Clindamycin Phosphate and Tretinoin

6 ADVERSE REACTIONS Observed local treatment-related adverse reactions (≥ 1%) in clinical studies with clindamycin phosphate and tretinoin gel were application site reactions, including dryness, irritation, exfoliation, erythema, pruritus, and dermatitis. Sunburn was also reported. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Solaris Pharma Corporation at 1-833-919-0527 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Adverse Reactions in Clinical Studies Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. The safety data reflect exposure to clindamycin phosphate and tretinoin gel in 1,104 patients with acne vulgaris. Patients were 12 years or older and were treated once daily in the evening for 12 weeks. Adverse reactions that were reported in ≥1% of patients treated with clindamycin phosphate and tretinoin gel are presented in Table 1 . Table 1: Treatment-Related Adverse Reactions Reported by ≥1% of Patients Clindamycin Phosphate and Tretinoin Gel N = 1,104 n (%) Clindamycin Gel N = 1,091 n (%) Tretinoin Gel N = 1,084 n (%) Vehicle Gel N = 552 n (%) Patients with at least one adverse reaction 140 (13) 38 (3) 141 (13) 17 (3) Application site dryness 64 (6) 12 (1) 62 (6) 3 (1) Application site irritation 50 (5) 4 (<1) 57 (5) 5 (1) Application site exfoliation 50 (5) 2 (<1) 56 (5) 2 (<1) Application site erythema 40 (4) 6 (1) 39 (4) 3 (1) Application site pruritus 26 (2) 7 (1) 23 (2) 6 (1) Sunburn 11 (1) 6 (1) 7 (1) 3 (1) Application site dermatitis 6 (1) 0 (0) 8 (1) 1 (<1) Local skin reactions actively assessed at baseline and end of treatment with a score >0 are presented in Table 2 . Table 2: Clindamycin Phosphate and Tretinoin Gel - Treated Patients with Local Skin Reactions Clindamycin Phosphate and Tretinoin Gel Vehicle Gel Local Reaction Baseline N = 476 (%) End of Treatment N = 409 (%) Baseline N = 219 (%) End of Treatment N = 209 (%) Erythema 24% 21% 31% 35% Scaling 8% 19% 14% 12% Dryness 11% 22% 18% 13% Burning 8% 13% 8% 4% Itching 17% 15% 22% 14% During the 12 weeks of treatment, each local skin reaction peaked at Week 2 and gradually reduced thereafter.

4 CONTRAINDICATIONS Clindamycin phosphate and tretinoin gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. Clindamycin phosphate and tretinoin gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. ( 4 )

11 DESCRIPTION Clindamycin phosphate and tretinoin gel, 1.2%/0.025%, is a fixed combination of 2 solubilized active ingredients in an aqueous-based gel. 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 ClN 2 O 8 PS Molecular Weight: 504.97 The chemical name for tretinoin is all-trans 3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. It is a member of the retinoid family of compounds. The structural formula for tretinoin is represented below: Molecular Formula: C 20 H 28 O 2 Molecular Weight: 300.44 Clindamycin phosphate and tretinoin gel contains the following inactive ingredients: anhydrous citric acid, butylated hydroxytoluene, carbomer homopolymer (type C), edetate disodium, laureth 4, methylparaben, propylene glycol, purified water, and tromethamine. structure1 structure2

2 DOSAGE AND ADMINISTRATION Clindamycin phosphate and tretinoin gel should be applied once daily in the evening, gently rubbing the medication to lightly cover the entire affected area. Approximately a pea-sized amount will be needed for each application. Avoid the eyes, lips, and mucous membranes. Clindamycin phosphate and tretinoin gel is not for oral, ophthalmic, or intravaginal use. Apply a pea-sized amount once daily in the evening lightly covering the entire affected area. Avoid the eyes, lips, and mucous membranes. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

1 INDICATIONS AND USAGE Clindamycin phosphate and tretinoin gel is indicated for the topical treatment of acne vulgaris in patients 12 years and older. Clindamycin phosphate and tretinoin gel is a lincosamide antibiotic and retinoid combination product indicated for the topical treatment of acne vulgaris in patients 12 years and older. ( 1 )

