Ziana

HOW SUPPLIED/STORAGE AND HANDLING

ZIANA (clindamycin phosphate 1.2% and tretinoin 0.025%) Gel is supplied as follows:

Storage and Handling

• Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
• 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

ZIANA Gel (clindamycin phosphate, tretinoin) is indicated for the topical treatment of acne vulgaris in patients 12 years or older.

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.

ZIANA Gel (clindamycin phosphate, tretinoin) is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.

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.

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.

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

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

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.

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.

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

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

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.

No information provided.