Clindamycin/Benzoyl Peroxide Mylan

Antibacterial. Serious infections caused by susceptible Gram-positive organisms, staphylococci (both penicillinase- and non-penicillinase-producing), streptococci (except Streptococcus faecalis) and pneumococci. It is also indicated in serious infections caused by susceptible anaerobic pathogens such as Bacteroides spp, Fusobacterium spp, Propionibacterium spp, Peptostreptococcus spp. and microaerophilic streptococci.

Clindamycin does not penetrate the blood/brain barrier in therapeutically effective quantities.

Clindamycin is indicated for the treatment of severe infections. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Clindamycin does not penetrate the blood/brain barrier in therapeutically effective quantities.

Clindamycin/Benzoyl Peroxide Mylan Topical Solution, Clindamycin/Benzoyl Peroxide Mylan Topical Gel and Clindamycin/Benzoyl Peroxide Mylan Topical Lotion are indicated in the treatment of acne vulgaris. In view of the potential for diarrhea, bloody diarrhea and pseudomembranous colitis, the physician should consider whether other agents are more appropriate (see CONTRAINDICATIONS, WARNINGS and ADVERSE REACTIONS).

Dalacin T Topical is indicated for the treatment of acne vulgaris.

Clindamycin/Benzoyl Peroxide Mylan Topical is indicated for the treatment of acne vulgaris.

Clindamycin/Benzoyl Peroxide Mylan Foam is indicated for topical application in the treatment of acne vulgaris in patients 12 years and older.

Treatment of Bacterial Vaginosis

Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) is indicated for the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in non-pregnant women.

Clindamycin/Benzoyl Peroxide Mylan^® (clindamycin phosphate pledget) is indicated in the treatment of moderate acne vulgaris.

Parenteral (IM or IV administration). Clindamycin/Benzoyl Peroxide Mylan C Phosphate must be diluted prior to IV administration and should be infused over at least 10-60 minutes.

Adults: Serious infections: 600 mg - 1.2 g/day in two, three or four equal doses.

More severe infections: l.2-2.7 g/day in two, three or four equal doses.

Single IM injections of greater than 600 mg are not recommended nor is administration of more than 1.2 g in a single one-hour infusion.

For more serious infections, these doses may have to be increased. In life-threatening situations, doses as high as 4.8 g daily have been given intravenously to adults.

Alternatively, the drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion.

Children (over 1 month of age): Serious infections: 15-25 mg/kg/day in three or four equal doses.

More severe infections: 25-40 mg/kg/day in three or four equal doses. In severe infections it is recommended that children be given no less than 300 mg/day regardless of body weight.

Elderly patients: The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin phosphate are not altered by increased age. Analysis of data from clinical studies has not revealed any age-related increase in toxicity. Dosage requirements in elderly patients should not be influenced, therefore, by age alone.

Dosage in Renal/Hepatic Impairment: clindamycin dosage modification is not necessary in patients with renal or hepatic insufficiency.

Treatment for infections caused by beta-haemolytic streptococci should be continued for at least 10 days to guard against subsequent rheumatic fever or glomerulonephritis.

The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL and INFUSION RATES SHOULD NOT EXCEED 30 MG PER MINUTE. The usual infusion rates are as follows:

Parenteral (IM or IV administration). Clindamycin 150mg/ml Solution for Injection and Infusion must be diluted prior to I.V. administration and should be infused over at least 10-60 minutes.

Adults: Serious infections: 600mg-1.2g/day in two, three or four equal doses.

More severe infections: 1.2-2.7g/day in two, three or four equal doses.

Single I.M. injections of greater than 600mg are not recommended nor is administration of more than 1.2g in a single one-hour infusion.

For more serious infections, these doses may have to be increased. In life-threatening situations, doses as high as 4.8g daily have been given intravenously to adults.

Alternatively, the drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion.

Children (over 1 month of age): Serious infections: 15-25mg/kg/day in three or four equal doses.

More severe infections: 25-40mg/kg/day in three or four equal doses. In severe infections it is recommended that children be given no less than 300mg/day regardless of body weight.

Elderly patients: The half-life, volume of distribution and clearance, and extent of absorption after administration of clindamycin phosphate are not altered by increased age. Analysis of data from clinical studies has not revealed any age-related increase in toxicity. Dosage requirements in elderly patients should not be influenced, therefore, by age alone.

Dosage in renal/hepatic impairment: clindamycin dosage modification is not necessary in patients with renal or hepatic insufficiency

Treatment for infections caused by beta-haemolytic streptococci should be continued for at least 10 days to guard against subsequent rheumatic fever or glomerulonephritis.

The concentration of clindamycin in diluent for infusion should not exceed 18mg per ml and INFUSION RATES SHOULD NOT EXCEED 30MG PER MINUTE. The usual infusion rates are as follows:

Apply a thin film of Clindamycin/Benzoyl Peroxide Mylan Topical Solution, Clindamycin/Benzoyl Peroxide Mylan Topical Lotion, Clindamycin/Benzoyl Peroxide Mylan Topical Gel, or use a Clindamycin/Benzoyl Peroxide Mylan Topical Solution pledget for the application of Clindamycin/Benzoyl Peroxide Mylan twice daily to affected area. More than one pledget may be used. Each pledget should be used only once and then be discarded.

Lotion: Shake well immediately before using.

Pledget: Remove pledget from foil just before use. Do not use if the seal is broken. Discard after single use.

Keep all liquid dosage forms in containers tightly closed.

