NURSING MOTHERS SECTION.

Nursing Mothers. Limited published data based on breast milk sampling reports that clindamycin appears in human breast milk in the range of less than 0.5 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. It is not known if clindamycin is excreted in human breast milk following the use of vaginally administered clindamycin phosphate.Clindamycin has the potential to cause adverse effects on the breast-fed infants gastrointestinal flora. If clindamycin is required by nursing mother, it is not reason to discontinue breastfeeding, but an alternate drug may be preferred. Monitor the breast-fed infant for possible adverse effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for clindamycin and any potential adverse effects on the breast-fed child from clindamycin or from the underlying maternal condition.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Clinical trials. Non-pregnant Women. In clinical trials involving non-pregnant women, 1.8% of 600 patients who received treatment with CLEOCIN Vaginal Cream 2% for days and 2.7% of 1325 patients who received treatment for days discontinued therapy due to drug-related adverse events. Medical events judged to be related, probably related, possibly related, or of unknown relationship to vaginally administered clindamycin phosphate vaginal cream 2%, were reported for 20.7% of the patients receiving treatment for days and 21.3% of the patients receiving treatment for days. Events occurring in >=1% of patients receiving clindamycin phosphate vaginal cream 2% are shown in Table 1.TABLE - Events Occurring in >=1% of Non-pregnant Patients Receiving Clindamycin Phosphate Vaginal Cream 2%EventCLEOCIN Vaginal Cream3 Dayn=6007 Dayn=1325Urogenital Vaginal moniliasis7.710.4 Vulvovaginitis6.04.4 Vulvovaginal disorder3.25.3 Trichomonal vaginitis01.3Body as Whole Moniliasis (body)1.30.2Other events occurring in <1% of the clindamycin vaginal cream 2% groups include:Urogenital system: vaginal discharge, metrorrhagia, urinary tract infection, endometriosis, menstrual disorder, vaginitis/vaginal infection, and vaginal pain.Body as whole: localized abdominal pain, generalized abdominal pain, abdominal cramps, halitosis, headache, bacterial infection, inflammatory swelling, allergic reaction, and fungal infection.Digestive system: nausea, vomiting, constipation, dyspepsia, flatulence, diarrhea, and gastrointestinal disorder.Endocrine system: hyperthyroidism.Central nervous system: dizziness and vertigo.Respiratory system: epistaxis.Skin: pruritus (non-application site), moniliasis, rash, maculopapular rash, erythema, and urticaria.Special senses: taste perversion.. Pregnant Women. In clinical trial involving pregnant women during the second trimester, 1.7% of 180 patients who received treatment for days discontinued therapy due to drug-related adverse events. Medical events judged to be related, probably related, possibly related, or of unknown relationship to vaginally administered clindamycin phosphate vaginal cream 2%, were reported for 22.8% of pregnant patients. Events occurring in >=1% of patients receiving either clindamycin phosphate vaginal cream 2% or placebo are shown in Table 2.TABLE - Events Occurring in >=1% of Pregnant Patients Receiving Clindamycin Phosphate Vaginal Cream 2% or PlaceboEventCLEOCIN Vaginal CreamPlacebo7 DAYn=1807 DAYn=184Urogenital Vaginal moniliasis13.37.1 Vulvovaginal disorder6.77.1 Abnormal labor1.10.5Body as Whole Fungal infection1.70Skin Pruritus, non-application site1.10Other events occurring in <1% of the clindamycin vaginal cream 2% group include:Urogenital system: dysuria, metrorrhagia, vaginal pain, and trichomonal vaginitis.Body as whole: upper respiratory infection.Skin: pruritus (topical application site) and erythema.. Post-marketing Experience. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.In the post-marketing period, there have been case reports of pseudomembranous colitis with the use of clindamycin phosphate vaginal cream. Other clindamycin formulations. Clindamycin vaginal cream affords minimal peak serum levels and systemic exposure (AUCs) of clindamycin compared to 100 mg oral clindamycin dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral clindamycin, the possibility of these and other reactions cannot be excluded presently. Data from well-controlled trials directly comparing clindamycin administered orally to clindamycin administered vaginally are not available.The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of clindamycin:Gastrointestinal: Abdominal pain, esophagitis, nausea, vomiting, diarrhea and pseudomembranous colitis. (See WARNINGS.)Hematopoietic: Transient neutropenia (leukopenia), eosinophilia, agranulocytosis, and thrombocytopenia have been reported. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of these reports.Hypersensitivity Reactions: Maculopapular rash and urticaria have been observed during drug therapy. Generalized mild to moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. few cases of anaphylactoid reactions have been reported. If hypersensitivity reaction occurs, the drug should be discontinued.Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.Musculoskeletal: Rare instances of polyarthritis have been reported.Renal: Acute Kidney Injury: Signs of renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria have been observed.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of Action. Clindamycin is an antibacterial drug (See MICROBIOLOGY).. Pharmacokinetics. Following once day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered to healthy female volunteers for days, approximately 5% (range 0.6% to 11%) of the administered dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 18 ng/mL (range to 47 ng/mL) and on day it averaged 25 ng/mL (range to 61 ng/mL). These peak concentrations were attained approximately 10 hours post-dosing (range 4-24 hours).Following once day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered for consecutive days to women with bacterial vaginosis, absorption was slower and less variable than that observed in healthy females. Approximately 5% (range 2% to 8%) of the dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 13 ng/mL (range to 34 ng/mL) and on day it averaged 16 ng/mL (range to 26 ng/mL). These peak concentrations were attained approximately 14 hours post-dosing (range 4-24 hours).There was little or no systemic accumulation of clindamycin after repeated vaginal dosing of clindamycin phosphate vaginal cream 2%. The systemic half-life was 1.5 to 2.6 hours.

