ZIANA

6 ADVERSE REACTIONS Observed local adverse reactions in patients treated with ZIANA Gel were skin erythema, scaling, itching, burning, and stinging. Other most commonly reported adverse events (≥1% in patients treated with ZIANA Gel) were nasopharyngitis, pharyngolaryngeal pain, dry skin, cough, and sinusitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Valeant Pharmaceuticals North America LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse reactions that appear to be related to drug use for approximating rates. The safety data presented in Table 1 (below) reflects exposure to ZIANA Gel in 1853 patients with acne vulgaris. Patients were 12 years and older and were treated once daily for 12 weeks. Adverse reactions that were reported in ≥1% of patients treated with ZIANA Gel were compared to adverse reactions in patients treated with clindamycin phosphate 1.2% in vehicle gel, tretinoin 0.025% in vehicle gel, and the vehicle gel alone: Table 1: Adverse Reactions Reported in at Least 1% of Patients Treated with ZIANA Gel: 12-Week Studies ZIANA Gel N=1853 N (%) Clindamycin N=1428 N (%) Tretinoin N=846 N (%) Vehicle N=423 N (%) PATIENTS WITH AT LEAST ONE AR 497 (27) 342 (24) 225 (27) 91 (22) Nasopharyngitis 65 (4) 64 (5) 16 (2) 5 (1) Pharyngolaryngeal pain 29 (2) 18 (1) 5 (1) 7 (2) Dry skin 23 (1) 7 (1) 3 (<1) 0 (0) Cough 19 (1) 21 (2) 9 (1) 2 (1) Sinusitis 19 (1) 19 (1) 15 (2) 4 (1) NOTE: Formulations used in all treatment arms were in the ZIANA vehicle gel. Cutaneous safety and tolerance evaluations were conducted at each study visit in all of the clinical trials by assessment of erythema, scaling, itching, burning, and stinging: Table 2: ZIANA Gel-Treated Patients with Local Skin Reactions Local Reaction Baseline N=1835 N (%) End of Treatment N=1614 N (%) Erythema 636 (35) 416 (26) Scaling 237 (13) 280 (17) Itching 189 (10) 70 (4) Burning 38 (2) 56 (4) Stinging 33 (2) 27 (2) At each study visit, application site reactions on a scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe), and the mean scores were calculated for each of the local skin reactions. In Studies 1 and 2, 1277 subjects enrolled with moderate to severe acne, 854 subjects treated with ZIANA Gel and 423 treated with vehicle. Analysis over the 12-week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at 2 weeks of therapy, and were slightly higher for the ZIANA-treated group, decreasing thereafter. One open-label 12-month safety study for ZIANA Gel showed a similar adverse reaction profile as seen in the 12-week studies. Eighteen out of 442 subjects (4%) reported gastrointestinal symptoms.

4 CONTRAINDICATIONS ZIANA Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis. ZIANA Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic–associated colitis. ( 4 )

11 DESCRIPTION ZIANA (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel is an antibiotic and retinoid combination gel product with two active ingredients. 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: Clindamycin phosphate: Molecular Formula: C 18 H 34 ClN 2 O 8 PS Molecular Weight: 504.97 The chemical name for tretinoin is 3,7-Dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8 nonatetraenoic acid (all- trans form). The structural formula for tretinoin is represented below: Tretinoin: Molecular Formula: C 20 H 28 O 2 Molecular Weight: 300.44 ZIANA Gel contains the following inactive ingredients: butylated hydroxytoluene NF, carbomer 981 NF, citric acid USP, edetate disodium USP, glycerin USP, methylparaben NF, polysorbate 80 NF, propylparaben NF, purified water USP and tromethamine USP. Chemical Structure Chemical Structure

2 DOSAGE AND ADMINISTRATION At bedtime, squeeze a pea-sized amount of medication onto one fingertip, dot onto the chin, cheeks, nose, and forehead, then gently rub over the entire face. ZIANA Gel should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. ZIANA Gel is not for oral, ophthalmic, or intravaginal use. • Apply a pea-sized amount to the entire face once daily at bedtime. Do not apply to eyes, mouth, angles of the nose, or mucous membranes. ( 2 ) • ZIANA Gel is not for oral, ophthalmic, or intravaginal use. ( 2 )

1 INDICATIONS AND USAGE ZIANA Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older. ZIANA ® Gel is a lincosamide antibiotic and retinoid combination product indicated for the topical treatment of acne vulgaris in patients 12 years or older. ( 1 )

7 DRUG INTERACTIONS • Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution. ( 7.1 ) • ZIANA Gel should not be used in combination with erythromycin-containing products because of its clindamycin component. ( 7.2 ) 7.1 Concomitant Topical Medication Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with ZIANA Gel, there may be increased skin irritation. 7.2 Erythromycin ZIANA Gel should not be used in combination with erythromycin-containing products due 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. 7.3 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, ZIANA Gel should be used with caution in patients receiving such agents.