Apply a thin film of Dalacin T Topical Lotion twice daily to the affected area.

Shake well before use.

Apply a thin film of Clindamycin/Benzoyl Peroxide Mylan Topical Lotion twice daily to the affected area.

Shake well before use.

Clindamycin/Benzoyl Peroxide Mylan Foam is for topical use only, and not for oral, ophthalmic, or intravaginal use.

Apply Clindamycin/Benzoyl Peroxide Mylan 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 Clindamycin/Benzoyl Peroxide Mylan Foam are flammable; avoid fire, flame and/or smoking during and immediately following application.

The recommended dose is the complete contents of a single pre-filled applicator containing 5 g of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) cream administered once intravaginally at any time of the day.

Not for ophthalmic, dermal, or oral use.

Clindamycin/Benzoyl Peroxide Mylan^® (clindamycin phosphate pledget) should be applied to areas affected by acne twice daily, in the morning and at night. The area to be treated should be washed first with a mild soap or cleanser, rinsed well and patted dry. A thin film of medication should be applied avoiding the eyes and mouth. Each pledget should be removed from the foil immediately before use, used only once and then discarded.

Hands should be washed after application. Clindamycin/Benzoyl Peroxide Mylan^® is not for oral, ophthalmic, or intravaginal use. Six to eight weeks of treatment may be required before a therapeutic effect is observed. Treatment should be discontinued if there has been no improvement or if the condition becomes worse.

Due to increased risk of antimicrobial resistance, the benefit of continuing treatment beyond 12 weeks should be evaluated.

Elderly

There are no specific recommendations for use in the elderly.

Renal Impairment

No dosage adjustment is necessary. As percutaneous absorption is low following topical application, renal impairment is not expected to result in systemic exposure of clinical significance.

Hepatic Impairment

No dosage adjustment is necessary. As percutaneous absorption is low following topical application, hepatic impairment is not expected to result in systemic exposure of clinical significance.

Clindamycin/Benzoyl Peroxide Mylan C Phosphate is contra-indicated in patients previously found to be sensitive to clindamycin, lincomycin or to any component of the formulation particularly benzyl alcohol.

Clindamycin 150mg/ml Solution for Injection and Infusion is contra-indicated in patients previously found to be sensitive to clindamycin, lincomycin or to any of the excipients.

Clindamycin/Benzoyl Peroxide Mylan Topical Solution, Clindamycin/Benzoyl Peroxide Mylan Topical Gel and Clindamycin/Benzoyl Peroxide Mylan Topical Lotion are contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis.

Clindamycin topical is contraindicated in individuals with a history of inflammatory bowel disease or a history of antibiotic-associated colitis.

Clindamycin topical is contraindicated in individuals with a history of inflammatory bowel disease or a history of antibiotic-associated colitis.

Clindamycin/Benzoyl Peroxide Mylan Foam is contraindicated in individuals with a history of regional enteritis or ulcerative colitis, or a history of antibiotic-associated colitis (including pseudomembranous colitis).

Hypersensitivity

Do not administer Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) to individuals with a history of hypersensitivity to clindamycin or other lincosamides. Reported reactions to other formulations of clindamycin include rashes, urticaria, erythema multiforme, and anaphylactoid reactions.

History of Bowel Disease

Do not administer Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) to patients with regional enteritis, ulcerative colitis, or a history of Clostridium difficile-associated diarrhea.

Clindamycin/Benzoyl Peroxide Mylan^® (clindamycin phosphate pledget) is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin, or any other component of the preparation. Clindamycin/Benzoyl Peroxide Mylan^® is also contraindicated in patients with or with a history of regional enteritis or ulcerative colitis, or a history of antibioticassociated colitis (including pseudomembranous colitis).

Warnings

This product contains benzyl alcohol. (9.45mg/ml as preservative). Intravenous administration of the preservative benzyl alcohol has been associated with serious adverse events, and death in paediatric patients including neonates characterized by central nervous system depression, metabolic acidosis, gasping respirations, cardio-vascular failure and haematological anomalies (“gasping syndrome”). Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. Use only if it is necessary and if there are no alternatives possible. If given in high volumes, should be used with caution and preferably for short term treatment in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis) due to benzoic acid (a metabolite of benzyl alcohol).

Premature and low-birth weight infants may be more likely to develop toxicity.

Benzyl Alcohol containing products should not be used in pre-term or full-term neonates unless strictly necessary.

Benzyl alcohol can cross the placenta and clindamycin should only be used during pregnancy if clearly needed.

Clindamycin/Benzoyl Peroxide Mylan C Phosphate should only be used in the treatment of serious infections. In considering the use of the product, the practitioner should bear in mind the type of infection and the potential hazard of the diarrhoea which may develop, since cases of colitis have been reported during, or even two or three weeks following, the administration of clindamycin.

Studies indicate a toxin(s) produced by clostridia (especially Clostridium difficile) is the principal direct cause of antibiotic-associated colitis. These studies also indicate that this toxigenic clostridium is usually sensitive in vitro to vancomycin. When 125 mg to 500 mg of vancomycin are administered orally four times a day for 7 - 10 days, there is a rapid observed disappearance of the toxin from faecal samples and a coincident clinical recovery from the diarrhoea. (Where the patient is receiving colestyramine in addition to vancomycin, consideration should be given to separating the times of administration).

