Dalacin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DАLACIN (DALACIN)

Composition:

Active substance: clindamycin;

1 suppository contains clindamycin phosphate equivalent to 100 mg of clindamycin;

Excipient: hard fat.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical properties: solid, almost white suppositories with a smooth surface.

Pharmacotherapeutic group. Antimicrobial and antiseptic agents used in gynecology, excluding combination 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.

Clindamycin, like most inhibitors of protein synthesis, 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 pathogen.

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

In vitro susceptibility. Clindamycin exhibits in vitro activity against the following registered strains of microorganisms associated with bacterial vaginosis: Bacteroides spp., Gardnerella vaginalis, Mobiluncus spp., Mycoplasma hominis, Peptostreptococcus spp.

Standard methodology for testing susceptibility of potential bacterial vaginosis pathogens, Gardnerella vaginalis and Mobiluncus spp., has not been established. Breakpoints 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 but 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 was evaluated following intravaginal administration of one clindamycin phosphate suppository once daily (equivalent to 100 mg clindamycin) for 3 days in 11 healthy female volunteers. Approximately 30% (ranging from 6% to 70%) of the administered dose was systemically absorbed on day 3, based on area under the concentration-time curve (AUC) measurements. Systemic absorption was also studied after 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). C_max on day 3 of suppository administration averaged 0.27 µg/mL (range: 0.03 to 0.67 µg/mL) and was observed approximately 5 hours after administration (range: 1 to 10 hours). For comparison, AUC and C_max after 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 limited by the rate of absorption.

These study results indicate that the systemic exposure to clindamycin (based on AUC) with suppository use was on average 3 times lower than after a single intravenous administration of the subtherapeutic 100 mg dose of clindamycin. Compared to the same dose administered as a vaginal cream, systemic absorption with the suppository was approximately 7 times higher than with the vaginal cream, 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 via suppositories for 3 days, the amount absorbed is approximately 30 mg per day, compared to 600–2700 mg per day for 10 days or more with oral or parenteral administration). Overall, systemic exposure to clindamycin following vaginal suppositories is significantly lower than systemic exposure from 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".

Dalacin 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 available on the concomitant use of Dalacin with other vaginal medicinal products.

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

The use of latex condoms is not recommended during treatment with Dalacin vaginal suppositories.

Special precautions for use.

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

Use of Dalacin 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 "Adverse reactions"). Cases of pseudomembranous colitis have been reported with nearly all antibacterial agents, including clindamycin, with severity ranging from mild to life-threatening. Therefore, this condition should be considered in patients who develop diarrhea following antibacterial therapy. Improvement is typically observed after discontinuation of the drug in cases of moderate severity.

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

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

As with any vaginal infection, sexual intercourse is not recommended during treatment with Dalacin vaginal suppositories. The base of the 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 Dalacin vaginal suppositories, the use of other intravaginal products (such as tampons or douching preparations) is not recommended.

Special precautions during handling and disposal of the medicinal product.

Do not use this medicinal product if the 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 on the use of Dalacin in the vaginal dosage form during the second trimester of pregnancy, as well as systemic use of clindamycin phosphate during the second and third trimesters, have not shown an increased risk of congenital anomalies.

Dalacin may be used during the second and third trimesters of pregnancy only if clearly necessary. During pregnancy, vaginal suppositories should be administered without using an applicator.

Breastfeeding.

It is not known whether clindamycin passes into human breast milk following vaginal administration. Although the dose used is significantly lower than systemic clindamycin, approximately 30% (ranging from 6% to 70%) is absorbed into the 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 Dalacin vaginal suppositories in breastfeeding women may be considered if the expected benefit to the mother outweighs the potential risks to the infant.

Fertility.

No effects on fertility were observed in animal studies.

Ability to affect reaction speed when driving vehicles or operating machinery.

Dalacin has no or negligible influence on the ability to drive vehicles or operate machinery.

Dosage and Administration.

Dosage.

The recommended dose is 1 suppository administered intravaginally at bedtime for 3 consecutive days.

Administration.

Dalacin is administered intravaginally.

• Remove the suppository from the foil.
• Lie on your back and draw your knees up toward your chest.
• Insert the suppository into the vagina as deeply as possible using the middle finger of your hand, without causing discomfort.

Use in elderly patients.

The use of Dalacin 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 Dalacin in the form of vaginal suppositories in patients with renal impairment has not been studied.

Note should be taken of official recommendations regarding the appropriate use of antibacterial agents.

Children.

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

Overdose.

There have been no reports of overdose with Dalacin in the form of vaginal suppositories.

Clindamycin phosphate contained in the 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, effects similar to those observed with oral therapeutic doses of clindamycin may occur.

Adverse Reactions

The safety of clindamycin administered as vaginal suppositories was evaluated in clinical trials involving non-pregnant patients. The following frequencies of adverse reactions were reported: common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 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 associated with 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 applicable legal requirements.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 3 suppositories per laminated foil strip (strip), in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmacia and Upjohn Company LLC.

Manufacturer's address.

7000 Portage Road, Kalamazoo, Michigan (MI) 49001, USA.