DESCRIPTION SECTION.

DESCRIPTION. Clindamycin phosphate is water soluble ester of the semi-synthetic antibiotic produced by 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--D-galacto-octopyranoside 2-(dihydrogen phosphate). It has molecular weight of 504.96, and the molecular formula is C18H34ClN2O8PS. The structural formula is represented below:CLEOCIN Vaginal Cream 2%, is semi-solid, white cream, which contains 2% clindamycin phosphate, USP, at concentration equivalent to 20 mg clindamycin per gram. The pH of the cream is between 3.0 and 6.0. The cream also contains benzyl alcohol, cetostearyl alcohol, mixed fatty acid esters, mineral oil, polysorbate 60, propylene glycol, purified water, sorbitan monostearate, and stearic acid.Each applicatorful of grams of vaginal cream contains approximately 100 mg of clindamycin phosphate.. Chemical Structure.

GENERAL PRECAUTIONS SECTION.

General. CLEOCIN Vaginal Cream 2%, contains ingredients that will cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.The use of CLEOCIN Vaginal Cream 2% may result in the overgrowth of nonsusceptible organisms in the vagina. In clinical studies involving 600 non-pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 8.8% of patients. In 9% of the patients, vaginitis was recorded. Inclinical studies involving 1325 non-pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 10.5% of patients. Vaginitis was recorded in 10.7% of the patients. In 180 pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 13.3% of patients. In 7.2% of the patients, vaginitis was recorded. Candida albicans, as reported here, includes the terms: vaginal moniliasis and moniliasis (body as whole). Vaginitis includes the terms: vulvovaginal disorder, vulvovaginitis, vaginal discharge, trichomonal vaginitis, and vaginitis.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. CLEOCIN Vaginal Cream 2%, is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis). CLEOCIN Vaginal Cream 2%, can be used to treat non-pregnant women and pregnant women during the second and third trimester. (See CLINICAL STUDIES.)NOTE: For purposes of this indication, clinical diagnosis of bacterial vaginosis is usually defined by the presence of homogeneous vaginal discharge that (a) has pH of greater than 4.5, (b) emits fishy amine odor when mixed with 10% KOH solution, and (c) contains clue cells on microscopic examination. Grams stain results consistent with 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, eg, Trichomonas vaginalis, Chlamydia trachomatis, N. gonorrhoeae, Candida albicans, and Herpes simplex virus should be ruled out.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Following once day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered to healthy female volunteers for days, approximately 5% (range 0.6% to 11%) of the administered dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 18 ng/mL (range to 47 ng/mL) and on day it averaged 25 ng/mL (range to 61 ng/mL). These peak concentrations were attained approximately 10 hours post-dosing (range 4-24 hours).Following once day intravaginal dose of 100 mg of clindamycin phosphate vaginal cream 2%, administered for consecutive days to women with bacterial vaginosis, absorption was slower and less variable than that observed in healthy females. Approximately 5% (range 2% to 8%) of the dose was absorbed systemically. The peak serum clindamycin concentration observed on the first day averaged 13 ng/mL (range to 34 ng/mL) and on day it averaged 16 ng/mL (range to 26 ng/mL). These peak concentrations were attained approximately 14 hours post-dosing (range 4-24 hours).There was little or no systemic accumulation of clindamycin after repeated vaginal dosing of clindamycin phosphate vaginal cream 2%. The systemic half-life was 1.5 to 2.6 hours.