Colitis is a disease, which has a clinical spectrum from mild, watery diarrhoea to severe, persistent diarrhoea, leucocytosis, fever, severe abdominal cramps, which may be associated with the passage of blood and mucus. If allowed to progress, it may produce peritonitis, shock and toxic megacolon. This may be fatal. The appearance of marked diarrhoea should be regarded as an indication that the product should be discontinued immediately. The disease is likely to follow a more severe course in older patients or patients who are debilitated. Diagnosis is usually made by the recognition of the clinical symptoms, but can be substantiated by endoscopic demonstration of pseudomembranous colitis. The presence of the disease may be further confirmed by culture of the stool for C. difficile on selective media and assay of the stool specimen for the toxin(s) of C. difficile.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Precautions

Caution should be used when prescribing Clindamycin/Benzoyl Peroxide Mylan C Phosphate to individuals with a history of gastro-intestinal disease, especially colitis.

Periodic liver and kidney function tests should be carried out during prolonged therapy. Such monitoring is also recommended in neonates and infants. Safety and appropriate dosage in infants less than one month old have not been established.

Prolonged administration of Clindamycin/Benzoyl Peroxide Mylan C Phosphate, as with any anti-infective, may result in super-infection due to organisms resistant to clindamycin.

Care should be observed in the use of Clindamycin/Benzoyl Peroxide Mylan C Phosphate in atopic individuals.

Warnings

Clindamycin 150mg/ml Solution for Injection and Infusion should only be used in the treatment of serious infections. In considering the use of the product, the practitioner should bear in mind the type of infection and the potential hazard of the diarrhoea which may develop, since cases of colitis have been reported during, or even two or three weeks following, the administration of clindamycin.

Studies indicate a toxin(s) produced by clostridia (especially Clostridium difficile) is the principal direct cause of antibiotic-associated colitis. These studies also indicate that this toxigenic clostridium is usually sensitive in vitro to vancomycin. When 125mg to 500mg of vancomycin are administered orally four times a day for 7-10 days, there is a rapid observed disappearance of the toxin from faecal samples and a coincident clinical recovery from the diarrhoea (where the patient is receiving cholestyramine in addition to vancomycin, consideration should be given to separating the times of administration).

Colitis is a disease which has a clinical spectrum from mild, watery diarrhoea to severe, persistent diarrhoea, leucocytosis, fever, severe abdominal cramps, which may be associated with the passage of blood and mucus. If allowed to progress, it may produce peritonitis, shock and toxic megacolon. This may be fatal. The appearance of marked diarrhoea should be regarded as an indication that the product should be discontinued immediately. The disease is likely to follow a more severe course in older patients or patients who are debilitated. Diagnosis is usually made by the recognition of the clinical symptoms, but can be substantiated by endoscopic demonstration of pseudomembranous colitis. The presence of the disease may be further confirmed by culture of the stool for C. difficile on selective media and assay of the stool specimen for the toxin(s) of C. difficile.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Precautions

Caution should be used when prescribing Clindamycin 150mg/ml Solution for Injection and Infusion to individuals with a history of gastro-intestinal disease, especially colitis.

Periodic liver and kidney function and haematology tests should be carried out during prolonged therapy. Such monitoring is also recommended in neonates and infants. Safety and appropriate dosage in infants less than one month old have not been established.

Prolonged administration of Clindamycin 150mg/ml Solution for Injection and Infusion, as with any anti-infective, may result in super-infection due to organisms resistant to clindamycin. The use of Clindamycin 150mg/ml Solution for Injection and Infusion may result in the overgrowth of non-susceptible organisms particularly yeasts.

Care should be observed in the use of Clindamycin 150mg/ml Solution for Injection and Infusion in atopic individuals, particularly those with asthma.

Since Clindamycin 150mg/ml Solution for Injection and Infusion does not diffuse adequately into cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

Antibiotics can reduce the efficacy of the combined oral contraceptive pill. Additional contraceptive precautions should be taken during treatment and for up to seven days after stopping treatment.

This medicinal product contains 0.286mMol (or 6.57mg) sodium per ml of solution (prior to dilution). To be taken into consideration by patients on a controlled sodium diet.

WARNINGS

Orally and parenterally administered clindamycin has been associated with severe colitis which may result in patient death. Use of the topical formulation of clindamycin results in absorption of the antibiotic from the skin surface. Diarrhea, bloody diarrhea, and colitis (including pseudomembranous colitis) have been reported with the use of topical and systemic clindamycin.

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. Endoscopic examination may reveal pseudomembranous colitis. Stool culture for Clostridium difficile and stool assay for C. difficile toxin may be helpful diagnostically.

When significant diarrhea occurs, the drug should be discontinued. Large bowel endoscopy should be considered to establish a definitive diagnosis in cases of severe diarrhea.

Antiperistaltic agents such as opiates and diphenoxylate with atropine may prolong and/or worsen the condition. Vancomycin has been found to be effective in the treatment of antibiotic-associated pseudomembranous colitis produced by Clostridium difficile. The usual adult dosage is 500 milligrams to 2 grams of vancomycin orally per day in three to four divided doses administered for 7 to 10 days. Cholestyramine or colestipol resins bind vancomycin in vitro. If both a resin and vancomycin are to be administered concurrently, it may be advisable to separate the time of administration of each drug.

Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

PRECAUTIONS

General

Clindamycin/Benzoyl Peroxide Mylan Topical Solution contains an alcohol base which will cause burning and irritation of the eye. In the event of accidental contact with sensitive surfaces (eye, abraded skin, mucous membranes), bathe with copious amounts of cool tap water. The solution has an unpleasant taste and caution should be exercised when applying medication around the mouth.

