Limenda-l

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIMENDA-L (LIMENDA-L)

Composition:

Active substances: metronidazole, miconazole, lidocaine;

1 suppository contains 750 mg of metronidazole, 200 mg of miconazole nitrate, and 100 mg of lidocaine;

Excipients: polyethylene glycol cetyl stearyl ether, Witepsol S55.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical characteristics: yellowish-white torpedo-shaped suppositories.

Pharmacotherapeutic group.

Antimicrobial, antiprotozoal, antifungal agents. ATC code G01AF20.

Pharmacological properties.

Pharmacodynamics.

The medicinal product contains miconazole with antifungal activity, metronidazole with antibacterial and antitrichomonal activity, and lidocaine with local anesthetic action.

Miconazole is an antifungal agent; it has a broad spectrum of activity and is particularly effective against pathogenic fungi, including Candida albicans. In addition, it is effective against gram-positive bacteria. The mechanism of action of miconazole involves inhibition of ergosterol biosynthesis, damage to fungal cell membranes, disruption of membrane lipid composition and cell wall permeability, leading to fungal cell death. In Candida species, it alters cell permeability and suppresses glucose utilization in vitro.

Metronidazole is an antiprotozoal and antibacterial agent; it is effective against several infections caused by facultative aerobic bacteria, particularly Gardnerella vaginalis, protozoa such as Trichomonas vaginalis, and anaerobic bacteria, including anaerobic streptococci.

Miconazole nitrate and metronidazole do not exhibit synergistic or antagonistic effects.

Lidocaine stabilizes the neuronal membrane by inhibiting ionic fluxes necessary for the initiation and conduction of pain impulses, providing local anesthetic action and relieving itching and irritation.

Pharmacokinetics.

Absorption.

Absorption of miconazole after intravaginal administration is very low (approximately 1.4% of the dose). After intravaginal administration, miconazole was not detectable in blood plasma.

The bioavailability of metronidazole after intravaginal administration is 20% compared to oral administration. Steady-state plasma concentrations of metronidazole ranged from 1.1 to 5 µg/mL after intravaginal administration at the daily dose.

When lidocaine is applied topically to damaged skin or mucous membranes, minimal absorption occurs. After intravaginal administration over 3 days, lidocaine was minimally absorbed, with steady-state plasma concentrations ranging from 0.04 to 1 µg/mL.

Distribution.

Plasma protein binding of miconazole is 90–93%. Penetration into cerebrospinal fluid is low, but it widely distributes into other tissues. The volume of distribution is 1400 L.

Metronidazole penetrates into tissues and body fluids, including bile, bones, mammary glands, breast milk, cerebral abscesses, cerebrospinal fluid, liver and hepatic abscesses, saliva, seminal fluid, and vaginal secretions, reaching concentrations similar to those in plasma. It crosses the placental barrier and rapidly penetrates into the fetal circulation. Plasma protein binding is not more than 20%. The volume of distribution is 0.25–0.85 L/kg.

Plasma protein binding ranges from 33% to 80% (primarily to alpha-1 acid glycoprotein, to a lesser extent to albumin). The volume of distribution is 0.8–1.3 L/kg.

After oral administration or intravenous injection, lidocaine is found in the intestine, urine (in unchanged form and as metabolites), and in small amounts in feces.

Metabolism.

Miconazole is metabolized in the liver. Two inactive metabolites have been identified: 2,4-dichlorophenyl-1H-imidazole ethanol and 2,4-dichloromandelic acid.

Metronidazole is metabolized in the liver via oxidation; the hydroxyl metabolite is active. The main metabolites of metronidazole, hydroxyl and acetic acid metabolites, are excreted in urine. The hydroxyl metabolite has 30% of the biological activity of metronidazole.

Lidocaine is metabolized in the liver, forming active metabolites: monoethylglycinexylidide and glycinexylidide.

Elimination.

The elimination half-life of miconazole is 24 hours. Less than 1% is excreted in urine. Approximately 50% is excreted in feces, usually in unchanged form.

The elimination half-life of metronidazole is 6–11 hours. Approximately 6–15% of the dose is excreted in feces, 60–80% is excreted unchanged in urine, along with its metabolites. Approximately 20% of metronidazole is excreted in urine as unchanged substance.

Lidocaine is eliminated by the kidneys, primarily as metabolites (approximately 90%) and to a small extent unchanged (10%).

Preclinical safety data.

Standard preclinical studies on repeated-dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity do not indicate any specific risk to humans.

In a microbiological in vitro study, no synergistic or antagonistic interaction between the active substances of the medicinal product was observed against Candida albicans, Streptococcus (gram B by Lancefield), Gardnerella vaginalis, and Trichomonas vaginalis.