PRECAUTIONS SECTION.

PRECAUTIONS. General. CLEOCIN Vaginal Cream 2%, contains ingredients that will cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.The use of CLEOCIN Vaginal Cream 2% may result in the overgrowth of nonsusceptible organisms in the vagina. In clinical studies involving 600 non-pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 8.8% of patients. In 9% of the patients, vaginitis was recorded. Inclinical studies involving 1325 non-pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 10.5% of patients. Vaginitis was recorded in 10.7% of the patients. In 180 pregnant women who received treatment for days, Candida albicans was detected, either symptomatically or by culture, in 13.3% of patients. In 7.2% of the patients, vaginitis was recorded. Candida albicans, as reported here, includes the terms: vaginal moniliasis and moniliasis (body as whole). Vaginitis includes the terms: vulvovaginal disorder, vulvovaginitis, vaginal discharge, trichomonal vaginitis, and vaginitis.. Information for the Patient. The patient should be instructed not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) during treatment with this product.The patient should also be advised that this cream contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, use of such products within 72 hours following treatment with CLEOCIN Vaginal Cream 2%, is not recommended.. Drug Interactions. Systemic clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Long term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential.Genotoxicity tests performed included rat micronucleus test and an Ames test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (31 times the human exposure based on mg/m2) revealed no effects on fertility or mating ability.. Pregnancy. Teratogenic effects. In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities.Clindamycin vaginal cream should be used during the first trimester of pregnancy only if clearly needed and the benefits outweigh the risks. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy.CLEOCIN Vaginal Cream 2% has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received clindamycin vaginal cream 2% compared with 0.5% of patients who received placebo.Reproduction studies have been performed in rats and mice using oral and parenteral doses of clindamycin up to 600 mg/kg/day (62 and 25 times, respectively, the maximum human exposure based on body surface area) and have revealed no evidence of harm to the fetus due to clindamycin. Cleft palates were observed in fetuses from one mouse strain treated intraperitoneally with clindamycin at 200 mg/kg/day (about 10 times the recommended dose based on body surface area conversions). Since this effect was not observed in other mouse strains or in other species, the effect may be strain specific.. Nursing Mothers. Limited published data based on breast milk sampling reports that clindamycin appears in human breast milk in the range of less than 0.5 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. It is not known if clindamycin is excreted in human breast milk following the use of vaginally administered clindamycin phosphate.Clindamycin has the potential to cause adverse effects on the breast-fed infants gastrointestinal flora. If clindamycin is required by nursing mother, it is not reason to discontinue breastfeeding, but an alternate drug may be preferred. Monitor the breast-fed infant for possible adverse effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for clindamycin and any potential adverse effects on the breast-fed child from clindamycin or from the underlying maternal condition.. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. Geriatric Use. Clinical studies for CLEOCIN Vaginal Cream 2% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

PREGNANCY SECTION.