Clindamycin/Benzoyl Peroxide Mylan should be prescribed with caution in atopic individuals.

Pregnancy

Teratogenic Effects

In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters has not been associated with an increased frequency of congenital abnormalities. There are no adequate studies in pregnant women during the first trimester of pregnancy. Clindamycin should be used during the first trimester of pregnancy only if clearly needed.

Nursing Mothers

It is not known whether clindamycin is excreted in human milk following use of Clindamycin/Benzoyl Peroxide Mylan. However, orally and parenterally administered clindamycin has been reported to appear in breast milk. Clindamycin has the potential to cause adverse effects on the breastfed infant's gastrointestinal flora. If oral or intravenous clindamycin is required by a nursing mother, it is not a reason to discontinue breastfeeding, but an alternate drug may be preferred. Monitor the infant for possible adverse effects on the gastrointestinal flora, such as diarrhea, candidiasis (thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis.

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

Pediatric Use

Safety and effectiveness in pediatric patients under the age of 12 have not been established.

Geriatric Use

Clinical studies for Clindamycin/Benzoyl Peroxide Mylan did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Oral and parenteral clindamycin, as well as most other antibiotics, have been associated with severe pseudomembranous colitis. However, post-marketing studies have indicated a very low incidence of colitis with Dalacin T Lotion. The physician should, nonetheless, be alert to the development of antibiotic-associated diarrhoea or colitis. If diarrhoea occurs, the product should be discontinued immediately.

Diarrhoea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

Studies indicate a toxin(s) produced by Clostridium difficile is the major cause of antibiotic-associated colitis. Colitis is usually characterized by persistent, severe diarrhoea and abdominal cramps.

Endoscopic examination may reveal pseudomembranous colitis. Stool culture for C. difficile and/or assay for C. difficile toxin may be helpful to diagnosis.

Vancomycin is effective in the treatment of antibiotic-associated colitis produced by C. difficile. The usual dose is 125 - 500 mg orally every 6 hours for 7 - 10 days. Additional supportive medical care may be necessary.

Mild cases of colitis may respond to discontinuance of clindamycin alone. Colestyramine and colestipol resins have been shown to bind C. difficile toxin in vitro, and cholestyramine has been effective in the treatment of some mild cases of antibiotic-associated colitis. Colestyramine resins have been shown to bind vancomycin; therefore, when both colestyramine and vancomycin are used concurrently, their administration should be separated by at least two hours.

The lotion has an unpleasant taste and caution should be exercised when applying medication around the mouth.

Topical clindamycin should be prescribed with caution to atopic individuals.

Oral and parenteral clindamycin, as well as most other antibiotics, have been associated with severe pseudomembranous colitis. However, post-marketing studies have indicated a very low incidence of colitis with Clindamycin/Benzoyl Peroxide Mylan Lotion. The physician should, nonetheless, be alert to the development of antibiotic-associated diarrhoea or colitis. If diarrhoea occurs, the product should be discontinued immediately.

Diarrhoea, colitis, and pseudomembranous colitis have been observed to begin up to several weeks following cessation of oral and parenteral therapy with clindamycin.

Studies indicate a toxin(s) produced by Clostridium difficile is the major cause of antibiotic-associated colitis. Colitis is usually characterized by persistent, severe diarrhoea and abdominal cramps.

Endoscopic examination may reveal pseudomembranous colitis. Stool culture for C. difficile and/or assay for C. difficile toxin may be helpful to diagnosis.

Vancomycin is effective in the treatment of antibiotic-associated colitis produced by C. difficile. The usual dose is 125 - 500 mg orally every 6 hours for 7 - 10 days. Additional supportive medical care may be necessary.

Mild cases of colitis may respond to discontinuance of clindamycin alone. Colestyramine and colestipol resins have been shown to bind C. difficile toxin in vitro, and cholestyramine has been effective in the treatment of some mild cases of antibiotic-associated colitis. Colestyramine resins have been shown to bind vancomycin; therefore, when both colestyramine and vancomycin are used concurrently, their administration should be separated by at least two hours.

The lotion has an unpleasant taste and caution should be exercised when applying medication around the mouth.

Topical clindamycin should be prescribed with caution to atopic individuals.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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, Clindamycin/Benzoyl Peroxide Mylan Foam 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.

Irritation

Clindamycin/Benzoyl Peroxide Mylan 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 Clindamycin/Benzoyl Peroxide Mylan Foam with eyes, mouth, lips, other mucous membranes or areas of broken skin. If contact occurs, rinse thoroughly with water.

Clindamycin/Benzoyl Peroxide Mylan Foam should be prescribed with caution in atopic individuals.

Patient Counseling Information

See FDA-Approved patient labeling (PATIENT INFORMATION).

Instructions for Use

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

Skin Irritation

Clindamycin/Benzoyl Peroxide Mylan 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.

Colitis

In the event a patient treated with Clindamycin/Benzoyl Peroxide Mylan Foam experiences severe diarrhea or gastrointestinal discomfort, Clindamycin/Benzoyl Peroxide Mylan Foam should be discontinued and a physician should be contacted.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenicity of a 1.2% clindamycin phosphate gel similar to Clindamycin/Benzoyl Peroxide Mylan Foam was evaluated by daily application to mice for two years. The daily doses used in this study were approximately 3 and 15 times higher than the human dose of clindamycin phosphate from 5 milliliters of Clindamycin/Benzoyl Peroxide Mylan Foam, assuming complete absorption and based on a body surface area comparison. No significant increase in tumors was noted in the treated animals.