7 DRUG INTERACTIONS Clindamycin phosphate and tretinoin gel should not be used in combination with erythromycin-containing products because of its clindamycin component. ( 7.1 ) 7.1 Erythromycin Clindamycin phosphate and tretinoin gel should not be used in combination with erythromycin-containing products due to possible antagonism to the clindamycin component. In vitro studies have shown antagonism between these 2 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 and tretinoin gel should be used with caution in patients receiving such agents.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Clindamycin: [See Microbiology ( 12.4 ).] Tretinoin: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones. 12.3 Pharmacokinetics In an open-label study of 17 patients with moderate-to-severe acne vulgaris, topical administration of approximately 3 grams of clindamycin phosphate and tretinoin gel once daily for 5 days, clindamycin concentrations were quantifiable in all 17 patients starting from 1 hour post-dose. All plasma clindamycin concentrations were ≤5.56 ng/mL on Day 5, with the exception of 1 subject who had a maximum clindamycin concentration of 8.73 ng/mL at 4 hours post-dose. There was no appreciable increase in systemic exposure to tretinoin, as compared with the baseline value. The average tretinoin concentration across all sampling times on Day 5 ranged from 1.19 to 1.23 ng/mL compared with the corresponding baseline mean tretinoin concentration range of 1.16 to 1.30 ng/mL. 12.4 Microbiology No microbiology studies were conducted in the clinical trials with this product. Mechanism of Action: Clindamycin binds to the 50S ribosomal subunit 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 and tretinoin gel. 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.

12.1 Mechanism of Action Clindamycin: [See Microbiology ( 12.4 ).] Tretinoin: Although the exact mode of action of tretinoin is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedone formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.

12.3 Pharmacokinetics In an open-label study of 17 patients with moderate-to-severe acne vulgaris, topical administration of approximately 3 grams of clindamycin phosphate and tretinoin gel once daily for 5 days, clindamycin concentrations were quantifiable in all 17 patients starting from 1 hour post-dose. All plasma clindamycin concentrations were ≤5.56 ng/mL on Day 5, with the exception of 1 subject who had a maximum clindamycin concentration of 8.73 ng/mL at 4 hours post-dose. There was no appreciable increase in systemic exposure to tretinoin, as compared with the baseline value. The average tretinoin concentration across all sampling times on Day 5 ranged from 1.19 to 1.23 ng/mL compared with the corresponding baseline mean tretinoin concentration range of 1.16 to 1.30 ng/mL.

20231018

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3 DOSAGE FORMS AND STRENGTHS Clindamycin phosphate and tretinoin gel, 1.2%/0.025%, containing clindamycin phosphate 1.2% and tretinoin 0.025%, is a yellow, opaque topical gel. Each gram of clindamycin phosphate and tretinoin gel, 1.2%/0.025% contains, as dispensed, 10 mg (1%) clindamycin as clindamycin phosphate, and 0.25 mg (0.025%) tretinoin solubilized in an aqueous-based gel. Topical gel: clindamycin phosphate 1.2% and tretinoin 0.025% in 30-gram and 60-gram tubes. ( 3 )

Clindamycin Phosphate and Tretinoin clindamycin phosphate and tretinoin CLINDAMYCIN PHOSPHATE CLINDAMYCIN TRETINOIN TRETINOIN

