Prescription Drugs

ZIANA Gel (clindamycin phosphate 1.2% and tretinoin 0.025%) 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: C18H34ClN2O8PS 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: C20H28O2 Molecular Weight: 300.44 ZIANA Gel (clindamycin phosphate, tretinoin) contains the following inactive ingredients: purified water USP, glycerin USP, carbomer 981 NF, methylparaben NF, polysorbate 80 NF, edetate disodium USP, citric acid USP, propylparaben NF, butylated hydroxytoluene NF, and tromethamine USP.

INDICATIONS ZIANA Gel (clindamycin phosphate, tretinoin) is indicated for the topical treatment of acne vulgaris in patients 12 years or older. 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 (clindamycin phosphate, tretinoin) should be kept away from the eyes, the mouth, angles of the nose, and mucous membranes. ZIANA Gel (clindamycin phosphate, tretinoin) is not for oral, ophthalmic, or intravaginal use. DOSAGE FORMS AND STRENGTHS ZIANA Gel (clindamycin phosphate, tretinoin) , 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 (clindamycin phosphate, tretinoin) contains, as dispensed, 10 mg (1%) clindamycin as phosphate, and 0.25 mg (0.025%) tretinoin in an aqueous based gel. ZIANA Gel (clindamycin phosphate, tretinoin) is available in 2 gram, 30 gram, and 60 gram tubes. HOW SUPPLIED HOW SUPPLIED/STORAGE AND HANDLING ZIANA (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel is supplied as follows: 2 gram tube NDC 99207-300-02 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 15-30°C (59-86°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. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. 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 (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) may cause irritation such as erythema, scaling, itching, burning, or stinging. Colitis In the event a patient treated with ZIANA Gel (clindamycin phosphate, tretinoin) experiences severe diarrhea or gastrointestinal discomfort, ZIANA Gel (clindamycin phosphate, tretinoin) should be discontinued and a physician should be contacted. Manufactured for: Medicis, The Dermatology Company® Scottsdale, AZ 85258 By: Contract Pharmaceuticals Limited Niagara Buffalo, NY 14213 U.S. Patent 5,721,275 U.S. Patent 6,387,383 FDA rev date: 11/7/2006

PATIENT INFORMATION PATIENT INFORMATION ZIANA (ZEE-AH-NA) (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel IMPORTANT: Not for mouth, eye, or vaginal use. Read the Patient Information that comes with ZIANA Gel (clindamycin phosphate, tretinoin) before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your acne or treatment. What is ZIANA Gel (clindamycin phosphate, tretinoin) ? ZIANA Gel (clindamycin phosphate, tretinoin) is an antibiotic and retinoid combination medicine used for the skin treatment of acne in patients 12 years and older. Who should not use ZIANA Gel (clindamycin phosphate, tretinoin) ? Do not use ZIANA Gel (clindamycin phosphate, tretinoin) if you: have Crohn's Disease have Ulcerative Colitis have developed colitis with past antibiotic use Tell your doctor: if you are pregnant or planning to become pregnant. It is not known if ZIANA Gel (clindamycin phosphate, tretinoin) may harm your unborn baby. if you are breastfeeding. ZIANA Gel (clindamycin phosphate, tretinoin) may pass through your milk and may harm your baby. about all the medicines and skin products you use: ZIANA Gel (clindamycin phosphate, tretinoin) should not be used with erythromycin-containing products. Avoid medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and skin products that contain alcohol, astringents, spices or lime. These products may cause increased skin irritation if used with ZIANA GEL (clindamycin phosphate, tretinoin) . How should I use ZIANA Gel (clindamycin phosphate, tretinoin) ? Use ZIANA Gel (clindamycin phosphate, tretinoin) exactly as prescribed. It may take some time for you to see improvement of your acne with ZIANA Gel (clindamycin phosphate, tretinoin) . Your doctor will tell you how long to use ZIANA Gel (clindamycin phosphate, tretinoin) . At bedtime: Wash your face gently with a mild soap and warm water. Pat the skin dry. Apply a pea-size amount of ZIANA Gel (clindamycin phosphate, tretinoin) to your fingertip and spread it over your face. Gently, smooth it into your skin. Do not get ZIANA Gel (clindamycin phosphate, tretinoin) in your eyes or mouth, on your lips, on the corners of your nose, or on open wounds. In the morning: Apply a sunscreen and reapply during the day as needed. Do not apply ZIANA Gel (clindamycin phosphate, tretinoin) more than once a day Do not use too much ZIANA Gel (clindamycin phosphate, tretinoin) . Too much ZIANA Gel (clindamycin phosphate, tretinoin) may irritate your skin. Do not wash your face more than 2 to 3 times a day. Washing your face too often or scrubbing it may make your acne worse. Avoid: excessive exposure to the sun, cold, and wind. Weather extremes can dry and burn the skin. Always use a sunscreen on ZIANA Gel (clindamycin phosphate, tretinoin) treated skin, even on cloudy days. Use other protective clothing such as a hat when you are in the sun. the use of sunlamps and tanning booths If your face becomes sunburned, stop ZIANA Gel (clindamycin phosphate, tretinoin) until your skin has healed. What are possible side effects with ZIANA Gel (clindamycin phosphate, tretinoin) ? Skin irritation. ZIANA Gel (clindamycin phosphate, tretinoin) may cause skin irritation such as dryness, redness, peeling, burning, or stinging. Stop ZIANA Gel (clindamycin phosphate, tretinoin) and call your doctor if your skin becomes very red, swollen, blistered, or crusted. Change in skin color. ZIANA Gel (clindamycin phosphate, tretinoin) may cause a temporary skin color change (lighter or darker). Colitis. This occurs rarely. Stop ZIANA Gel (clindamycin phosphate, tretinoin) and call your doctor if you develop severe watery diarrhea, or bloody diarrhea. Talk to your doctor about any side effect that bothers you or that does not go away. These are not all the side effects with ZIANA Gel (clindamycin phosphate, tretinoin) . Ask your doctor or pharmacist for more information. How should I store ZIANA Gel (clindamycin phosphate, tretinoin) ? Store ZIANA Gel (clindamycin phosphate, tretinoin) at room temperature, 59 to 86°F (15 to 30°C). Do not freeze. Keep ZIANA Gel (clindamycin phosphate, tretinoin) away from heat and light. Keep the tube tightly closed. Keep ZIANA Gel (clindamycin phosphate, tretinoin) and all medicines out of the reach of children General information about ZIANA Gel (clindamycin phosphate, tretinoin) Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use ZIANA Gel (clindamycin phosphate, tretinoin) for a condition for which it was not prescribed. Do not give ZIANA Gel (clindamycin phosphate, tretinoin) to other people, even if they have the same symptoms you have. It may harm them. This leaflet summarizes the most important information about ZIANA Gel (clindamycin phosphate, tretinoin) . If you would like more information, talk with your doctor. You can also ask your pharmacist or doctor for information about ZIANA Gel (clindamycin phosphate, tretinoin) that is written for healthcare professionals. If you have questions about ZIANA Gel (clindamycin phosphate, tretinoin) you can also call: 1-800-900-6389 (this is a toll-free number) between 10:00 a.m. and 4:00 p.m. Eastern Time, Monday through Friday. What are the ingredients in ZIANA Gel (clindamycin phosphate, tretinoin) ? Active Ingredients: clindamycin phosphate 1.2% and tretinoin 0.025% Inactive Ingredients: purified water USP, glycerin USP, carbomer 981 NF, methylparaben NF, polysorbate 80 NF, edetate disodium USP, citric acid USP, propylparaben NF, butylated hydroxytoluene NF, and tromethamine USP.