Pregnancy. Teratogenic effects. In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities.Clindamycin vaginal cream should be used during the first trimester of pregnancy only if clearly needed and the benefits outweigh the risks. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy.CLEOCIN Vaginal Cream 2% has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received clindamycin vaginal cream 2% compared with 0.5% of patients who received placebo.Reproduction studies have been performed in rats and mice using oral and parenteral doses of clindamycin up to 600 mg/kg/day (62 and 25 times, respectively, the maximum human exposure based on body surface area) and have revealed no evidence of harm to the fetus due to clindamycin. Cleft palates were observed in fetuses from one mouse strain treated intraperitoneally with clindamycin at 200 mg/kg/day (about 10 times the recommended dose based on body surface area conversions). Since this effect was not observed in other mouse strains or in other species, the effect may be strain specific.

SPL PATIENT PACKAGE INSERT SECTION.

DIRECTIONS FOR USE. Disposable plastic applicators are provided with this package. They are designed to allow proper vaginal administration of the cream.Remove cap from cream tube. Screw plastic applicator on the threaded end of the tube.Rolling tube from the bottom, squeeze gently and force the medication into the applicator. The applicator is filled when the plunger reaches its predetermined stopping point.Unscrew the applicator from the tube and replace the cap.While lying on your back, firmly grasp the applicator barrel and insert into vagina as far as possible without causing discomfort.Slowly push the plunger until it stops.Carefully withdraw applicator from vagina, and discard applicator.REMEMBER TO APPLY ONE APPLICATORFUL EACH NIGHT BEFORE BEDTIME, OR AS PRESCRIBED BY YOUR DOCTOR.INSTRUCCIONES PARA LA PACIENTEEste envase contiene aplicadores de plastico desechables. Los aplicadores estan disenados para la administracion apropiada de la crema en la vagina.Remueva la tapa del tubo de crema enrosque el aplicador de plastico al tubo.Exprima el tubo suavemente desde el extremo inferior fuerce el medicamento al aplicador. El aplicador estara lleno cuando el embolo llega su maxima longitud. Desenrosque el aplicador del tubo vuelva poner la tapa.Acuestese de espalda agarrando firmemente el aplicador, introduzcalo en la vagina tanto como sea posible sin causar molestias.Empuje lentamente el embolo hasta que se detenga.Saque el aplicador cuidadosamente de la vagina descartelo.RECUERDE APLICARSE UN APLICADOR LLENO TODAS LAS NOCHES AL ACOSTARSE, DE ACUERDO CON LAS INDICACIONES DE SU MEDICO.LAB-1058-1.0. image. image. image. image.

TERATOGENIC EFFECTS SECTION.

Teratogenic effects. In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities.Clindamycin vaginal cream should be used during the first trimester of pregnancy only if clearly needed and the benefits outweigh the risks. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy.CLEOCIN Vaginal Cream 2% has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received clindamycin vaginal cream 2% compared with 0.5% of patients who received placebo.Reproduction studies have been performed in rats and mice using oral and parenteral doses of clindamycin up to 600 mg/kg/day (62 and 25 times, respectively, the maximum human exposure based on body surface area) and have revealed no evidence of harm to the fetus due to clindamycin. Cleft palates were observed in fetuses from one mouse strain treated intraperitoneally with clindamycin at 200 mg/kg/day (about 10 times the recommended dose based on body surface area conversions). Since this effect was not observed in other mouse strains or in other species, the effect may be strain specific.

WARNINGS SECTION.

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 clindamycin, even when administered by the vaginal route, because approximately 5% 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 toxin produced by Clostridium difficile is 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 Clostridium difficile colitis.Onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.