A 1.2% clindamycin phosphate gel similar to Clindamycin/Benzoyl Peroxide Mylan Foam caused a statistically significant shortening of the median time to tumor onset in a study in hairless mice in which tumors were induced by exposure to simulated sunlight.

Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion 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.

Use In Specific Populations

Pregnancy

Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women treated with Clindamycin/Benzoyl Peroxide Mylan Foam. Clindamycin/Benzoyl Peroxide Mylan Foam should be used during pregnancy only if the potential benefit clearly outweighs the potential risk to the fetus.

Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin phosphate, clindamycin hydrochloride and clindamycin palmitate hydrochloride. These studies revealed no evidence of fetal harm. The highest dose used in the rat and mouse teratogenicity studies was equivalent to a clindamycin phosphate dose of 432 mg/kg. For a rat, this dose is 84 fold higher, and for a mouse 42 fold higher, than the anticipated human dose of clindamycin phosphate from Clindamycin/Benzoyl Peroxide Mylan Foam based on a mg/m² comparison.

Nursing Mothers

It is not known whether clindamycin is excreted in human milk following use of Clindamycin/Benzoyl Peroxide Mylan Foam. 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.

If used during lactation and Clindamycin/Benzoyl Peroxide Mylan Foam is applied to the chest, care should be taken to avoid accidental ingestion by the infant.

Pediatric Use

Safety and effectiveness of Clindamycin/Benzoyl Peroxide Mylan Foam in children under the age of 12 have not been studied.

Geriatric Use

The clinical study with Clindamycin/Benzoyl Peroxide Mylan Foam did not include sufficient numbers of subjects aged 65 and over to determine if they respond differently than younger subjects.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Clostridium difficile-Associated Diarrhea (CDAD)

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Use with Condoms and Vaginal Contraceptive Diaphragms

This cream contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, the use of such barrier contraceptives is not recommended concurrently or for 5 days following treatment with Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate). During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases.

Patient Counseling Information

Vaginal Intercourse and Use with Vaginal Products

Instruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) during treatment with this product.

Use with Condoms and Vaginal Contraceptive Diaphragms

Advise the patient that this cream contains mineral oil that may weaken latex or rubber products such as condoms or vaginal contraceptive diaphragms. Therefore, do not use barrier contraceptives concurrently or for 5 days following treatment with Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate). During this time period, condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases.

Fungal Vaginal Infections

Inform the patient that vaginal fungal infections can occur following use of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) and may require treatment with an antifungal drug.

Accidental Exposure to the Eye

Inform the patient that Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) contains ingredients which cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water and consult a physician.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (29 times the recommended human dose based on body surface area comparisons) revealed no effects on fertility or mating ability.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) in pregnant women.

Another intravaginal formulation containing 2% clindamycin phosphate has been studied in pregnant women during the second trimester. In women treated for seven days, abnormal labor was reported in 1.1% of patients who received that clindamycin vaginal cream formulation compared with 0.5% of patients who received placebo.

Reproduction studies have been performed in rats and mice using oral and parenteral doses of clindamycin up to 600 mg/kg/day (58 and 29 times, respectively, the recommended human dose based on body surface area comparisons) and have revealed no evidence of harm to the fetus due to clindamycin.

Because animal reproduction studies are not always predictive of human response, Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) should be used during pregnancy only if clearly needed.

Nursing Mothers

Caution should be exercised when Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) is administered to a nursing woman. It is not known if clindamycin is excreted in human milk following the use of vaginally administered clindamycin. Clindamycin has been detected in human milk after oral or parenteral administration.

Because of the potential for serious adverse reactions in nursing infants, a decision to continue or discontinue nursing should take into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) in the treatment of bacterial vaginosis in post-menarchal females have been established on the extrapolation of clinical trial data from adult women. The safety and efficacy of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) in pre-menarchal females have not been established.

Geriatric Use

Clinical studies with Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

WARNINGS

Skin

FOR EXTERNAL USE ONLY. NOT FOR OPHTHALMIC USE. Clindamycin/Benzoyl Peroxide Mylan^® (clindamycin phosphate pledget) is known to be a mild irritant in humans and animals. Avoid contact with eyes, mouth, lips, other mucous membranes, or areas of broken skin. In the event of sensitization or severe local irritation from Clindamycin/Benzoyl Peroxide Mylan ^®, usage should be discontinued immediately, the solution carefully washed off, and appropriate therapy initiated.

The solution contains isopropyl alcohol. In the event of accidental contact with sensitive surfaces (eyes, abraded skin, mucous membranes), wash with large amounts of cool tap water.

Gastrointestinal

Clostridium Difficile-Associated Disease (CDAD)

Use of topical formulation of clindamycin results in absorption of clindamycin from the skin surface. Clostridium difficile-associated disease (CDAD), including pseudomembranous colitis has been reported with the use of topical, oral and parenteral administration of clindamycin (see ADVERSE REACTIONS). CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic mega colon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases.

PRECAUTIONS

General

The use of preparations containing antibiotics such as clindamycin may be associated with overgrowth of antibiotic resistant microorganisms including those initially sensitive to the drug. The treatment of acne with topical antibiotics is associated with the development of antimicrobial resistance in Propionibacterium 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. If this occurs, therapy should be discontinued and alternative acne therapy should be initiated. Resistance to clindamycin is often associated with resistance to erythromycin. It is therefore advisable to avoid concurrent use of the two agents either by topical or oral treatment.

