Milagin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MİLAGİN (MILAGIN)

Composition:

Active substance: clindamycin;

1 suppository contains 100 mg of clindamycin phosphate, calculated as clindamycin;

Excipient: lipophilic base.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical properties: white or almost white cigar-shaped suppositories.

Pharmacotherapeutic group. Antimicrobial and antiseptic agents used in gynecology, excluding combined medicinal products containing corticosteroids. Antibiotics. ATC code G01A A10.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis by acting on bacterial ribosomes. The antibiotic binds predominantly to the 50S ribosomal subunit and interferes with the translation process. Although clindamycin phosphate is inactive in vitro, it is rapidly hydrolyzed in vivo to clindamycin, which exhibits antibacterial activity.

Like most inhibitors of protein synthesis, clindamycin exerts primarily a bacteriostatic effect; its efficacy is related to the duration of time during which the concentration of the active substance remains above the MIC (minimum inhibitory concentration) of the infecting organism.

Resistance to clindamycin most commonly arises due to modification of the ribosomal target site, usually through chemical modification of ribosomal RNA bases or point mutations in RNA, or sometimes in proteins. Cross-resistance has been demonstrated in vitro between lincosamides, macrolides, and streptogramin B in certain organisms. Cross-resistance between clindamycin and lincomycin has also been demonstrated.

In vitro susceptibility. Clindamycin demonstrates in vitro activity against the following recognized microbial strains associated with bacterial vaginosis: Bacteroides spp., Gardnerella vaginalis, Mobiluncus spp., Mycoplasma hominis, Peptostreptococcus spp.

Standard methodology for susceptibility testing of potential pathogens in bacterial vaginosis, Gardnerella vaginalis and Mobiluncus spp., has not been established. Breakpoint values for susceptibility of gram-negative and gram-positive anaerobes to clindamycin have been published by EUCAST. For clinical isolates found to be susceptible to clindamycin and resistant to erythromycin, testing for inducible clindamycin resistance using the D-test should also be performed. However, the breakpoints are intended more for guiding systemic antibiotic therapy rather than topical treatment.

Pharmacokinetics.

Absorption. Systemic absorption of clindamycin following intravaginal administration of one clindamycin phosphate suppository once daily (equivalent to 100 mg of clindamycin) was evaluated over 3 days in 11 healthy female volunteers. Approximately 30% (range: 6% to 70%) of the administered dose underwent systemic absorption on day 3 based on area under the concentration-time curve (AUC) measurements. Systemic absorption was also assessed following intravenous administration of a subtherapeutic dose of 100 mg clindamycin phosphate as a comparator in the same volunteers who received a vaginal cream containing 100 mg clindamycin phosphate. The mean AUC value after three days of suppository use was 3.2 µg•h/mL (range: 0.42 to 11 µg•h/mL). The mean C_max observed on day 3 of suppository use was 0.27 µg/mL (range: 0.03 to 0.67 µg/mL), reached approximately 5 hours after administration (range: 1 to 10 hours). For comparison, the AUC and C_max following a single intravenous dose averaged 11 µg•h/mL (range: 5.1 to 26 µg•h/mL) and 3.7 µg/mL (range: 2.4 to 5 µg/mL), respectively. The mean elimination half-life after suppository administration was 11 hours (range: 4 to 35 hours) and is considered to be absorption-rate limited.

These study results indicate that systemic exposure to clindamycin (based on AUC) following suppository use was on average 3 times lower than after a single intravenous administration of the subtherapeutic 100 mg dose. Compared to the same dose of clindamycin administered as a vaginal cream, systemic absorption following suppository use was approximately 7 times higher than after vaginal cream administration, for which mean AUC and C_max values were 0.4 µg•h/mL (range: 0.13 to 1.16 µg•h/mL) and 0.02 µg/mL (range: 0.01 to 0.07 µg/mL), respectively. Furthermore, the recommended daily and total dose of clindamycin in intravaginal suppositories is substantially lower than that typically used during oral or parenteral administration of clindamycin (with 100 mg clindamycin administered daily for 3 days in suppository form, the absorbed amount of clindamycin is approximately 30 mg per day, compared to 600–2700 mg per day over 10 days or more with oral or parenteral administration). Overall, systemic exposure to clindamycin following vaginal suppositories is significantly lower than systemic exposure following therapeutic doses of orally administered clindamycin hydrochloride (2–20 times lower) or parenterally administered clindamycin phosphate (40–50 times lower).

Clinical characteristics.

Indications.

Treatment of bacterial vaginosis (previous names – haemophilus vaginitis, gardnerella vaginitis, nonspecific vaginitis, corynebacterial vaginitis, or anaerobic vaginosis).

Contraindications.

Hypersensitivity to the active substance, lincomycin, or any excipient listed in the section "Composition".

Milagyn is also contraindicated in patients with a history of antibiotic-associated colitis.

Interaction with other medicinal products and other forms of interaction.

There is no information regarding concomitant use of Milagyn with other vaginal medicinal products.

When clindamycin phosphate is administered systemically, it has neuromuscular blocking properties that may enhance the effect of other neuromuscular blocking agents. Therefore, it should be used with caution in patients taking such agents (see sections "Overdose" and "Pharmacokinetics").

Use of latex condoms is not recommended during treatment with Milagyn in the form of vaginal suppositories.

Special precautions for use.

Before or immediately after starting treatment with Miragyn, it may be necessary to perform laboratory tests to detect other infectious agents, including Trichomonas vaginalis, Candida albicans, Chlamydia trachomatis, and gonococci.

