Ultrex fl

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ULTREX FL (ULTREX FL)

Composition:

Active substance: clindamycin;

1 suppository contains 100 mg of clindamycin in the form of clindamycin phosphate;

Excipient: lipophilic base*.

* Solid fat with added glycerol monooleate.

Pharmaceutical form. Vaginal suppositories.

Main physicochemical properties: white or almost white suppositories of cigar-like shape.

Pharmacotherapeutic group. Antimicrobial and antiseptic agents, excluding combinations with corticosteroids. Antibiotics. Clindamycin. 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 organism.

Resistance to clindamycin most commonly arises due to modification of the ribosomal target site, usually through chemical modification of 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 exhibits in vitro activity against the following recognized strains of microorganisms associated with bacterial vaginosis: Bacteroides spp., Gardnerella vaginalis, Mobiluncus spp., Mycoplasma hominis, Peptostreptococcus spp.

Standard methodology for susceptibility testing of potential pathogens of bacterial vaginosis—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, these breakpoints are more applicable to guiding systemic antibiotic therapy 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 of clindamycin) for 3 days in 11 healthy female volunteers. Approximately 30% (range: 6% to 70%) of the administered dose was systemically absorbed on day 3, based on area under the concentration-time curve (AUC) values. For comparison, systemic absorption after intravenous administration of a subtherapeutic dose of 100 mg clindamycin phosphate was studied 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 was reached on day 3 of suppository use, averaging 0.27 µg/mL (range: 0.03 to 0.67 µg/mL), observed approximately 5 hours after administration (range: 1 to 10 hours). For comparison, AUC and C_max values after single intravenous administration 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.

The results of this study showed that the systemic exposure to clindamycin (based on AUC) with suppository use was on average 3 times lower than after single intravenous administration of a subtherapeutic dose of 100 mg clindamycin. Compared to the same dose of clindamycin administered as a vaginal cream, systemic absorption with the suppository was approximately 7 times higher than with the vaginal cream, where 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 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 intravaginal 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.

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".

ULTRIX FL 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 regarding concomitant use of ULTRIX FL with other vaginal medicinal products.

When administered systemically, clindamycin phosphate has neuromuscular blocking properties that 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").

Antagonism (induced resistance) has been observed in vitro between clindamycin and erythromycin against a subgroup of macrolide-resistant bacterial isolates. These two agents should not be used simultaneously due to potential clinical significance, except in cases where appropriate sensitivity testing has been performed.

Pathogenic microorganisms show cross-resistance between clindamycin and lincomycin.

Vitamin K antagonists. Increased coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding have been reported in patients receiving clindamycin in combination with vitamin K antagonists (e.g., warfarin, acenocoumarol, and fluindione). Therefore, these patients should be frequently monitored for coagulation parameters.

The use of latex condoms is not recommended during treatment with ULTRIX FL, which is available in the medicinal form of vaginal suppositories.

Special precautions for use.

Before or immediately after starting treatment with ULTREX FL, laboratory testing for other infectious agents, including Trichomonas vaginalis, Candida albicans, Chlamydia trachomatis, and gonococci, may be necessary.

Use of ULTREX FL may result in overgrowth of microorganisms not susceptible to the drug, particularly yeasts.

Symptoms indicative of 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. In cases of moderate pseudomembranous colitis, improvement is usually observed after discontinuation of the drug.

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

ULTREX FL 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 ULTREX FL vaginal suppositories is not recommended. The suppository base may reduce the strength of 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 ULTREX FL vaginal suppositories, the use of other intravaginal products (such as tampons or douching preparations) is not recommended.

Acute kidney injury

Rare cases of acute kidney injury, including acute renal failure, have been reported. Therefore, in patients receiving prolonged clindamycin therapy, particularly those with impaired renal function or those taking concomitant nephrotoxic drugs, monitoring of renal function should be considered (see section "Adverse reactions").

Special precautions for handling and disposal

Do not use this medicine 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 clindamycin in a vaginal formulation during the second trimester of pregnancy and systemic use of clindamycin phosphate during the second and third trimesters have not resulted in congenital anomalies.

ULTREX FL 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 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. Following systemic administration, clindamycin has been detected in human breast milk at concentrations ranging from < 0.5 to 3.8 mcg/mL.

When clindamycin is administered systemically to breastfeeding women, there is a risk of adverse effects on the gastrointestinal flora of the breastfed infant, including diarrhea, blood in stool, or rash. Use of the medicinal product ULTREX FL vaginal suppositories in breastfeeding women may be considered if the expected benefit to the mother outweighs the potential risk 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 ULTREX FL on the ability to drive or operate machinery is absent or negligible.

Method of Administration and Dosage

One suppository intravaginally once daily at night 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 but without causing discomfort.

Use in elderly patients

The use of ULTREX FL 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 ULTREX FL 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 ULTREX FL vaginal suppositories in children have not been established.

Overdose

There have been no reports of overdose with ULTREX FL administered 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 is indicated, if necessary.

In the event of accidental oral ingestion, effects similar to those observed with 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 studies involving non-pregnant patients. The following frequencies of adverse reactions were reported: common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100); frequency unknown (cannot be estimated based on available data).

• Pseudomembranous colitis as an adverse reaction is characteristic of the entire class of antibacterial agents.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

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 reach and sight of children.

Packaging.

3 suppositories per strip. 1 strip per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Ukrainian-Spanish joint venture limited liability company "Sperko Ukraine".

Manufacturer's address and place of business.

21027, Ukraine, Vinnytsia, 600-Richchya St., 25.

Marketing Authorization Holder.

JSC "Farmliga" / UAB "Farmlyga".

Address of the Marketing Authorization Holder.

Antakalnio St. 48A-304, Vilnius, Republic of Lithuania / Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.