Limenda^® (Suppositories) Instructions for Use

Marketing Authorization Holder

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

Contact Information

World Medicine İlaç San. ve Tic. A.Ş. (Turkey)

ATC Code

G01AF20 (Imidazole derivative combinations)

Active Substances

Metronidazole (Rec.INN registered by WHO)

Miconazole (Rec.INN registered by WHO)

Dosage Form

Limenda®

Vaginal suppositories 750 mg+200 mg: 7 or 14 pcs. in a kit with a pack of finger cots (7 or 14 pcs.)

Dosage Form, Packaging, and Composition

Vaginal suppositories white with a yellowish or yellowish-greenish tint, torpedo-shaped, homogeneous on the longitudinal section, without inclusions.

Excipients: Witepsol S55.

7 pcs. – blisters (1) in a kit with a pack of finger cots (7 pcs.) – cardboard packs.
7 pcs. – blisters (2) in a kit with a pack of finger cots (14 pcs.) – 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

The drug Limenda^® contains Metronidazole, which has antibacterial and antitrichomonal action, and Miconazole nitrate, which has an antifungal effect.

Metronidazole is an antibacterial and antiprotozoal agent and is active against Gardnerella vaginalis and anaerobic bacteria, including anaerobic streptococcus and Trichomonas vaginalis.

Miconazole is an antifungal agent, an azole derivative. When applied intravaginally, it is active mainly against Candida albicans. The fungicidal and fungistatic effect of miconazole is due to the inhibition of the biosynthesis of ergosterol in the fungal envelope and plasma membranes, changing the lipid composition and permeability of the cell wall, causing fungal cell death.

Pharmacokinetics

Metronidazole

Absorption

When applied 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.

Distribution

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

Metabolism

It is 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.

Elimination

It is 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. 6-15% of the systemically administered drug dose is excreted through the intestines.

Miconazole

Systemic absorption of miconazole after intravaginal administration is low. It is rapidly degraded in the liver. It poorly crosses histohematic barriers. 8 hours after application of the drug, 90% of miconazole is still present in the vagina. Unchanged miconazole is not detected either in plasma or in urine.

Indications

Adults aged 18 years and older for the treatment of the following diseases

• Vaginal candidiasis;
• Bacterial vaginosis;
• Trichomonal vaginitis;
• Vaginitis caused by mixed infections.

ICD codes

Dosage Regimen

1 vaginal suppository once/day (at night) for 7 days.

For recurrent vaginitis or vaginitis resistant to other types of treatment, the drug Limenda^® should be applied once/day (at night) for 14 days.

Special patient groups

Elderly patients

For elderly patients over 65 years of age, no dose adjustment is required.

Children

Safety and efficacy in children from 0 to 18 years have not been established to date. Data are not available.

Method of administration

Intravaginally. The suppository, after removing it from the contour packaging, is inserted deep into the vagina, lying on the back with bent legs.

Adverse Reactions

Summary of the safety profile

When using the drug, the most frequent were local adverse reactions: vaginal itching, burning and irritation of the vaginal mucosa, and increased swelling. Due to inflammation of the vaginal mucosa in vaginitis, irritation may increase after the insertion of the first suppository or by the third day of treatment. These complications quickly disappear as treatment continues.

Summary of adverse reactions

Nervous system disorders: increased fatigue, dizziness, headache, peripheral sensory neuropathy, convulsions.

Encephalopathy (e.g., confusion, vertigo) and subacute cerebellar syndrome (impaired coordination and synergy of movements, ataxia, dysarthria, gait disturbances, nystagmus, and tremor) have been reported, which are reversible after discontinuation of metronidazole.

Gastrointestinal disorders: nausea, vomiting, abdominal pain or cramps, diarrhea, constipation, inflammation of the oral mucosa (glossitis, stomatitis), taste disturbances (“metallic” taste in the mouth), decreased appetite, anorexia, dry oral mucosa, pancreatitis (reversible cases), tongue discoloration/”coated” tongue (due to excessive growth of fungal flora).