12 CLINICAL PHARMACOLOGY 12.1 Mechanisms 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 microcomedo 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, multiple-dose study treating 12 subjects with moderate to severe acne, the percutaneous absorption of tretinoin following 14 consecutive daily applications of approximately 4 g of ZIANA Gel was minimal. Quantifiable tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/mL, with unquantifiable plasma concentrations in 50% to 92% of subjects at any given timepoint following administration. The plasma concentrations of the key tretinoin metabolites, 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid, ranged from 1.0 to 1.4 ng/mL and from 1.6 to 6.5 ng/mL, respectively. Plasma concentrations for clindamycin generally did not exceed 3.5 ng/mL, with the exception of one subject whose plasma concentration reached 13.1 ng/mL. 12.4 Microbiology Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing bacterial protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes , an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with ZIANA Gel. P. acnes resistance to clindamycin has been documented. Resistance to clindamycin is often associated with resistance to erythromycin.

12.1 Mechanisms 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 microcomedo 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, multiple-dose study treating 12 subjects with moderate to severe acne, the percutaneous absorption of tretinoin following 14 consecutive daily applications of approximately 4 g of ZIANA Gel was minimal. Quantifiable tretinoin plasma concentrations ranged from 1.0 to 1.6 ng/mL, with unquantifiable plasma concentrations in 50% to 92% of subjects at any given timepoint following administration. The plasma concentrations of the key tretinoin metabolites, 13-cis-retinoic acid and 4-oxo-13-cis-retinoic acid, ranged from 1.0 to 1.4 ng/mL and from 1.6 to 6.5 ng/mL, respectively. Plasma concentrations for clindamycin generally did not exceed 3.5 ng/mL, with the exception of one subject whose plasma concentration reached 13.1 ng/mL.

20170301

8

3 DOSAGE FORMS AND STRENGTHS ZIANA Gel, a combination of a lincosamide antibiotic and a retinoid, contains clindamycin phosphate 1.2% and tretinoin 0.025%, formulated as a topical gel. Each gram of ZIANA Gel contains, as dispensed, 10 mg (1%) clindamycin as phosphate, and 0.25 mg (0.025%) tretinoin in an aqueous-based gel. ZIANA Gel is available in 30 gram and 60 gram tubes. Topical gel: Clindamycin phosphate 1.2% and tretinoin 0.025% gel in 30 and 60 gram tubes. ( 3 )

ZIANA clindamycin phosphate and tretinoin clindamycin phosphate clindamycin tretinoin tretinoin water glycerin CARBOMER HOMOPOLYMER TYPE A (ALLYL PENTAERYTHRITOL CROSSLINKED) methylparaben polysorbate 80 edetate disodium ANHYDROUS CITRIC ACID propylparaben butylated hydroxytoluene tromethamine