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of clindamycin phosphate and tretinoin gel or the effect of clindamycin phosphate and tretinoin gel on fertility. Clindamycin phosphate and tretinoin gel was negative for mutagenic potential when evaluated in an in vitro Ames Salmonella reversion assay. Clindamycin phosphate and tretinoin gel was equivocal for clastogenic potential in the absence of metabolic activation when tested in an in vitro chromosomal aberration assay. Clindamycin: Once-daily dermal administration of 1% clindamycin as clindamycin phosphate in the gel vehicle (32 mg/kg/day, 13 times the recommended clinical dose based on body surface area comparison) to mice for up to 2 years did not produce evidence of tumorigenicity. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (240 times the recommended clinical dose based on body surface area comparison) revealed no effects on fertility or mating ability. Tretinoin: In 2 independent mouse studies where tretinoin was administered topically (0.025% or 0.1%) 3 times per week for up to 2 years no carcinogenicity was observed, with maximum effects of dermal amyloidosis. However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 mcg (1.4 times the recommended clinical dose based on body surface area comparison) 3 times per week for 20 weeks acted as a weak promoter of skin tumor formation following a single application of dimethylbenz[α]anthracene (DMBA). In a study in female SENCAR mice, papillomas were induced by topical exposure to DMBA followed by promotion with 12-O-tetradecanoylphorbol-13-acetate or mezerein for up to 20 weeks. Topical application of tretinoin prior to each application of promoting agent resulted in a reduction in the number of papillomas per mouse. However, papillomas resistant to topical tretinoin suppression were at higher risk for pre-malignant progression. Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to tretinoin and UV radiation. The photoco-carcinogenic potential of the clindamycin tretinoin combination is unknown. Although the significance of these studies to humans is not clear, patients should avoid exposure to sun. The genotoxic potential of tretinoin was evaluated in an in vitro Ames Salmonella reversion test and an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Both tests were negative. In oral fertility studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (64 times the recommended clinical dose based on body surface area comparison).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to evaluate the carcinogenic potential of clindamycin phosphate and tretinoin gel or the effect of clindamycin phosphate and tretinoin gel on fertility. Clindamycin phosphate and tretinoin gel was negative for mutagenic potential when evaluated in an in vitro Ames Salmonella reversion assay. Clindamycin phosphate and tretinoin gel was equivocal for clastogenic potential in the absence of metabolic activation when tested in an in vitro chromosomal aberration assay. Clindamycin: Once-daily dermal administration of 1% clindamycin as clindamycin phosphate in the gel vehicle (32 mg/kg/day, 13 times the recommended clinical dose based on body surface area comparison) to mice for up to 2 years did not produce evidence of tumorigenicity. Fertility studies in rats treated orally with up to 300 mg/kg/day of clindamycin (240 times the recommended clinical dose based on body surface area comparison) revealed no effects on fertility or mating ability. Tretinoin: In 2 independent mouse studies where tretinoin was administered topically (0.025% or 0.1%) 3 times per week for up to 2 years no carcinogenicity was observed, with maximum effects of dermal amyloidosis. However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 mcg (1.4 times the recommended clinical dose based on body surface area comparison) 3 times per week for 20 weeks acted as a weak promoter of skin tumor formation following a single application of dimethylbenz[α]anthracene (DMBA). In a study in female SENCAR mice, papillomas were induced by topical exposure to DMBA followed by promotion with 12-O-tetradecanoylphorbol-13-acetate or mezerein for up to 20 weeks. Topical application of tretinoin prior to each application of promoting agent resulted in a reduction in the number of papillomas per mouse. However, papillomas resistant to topical tretinoin suppression were at higher risk for pre-malignant progression. Tretinoin has been shown to enhance photoco-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to tretinoin and UV radiation. The photoco-carcinogenic potential of the clindamycin tretinoin combination is unknown. Although the significance of these studies to humans is not clear, patients should avoid exposure to sun. The genotoxic potential of tretinoin was evaluated in an in vitro Ames Salmonella reversion test and an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Both tests were negative. In oral fertility studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (64 times the recommended clinical dose based on body surface area comparison).