Cardiac disorders: QT interval prolongation (especially when metronidazole is used concomitantly with drugs that can prolong the QT interval).

Blood and lymphatic system disorders: agranulocytosis, leukopenia, neutropenia, and thrombocytopenia.

Hepatobiliary disorders: increased activity of liver enzymes (AST, ALT, alkaline phosphatase), development of cholestatic or mixed hepatitis and hepatocellular liver damage, sometimes accompanied by jaundice. In patients treated with metronidazole in combination with other antibiotics, cases of liver failure requiring liver transplantation have been observed.

Immune system disorders: angioedema, anaphylactic shock.

Psychiatric disorders: psychotic disorders including confusion, hallucinations, depression, insomnia, irritability, increased excitability.

Eye disorders: transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, impaired color perception, optic neuropathy/neuritis.

Ear and labyrinth disorders: hearing impairment/hearing loss (including sensorineural deafness), tinnitus.

Skin and subcutaneous tissue disorders: rash, skin itching, flushing, skin hyperemia, urticaria, pustular skin rash, acute generalized exanthematous pustulosis, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary disorders: possible brownish-reddish discoloration of urine due to the presence of a water-soluble metabolite of metronidazole in the urine, dysuria, polyuria, cystitis, urinary incontinence, candidiasis.

General disorders and administration site conditions: fever, nasal congestion, arthralgia, weakness, burning sensation or irritation of the penis in the sexual partner, burning sensation or frequent urination, vulvitis (itching, burning pain or hyperemia of the mucous membrane in the external genital area).

Infections and infestations: vaginal candidiasis may develop after discontinuation of the drug.

Investigations: T-wave flattening on ECG.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of the medicinal product in order to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended 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, miconazole and other components of the drug;
• Severe liver dysfunction;
• Organic lesions of the central nervous system (including epilepsy);
• Porphyria;
• Leukopenia (including history);
• First trimester of pregnancy;
• Breastfeeding period;
• Virginity.

Use in Pregnancy and Lactation

Pregnancy

Since Metronidazole passes through the placental barrier and its effect on human fetal organogenesis is unknown, it is not recommended to prescribe the drug Limenda^® during pregnancy.

Breastfeeding period

Metronidazole penetrates into breast milk, so its use should be avoided during breastfeeding.

Use in Hepatic Impairment

Contraindication: severe liver dysfunction.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age (insufficient data on efficacy and safety). Contraindicated for use in virgins.

Geriatric Use

For elderly patients over 65 years of age, no dose adjustment is required.

Special Precautions

For intravaginal use only. Do not use by other methods.

The drug Limenda^® is not recommended for use in virgins.

During treatment, it is recommended to refrain from sexual intercourse.

In patients with trichomonal vaginitis, simultaneous treatment of the sexual partner is necessary.

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

When treating with gynecological dosage forms containing miconazole, the effectiveness of latex protective devices (condoms or diaphragms) may decrease. For this reason, the drug Limenda^® should not be used simultaneously with a latex condom or latex diaphragm.

Leukopenia may occur when using the drug, so it is advisable to monitor the blood picture at the beginning and at the end of therapy. The indications for long-term use of the drug Limenda^® 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, the drug is used for longer than is usually recommended, then treatment should be carried out under the control of hematological parameters.

Treatment should not be interrupted during menstruation. After therapy for trichomoniasis, control tests should be performed during 3 subsequent cycles before and after menstruation.

Metronidazole should be used with caution in patients with hepatic encephalopathy, as well as in patients with acute or chronic diseases of the central or peripheral nervous system due to the possible risk of neurological deterioration.

If adverse reactions occur that indicate hypersensitivity or irritation of the vaginal mucosa, treatment should be discontinued.

