Clindamycin Phosphate

Clindamycin phosphate foam is indicated for topical application in the treatment of acne vulgaris in patients 12 years and older. Clindamycin phosphate foam is a lincosamide product indicated for acne vulgaris in patients 12 years and older. ( 1 )

Clindamycin phosphate foam is for topical use only, and not for oral, ophthalmic or intravaginal use. Apply clindamycin phosphate foam once daily to affected areas after the skin is washed with mild soap and allowed to fully dry. Use enough to cover the entire affected area. If there has been no improvement after 6 to 8 weeks or if the condition becomes worse, treatment should be discontinued. The contents of clindamycin phosphate foam are flammable; avoid fire, flame and/or smoking during and immediately following application.

• For topical use only; not for oral, ophthalmic, or intravaginal use. ( 2 )
• Apply clindamycin phosphate foam once daily to affected areas. ( 2 )
• Flammable; avoid fire, flame and/or smoking during and immediately following application. ( 2 )

Clindamycin phosphate foam is a white to off-white thermolabile foam. Clindamycin phosphate foam, 1% contains 10 mg of clindamycin as clindamycin phosphate, USP per gram. Foam containing 1% clindamycin as clindamycin phosphate. ( 3 )

Clindamycin phosphate foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis (including pseudomembranous colitis). Clindamycin phosphate foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis, (including pseudomembranous colitis). ( 4 )

5 WARNINGS AND PRECAUTIONS

• Colitis: Clindamycin can cause severe colitis, which may result in death. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of clindamycin. Clindamycin phosphate foam should be discontinued if significant diarrhea occurs. ( 5.1 )

5.1 Colitis Systemic absorption of clindamycin has been demonstrated following topical use of this product. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. If significant diarrhea occurs, clindamycin phosphate foam should be discontinued [ s ee Adverse Reactions ( 6.2 )] . Severe colitis has occurred following oral or parenteral administration of clindamycin with an onset of up to several weeks following cessation of therapy. Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen severe colitis. Severe colitis may result in death. Studies indicate a toxin(s) produced by Clostridia is one primary cause of antibiotic-associated colitis. The colitis is usually characterized by severe persistent diarrhea and severe abdominal cramps and may be associated with the passage of blood and mucus. Stool cultures for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

5.2 Irritation Clindamycin phosphate foam can cause irritation. Concomitant topical acne therapy should be used with caution since a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. If irritation or dermatitis occurs, clindamycin should be discontinued. Avoid contact of clindamycin phosphate foam with eyes, mouth, lips, other mucous membranes or areas of broken skin. If contact occurs, rinse thoroughly with water. Clindamycin phosphate foam should be prescribed with caution in atopic individuals.

7.1 Erythromycin Clindamycin phosphate foam should not be used in combination with topical or oral erythromycin-containing products due to possible antagonism to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.

7.2 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, clindamycin phosphate foam should be used with caution in patients receiving such agents.

The most common adverse reactions (>1%) are headache and application site reactions including burning, pruritus, and dryness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 439 subjects with mild to moderate acne vulgaris were treated once daily for 12 weeks with clindamycin phosphate foam. The incidence of adverse reactions occurring in > 1% of the subjects in clinical trials comparing clindamycin phosphate foam and its vehicle is presented in Table 1. Table 1: Adverse Reactions Occurring in ≥ 1% of Subjects Adverse Reactions Number (%) of Subjects Clindamycin Phosphate Foam N = 439 Vehicle Foam N = 154 Headache 12 (3%) 1 (1%) Application site burning 27 (6%) 14 (9%) Application site pruritus 5 (1%) 5 (3%) Application site dryness 4 (1%) 5 (3%) Application site reaction, not otherwise specified 3 (1%) 4 (3%) In a contact sensitization study, none of the 203 subjects developed evidence of allergic contact sensitization to clindamycin phosphate foam.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of clindamycin phosphate foam: application site pain, application site erythema, diarrhea, urticaria, abdominal pain, hypersensitivity, rash, abdominal discomfort, nausea, seborrhea, application site rash, dizziness, pain of skin, colitis (including pseudomembranous colitis), and hemorrhagic diarrhea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, have also been reported in association with the use of topical formulations of clindamycin. Orally and parenterally administered clindamycin have been associated with severe colitis, which may end fatally.

8.1 Pregnancy Risk Summary There are no available data on clindamycin phosphate foam use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with clindamycin phosphate foam. No evidence of fetal harm or malformations was observed in pregnant rats and mice administered daily subcutaneous or oral doses of clindamycin salts during organogenesis at doses that produced exposures up to 84 and 42 times, respectively, the maximum recommended human dose (MRHD) of clindamycin phosphate foam based on body surface area (BSA) comparisons and assuming 100% absorption [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies have been conducted in rats and mice using subcutaneous or oral doses of clindamycin phosphate, clindamycin hydrochloride or clindamycin palmitate hydrochloride administered daily during organogenesis at doses up to the equivalent of 432 mg/kg/day clindamycin phosphate. These studies produced no evidence of fetal harm or malformations in rats or mice at exposures 84 or 42 times, respectively, the MRHD of clindamycin phosphate (i.e., 5 milliliters of clindamycin phosphate foam) based on BSA comparison and assuming 100% absorption.

8.2 Lactation Risk Summary There is no information on the presence of clindamycin in human milk, or the effects on the breast-fed child, or the effects on milk production following use of clindamycin phosphate foam. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for clindamycin phosphate foam and any potential adverse effects on the breast-fed child from clindamycin phosphate foam or from the underlying maternal condition. Clinical Considerations If used during lactation and clindamycin phosphate foam is applied to the chest, care should be taken to avoid accidental ingestion by the infant.