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and impairment of fertility testing of ZIANA Gel have not been performed in any species. Clindamycin The carcinogenicity of a 1% clindamycin phosphate gel similar to ZIANA Gel was evaluated by daily application to mice for 2 years. The daily doses used in this study were approximately 13 and 72 times higher than the human dose of clindamycin phosphate from ZIANA Gel, assuming complete absorption and based on body surface area comparison. No significant increase in tumors was noted in the treated animals. For purposes of comparisons of the animal exposure to human exposure, the recommended human topical clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person. Fertility (Segment 1) studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 290 times the amount of clindamycin delivered from the recommended clinical dose for ZIANA Gel, based on body surface area comparison) revealed no effects on fertility or mating ability. Tretinoin In two independent studies with long-term topical application of tretinoin in mice, carcinogenicity was not observed. In both studies, tretinoin was administered topically (0.025% or 0.1%) three times per week for up to 2 years. No carcinogenicity was observed with maximum effects of dermal amyloidosis in the basal layer of the skin. Tretinoin has been shown to enhance photo co-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to the drug and UV radiation. The contribution of clindamycin to that effect is unknown. Although the significance of these studies to humans is not clear, patients should minimize 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 Segment 1 studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, mutagenicity and impairment of fertility testing of ZIANA Gel have not been performed in any species. Clindamycin The carcinogenicity of a 1% clindamycin phosphate gel similar to ZIANA Gel was evaluated by daily application to mice for 2 years. The daily doses used in this study were approximately 13 and 72 times higher than the human dose of clindamycin phosphate from ZIANA Gel, assuming complete absorption and based on body surface area comparison. No significant increase in tumors was noted in the treated animals. For purposes of comparisons of the animal exposure to human exposure, the recommended human topical clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person. Fertility (Segment 1) studies in rats treated orally with up to 300 mg/kg/day of clindamycin (approximately 290 times the amount of clindamycin delivered from the recommended clinical dose for ZIANA Gel, based on body surface area comparison) revealed no effects on fertility or mating ability. Tretinoin In two independent studies with long-term topical application of tretinoin in mice, carcinogenicity was not observed. In both studies, tretinoin was administered topically (0.025% or 0.1%) three times per week for up to 2 years. No carcinogenicity was observed with maximum effects of dermal amyloidosis in the basal layer of the skin. Tretinoin has been shown to enhance photo co-carcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to the drug and UV radiation. The contribution of clindamycin to that effect is unknown. Although the significance of these studies to humans is not clear, patients should minimize 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 Segment 1 studies in rats treated with tretinoin, the no-observed-effect-level was 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison).

NDA050802

ZIANA

clindamycin phosphate and tretinoin

99207-300

HUMAN PRESCRIPTION DRUG

TOPICAL

12.4 Microbiology Clindamycin binds to the 50S ribosomal subunits of susceptible bacteria and prevents elongation of peptide chains by interfering with peptidyl transfer, thereby suppressing bacterial protein synthesis. Clindamycin has been shown to have in vitro activity against Propionibacterium acnes , an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with ZIANA Gel. P. acnes resistance to clindamycin has been documented. Resistance to clindamycin is often associated with resistance to erythromycin.

PRINCIPAL DISPLAY PANEL - 30 g Carton NDC 99207-300-30 ZIANA ® (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel Rx only Net Wt. 30 g FOR TOPICAL USE ONLY NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE ziana.jpg

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Instructions for Use • At bedtime, the face should be gently washed with a mild soap and warm water. After patting the skin dry, apply ZIANA Gel as a thin layer over the entire face (excluding the eyes and lips). • Patients should be advised not to use more than the recommended pea-sized amount 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. Skin Irritation ZIANA Gel may cause irritation such as erythema, scaling, itching, burning, or stinging. Colitis In the event a patient treated with ZIANA Gel experiences severe diarrhea or gastrointestinal discomfort, ZIANA Gel should be discontinued and a physician should be contacted. Manufactured for: Valeant Pharmaceuticals North America LLC Bridgewater, NJ 08807 USA By: Valeant Pharmaceuticals International, Inc. Laval, Quebec H7L 4A8, Canada U.S. Patent 6,387,383 Ziana is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. ©Valeant Pharmaceuticals North America LLC 9480201 20001130B

