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, VELTIN 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 VELTIN 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 VELTIN Gel.

6.1 Adverse Reactions in Clinical Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety data reflect exposure to VELTIN Gel in 1,104 subjects with acne vulgaris. Subjects were 12 years and older and were treated once daily in the evening for 12 weeks. Adverse reactions that were reported in ≥1% of subjects treated with VELTIN 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.

7.1 Erythromycin

VELTIN Gel should not be used in combination with erythromycin-containing products due to possible antagonism to the clindamycin component. In vitrostudies have shown antagonism between these 2 antimicrobials. The clinical significance of this in vitroantagonism 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, VELTIN Gel should be used with caution in patients receiving such agents.

8.1 Pregnancy

Pregnancy Category C.

There are no well-controlled studies in pregnant women treated with VELTIN Gel. VELTIN Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A limit teratology study performed in Sprague Dawley rats treated topically with VELTIN Gel or 0.025% tretinoin gel at a dose of 2 mL/kg during gestation days 6 to 15 did not result in teratogenic effects. Although no systemic levels of tretinoin were detected, craniofacial and heart abnormalities were described in drug-treated groups. These abnormalities are consistent with retinoid effects and occurred at 16 times the recommended clinical dose assuming 100% absorption and based on body surface area comparison. For purposes of comparison of the animal exposure to human exposure, the recommended clinical dose is defined as 1 g of VELTIN Gel applied daily to a 50-kg person.

Clindamycin: Reproductive developmental toxicity studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (480 and 240 times the recommended clinical dose based on body surface area comparison, respectively) or subcutaneous doses of clindamycin up to 180 mg/kg/day (140 and 70 times the recommended clinical dose based on body surface area comparison, respectively) revealed no evidence of teratogenicity.

Tretinoin: Oral tretinoin has been shown to be teratogenic in mice, rats, hamsters, rabbits, and primates. It was teratogenic and fetotoxic in Wistar rats when given orally at doses greater than 1 mg/kg/day (32 times the recommended clinical dose based on body surface area comparison). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomologous monkey, a species in which tretinoin metabolism is closer to humans than in other species examined, fetal malformations were reported at oral doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (324 times the recommended clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related teratogenic effects and increased abortion rates were reported in pigtail macaques.

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 2 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 fetus is not known.

8.3 Nursing Mothers

It is not known whether clindamycin is excreted in human milk following use of VELTIN 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 VELTIN Gel is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of VELTIN Gel in pediatric patients younger than 12 years have not been established.

Clinical trials of VELTIN Gel included 2,086 subjects aged 12 through 17 years with acne vulgaris. [See Clinical Studies (14).]

8.5 Geriatric Use

Clinical trials of VELTIN Gel did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

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 folliculare 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 trial of 17 subjects with moderate-to-severe acne vulgaris, topical administration of approximately 3 grams of VELTIN Gel once daily for 5 days, clindamycin concentrations were quantifiable in all 17 subjects 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 trials with VELTIN 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of VELTIN Gel or the effect of VELTIN Gel on fertility. VELTIN Gel was negative for mutagenic potential when evaluated in an in vitroAmes Salmonella reversion assay. VELTIN Gel was equivocal for clastogenic potential in the absence of metabolic activation when tested in an in vitrochromosomal 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 photocarcinogenicity in properly performed specific studies, employing concurrent or intercurrent exposure to tretinoin and UV radiation. The photocarcinogenic 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 vitroAmes Salmonella reversion test and an in vitrochromosomal 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).

Instructions for Use

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At bedtime, the face should be gently washed with a mild soap and water. After patting the skin dry, apply VELTIN Gel as a thin layer over the entire affected area (excluding the eyes and lips).

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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.

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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.

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Other topical products with a strong drying effect such as abrasive soaps or cleansers may cause an increase in skin irritation with VELTIN Gel.

Skin Irritation

VELTIN Gel may cause irritation such as erythema, scaling, itching, burning, or stinging.

Colitis

In the event a patient treated with VELTIN Gel experiences severe diarrhea or gastrointestinal discomfort, VELTIN Gel should be discontinued and a physician should be contacted.

Almirall

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