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 irritancy or dermatitis occurs, clindamycin should be discontinued.

Flammability

Due to the flammable nature of Clindamycin/Benzoyl Peroxide Mylan^®, patients should avoid smoking or being near an open flame during application and immediately after use.

Use In Pregnancy

The safety of Clindamycin/Benzoyl Peroxide Mylan^® during pregnancy has not been established. No adequate and well-controlled reproduction studies have been conducted with clindamycin in pregnant women. Systemic absorption of clindamycin following topical administration of clindamycin phosphate is less than 5%. Clindamycin readily crosses placental barrier. Animal reproduction studies have not been conducted with Clindamycin/Benzoyl Peroxide Mylan^® (clindamycin phosphate pledget) and it is not known whether Clindamycin/Benzoyl Peroxide Mylan^® can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Clindamycin/Benzoyl Peroxide Mylan^® should not be administered to a pregnant woman unless the potential benefits to the mother clearly outweigh the possible risks to the fetus.

Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin ranging from 100 to 600 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to clindamycin (see Toxicology). Conclusions from such animal studies may not always be predictive of the effects on human reproduction.

Use In Nursing Mothers

The safety of Clindamycin/Benzoyl Peroxide Mylan^® in nursing women has not been established. No adequate and well-controlled data in nursing women treated with clindamycin 1% (clindamycin as clindamycin phosphate) solution are available. It is not known if topically applied clindamycin is excreted in human milk following the topical use of Clindamycin/Benzoyl Peroxide Mylan^®. Orally and parenterally administered clindamycin is excreted 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 Clindamycin/Benzoyl Peroxide Mylan^® therapy to the mother. If used during lactation, clindamycin should not be applied to the breast area to avoid accidental ingestion by the infant.

Pediatric Use

Safety and effectiveness in the pediatric population under the age of 13 have not been established.

Blood and Lymphatic System Disorders: Transient neutropenia (leucopenia), eosinophilia, agranulocytosis and thrombocytopenia have been reported. No direct aetiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing.

Immune System Disorders: A few cases of anaphylactoid reactions have been reported.

Skin and Subcutaneous Tissue Disorders: Maculopapular rash and urticaria have been observed during drug therapy. Generalised mild to moderate morbilliform-like skin rashes are the most frequently reported reactions. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. Pruritus, vaginitis and rare instances of exfoliative and vesiculobullous dermatitis have been reported. Serious cutaneous adverse reaction (SCAR) and rare cases of toxic epidermal necrolysis have been reported during postmarketing surveillance.

Hepatobiliary disorders: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.

Nervous System Disorders: Frequent cases of Dysgeusia have been observed upon systemic administration of clindamycin using injectables (IM or IV), capsules, or oral granulate solutions, which include a few (non-frequent) serious adverse events.

General Disorders and Administration Site Conditions: Local irritation, pain, abscess formation have been observed in conjunction with IM injection. These reactions can be minimized by deep IM injection and avoiding the use of an indwelling catheter.

Thrombophlebitis has been reported with IV injection.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Gastro-intestinal tract disorders: Oesophageal ulcers have been reported as serious adverse events during postmarketing surveillance, and oesophagitis with oral preparations, nausea, vomiting, abdominal pain and diarrhoea (See Section 4.4 Special Warnings and Precautions for use: Warnings).

Blood and lymphatic system disorders: Transient neutropenia (leucopenia), eosinophilia, agranulocytosis and thrombocytopenia have been reported.)

Nervous system disorders: Frequent cases of dysgeusia have been observed upon systemic administration of clindamycin using injectables (IM or IV), capsules or oral granulate solutions, which include a few (non-frequent) serious adverse events.

General disorders and administration site conditions: Local irritation, pain, abscess formation have been observed in conjunction with IM injection. These reactions can be minimised by deep IM injection and avoiding the use of an indwelling catheter.

Thrombophlebitis has been reported with IV injection.

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

In 18 clinical studies of various formulations of Clindamycin/Benzoyl Peroxide Mylan using placebo vehicle and/or active comparator drugs as controls, patients experienced a number of treatment emergent adverse dermatologic events.

Number of Patients Reporting Events

Orally and parenterally administered clindamycin has been associated with severe colitis which may end fatally.

Cases of diarrhea, bloody diarrhea and colitis (including pseudomembranous colitis) have been reported as adverse reactions in patients treated with oral and parenteral formulations of clindamycin and rarely with topical clindamycin (see WARNINGS).

Abdominal pain, gastrointestinal disturbances, gram-negative folliculitis, eye pain and contact dermatitis have also been reported in association with the use of topical formulations of clindamycin.

The table below lists the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency. The frequency grouping is defined using the following convention: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very Rare (<1/10,000) and Not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to Clindamycin/Benzoyl Peroxide Mylan Topical lotion based on clinical trial experience and post-marketing surveillance:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

The table below lists the adverse reactions identified through clinical trial experience and post-marketing surveillance by system organ class and frequency. The frequency grouping is defined using the following convention: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very Rare (<1/10,000) and Not known (frequency cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to Clindamycin Phosphate Topical lotion based on clinical trial experience and post-marketing surveillance:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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/Benzoyl Peroxide Mylan Foam.

The incidence of adverse reactions occurring in ≥1% of the subjects in clinical trials comparing Clindamycin/Benzoyl Peroxide Mylan 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/Benzoyl Peroxide Mylan Foam.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Clindamycin/Benzoyl Peroxide Mylan 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.

Clinical Study 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 practice.