Cases of severe hepatotoxicity/acute liver failure, including fatal cases with very rapid development after the start of treatment in patients with Cockayne syndrome with products containing Metronidazole for systemic use have been reported. Therefore, in this population, Metronidazole should be used after a careful risk-benefit assessment and only in the absence of alternative treatment. Liver function diagnostics should be performed immediately before starting therapy, during and after the end until liver function is within normal limits or until baseline values are reached. If liver function tests become significantly elevated during treatment, the drug should be discontinued. Patients with Cockayne syndrome should immediately report any symptoms of liver dysfunction to their doctor and discontinue metronidazole.

Cases of severe bullous skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or acute generalized exanthematous pustulosis, have been reported after the use of metronidazole. If symptoms or signs of these diseases develop, treatment with the drug Limenda^® should be stopped immediately. Cases of suicidal thoughts with or without depression have been reported during treatment with metronidazole. Patients should be advised to discontinue treatment and immediately consult their doctor if mental disorders occur during treatment with the drug Limenda^®.

Long-term use of metronidazole should be carefully justified due to possible mutagenicity and carcinogenicity.

Effect on laboratory test results

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

Metronidazole may distort the results of some blood tests (determination of ALT, AST, lactate dehydrogenase, triglycerides, glucose). This may lead to a false-negative result or an extremely low value when analytical determination methods are based on the reduction of absorption in the ultraviolet region associated with the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide (NAD). The effect of the drug is due to the similarity of the absorption peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Effect on ability to drive vehicles and mechanisms

Given the profile of adverse reactions such as confusion, dizziness, vertigo, hallucinations, convulsions, and visual impairment, it is recommended to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during treatment.

Overdose

There are no data regarding overdose with intravaginal use of metronidazole. After insertion into the vagina, Metronidazole can be absorbed in amounts sufficient to cause systemic effects.

Symptoms of metronidazole overdose: nausea, vomiting, abdominal pain, diarrhea, generalized itching, “metallic” taste in the mouth, movement disorders (ataxia), dizziness, paresthesia, convulsions, peripheral neuropathy (including after prolonged use in high doses), leukopenia, darkening of urine.

Symptoms of miconazole overdose: not identified.

Treatment: in case of accidental ingestion, gastric lavage may be performed if necessary. There is no specific antidote. Metronidazole and its metabolites are well eliminated by hemodialysis. Symptomatic and supportive therapy is recommended.

Drug Interactions

Since the systemic absorption of miconazole is low, interaction with other drugs is due to metronidazole.

As a result of metronidazole absorption, the following types of drug interactions may be observed when used concomitantly with the drugs listed below.

Alcohol: alcohol intolerance (risk of disulfiram-like reactions).

Astemizole and terfenadine: possible inhibition of the metabolism of these compounds and an increase in their plasma concentration.

Cimetidine: risk of increased metronidazole plasma concentration, and consequently, risk of adverse reactions from the central nervous system.

Cyclosporine: an increase in the toxic effect of cyclosporine due to an increase in its blood concentration may be observed.

Disulfiram: possible disorders of the central nervous system (e.g., psychotic reactions).

Lithium: risk of increased toxic effect of lithium.

Phenytoin: possible increase in phenytoin concentration and decrease in metronidazole concentration.

Phenobarbital: possible decrease in metronidazole concentration.

Fluorouracil: risk of increased plasma concentration of fluorouracil and its toxic effect.

Non-depolarizing muscle relaxants: concomitant use with non-depolarizing muscle relaxants (vecuronium bromide) is not recommended.

Sulfonamides: enhance the antimicrobial effect of metronidazole.

Busulfan: Metronidazole increases the concentration of busulfan in the blood, which can lead to the development of a severe toxic effect of busulfan.

Oral anticoagulants: an increase in the anticoagulant effect may be observed (high risk of bleeding).

Drugs that prolong the QT interval (drugs that slow down the conduction of electrical impulses between the atria and ventricles of the heart): QT interval prolongation has been reported, especially when metronidazole is used concomitantly with drugs that can prolong the QT interval.

Storage Conditions

The drug should be stored in the original packaging (pack), in a place inaccessible to children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 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.