14 CLINICAL STUDIES The safety and efficacy of once daily use of ZIANA Gel for treatment of acne vulgaris were assessed in three 12-week prospective, multi-center, randomized, blinded studies in patients 12 years and older. Studies 1 and 2 were of identical design, and compared ZIANA Gel to clindamycin in the vehicle gel, tretinoin in the vehicle gel, and the vehicle gel alone. Patients with mild, moderate, or severe acne were enrolled in the studies. The co-primary efficacy variables were: 1. Mean percent change from baseline at Week 12 in 1. inflammatory lesion counts, 2. non-inflammatory lesion counts, and 3. total lesion counts 2. Percent of subjects who cleared or almost cleared at Week 12 as judged by an Evaluator's Global Severity (EGS) score. The EGS scoring scale used in all of the clinical trials for ZIANA Gel is as follows: Grade Description Clear Normal, clear skin with no evidence of acne vulgaris Almost Clear Rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) Mild Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only; no nodulocystic lesions) Moderate Non-inflammatory lesions predominate, with multiple inflammatory lesions evident: several to many comedones and papules/pustules, and there may or may not be one small nodulo-cystic lesion Severe Inflammatory lesions are more apparent, many comedones and papules/pustules, there may or may not be a few nodulocystic lesions Very Severe Highly inflammatory lesions predominate, variable number of comedones, many papules/pustules and many nodulocystic lesions In Study 1, a total of 1252 patients were enrolled, and in Study 2, a total of 1288 patients were enrolled. The combined results are presented in Table 3. Table 3: Efficacy Results at Week 12 in Studies 1 and 2 ZIANA Gel N=845 Clindamycin N=426 Tretinoin N=846 Vehicle N=423 Evaluator's Global Severity: N (%) Patients achieving success Success was defined as cleared or almost cleared at Week 12. 180 (21%) 70 (16%) 122 (14%) 34 (8%) Inflammatory Lesion Count (% reduction from baseline) Mean 48% 42% 39% 26% Non-inflammatory Lesion Count (% reduction from baseline) Mean 36% 27% 31% 16% Total Lesion Count (% reduction from baseline) Mean 41% 34% 34% 20% In Study 3, ZIANA Gel was compared to clindamycin gel in a total of 2010 patients with moderate or severe acne vulgaris (see Table 3 ). As with Studies 1 and 2, the co-primary endpoints were mean percent reduction in lesion counts (inflammatory, non-inflammatory and total) and the EGS score. In Study 3, success on the EGS score was assessed by the percentage of subjects who had at least 2 grades of improvement from Baseline to Week 12. Table 4: Efficacy Results at Week 12 in Study 3 ZIANA Gel N=1008 Clindamycin N=1002 Evaluator's Global Severity: N (%) Patients achieving success Success was defined as at least a 2-grade improvement at Week 12 from baseline. 415 (41%) 345 (34%) Inflammatory Lesion Count (% reduction from baseline) Mean 61% 55% Non-inflammatory Lesion Count (% reduction from baseline) Mean 50% 41% Total Lesion Count (% reduction from baseline) Mean 54% 47%

8.5 Geriatric Use Clinical studies of ZIANA 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 ZIANA 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 ZIANA Gel is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness of ZIANA Gel in pediatric patients under the age of 12 have not been established. Clinical trials of ZIANA Gel included patients 12–17 years of age. [See Clinical Studies (14) .]

8.1 Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA Gel. ZIANA Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of ZIANA Gel for 2 weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person. Clindamycin Teratology (Segment II) studies using clindamycin were performed orally in rats (up to 600 mg/kg/day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) or with subcutaneous doses of clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity. Tretinoin In oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison). 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 two 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, five 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 the fetus is not known. Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on body surface area comparison. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on body surface area comparison.

Pregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA Gel. ZIANA Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of ZIANA Gel for 2 weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person. Clindamycin Teratology (Segment II) studies using clindamycin were performed orally in rats (up to 600 mg/kg/day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) or with subcutaneous doses of clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity. Tretinoin In oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison). 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 two 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, five 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 the fetus is not known. Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on body surface area comparison. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on body surface area comparison.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA Gel. ZIANA Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel was tested for maternal and developmental toxicity in New Zealand White Rabbits with topical doses of 60, 180 and 600 mg/kg/day. ZIANA Gel at 600 mg/kg/day (approximately 12 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity following dermal administration of ZIANA Gel for 2 weeks prior to artificial insemination and continuing until gestation day 18, inclusive. For purposes of comparisons of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of ZIANA Gel applied daily to a 60 kg person. Clindamycin Teratology (Segment II) studies using clindamycin were performed orally in rats (up to 600 mg/kg/day) and mice (up to 100 mg/kg/day) (583 and 49 times amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) or with subcutaneous doses of clindamycin up to 180 mg/kg/day (175 and 88 times the amount of clindamycin in the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity. Tretinoin In oral Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (~78 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison). 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 two 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, five 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 the fetus is not known. Dermal tretinoin has been shown to be fetotoxic in rabbits when administered in doses 40 times the recommended human clinical dose based on body surface area comparison. Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 78 times the recommended clinical dose based on body surface area comparison. 8.3 Nursing Mothers It is not known whether clindamycin is excreted in human milk following use of ZIANA 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 ZIANA Gel is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ZIANA Gel in pediatric patients under the age of 12 have not been established. Clinical trials of ZIANA Gel included patients 12–17 years of age. [See Clinical Studies (14) .] 8.5 Geriatric Use Clinical studies of ZIANA 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 ZIANA ® (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel is supplied as follows: 30 gram tube NDC 99207-300-30 60 gram tube NDC 99207-300-60 Storage and Handling • Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. • Protect from light. • Protect from freezing. • Keep out of the reach of children. • Keep away from heat. • Keep tube tightly closed.

Storage and Handling • Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. • Protect from light. • Protect from freezing. • Keep out of the reach of children. • Keep away from heat. • Keep tube tightly closed.