PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

CARTON LABEL - 30g

NDC 21922-050-05

Clindamycin Phosphate and Tretinoin Gel 1.2%/0.025%

For Topical use only

Rx only

** CARTON LABEL - 60g**

NDC 21922-050-07

Clindamycin Phosphate and Tretinoin Gel 1.2%/0.025%

For Topical use only

Rx only

5 WARNINGS AND PRECAUTIONS

5.1 Colitis

Systemic absorption of clindamycin has been demonstrated following topical use. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical clindamycin. If significant diarrhea occurs, clindamycin phosphate and tretinoin 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 clindamycin phosphate and tretinoin gel. 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 clindamycin phosphate and tretinoin gel.

6 ADVERSE REACTIONS

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 with 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 and 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.

Local skin reactions actively assessed at baseline and end of treatment with a score >0 are presented in Table 2.

During the 12 weeks of treatment, each local skin reaction peaked at Week 2 and gradually reduced thereafter.

7 DRUG INTERACTIONS

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.

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: C18H34ClN2O8PS
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: C20H28O2
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.

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.

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).

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:

In Studies 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

The safety and efficacy of clindamycin-tretinoin gel was also evaluated in 2 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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

17.1 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.

17.2 Skin Irritation

Clindamycin phosphate and tretinoin gel may cause irritation such as erythema, scaling, itching, burning, or stinging.

17.3 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 by:
Encube Ethicals Private Limited,
Plot No C-1, Madkaim Industrial Estate, Ponda, Goa 403404, India.

Distributed by:
Encube Ethicals, Inc.,
200 Meredith Drive, Suite 202, Durham, North Carolina (NC) 27713, United States (USA).