Preclinical studies with the combination of 750 mg metronidazole and 200 mg miconazole showed no enhancement or synergy of lethal or toxic effects of either component in female rats.

In a vaginal mucosa irritation study in female Beagle dogs using the same drug combination, no irritation of the vaginal mucosa was observed, and no clinical, biochemical, or hematological abnormalities were detected. No local or systemic toxic effects were observed in this study.

Clinical characteristics.

Indications.

• Candidal vulvovaginitis caused by Candida albicans;
• bacterial vaginosis caused by anaerobic bacteria and Gardnerella vaginalis;
• trichomonal vaginitis caused by Trichomonas vaginalis;
• mixed vaginal infections.

Contraindications.

• Hypersensitivity to the active substances and/or to any of the excipients of the medicinal product.

• Consumption of alcoholic beverages during treatment or within 3 days after treatment.

• Use of disulfiram during treatment or within 2 weeks after treatment.

• Porphyria.

• Epilepsy.

• Severe impairment of liver function.

• Patients with Cockayne syndrome (see section "Adverse reactions").

• First trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Interactions related to metronidazole.

Alcoholic beverages: disulfiram-like reaction may occur. Alcohol should not be consumed during treatment and for 3 days after its completion.

Amiodarone: increased risk of cardiotoxicity (prolongation of QT interval, ventricular fibrillation, cardiac arrest).

Astemizole, terfenadine: reduced metabolism of these medicinal products and increased plasma concentrations.

Busulfan: increased plasma concentration of busulfan and enhanced toxicity. If used concomitantly, prothrombin levels and international normalized ratio (INR) should be monitored more frequently during treatment and for 8 days after its completion.

Disulfiram: increased risk of central nervous system effects (e.g., psychotic reactions).

Carbamazepine: increased plasma concentration of carbamazepine.

Oral anticoagulants: enhanced anticoagulant effect and increased risk of bleeding.

Cimetidine: increased plasma concentration of metronidazole and increased risk of neurological adverse reactions.

Cyclosporine: increased risk of cyclosporine toxicity.

Lithium: increased plasma concentration of lithium and enhanced toxicity.

Phenytoin: increased plasma concentration of phenytoin and decreased plasma concentration of metronidazole.

Phenobarbital: decreased plasma concentration of metronidazole.

Fluorouracil: increased plasma concentration of fluorouracil and enhanced toxicity.

During metronidazole use, effects on blood levels of liver enzymes, glucose (hexokinase method), theophylline, and procainamide have been observed.

Interactions related to miconazole.

Acenocoumarol, anisindione, dicumarol, phenidione, phenprocoumon, warfarin: increased risk of bleeding.

Astemizole, cisapride, terfenadine: reduced metabolism of these medicinal products and increased plasma concentrations.

Glibenclamide: enhanced hypoglycemic effect.

Carbamazepine: reduced metabolism of carbamazepine.

Oxybutynin: increased plasma concentration of oxybutynin and enhanced effect (dry mouth, constipation, headache).

Oxycodone: increased plasma concentration of oxycodone and reduced plasma clearance.

Pimozide: increased risk of cardiotoxicity (prolongation of QT interval, ventricular fibrillation, cardiac arrest).

Solifenacin: increased bioavailability of solifenacin in individuals with cytochrome P450 2D6 deficiency.

Trimetrexate: enhanced trimetrexate toxicity (bone marrow suppression, renal and hepatic dysfunction, and ulceration in the stomach and intestine).

Cyclosporine: increased risk of cyclosporine toxicity (renal dysfunction, cholestasis, paresthesia).

Fentanyl: enhanced or prolonged opioid effects (central nervous system depression, sedation, respiratory depression).

Phenytoin, fosphenytoin: increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor).

Interactions related to lidocaine.

Antiarrhythmics: increased lidocaine toxicity.

Phenytoin, barbiturates: decreased plasma concentration of lidocaine.

Propranolol: reduced plasma clearance of lidocaine.

Cimetidine: reduced plasma clearance of lidocaine.

Special patient categories

Interaction studies involving special patient groups have not been conducted.

Children.

Interaction studies involving children have not been conducted.

Special precautions for use.

Alcohol consumption.

Patients should be advised not to consume alcohol during treatment and for 3 days after its completion due to the possibility of developing central nervous system reactions similar to those caused by disulfiram.

Prolonged use and use at high doses.

Prolonged use and use at high doses of the medicinal product may cause peripheral neuropathy and seizures.

Concomitant use with other intravaginal products.

