Clindacin ETZ (Clindamycin phosphate) Package Insert

1 INDICATIONS AND USAGE

Clindacin^® (clindamycin phosphate) Foam, 1% is indicated for topical application in the treatment of acne vulgaris in patients 12 years and older.

2 DOSAGE AND ADMINISTRATION

Clindacin Foam is for topical use only, and not for oral, ophthalmic or intravaginal use.

Apply Clindacin Foam once daily to affected areas after the skin is washed with mild soap and allowed to fully dry. Use enough to cover the entire affected area.

If there has been no improvement after 6 to 8 weeks or if the condition becomes worse, treatment should be discontinued.

The contents of Clindacin Foam are flammable; avoid fire, flame and/or smoking during and immediately following application.

3 DOSAGE FORMS AND STRENGTHS

Clindacin Foam is a white to off-white thermolabile foam. Clindacin Foam contains 10 mg of clindamycin as clindamycin phosphate, USP per gram.

4 CONTRAINDICATIONS

Clindacin Foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis (including pseudomembranous colitis).

5 WARNINGS AND PRECAUTIONS

5.1 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. If significant diarrhea occurs, Clindacin Foam should be discontinued [see Adverse Reactions (6.2)].

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 Irritation

Clindacin Foam can cause irritation. Concomitant topical acne therapy should be used with caution since a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. If irritation or dermatitis occurs, clindamycin should be discontinued.

Avoid contact of Clindacin Foam with eyes, mouth, lips, other mucous membranes or areas of broken skin. If contact occurs, rinse thoroughly with water.

Clindacin Foam should be prescribed with caution in atopic individuals.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

A total of 439 subjects with mild to moderate acne vulgaris were treated once daily for 12 weeks with clindamycin phosphate foam.

The incidence of adverse reactions occurring in ≥1% of the subjects in clinical trials comparing clindamycin phosphate foam and its vehicle is presented in Table 1.

Table 1: Adverse Reactions Occurring in ≥ 1% of Subjects

In a contact sensitization study, none of the 203 subjects developed evidence of allergic contact sensitization to clindamycin phosphate foam.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of clindamycin phosphate foam: application site pain, application site erythema, diarrhea, urticaria, abdominal pain, hypersensitivity, rash, abdominal discomfort, nausea, seborrhea, application site rash, dizziness, pain of skin, colitis (including pseudomembranous colitis), and hemorrhagic diarrhea. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Abdominal pain and gastrointestinal disturbances, as well as gram-negative folliculitis, have also been reported in association with the use of topical formulations of clindamycin. Orally and parenterally administered clindamycin have been associated with severe colitis, which may end fatally.

7 DRUG INTERACTIONS

7.1 Erythromycin

Clindamycin phosphate foam should not be used in combination with topical or oral erythromycin-containing products due to possible antagonism 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.

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 foam should be used with caution in patients receiving such agents.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on clindamycin phosphate foam use in pregnant women to inform a drug-associated risk for adverse developmental outcomes.

Animal reproduction studies have not been conducted with clindamycin phosphate foam. No evidence of fetal harm or malformations was observed in pregnant rats and mice administered daily subcutaneous or oral doses of clindamycin salts during organogenesis at doses that produced exposures up to 84 and 42 times, respectively, the maximum recommended human dose (MRHD) of clindamycin phosphate foam based on body surface area (BSA) comparisons and assuming 100% absorption [see Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Reproduction studies have been conducted in rats and mice using subcutaneous or oral doses of clindamycin phosphate, clindamycin hydrochloride or clindamycin palmitate hydrochloride administered daily during organogenesis at doses up to the equivalent of 432 mg/kg/day clindamycin phosphate. These studies produced no evidence of fetal harm or malformations in rats or mice at exposures 84 or 42 times, respectively, the MRHD of clindamycin phosphate (i.e., 5 milliliters of clindamycin phosphate foam) based on BSA comparison and assuming 100% absorption.

8.2 Lactation

Risk Summary

There is no information on the presence of clindamycin in human milk, or the effects on the breast-fed child, or the effects on milk production following use of clindamycin phosphate foam. However, orally and parenterally administered clindamycin has been reported to appear in breast milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin phosphate foam and any potential adverse effects on the breast-fed child from clindamycin phosphate foam or from the underlying maternal condition.

