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clindamycin phosphate and
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ZIANA® Gel is indicated for the topical treatment of acne vulgaris in patients 12 years or older.
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.
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 2 gram, 30 gram, and 60 gram tubes.
ZIANA® Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated colitis.
5 WARNINGS AND PRECAUTIONS
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 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.
5.2 Ultraviolet Light and Environmental Exposure
Exposure to sunlight, including sunlamps, should be avoided during the use of ZIANA® Gel, 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.
6 ADVERSE REACTIONS
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 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 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:
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:
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 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 showed a similar adverse reaction profile as seen in the 12-week studies. Eighteen out of 442 subjects (4%) reported gastrointestinal symptoms.
7 DRUG INTERACTIONS
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.
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.
8 USE IN SPECIFIC POPULATIONS
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 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 applied daily to a 60 kg person.
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.
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.
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)]
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:
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:
Molecular Formula: C20H28O2 Molecular Weight: 300.44
ZIANA® Gel 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.
12 CLINICAL PHARMACOLOGY
12.1 Mechanisms of Action
[see Microbiology (12.4)].
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.
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.
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.
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.
The carcinogenicity of a 1% clindamycin phosphate gel similar to ZIANA Gel was evaluated by daily application to mice for two 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 a 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 a body surface area comparison) revealed no effects on fertility or mating ability.
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 two years. No carcinogenicity was observed with maximum effects of dermal amyloidosis in the basal layer of the skin.
Tretinoin has been shown to enhance photoco-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).
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:
The EGS scoring scale used in all of the clinical trials for ZIANA Gel is as follows:
In Study 1, a total of 1,252 patients were enrolled, and in Study 2, a total of 1,288 patients were enrolled. The combined results are presented in Table 3.
In Study 3, ZIANA® Gel was compared to clindamycin gel in a total of 2,010 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 Evaluator's Global Severity 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.
16 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
17 PATIENT COUNSELING INFORMATION
17.1 Instructions for Use
17.2 Skin Irritation
ZIANA® Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.
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.
IMPORTANT: Not for mouth, eye, or vaginal use.
Read the Patient Information that comes with ZIANA® Gel 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?
ZIANA® Gel 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?
Do not use ZIANA® Gel if you:
Tell your doctor:
How should I use ZIANA® Gel?
Use ZIANA® Gel exactly as prescribed. It may take some time for you to see improvement of your acne with ZIANA Gel. Your doctor will tell you how long to use ZIANA Gel.
In the morning:
If your face becomes sunburned, stop ZIANA® Gel until your skin has healed.
What are possible side effects with ZIANA® Gel?
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. Ask your doctor or pharmacist for more information.
How should I store ZIANA® Gel?
General information about ZIANA® Gel
Medicines are sometimes prescribed for purposes other than those listed in patient information leaflet. Do not use ZIANA® Gel for a condition for which it was not prescribed. Do not give ZIANA Gel 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. If you would like more information, talk with your doctor. You can also ask your pharmacist or doctor for information about ZIANA® Gel that is written for healthcare professionals.
If you have questions about ZIANA Gel 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?
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.
By: Contract Pharmaceuticals Limited Niagara
U.S. Patent 5,721,275
PRINCIPAL DISPLAY PANEL - 2 g Sample Carton
Sample—Not for Sale.
FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC,
Contains 12 sample tubes. Each tube contains 2 g.
PRINCIPAL DISPLAY PANEL - 30 g Carton
Net wt. 30 g
PRINCIPAL DISPLAY PANEL - 60 g Carton
Net wt. 60 g
Revised: 10/2009 Medicis Pharmaceutical Corp
Reproduced with permission of U.S. National Library of Medicine
Copyright © 2018
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