The base of the suppository may adversely interact with rubber or latex, from which contraceptive diaphragms and condoms are made; therefore, their concomitant use with this medicinal product is not recommended.

Other intravaginal products (e.g., tampons, douching, or spermicides) should not be used simultaneously with this medicinal product.

Use in trichomonal vaginitis.

Sexual partners of patients with trichomonal vaginitis should also undergo treatment.

Use in patients of different age groups.

The medicinal product is not recommended for use in virgin girls.

Recommendations for use in elderly patients (aged 65 years and older) are the same as for other patients.

Risk of hypersensitivity reactions.

Hypersensitivity reactions, including anaphylaxis and angioedema, may occur during use of the medicinal product. If hypersensitivity reactions develop, treatment should be discontinued.

Risk of cardiac and respiratory disturbances.

Lidocaine may cause cardiac arrhythmias and respiratory depression, which may lead to coma, including fatal outcomes, particularly when applied to large skin areas, especially under occlusive dressings. Such effects are not expected with intravaginal administration in the form of suppositories as described in the section "Method of administration and dosage."

Use in patients with impaired liver function.

In severe hepatic insufficiency, the clearance of metronidazole may be altered. Increased plasma levels of metronidazole may exacerbate symptoms of encephalopathy. Therefore, metronidazole should be used with caution in patients with hepatic encephalopathy. The daily dose of metronidazole in such patients should be reduced to one-third of the standard dose.

Use in patients with impaired renal function.

The dose of metronidazole should be reduced in patients with renal insufficiency. Impaired renal function does not affect the pharmacokinetics of lidocaine but may lead to its accumulation.

Use during pregnancy or breastfeeding.

Use in women of reproductive age.

Since the effects of the active substances of the medicinal product on the fetus and neonatal development have not been fully studied, women who need to use this medicinal product should avoid pregnancy by using an effective contraceptive method.

Pregnancy.

Preclinical data in animals regarding pregnancy, embryonal development, fetal development, perinatal and/or postnatal development are insufficient. The potential risk to humans is unknown.

The medicinal product should not be used during the first trimester of pregnancy. During the second and third trimesters of pregnancy, the medicinal product may be used only if necessary, when the physician determines that the benefit outweighs the risk.

Breastfeeding period.

Breastfeeding should be discontinued during treatment with this medicinal product, as metronidazole, one of the active components, passes into breast milk. Breastfeeding may be resumed 1–2 days after completion of treatment.

Fertility.

There is no evidence of harmful effects on fertility in humans or animals with the use of metronidazole or miconazole alone.

Ability to influence reaction rate when driving or operating machinery.

Systemic use of metronidazole may affect the ability to drive or operate machinery. Compared to systemic administration, vaginal administration results in significantly lower absorption of metronidazole. However, dizziness, ataxia, and psychoemotional disturbances may occur. If such symptoms develop, driving or operating machinery is not recommended.

Method of Administration and Dosage

The medicinal product is intended for intravaginal administration. Do not swallow the suppositories or use the medicinal product by any route of administration not specified in the instructions for medical use.

Dosage.

One vaginal suppository should be administered deeply into the vagina at night using the disposable finger cots provided in the package, for 7 consecutive days.

In cases of recurrent infections or vaginitis resistant to other treatments, the medicinal product should be used at night for 14 days.

The medicinal product is not recommended during menstruation due to reduced efficacy and the possibility of certain complications during administration.

Elderly patients (aged 65 years and older) do not require dose adjustment.

Method of Administration.

Hands should be thoroughly washed before using the medicinal product.

Vaginal suppositories should be administered in the lying position deeply into the vagina.

If possible, avoid assuming an upright position for at least half an hour after suppository insertion.

Hands should be thoroughly washed after administration of the medicinal product.

Do not use a double dose of the medicinal product to replace a missed dose.

Children.

The medicinal product is not recommended for use in children.

Overdose.

There is no data on metronidazole overdose following vaginal administration. However, when administered intravaginally, metronidazole may be absorbed in amounts sufficient to cause systemic effects.

If a large amount of the medicinal product accidentally enters the gastrointestinal tract, gastric lavage should be performed as appropriate. Treatment is indicated if 12 g of metronidazole has entered the gastrointestinal tract. There is no specific antidote; symptomatic treatment is recommended. Symptoms of metronidazole overdose include: nausea, vomiting, abdominal pain, diarrhea, itching, metallic taste in the mouth, ataxia, vertigo, paresthesia, seizures, leukopenia, and darkening of urine.

Symptoms of miconazole overdose include: nausea, vomiting, inflammation of the throat and oral cavity, anorexia, headache, diarrhea.