The data described below reflect exposure to Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) in 368 patients. Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) was studied in three clinical studies: placebo-controlled (n=85), active-controlled (n=263), and single-arm (n=20). The population was female, aged 18 to 78, who were diagnosed with bacterial vaginosis. Patient demographics in the trials were 51% Caucasian, 36% Black, 10% Hispanic, and 3% Asian, other or unknown. All patients received 100 mg clindamycin phosphate cream intravaginally in a single dose.

Of the 368 women treated with a single dose of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) , 1.6% of the patients discontinued therapy due to adverse reactions. Adverse reactions occurred in 126 of 368 patients (34%) treated with Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) and in 32 of 85 patients (38%) treated with placebo.

Adverse reactions occurring in ≥ 1% of patients receiving Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) in the three clinical studies are shown in Table 1.

Table 1: Adverse Reactions Occurring in ≥ 1% of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) -Treated Patients and at a Higher Rate than Placebo-Treated Patients

Other reactions reported by < 1% of those women treated with Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) include:

Dermatologic: Pruritic rash

Gastrointestinal: Diarrhea, vomiting

General: Fatigue

Immune System: Hypersensitivity

Nervous System: Dizziness

Reproductive System: Dysfunctional uterine bleeding, dysmennorrhea, intermenstrual bleeding, pelvic pain, vaginal burning, vaginal irritation, vulvar erythema<, vulvitis, vulvovaginal discomfort, vulvovaginal dryness, vulvovaginitis

Other Clindamycin Formulations

Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) affords minimal peak serum levels and systemic exposure (AUCs) of clindamycin compared to an oral or intravenous dose of clindamycin. Data from well-controlled trials directly comparing clindamycin administered orally to clindamycin administered vaginally are not available.

The following additional adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of clindamycin:

Gastrointestinal: Abdominal pain, esophagitis, nausea, Clostridium difficile-associated diarrhea

Hematopoietic: Transient neutropenia (leukopenia), eosinophilia, agranulocytosis, and thrombocytopenia have been reported. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of these reports.

Hypersensitivity Reactions: Maculopapular rash, vesiculobullous rash, and urticaria have been observed during drug therapy. Generalized mild to moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions. Cases of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. A few cases of anaphylactoid reactions have been reported.

Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy.

Musculoskeletal: Cases of polyarthritis have been reported.

Renal: Although no direct relationship of clindamycin to renal damage has been established, renal dysfunction as evidenced by azotemia, oliguria, and/or proteinuria has been observed in rare instances.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate). 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.

Dermatologic: Rash

Gastrointestinal: Hematochezia

Reproductive System: Vaginal erythema, vulvovaginal pruritis, vaginal discharge, vaginal swelling, vaginal bleeding, vaginal pain

Clinical Trial Adverse Drug Reactions

The safety was assessed in 150 acne vulgaris patients from a placebo-controlled study in which Clindamycin/Benzoyl Peroxide Mylan^® or placebo (vehicle) pledgets were applied twice daily over a period of 11 weeks. The number of patients with worsening scores of erythema, peeling and burning is presented in Table 1.

Table 1: Patients with worsening signs or symptoms of acne in a Clindamycin/Benzoyl Peroxide Mylan^® Clinical Trial

Number of patients reporting common (≥1%) treatment emergent adverse reactions are provided in Table 2.

Table 2: Most common drug related adverse reactions reported by ≥1% of patients in a Clindamycin/Benzoyl Peroxide Mylan^® Clinical Trial

Additional Adverse Drug Reactions Reported In Other Clindamycin Phosphate Clinical Trials

The following additional common adverse drug reactions (≥ 1%) have been reported in clinical trials involving other clindamycin phosphate formulations:

Skin and subcutaneous disorders: pruritus, rash, stinging, dryness, oiliness, small red bumps (including gram negative folliculitis pustules).

Immune system disorders: urticaria, whealing, swollen lips.

Gastrointestinal disorders: abdominal cramping.

Post-Market Adverse Drug Reactions

Immune system disorders: allergic reaction.

Gastrointestinal disorders: bloody diarrhea, colitis (including pseudomembranous colitis) (See WARNINGS, Gastrointestinal, CDAD).

No information provided.

Vaginally applied clindamycin phosphate vaginal cream 2% could be absorbed in sufficient amounts to produce systemic effects.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Symptoms

Topically applied clindamycin phosphate from Clindamycin/Benzoyl Peroxide Mylan^® can be absorbed in sufficient amounts to produce systemic gastrointestinal side effects including abdominal pain, nausea, vomiting and diarhhea (see WARNINGS). In the case of excessive application or accidental ingestion of Clindamycin/Benzoyl Peroxide Mylan^®, the use of the pledgets should be discontinued for several days before resuming therapy (see WARNINGS).

Clindamycin/Benzoyl Peroxide Mylan^® contains a significant quantity of isopropyl alcohol (44%). Systemic absorption of isopropyl alcohol should be considered a possibility in the event of accidental ingestion.

Treatment

No specific antidote is available. In the case of excessive application or accidental ingestion of Clindamycin/Benzoyl Peroxide Mylan^® the application site should be washed off with lukewarm water and the use of the pledgets should be discontinued for several days before resuming therapy (see WARNINGS).

Pharmacotherapeutic group: Lincocosamide antibiotics, ATC Code D10AF01.