ANDA212845

Clindamycin Phosphate and Tretinoin

clindamycin phosphate and tretinoin

73473-306

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE LABEL PRINCIPAL DISPLAY PANEL 60 g Carton NDC 73473-306-60 Clindamycin Phosphate and Tretinoin Gel, 1.2%/0.025% For Topical Use Only Rx Only 60 gram carton

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( Patient Information ). Instructions for Use At bedtime, the face should be gently washed with a mild soap and water. After patting the skin dry, apply clindamycin phosphate and tretinoin gel as a thin layer over the entire affected area (excluding the eyes and lips). Patients should be advised not to use more than a pea-sized amount to cover the face and not to apply more often than once daily (at bedtime) as this will not make for faster results and may increase irritation. A sunscreen should be applied every morning and reapplied over the course of the day as needed. Patients should be advised to avoid exposure to sunlight, sunlamp, ultraviolet light, and other medicines that may increase sensitivity to sunlight. Other topical products with a strong drying effect such as abrasive soaps or cleansers may cause an increase in skin irritation with clindamycin phosphate and tretinoin gel. Skin Irritation Clindamycin phosphate and tretinoin gel may cause irritation such as erythema, scaling, itching, burning, or stinging. Colitis In the event a patient treated with clindamycin phosphate and tretinoin gel experiences severe diarrhea or gastrointestinal discomfort, clindamycin phosphate and tretinoin gel should be discontinued and a physician should be contacted. Manufactured for: Solaris Pharma Corporation Bridgewater, NJ 08807

14 CLINICAL STUDIES The safety and efficacy of clindamycin phosphate and tretinoin gel, applied once daily for the treatment of acne vulgaris, was evaluated in 12-week multi-center, randomized, blinded studies in subjects 12 years and older. Treatment response was defined as the percent of subjects who had a 2-grade improvement from baseline to Week 12 based on the Investigator’s Global Assessment (IGA) and a mean absolute change from baseline to Week 12 in 2 out of 3 (total, inflammatory and non-inflammatory) lesion counts. The IGA scoring scale used in all the clinical trials for clindamycin phosphate and tretinoin gel is as follows: 0 Clear Normal, clear skin with no evidence of acne vulgaris. 1 Almost Clear Skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) requiring no further treatment in the Investigator’s opinion. 2 Mild Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only, no nodulo-cystic lesions). 3 Moderate Non-inflammatory lesions predominate, with multiple inflammatory lesions evident; several-to-many comedones and papules/pustules, and there may or may not be 1 small nodulo-cystic lesion. 4 Severe Inflammatory lesions are more apparent; many comedones and papules/pustules, there may or may not be a few nodulo-cystic lesions. 5 Very Severe Highly inflammatory lesions predominate; variable numbers of comedones, many papules/pustules and nodulo-cystic lesions. In Study 1, 1,649 subjects were randomized to clindamycin phosphate and tretinoin gel, clindamycin gel, tretinoin gel, and vehicle gel. The median age of subjects was 17 years and 58% were females. At baseline, subjects had an average of 71 total lesions of which the mean number of inflammatory lesions was 25.5 lesions and the mean number of non-inflammatory lesions was 45.1 lesions. The majority of subjects enrolled with a baseline IGA score of 3. The efficacy results at Week 12 are presented in Table 3 . Table 3: Efficacy Results at Week 12 Study 1 Clindamycin Phosphate and Tretinoin Gel N = 476 Clindamycin Gel N = 467 Tretinoin Gel N = 464 Vehicle Gel N = 242 Investigator’s Global Assessment Percentage of subjects achieving 2-Grade Improvement 36.3% 26.6% 26.1% 20.2% Percentage of subjects achieving an IGA of 0 or 1 with a 2-Grade Improvement 33.2% 24.0% 22.6% 17.8% Inflammatory Lesions: Mean absolute reduction Mean percentage (%) reduction 15.5 60.4% 14.5 56.5% 13.9 54.5% 11.1 43.3% Non-inflammatory Lesions: Mean absolute reduction Mean percentage (%) reduction 23.2 51.0% 19.5 42.9% 22.1 47.3% 17.0 36.0% Total Lesions: Mean absolute reduction Mean percentage (%) reduction 38.7 55.0% 34.0 49.0% 36.0 50.5% 28.1 39.1% The safety and efficacy of clindamycin-tretinoin gel was also evaluated in two additional 12-week, multi-centered, randomized, blinded, studies in patients 12 years and older. A total of 2,219 subjects with mild-to-moderate acne vulgaris were treated once daily for 12 weeks. Of the 2,219 subjects, 634 subjects were treated with clindamycin-tretinoin gel. These studies demonstrated consistent outcomes.