Overdose of lidocaine may lead to cardiac arrhythmias and respiratory depression, which may result in coma, including fatal outcomes, particularly when applied to large skin areas or used in high doses.

Side effects

The frequency of the side effects listed below is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

In individual cases, the following adverse reactions may occur: hypersensitivity reactions (including skin rash), abdominal pain, headache, itching, burning, and vaginal irritation. The incidence of systemic adverse reactions is very low due to the extremely low plasma levels of metronidazole achieved after vaginal administration of the medicinal product (2–12% of the levels reached with oral metronidazole). The other active ingredient of the medicinal product, miconazole, may cause vaginal irritation (burning, itching), as do all other imidazole-derivative antifungal agents administered vaginally (2–6%). In case of severe irritation, treatment should be discontinued.

The occurrence of the above symptoms may be prevented by using the local anesthetic lidocaine. Since inflammation of the vaginal mucosa may occur during vaginitis, symptoms such as burning, itching, and irritation may appear either upon first insertion of the suppository or on the third day of treatment. These symptoms rapidly diminish and disappear with continued therapy. If pronounced irritation occurs, treatment should be discontinued. The extent of lidocaine absorption is very low. Adverse reactions with local anesthetics are reported in less than 1 patient per 1,000 patients.

Systemic side effects related to the active ingredients are listed below.

Blood and lymphatic system disorders:

very rare – agranulocytosis, neutropenia, thrombocytopenia, pancytopenia; frequency not known – leukopenia, methemoglobinemia.

Immune system disorders:

rare – anaphylactic shock; frequency not known – hypersensitivity reactions, allergic reactions, angioedema, urticaria, fever.

Metabolism and nutrition disorders:

frequency not known – anorexia.

Psychiatric disorders:

very rare – disturbances of consciousness, including confusion and hallucinations; frequency not known – depression.

Nervous system disorders:

common – dizziness, headache; very rare – encephalopathy (e.g., confusion, fever, photophobia, torticollis, hallucinations, paralysis, visual and motor disturbances) and subacute cerebellar syndrome (e.g., ataxia, dysarthria, gait disturbances, nystagmus, tremor), which may resolve after discontinuation of treatment; frequency not known – increased fatigue or weakness, seizures, malaise, tingling, loss of sensation, paresthesia, numbness, peripheral neuropathy due to intensive and/or prolonged metronidazole therapy, aseptic meningitis, somnolence, loss of consciousness, coma, anxiety, insomnia, disorientation, agitation, psychosis, speech disorders, hyperesthesia, hypoesthesia, lethargy, nervousness, restlessness, euphoria.

Eye disorders:

very rare – transient visual disturbances such as diplopia, myopia, blurred vision, decreased visual acuity, color vision changes; frequency not known – optic neuropathy/neuritis.

Ear and labyrinth disorders:

frequency not known – tinnitus.

Cardiac disorders:

frequency not known – arrhythmia, bradycardia, increased defibrillation threshold, heart block, sinus node depression.

Vascular disorders:

frequency not known – arterial spasm, hypotension, cardiovascular collapse, edema, flushing, arterial hypotension.

Gastrointestinal disorders:

frequency not known – taste disturbances, stomatitis, metallic taste, coated tongue, nausea, vomiting, constipation, gastrointestinal disorders such as epigastric pain and diarrhea, dry mouth, decreased appetite, stomach pain, abdominal pain, and spasms.

Hepatobiliary disorders:

very rare – elevated liver enzymes (AST, ALT, alkaline phosphatase), cholestatic or mixed hepatitis, and hepatocellular damage, sometimes with jaundice; cases of liver failure requiring liver transplantation have been reported in patients treated with metronidazole and other antibiotics.

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").

Skin and subcutaneous tissue disorders:

very rare – skin rashes, pustular rashes, flushing with hyperemia, itching; frequency not known – polymorphic erythema, Stevens-Johnson syndrome, or toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:

very rare – myalgia, arthralgia.

Renal and urinary disorders:

very rare – darkening of urine (due to metronidazole metabolism).

General disorders and administration site conditions:

very common – vaginal discharge; common – vaginitis, vulvovaginal irritation, pelvic discomfort; uncommon – sensation of thirst; rare – burning in the vagina, itching, irritation, rash; frequency not known – local irritation and hypersensitivity, contact dermatitis, feeling of warmth, chills.

The aforementioned adverse reactions are rarely observed due to the low plasma concentrations of metronidazole and lidocaine achieved after intravaginal administration.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after the medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Packaging.

7 vaginal suppositories per blister, 1 blister with 7 single-use applicators.

Prescription status.

Prescription only.

Manufacturer.

UORLDMEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of business operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.