8.4 Pediatric Use Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied.

8.5 Geriatric Use The clinical study with clindamycin phosphate foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

Risk Summary There are no available data on clindamycin phosphate foam use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with clindamycin phosphate foam. No evidence of fetal harm or malformations was observed in pregnant rats and mice administered daily subcutaneous or oral doses of clindamycin salts during organogenesis at doses that produced exposures up to 84 and 42 times, respectively, the maximum recommended human dose (MRHD) of clindamycin phosphate foam based on body surface area (BSA) comparisons and assuming 100% absorption [see Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Reproduction studies have been conducted in rats and mice using subcutaneous or oral doses of clindamycin phosphate, clindamycin hydrochloride or clindamycin palmitate hydrochloride administered daily during organogenesis at doses up to the equivalent of 432 mg/kg/day clindamycin phosphate. These studies produced no evidence of fetal harm or malformations in rats or mice at exposures 84 or 42 times, respectively, the MRHD of clindamycin phosphate (i.e., 5 milliliters of clindamycin phosphate foam) based on BSA comparison and assuming 100% absorption.

Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied.

The clinical study with clindamycin phosphate foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

Clindamycin phosphate foam contains clindamycin (1%) as clindamycin phosphate. Clindamycin phosphate is a water-soluble ester of the semi-synthetic 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 structural formula for clindamycin phosphate is represented below: Molecular Formula: C 18 H 34 CIN 2 O 8 PS Molecular Weight: 504.97 g/mol Clindamycin phosphate foam contains clindamycin (1%) as clindamycin phosphate, USP at a concentration equivalent to 10 mg clindamycin per gram in a thermolabile hydroethanolic foam vehicle consisting of cetyl alcohol, ethanol (58%), polysorbate 60, propylene glycol, purified water, and stearyl alcohol pressurized with a hydrocarbon (propane/butane) propellant. clindamycin phosphate structural formula

12.1 Mechanism of Action Mechanism of action of clindamycin in acne vulgaris is unknown [see Microbiology (12.4) ] .

12.2 Pharmacodynamics Pharmacodynamics of clindamycin phosphate foam is unknown.

12.3 Pharmacokinetics In an open label, parallel group study in 24 subjects with acne vulgaris, 12 subjects (3 male and 9 female) applied 4 grams of clindamycin phosphate foam once-daily for five days, and 12 subjects (7 male and 5 female) applied 4 grams of a clindamycin gel, 1%, once daily for five days. On Day 5, the mean C max and AUC (0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for the clindamycin gel, 1%. Following multiple applications of clindamycin phosphate foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

12.4 Microbiology No microbiology studies were conducted in the clinical trials with this product. Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes ( P. acnes ), an organism that has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical studies with clindamycin phosphate foam. P. acnes resistance to clindamycin has been documented. Inducible Clindamycin Resistance: The treatment of acne with antimicrobials is associated with the development of antimicrobial resistance in P. acnes as well as other bacteria (e.g. Staphylococcus aureus, Streptococcus pyogenes ). The use of clindamycin may result in developing inducible resistance in these organisms. This resistance is not detected by routine susceptibility testing. Cross Resistance: Resistance to clindamycin is often associated with resistance to erythromycin.

Mechanism of action of clindamycin in acne vulgaris is unknown [see Microbiology (12.4) ] .

Pharmacodynamics of clindamycin phosphate foam is unknown.

In an open label, parallel group study in 24 subjects with acne vulgaris, 12 subjects (3 male and 9 female) applied 4 grams of clindamycin phosphate foam once-daily for five days, and 12 subjects (7 male and 5 female) applied 4 grams of a clindamycin gel, 1%, once daily for five days. On Day 5, the mean C max and AUC (0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for the clindamycin gel, 1%. Following multiple applications of clindamycin phosphate foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

, Mutagenesis, Impairment of Fertility The carcinogenicity of a 1.2% clindamycin phosphate gel similar to clindamycin phosphate foam was evaluated by daily topical administration to mice for two years. The topical doses used in this study were approximately 3 and 15 times higher than the MRHD of clindamycin phosphate from clindamycin phosphate foam, based on BSA comparison and assuming 100% absorption. No significant increase in tumors was noted in the treated animals. The genotoxic potential of clindamycin was evaluated in an in vitro Ames assay and in an in vivo rat micronucleus test. Both tests were negative. Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility.

17 PATIENT COUNSELING INFORMATION See FDA-Approved patient labeling (Patient Information) .

17.1 Instructions for Use

• Patients should be advised to wash their skin with mild soap and allow it to dry before applying clindamycin phosphate foam.
• Patients should use enough clindamycin phosphate foam to cover the face and to apply once daily.
• Patients should dispense clindamycin phosphate foam directly into the cap or onto a cool surface.
• Patients should wash their hands after applying clindamycin phosphate foam.

17.2 Skin Irritation Clindamycin phosphate foam may cause irritation such as erythema, scaling, itching, burning, or stinging. Patients should be advised to discontinue use if excessive irritancy or dermatitis occur.

17.3 Colitis In the event a patient treated with clindamycin phosphate foam experiences severe diarrhea or gastrointestinal discomfort, clindamycin phosphate foam should be discontinued and a physician should be contacted. Manufactured by Padagis Yeruham, Israel Distributed By Padagis Allegan, MI 49010 www.padagis.com Rev 02-22 4T500 RC J5 Pharmacist-Detach here and Give Instructions to Patient

Store at 20º to 25°C (68º to 77°F) [See USP Controlled Room Temperature]. Flammable. Avoid fire, flame or smoking during and immediately following application. Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperature above 120°F (49°C). Keep out of reach of children.