8.5 Geriatric Use Clinical studies of clindamycin phosphate and tretinoin gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.3 Nursing Mothers It is not known whether clindamycin is excreted in human milk following use of clindamycin phosphate and tretinoin gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clindamycin phosphate and tretinoin gel is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness of clindamycin phosphate and tretinoin gel in pediatric patients below the age of 12 years have not been established. Clinical trials of clindamycin phosphate and tretinoin gel included 2,086 patients aged 12 - 17 years of age with acne vulgaris. [See Clinical Studies ( 14 ).]

8.1 Pregnancy Pregnancy Category C. There are no well-controlled studies in pregnant women treated with clindamycin phosphate and tretinoin gel. Clindamycin phosphate and tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A limit teratology study performed in Sprague Dawley rats treated topically with clindamycin phosphate and tretinoin gel or 0.025% tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15 did not result in teratogenic effects. Although no systemic levels of tretinoin were detected, craniofacial and heart abnormalities were described in drug-treated groups. These abnormalities are consistent with retinoid effects and occurred at 16 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison. For purposes of comparison of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of clindamycin phosphate and tretinoin gel applied daily to a 50-kg person. Clindamycin: Reproductive developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (480 and 240 times the recommended clinical dose based on body surface area comparison, respectively) or subcutaneous doses of clindamycin up to 180 mg/kg/day (140 and 70 times the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity. Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose based on body surface area comparison). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomologous monkey, a species in which tretinoin metabolism is closer to humans than in other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (324 times the recommended clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related teratogenic effects and increased abortion rates were reported in pigtail macaques. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during 2 decades of clinical use of another formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to fetus is not known.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: The efficacy and safety have not been established in pediatric patients below the age of 12 years. ( 8.4 ) 8.1 Pregnancy Pregnancy Category C. There are no well-controlled studies in pregnant women treated with clindamycin phosphate and tretinoin gel. Clindamycin phosphate and tretinoin gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A limit teratology study performed in Sprague Dawley rats treated topically with clindamycin phosphate and tretinoin gel or 0.025% tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15 did not result in teratogenic effects. Although no systemic levels of tretinoin were detected, craniofacial and heart abnormalities were described in drug-treated groups. These abnormalities are consistent with retinoid effects and occurred at 16 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison. For purposes of comparison of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of clindamycin phosphate and tretinoin gel applied daily to a 50-kg person. Clindamycin: Reproductive developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (480 and 240 times the recommended clinical dose based on body surface area comparison, respectively) or subcutaneous doses of clindamycin up to 180 mg/kg/day (140 and 70 times the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity. Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose based on body surface area comparison). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomologous monkey, a species in which tretinoin metabolism is closer to humans than in other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (324 times the recommended clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related teratogenic effects and increased abortion rates were reported in pigtail macaques. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty cases of temporally associated congenital malformations have been reported during 2 decades of clinical use of another formulation of topical tretinoin. Although no definite pattern of teratogenicity and no causal association have been established from these cases, 5 of the reports describe the rare birth defect category, holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to fetus is not known. 8.3 Nursing Mothers It is not known whether clindamycin is excreted in human milk following use of clindamycin phosphate and tretinoin gel. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known whether tretinoin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clindamycin phosphate and tretinoin gel is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of clindamycin phosphate and tretinoin gel in pediatric patients below the age of 12 years have not been established. Clinical trials of clindamycin phosphate and tretinoin gel included 2,086 patients aged 12 - 17 years of age with acne vulgaris. [See Clinical Studies ( 14 ).] 8.5 Geriatric Use Clinical studies of clindamycin phosphate and tretinoin gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Clindamycin phosphate and tretinoin gel, 1.2%/0.025% is supplied as follows: 30 g aluminum tubes NDC 73473-306-30 60 g aluminum tubes NDC 73473-306-60 Storage and Handling Store at 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from heat. Protect from light. Protect from freezing. Keep out of reach of children. Keep tube tightly closed.