Use of Miragyn may lead to overgrowth of microorganisms not susceptible to the drug, particularly yeasts.

Symptoms indicating pseudomembranous colitis may occur during or after antimicrobial therapy (see section "Side effects"). Cases of pseudomembranous colitis have been reported with nearly all antibacterial agents, including clindamycin; severity may range from mild to life-threatening. Therefore, this diagnosis should be considered in patients who develop diarrhea following antibacterial therapy. In mild to moderate cases, improvement is usually observed after discontinuation of the drug.

If pseudomembranous colitis occurs, clindamycin should be discontinued immediately. Appropriate antibacterial therapy should be initiated. Antiperistaltic agents are contraindicated in this situation.

Miragyn should be prescribed with caution in patients with inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis.

As with any vaginal infections, sexual intercourse during treatment with Miragyn in the form of vaginal suppositories is not recommended. The base of vaginal suppositories may weaken latex condoms and diaphragms (see section "Interaction with other medicinal products and other forms of interaction"). Use of such contraceptive methods is not recommended within 72 hours after treatment, as their contraceptive effectiveness and protection against sexually transmitted infections may be reduced.

During treatment with Miragyn vaginal suppositories, the use of other intravaginal products (such as tampons or douching solutions) is not recommended.

Special precautions during handling and disposal of the medicinal product.

Do not use this medicinal product if the polyvinyl chloride foil packaging containing the vaginal suppositories is damaged, opened, or not hermetically sealed.

Use during pregnancy or breastfeeding.

Pregnancy.

Reproductive toxicity has been demonstrated in animal studies.

Use during the first trimester of pregnancy is not recommended due to the lack of adequate and well-controlled studies on the use of the drug in pregnant women during this period.

Clinical data indicate that use of Miragyn in the vaginal dosage form during the second trimester of pregnancy and systemic use of clindamycin phosphate during the second and third trimesters do not lead to the development of congenital anomalies.

Miragyn may be used during the second and third trimesters of pregnancy only if clearly needed.

Breastfeeding.

It is not known whether clindamycin passes into human breast milk after vaginal administration. Although administered at much lower doses than systemic clindamycin, approximately 30% (ranging from 6% to 70%) is absorbed into systemic circulation. After systemic administration, clindamycin has been detected in human breast milk at concentrations ranging from < 0.5 to 3.8 mcg/mL.

Systemic use of clindamycin in breastfeeding women may pose a risk of adverse effects on the gastrointestinal flora of the breastfed infant, such as diarrhea, blood in stool, or rash. Use of Miragyn vaginal suppositories in breastfeeding women may be considered if the expected benefit to the mother outweighs the potential risks to the infant.

Fertility.

Animal studies have not shown any effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

The effect of Miragyn on the ability to drive or operate machinery is absent or negligible.

Method of Administration and Dosage.

One suppository intravaginally once daily at bedtime for 3 consecutive days. Remove the suppository from its contour packaging and insert into the vagina while lying on the back with knees bent and drawn up toward the chest, using the middle finger of the hand as deeply as possible without causing discomfort.

Use in elderly patients.

The use of Miragin in the form of vaginal suppositories in patients aged 65 years and older has not been studied.

Use in patients with renal impairment.

The use of Miragin in the form of vaginal suppositories in patients with impaired renal function has not been studied.

Attention should be paid to official recommendations regarding the appropriate use of antibacterial agents.

Children.

The safety and efficacy of Miragin in the form of vaginal suppositories in children have not been established.

Overdose.

Cases of overdose with Miragin in the form of vaginal suppositories have not been reported.

Clindamycin phosphate contained in the medicinal product and administered vaginally may be absorbed in amounts sufficient to produce systemic effects.

In case of overdose, general symptomatic and supportive treatment should be administered, if necessary.

Following accidental oral ingestion of the medicinal product, effects similar to those observed after oral administration of therapeutic doses of clindamycin may occur.

Adverse Reactions

The safety of clindamycin in the form of vaginal suppositories was evaluated during clinical trials involving non-pregnant patients. The following frequencies of adverse reactions have been reported: common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100).

Infections and infestations.

Common: fungal infections, candida infections.

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

Common: abdominal pain, diarrhea, nausea.

Uncommon: vomiting.

Skin and subcutaneous tissue disorders.

Common: pruritus (not at application site).

Uncommon: rash.

Musculoskeletal and connective tissue disorders.

Uncommon: flank pain.

Renal and urinary disorders.

Uncommon: pyelonephritis, dysuria.

Reproductive system and breast disorders.

Common: vulvovaginal candidiasis, vulvovaginal pain, vulvovaginal disorders.
Uncommon: vaginal infections, vaginal discharge, menstrual irregularities.

General disorders and administration site conditions.

Uncommon: application site pain, pruritus (at application site), local swelling, pain, fever.

Pseudomembranous colitis is a phenomenon characteristic of the entire class of antibacterial agents.

Reporting of suspected adverse reactions.

It is very important to report suspected adverse reactions after marketing authorization of the medicinal product. This ensures continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with legislative requirements.

Shelf life.

2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging.

3 suppositories per strip made of polyvinyl chloride film, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ukrainian-Spanish joint venture "Sperco Ukraine".

Manufacturer's address and place of business.

21027, Vinnytsia, vul. 600-richchia, 25, Ukraine.

Tel.: + 38(0432)52-30-36. E-mail: [email protected]

www.sperco.com.ua