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These highlights do not include all the information needed to use VELTIN Gel safely and effectively. See full prescribing information for VELTIN Gel. VELTIN™ (clindamycin phosphate and tretinoin) Gel 1.2%/0.025%For topical use onlyInitial U.S. App | VELTIN

04:57 EDT 27th August 2014 | BioPortfolio

Note: While we endeavour to keep our records up-to-date one should not rely on these details being accurate without first consulting a professional. Click here to read our full medical disclaimer.

VELTIN™ (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025% is indicated for the topical treatment of acne vulgaris in patients 12 years or older.

VELTIN Gel should be applied once daily in the evening, gently rubbing the medication to lightly cover the entire affected area. Approximately a pea sized amount will be needed for each application. Avoid the eyes, lips, and mucous membranes.

VELTIN Gel is not for oral, ophthalmic, or intravaginal use.

VELTIN Gel, containing clindamycin phosphate 1.2% and tretinoin 0.025%, is a yellow, opaque topical gel. Each gram of VELTIN Gel contains, as dispensed, 10 mg (1%) clindamycin as clindamycin phosphate, and 0.25 mg (0.025%) tretinoin solubilized in an aqueous based gel.

VELTIN Gel is contraindicated in patients with regional enteritis, ulcerative colitis, or history of antibiotic-associated 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.

Exposure to sunlight, including sunlamps, should be avoided during the use of VELTIN 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 VELTIN Gel.

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

The safety data reflect exposure to VELTIN Gel in 1,104 patients with acne vulgaris. Patients were 12 years or older and were treated once daily in the evening for 12 weeks. Adverse reactions that were reported in ≥1% of patients 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 twelve weeks of treatment, each local skin reaction peaked at week 2 and gradually reduced thereafter.

Table 1: Treatment-Related Adverse Reactions Reported by ≥1% of Subjects
VELTIN Gel
N=1104
n (%)
Clindamycin Gel
N=1091
n (%)
Tretinoin Gel
N=1084
n (%)
Vehicle Gel
N=552
n (%)
Patients with at least one adverse reaction 140 (13) 38 (3) 141 (13) 17 (3)
Application site dryness 64 (6) 12 (1) 62 (6) 3 (1)
Application site irritation 50 (5) 4 (<1) 57 (5) 5 (1)
Application site exfoliation 50 (5) 2 (<1) 56 (5) 2 (<1)
Application site erythema 40 (4) 6 (1) 39 (4) 3 (1)
Application site pruritus 26 (2) 7 (1) 23 (2) 6 (1)
Sunburn 11 (1) 6 (1) 7 (1) 3 (1)
Application site dermatitis 6 (1) 0 (0) 8 (1) 1 (<1)
Table 2: VELTIN GEL-Treated Patients with Local Skin Reactions
VELTIN GEL VEHICLE GEL
Local Reaction Baseline N= 476N (%) End of Treatment N= 409N (%) Baseline N= 219N (%) End of Treatment N= 209N (%)
Erythema 24% 21% 31% 35%
Scaling 8% 19% 14% 12%
Dryness 11% 22% 18% 13%
Burning 8% 13% 8% 4%
Itching 17% 15% 22% 14%

VELTIN 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.

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.

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 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 fetus is not known.

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.

Safety and effectiveness of VELTIN Gel in pediatric patients below the age of 12 years have not been established.

Clinical trials of VELTIN Gel included 2,086 patients 12-17 years of age with acne vulgaris. [See Clinical Studies (14).]

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

VELTIN (clindamycin phosphate and tretinoin) Gel, 1.2%/0.025%, is a fixed combination of two 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:

Clindamycin phosphate:

Molecular Formula: CHClNOPS

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:

Tretinoin:

Molecular Formula: CHO

Molecular Weight: 300.44

VELTIN Gel contains the following inactive ingredients: butylated hydroxytoluene, carbomer 940, anhydrous citric acid, edetate disodium, methylparaben, laureth 4, propylene glycol, tromethamine, and purified water.

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.

In an open-label study of 17 patients 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 patients starting from 1 hour post dose. All plasma clindamycin concentrations were ≤5.56 ng/mL on day 5, with the exception of one 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 to 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.

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 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.

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 vitro Ames Salmonella reversion assay. VELTIN 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 VELTIN 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 two independent mouse studies where 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. However, in a dermal carcinogenicity study in mice, tretinoin applied at a dose of 5.1 μg (1.4 times the recommended clinical dose based on body surface area comparison) three 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-tetradecanoyl-phorbol 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).

The safety and efficacy of VELTIN Gel, applied once daily for the treatment of acne vulgaris, was evaluated in 12-week multicenter, randomized, blinded studies in subjects 12 years and older.

Treatment response was defined as the percent of subjects who had a two 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 two out of three (total, inflammatory and non-inflammatory) lesion counts. The IGA scoring scale used in all the clinical trials for VELTIN Gel is as follows:

In Study 1, 1649 subjects were randomized to VELTIN Gel, Clindamycin gel, Tretinoin gel, and vehicle gel. The median age of subjects was 17 years old 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.

The safety and efficacy of clindamycin-tretinoin gel was also evaluated in two additional 12-week, multi-centered, randomized, blinded, studies in patients 12 years and older. A total of 2219 subjects with mild-to-moderate acne vulgaris were treated once daily for 12 weeks. Of the 2219 subjects, 634 subjects were treated with clindamycin-tretinoin gel. These studies demonstrated consistent outcomes.

