal cases with a very rapid onset after initiation of therapy, have been reported in patients with Cockayne syndrome with systemic use of drugs containing Metronidazole. Thus, in this population, Metronidazole should be used after a careful benefit/risk assessment, only if the potential benefit of treatment outweighs the risks and only in the absence of alternative treatment. Liver function tests should be performed immediately before starting treatment, during therapy, and after its completion until liver function values return to normal, or until baseline values of these parameters are reached. In case of a noticeable increase in liver function parameters during treatment, the use of the drug should be discontinued.

Patients with Cockayne syndrome should be advised to immediately report to their physician any symptoms of potential liver damage and to discontinue metronidazole (see the “Adverse Reactions” section).

It must be taken into account that Metronidazole can immobilize treponemes, which leads to a false-positive Nelson test.

It must be taken into account that Metronidazole can immobilize treponemes, which leads to a false-positive Nelson test.

Excipients

The drug contains sodium lauryl sulfate, which can cause local skin reactions (such as a tingling or burning sensation) or enhance skin reactions caused by other medicines when applied to the same area.

Effect on ability to drive vehicles and mechanisms

When using the drug Klion^®-D 100 intravaginally, no negative effect on the ability to drive vehicles was detected; however, given the risk of developing such adverse reactions as confusion, dizziness, hallucinations, visual disturbances, it is recommended to refrain from driving a car and from engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during treatment.

Overdose

The drug is intended for intravaginal use only. In case of unintentional ingestion of a large amount of the drug, gastric lavage is necessary.

Symptoms: nausea, vomiting, ataxia.

Treatment: There is no specific antidote for metronidazole overdose. If symptoms of intoxication appear in case of overdose, symptomatic therapy such as gastric lavage, activated charcoal, and hemodialysis should be performed. Metronidazole and its metabolites are well removed by dialysis.

Drug Interactions

There are no data on the interaction of metronidazole and miconazole with intravaginal use. If Klion^®-D 100 vaginal tablets are used with oral metronidazole tablets, the following types of interactions related to metronidazole must be considered.

With disulfiram: psychotic reactions have been reported in patients receiving Metronidazole and disulfiram simultaneously (the interval between the use of these drugs should be at least 2 weeks).

With ethanol: disulfiram-like reactions may occur (skin hyperemia, flushing, vomiting, tachycardia).

With indirect anticoagulants (warfarin): enhancement of the anticoagulant effect and increased risk of bleeding associated with a decrease in the hepatic metabolism of indirect anticoagulants, which may lead to prolongation of prothrombin time. In case of simultaneous use of metronidazole and indirect anticoagulants, more frequent monitoring of prothrombin time and, if necessary, dose adjustment of anticoagulants is required.

With lithium preparations: when metronidazole is used concomitantly with lithium preparations, the plasma concentration of the latter may increase. With simultaneous use, plasma concentrations of lithium, creatinine, and electrolytes should be monitored.

With cyclosporine: when metronidazole is used concomitantly with cyclosporine, the plasma concentration of cyclosporine may increase. If simultaneous use of metronidazole and cyclosporine is necessary, plasma concentrations of cyclosporine and creatinine should be monitored.

With cimetidine cimetidine inhibits the metabolism of metronidazole, which may lead to an increase in its plasma concentration and an increased risk of adverse reactions.

With drugs that induce microsomal oxidation isoenzymes in the liver (phenobarbital, phenytoin): simultaneous use of metronidazole with drugs that induce microsomal oxidation isoenzymes in the liver (phenobarbital, phenytoin) may accelerate the elimination of metronidazole, resulting in a decrease in its plasma concentration.

With fluorouracil: Metronidazole reduces the clearance of fluorouracil, leading to increased toxicity.

With busulfan : Metronidazole increases the plasma concentration of busulfan, which may lead to the development of severe toxic effects of busulfan.

With non-depolarizing muscle relaxants (vecuronium bromide) it is not recommended to use with non-depolarizing muscle relaxants (vecuronium bromide).

With sulfonamides : sulfonamides enhance the antimicrobial effect of metronidazole.

Laboratory tests

Metronidazole may affect the results of the assessment of certain serum biochemical parameters, such as AST, ALT, LDH, triglycerides, and glucose hexokinase.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.