Clinical Considerations

If used during lactation and clindamycin phosphate foam is applied to the chest, care should be taken to avoid accidental ingestion by the infant.

8.4 Pediatric Use

Safety and effectiveness of clindamycin phosphate foam in children under the age of 12 have not been studied.

8.5 Geriatric Use

The clinical study with clindamycin phosphate foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

11 DESCRIPTION

Clindacin Foam contains clindamycin (1%) as clindamycin phosphate.

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: C₁₈H₃₄CIN₂O₈PS Molecular Weight: 504.97 g/mol

Clindacin Foam contains clindamycin (1%) as clindamycin phosphate, USP at a concentration equivalent to 10 mg clindamycin per gram in a thermolabile hydroethanolic foam vehicle consisting of cetyl alcohol, ethanol (58%), polysorbate 60, propylene glycol, purified water, and stearyl alcohol pressurized with a hydrocarbon (propane/butane) propellant.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mechanism of action of clindamycin in acne vulgaris is unknown [see Microbiology (12.4)].

12.2 Pharmacodynamics

Pharmacodynamics of clindamycin phosphate foam is unknown.

12.3 Pharmacokinetics

In an open label, parallel group study in 24 subjects with acne vulgaris, 12 subjects (3 male and 9 female) applied 4 grams of clindamycin phosphate foam once-daily for five days, and 12 subjects (7 male and 5 female) applied 4 grams of a clindamycin gel, 1%, once daily for five days. On Day 5, the mean C_max and AUC_(0-12) were 23% and 9% lower, respectively, for clindamycin phosphate foam than for the clindamycin gel, 1%.

Following multiple applications of clindamycin phosphate foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

12.4 Microbiology

No microbiology studies were conducted in the clinical trials with this product.

Clindamycin binds to the 50S ribosomal subunits 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 foam. 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

The carcinogenicity of a 1.2% clindamycin phosphate gel similar to clindamycin phosphate foam was evaluated by daily topical administration to mice for two years. The topical doses used in this study were approximately 3 and 15 times higher than the MRHD of clindamycin phosphate from clindamycin phosphate foam, based on BSA comparison and assuming 100% absorption. No significant increase in tumors was noted in the treated animals.

The genotoxic potential of clindamycin was evaluated in an in vitro Ames assay and in an in vivo rat micronucleus test. Both tests were negative.

Reproduction studies in rats using oral doses of clindamycin hydrochloride and clindamycin palmitate hydrochloride have revealed no evidence of impaired fertility.

14 CLINICAL STUDIES

In one multicenter, randomized, double-blind, vehicle-controlled clinical trial, subjects with mild to moderate acne vulgaris used clindamycin phosphate foam or the vehicle foam once daily for twelve weeks. Treatment response, defined as the proportion of subjects clear or almost clear, based on the Investigator Static Global Assessment (ISGA), and the mean percent reductions in lesion counts at the end of treatment in this study are shown in Table 2.

Table 2: Efficacy Results at Week 12

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Clindacin^® (clindamycin phosphate) Foam, 1% contains 10 mg of clindamycin as clindamycin phosphate, USP per gram. The white to off-white thermolabile foam is available as follows:

• 100 gram aerosol can - NDC 43538-179-10

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Flammable. Avoid fire, flame or smoking during and immediately following application.

Contents under pressure. Do not puncture or incinerate. Do not expose to heat or store at temperature above 120°F (49°C).

Keep out of reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved patient labeling (Patient Information).

17.1 Instructions for Use

• Patients should be advised to wash their skin with mild soap and allow it to dry before applying Clindacin Foam.
• Patients should use enough Clindacin Foam to cover the face and to apply once daily.
• Patients should dispense Clindacin Foam directly into the cap or onto a cool surface.
• Patients should wash their hands after applying Clindacin Foam.

17.2 Skin Irritation

Clindacin Foam may cause irritation such as erythema, scaling, itching, burning, or stinging.

Patients should be advised to discontinue use if excessive irritancy or dermatitis occur.

17.3 Colitis

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

Manufactured for:

MEDIMETRIKS

PHARMACEUTICALS, INC.

383 Route 46 West • Fairfield, NJ 07004-2402 US • www.medimetriks.com

Manufactured by Padagis, Yeruham, Israel

Iss: 4/22

IP053

4T500 EK J1