0 Clear Normal, clear skin with no evidence of acne vulgaris.
1 Almost Clear Skin almost clear; rare non-inflammatory lesions present, with rare non-inflamed papules (papules must be resolving and may be hyperpigmented, though not pink-red) requiring no further treatment in the Investigator’s opinion.
2 Mild Some non-inflammatory lesions are present, with few inflammatory lesions (papules/pustules only, no nodulo-cystic lesions).
3 Moderate Non-inflammatory lesions predominate, with multiple inflammatory lesions evident; several to many comedones and papules/pustules, and there may or may not be 1 small nodulo-cystic lesion.
4 Severe Inflammatory lesions are more apparent; many comedones and papules/pustules, there may or may not be a few nodulo-cystic lesions.
5 Very Severe Highly inflammatory lesions predominate; variable numbers of comedones, many papules/pustules and nodulo-cystic lesions.
Table 3: Efficacy Results at Week 12
Study 1 VELTIN Gel
N=476
Clindamycin Gel
N=467
Tretinoin Gel
N=464
Vehicle Gel
N=242
Investigator’s Global Assessment
Percentage of subjects achieving Two Grade Improvement 36.3% 26.6% 26.1% 20.2%
Percentage of subjects achieving an IGA of 0 or 1 with a Two Grade Improvement 33.2% 24.0% 22.6% 17.8%
Inflammatory Lesions:
Mean absolute reduction 15.5 14.5 13.9 11.1
Mean percentage (%) reduction 60.4% 56.5% 54.5% 43.3%
Non-inflammatory Lesions:
Mean absolute reduction 23.2 19.5 22.1 17.0
Mean percentage (%) reduction 51.0% 42.9% 47.3% 36.0%
Total Lesions:
Mean absolute reduction 38.7 34.0 36.0 28.1
Mean percentage (%) reduction 55.0% 49.0% 50.5% 39.1%

How Supplied

VELTIN Gel is supplied as follows:

30 g aluminum tubes NDC 0145-0071-30

60 g aluminum tubes NDC 0145-0071-60

Storage and Handling

[See FDA-approved Patient Labeling].

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

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.

VEL:PI2

PATIENT INFORMATION

VELTIN (vel-tin)

(clindamycin phosphate and tretinoin) Gel

_________________________________________________________________________

IMPORTANT: For use on skin only (topical use). Do not get VELTIN Gel in your mouth, eyes, or vagina.

_________________________________________________________________________

Read the Patient Information that comes with VELTIN 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 medical condition or your treatment.

What is VELTIN Gel?

VELTIN Gel is prescription medicine used on the skin to treat acne in people 12 years and older.

It is not known if VELTIN Gel is safe and effective in children under 12 years of age.

Who should not use VELTIN Gel?

Do not use VELTIN Gel if you have:

Talk to your doctor if you are not sure if you have one of these conditions.

What should I tell my doctor before using VELTIN Gel?

Before using VELTIN Gel, tell your doctor if you:

Tell your doctor about all the medicines and skin products you use. Especially tell your doctor if you take medicine that contains erythromycin. VELTIN Gel should not be used with products that contain erythromycin.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I use VELTIN Gel?

Instructions for applying VELTIN Gel:

What should I avoid while using VELTIN Gel?

What are the possible side effects of VELTIN Gel?

VELTIN Gel may cause serious side effects, including:

Common side effects of VELTIN Gel include:

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 VELTIN Gel. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store VELTIN Gel?

General information about VELTIN Gel

Medicines are sometimes prescribed for purposes other than those listed in the patient information leaflet. Do not use VELTIN Gel for a condition for which it was not prescribed. Do not give VELTIN Gel to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about VELTIN Gel. If you would like more information, talk with your doctor. You can also ask your pharmacist or doctor for information about VELTIN Gel that is written for healthcare professionals. For more information call 1-888-784-3335.

What are the ingredients in VELTIN Gel?

Active Ingredients: clindamycin phosphate and tretinoin

Inactive Ingredients: butylated hydroxytoluene, carbomer 940, anhydrous citric acid, edetate disodium, methylparaben, laureth 4, propylene glycol, tromethamine, and purified water.

Manufactured for:

Stiefel Laboratories, Inc.

Research Triangle Park, NC 27709

Manufactured by:

DPT Laboratories, Ltd.

307 E. Josephine Street

San Antonio, TX 78215

Issued July 2010

VEL:PIL1

STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.

VELTIN is a trademark of Astellas Pharma Europe B.V.

©2010 Stiefel Laboratories, Inc.

Principal Display Panel

NDC 0145-0071-30

VELTIN

(clindamycin phosphate and tretinoin) Gel

1.2%/0.025%

30 grams

Rx only

For topical use only

Usual Dosage: See package insert for full prescribing information.

Use for ages 12 and older. Avoid the eyes, lips, and mucous membranes.

Keep out of reach of children. Keep away from light and heat. Keep tube tightly closed.

Description: Each gram of VELTIN Gel contains 12 mg (1.2%) clindamycin phosphate and 0.25mg (0.025%) tretinoin solubilized in a gel consisting of butylated hydroxytoluene, carbomer 940, anhydrous citric acid, edetate disodium, methylparaben, laureth 4, propylene glycol, tromethanime, and purified water.

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

Protect from freezing.

See tube crimp for lot number ad expiration date.

Manufactured for:

Stiefel Laboratories, Inc.

Research Triangle Park, NC 27709

For additional information: visit www.veltingel.com

Questions?: call 1-888-500-DERM (3376). Side effects associated with the use of this product may be reported to this number.

STIEFEL and STIEFEL & Design are registered trademarks of Stiefel Laboratories, Inc.

VELTIN is a trademark of Astellas Pharma Europe B.V.

©2010 Stiefel Laboratories, Inc.

304004 P/N: 111576 FG: 304003

Manufacturer

Stiefel Laboratories Inc

Active Ingredients

Source

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