Cleocin

CLEOCIN- clindamycin phosphate suppository
Pharmacia & Upjohn Company LLC

FOR INTRAVAGINAL USE ONLY

DESCRIPTION

Clindamycin phosphate is a water-soluble ester of the semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent antibiotic lincomycin. The chemical name for clindamycin phosphate is methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans -4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo -α-D-galacto -octopyranoside 2-(dihydrogen phosphate). The monohydrate form has a molecular weight of 522.98, and the molecular formula is C18 H34 ClN2 O8 PS•H2 O. The structural formula is represented below:

Chemical Structure
(click image for full-size original)

CLEOCIN Vaginal Ovules are semisolid, white to off-white suppositories for intravaginal administration. Each 2.5 g suppository contains clindamycin phosphate equivalent to 100 mg clindamycin in a base consisting of a mixture of glycerides of saturated fatty acids.

CLINICAL PHARMACOLOGY

Mechanism of Action

Clindamycin is an antibacterial drug (See MICROBIOLOGY).

Pharmacokinetics

Systemic absorption of clindamycin was estimated following a once-a-day intravaginal dose of one clindamycin phosphate vaginal suppository (equivalent to 100 mg clindamycin) administered to 11 healthy female volunteers for 3 days. Approximately 30% (range 6% to 70%) of the administered dose was absorbed systemically on day 3 of dosing based on area under the concentration-time curve (AUC). Systemic absorption was estimated using a subtherapeutic 100 mg intravenous dose of clindamycin phosphate as a comparator in the same volunteers. The mean AUC following day 3 of dosing with the suppository was 3.2 µg hr/mL (range 0.42 to 11 µg hr/mL). The Cmax observed on day 3 of dosing with the suppository averaged 0.27 µg/mL (range 0.03 to 0.67 µg/mL) and was observed about 5 hours after dosing (range 1 to 10 hours). In contrast, the AUC and Cmax after the single intravenous dose averaged 11 µg hr/mL (range 5.1 to 26 µg hr/mL) and 3.7 µg/mL (range 2.4 to 5.0 µg/mL), respectively. The mean apparent elimination half-life after dosing with the suppository was 11 hours (range 4 to 35 hours) and is considered to be limited by the absorption rate.

The results from this study showed that systemic exposure to clindamycin (based on AUC) from the suppository was, on average, three-fold lower than that from a single subtherapeutic 100 mg intravenous dose of clindamycin. In addition, the recommended daily and total doses of intravaginal clindamycin suppository are far lower than those typically administered in oral or parenteral clindamycin therapy (100 mg of clindamycin per day for 3 days equivalent to about 30 mg absorbed per day from the ovule relative to 600 to 2700 mg/day for up to 10 days or more, orally or parenterally). The overall systemic exposure to clindamycin from Cleocin Vaginal Ovules is substantially lower than the systemic exposure from therapeutic doses of oral clindamycin hydrochloride (two-fold to 20-fold lower) or parenteral clindamycin phosphate (40-fold to 50-fold lower).

MICROBIOLOGY

Mechanism of Action

Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is predominantly bacteriostatic.

Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts it to active clindamycin.

Resistance

Resistance to clindamycin is most often caused by modification of the target site on the ribosome, usually by chemical modification of RNA bases or by point mutations in RNA or occasionally in proteins. Cross resistance has been demonstrated between lincosamides, macrolides and streptogramins B in some organisms. Cross resistance has been demonstrated between clindamycin and lincomycin.

Antibacterial Activity

Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis (see INDICATIONS AND USAGE); standard methodology for the susceptibility testing of the potential bacterial pathogens, Gardnerella vaginalis, Mobiluncus spp., or Mycoplasma hominis , has not been defined.

The following in vitro data are available but their clinical significance is unknown. Clindamycin is active in vitro against most isolates of the following organisms reported to be associated with bacterial vaginosis:

Bacteroides spp.
Gardnerella vaginalis
Mobiluncus spp.
Mycoplasma hominis
Peptostreptococcus spp.

INDICATIONS AND USAGE

CLEOCIN Vaginal Ovules are indicated for 3-day treatment of bacterial vaginosis in non-pregnant women. There are no adequate and well-controlled studies of CLEOCIN Vaginal Ovules in pregnant women.

NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells.

Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis , Chlamydia trachomatis , Neisseria gonorrhoeae , Candida albicans , and herpes simplex virus, should be ruled out.

CONTRAINDICATIONS

CLEOCIN Vaginal Ovules are contraindicated in individuals with a history of hypersensitivity to clindamycin, lincomycin, or any of the components of this vaginal suppository. CLEOCIN Vaginal Ovules are also contraindicated in individuals with a history of regional enteritis, ulcerative colitis, or a history of “antibiotic-associated” colitis.

WARNINGS

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life-threatening. Orally and parenterally administered clindamycin has been associated with severe colitis, which may end fatally. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of orally and parenterally administered clindamycin, as well as with topical (dermal and vaginal) formulations of clindamycin. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of CLEOCIN Vaginal Ovules, because approximately 30% of the clindamycin dose is systemically absorbed from the vagina.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridioides difficile is a primary cause of “antibiotic-associated” colitis.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridioides difficile colitis.

Onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.

PRECAUTIONS

General

The use of CLEOCIN Vaginal Ovules may result in the overgrowth of nonsusceptible organisms in the vagina. In clinical studies using CLEOCIN Vaginal Ovules, treatment-related moniliasis was reported in 2.7% and vaginitis in 3.6% of 589 nonpregnant women. Moniliasis, as reported here, includes the terms: vaginal or nonvaginal moniliasis and fungal infection. Vaginitis includes the terms: vulvovaginal disorder, vaginal discharge, and vaginitis/vaginal infection.

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