OVERDOSE No information provided. CONTRAINDICATIONS ZIANA Gel (clindamycin phosphate, tretinoin) is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.

SIDE EFFECTS 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 (clindamycin phosphate, tretinoin) in 1,853 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 (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) : 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 (clindamycin phosphate, tretinoin) -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 (clindamycin phosphate, tretinoin) and 423 treated with vehicle. Analysis over the twelve week period demonstrated that cutaneous irritation scores for erythema, scaling, itching, burning, and stinging peaked at two weeks of therapy, and were slightly higher for the ZIANA-treated group, decreasing thereafter. One open-label 12-month safety study for ZIANA Gel (clindamycin phosphate, tretinoin) showed a similar adverse reaction profile as seen in the 12-week studies. Eighteen out of 442 subjects (4%) reported gastrointestinal symptoms. DRUG INTERACTIONS 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 (clindamycin phosphate, tretinoin) , there may be increased skin irritation. Erythromycin ZIANA Gel (clindamycin phosphate, tretinoin) 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. 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 (clindamycin phosphate, tretinoin) should be used with caution in patients receiving such agents.

WARNINGS No information provided. Please see PRECAUTIONS below and SIDE EFFECTS & DRUG INTERACTIONS. PRECAUTIONS 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. When significant diarrhea occurs, ZIANA Gel (clindamycin phosphate, tretinoin) should be discontinued. 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. Ultraviolet Light and Environmental Exposure Exposure to sunlight, including sunlamps, should be avoided during the use of ZIANA Gel (clindamycin phosphate, tretinoin) , and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Daily use of sunscreen products and protective apparel (e.g., a hat) are recommended. Weather extremes, such as wind or cold, also may be irritating to patients under treatment with ZIANA Gel (clindamycin phosphate, tretinoin) . USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with ZIANA Gel (clindamycin phosphate, tretinoin) . ZIANA Gel (clindamycin phosphate, tretinoin) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ZIANA Gel (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) 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 (clindamycin phosphate, tretinoin) for two 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 (clindamycin phosphate, tretinoin) 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 a 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 a 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, 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 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 a 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 a body surface area comparison. Nursing Mothers It is not known whether clindamycin is excreted in human milk following use of ZIANA Gel (clindamycin phosphate, tretinoin) . 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 (clindamycin phosphate, tretinoin) is administered to a nursing woman. Pediatric Use Safety and effectiveness of ZIANA Gel (clindamycin phosphate, tretinoin) 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] Geriatric Use Clinical studies of ZIANA Gel (clindamycin phosphate, tretinoin) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.