Mode of action

Clindamycin is a lincosamide antibiotic with a primarily bacteriostatic action against Gram-positive aerobes and a wide range of anaerobic bacteria. Lincosamides such as clindamycin bind to the 50S subunit of the bacterial ribosome similarly to macrolides such as erythromycin and inhibit protein synthesis. The action of clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains. Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Resistance

Resistance to clindamycin usually occurs via macrolide-lincosamide-streptogramin B (MLSB) type of resistance, which may be constitutive or inducible.

Breakpoints

The minimum inhibitory concentrations (MIC) breakpoints are as follows:

EUCAST

Staphylococci: sensitive ≤ 0.25 resistant > 0.5

Streptococci ABCG and pneumoniae: sensitive ≤ 0.5 resistant > 0.5

Gram positive anaerobes: sensitive ≤ 4 resistant > 4

Gram negative anaerobes: ≤ 4 resistant > 4

PK/PD relationship

Efficacy is related to the ratio of the area of the concentration-time curve of unbound antibiotic to the MIC for the pathogen (fAUC/MIC).

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Species

Susceptible

Gram-positive aerobes

Staphylococcus aureus*

Staphylococcus epidermidis

Streptococcus pneumonia

Streptococcus pyogenes

Viridans streptococci

Anaerobes

Bacteriodes fragilis group

Prevotella formerly known as Bacteroides melaninogenicus

Bifidobacterium spp.

Clostridium perfringens

Eubacterium spp.

Fusobacterium spp.

Peptococcus spp.

Peptostreptococcus spp.

Propionibacterium spp.

Veillonella spp.

Resistant

Clostridia spp.

Enterococci

Enterobacteriaceae

*Up to 50% of methicillin-susceptible S. aureus have been reported to be resistant to clindamycin in some areas. More than 90% of methicillin-resistant S.aureus (MRSA) are resistant to clindamycin and it should not be used while awaiting susceptibility test results if there is any suspicion of MRSA.

Most Gram-negative aerobic bacteria, including the Enterobacteriaceae, are resistant to clindamycin. Clindamycin demonstrates cross-resistance with lincomycin. When tested by in vitro methods, some staphylococcal strains originally resistant to erythromycin rapidly developed resistance to clindamycin. The mechanisms for resistance are the same as for erythromycin, namely methylation of the ribosomal binding site, chromosomal mutation of the ribosomal protein and in a few staphylococcal isolates enzymatic inactivation by a plasmid-mediated adenyltransferase.

Pharmacotherapeutic group: Lincosamides

ATC Code: J01 FF01

Mode of action

Clindamycin is a lincosamide antibiotic with a primarily bacteriostatic action against Gram-positive aerobes and a wide range of anaerobic bacteria. Lincosamides such as clindamycin bind to the 50S subunit of the bacterial ribosome similarly to macrolides such as erythromycin and inhibit the early stages of protein synthesis. The action of clindamycin is predominantly bacteriostatic although high concentrations may be slowly bactericidal against sensitive strains.

Mechanism of resistance

Resistance to clindamycin usually occurs via macrolide-lincosamide-streptogramin B (MLS_B) type of resistance, which may be constitutive or inducible. Clindamycin demonstrates cross-resistance with lincomycin. When tested by in vitro methods, some staphylococcal strains originally resistant to erythromycin rapidly developed resistance to clindamycin. The mechanisms for resistance are the same as for erythromycin, namely methylation of the ribosome binding site, chromosomal mutation of the ribosomal protein and in a few staphylococcal isolates emzymatic inactivation by a plasmid-mediated adenyltransferase.

Breakpoints

The minimum inhibitory concentrations (MIC) breakpoints are as follows:

Eucast

Staphylococci: sensitive ≤ 0.5 resistant > 0.5

Streptococci ABCG and pneumoniae: sensitive ≤ 0.5 resistant > 0.5

Gram positive anaerobes: sensitive ≤ 4 resistant > 4

Gram negative anaerobes: sensitive ≤ 4 resistant > 4

Susceptibility

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

* Up to 50% of methicillin-susceptible S. aureus have been reported to be resistant to clindamycin in some areas. More than 90% of methicillin-resistant S.aureus (MRSA) are resistant to clindamycin and it should not be used while awaiting susceptibility test results if there is any suspicion of MRSA.

Pharmacotherapeutic group: Anti-infectives for treatment of acne, ATC Code: DA10AF01.

Microbiology

Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis. It binds to the 50S ribosomal subunit and affects both ribosome assembly and the translation process. Although Clindamycin/Benzoyl Peroxide Mylan is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Clindamycin has been shown to have in vitro activity against isolates of the following organisms:

Anaerobic gram positive nonsporeforming bacilli, including:

- Propionibacterium acnes.

EUCAST has established susceptibility interpretive criteria for gram-negative and gram-positive anaerobes (with the exception of C. difficile): susceptible, ≤4 mg/L; resistant, >4 mg/L.

In a U.S. surveillance study, clindamycin MICs were ≤4 mg/L for 97% of P. acnes isolates tested.

In some bacterial species, cross resistance has been demonstrated in vitro among lincosamides, macrolides, and streptogramins B.

Clinical efficacy and safety

P. acnes produces an extracellular lipase that hydrolyses sebum triglycerides to glycerol, used by the organism as a growth substrate, and free fatty acids, which have pro-inflammatory and comedogenic properties. A double-blind study had been conducted to examine the effect of topical 1% clindamycin hydrochloride hydrate in a hydroalcoholic vehicle as compared to the effect of the vehicle alone. Fourteen patients applied clindamycin or vehicle alone twice daily for eight weeks. Free fatty acid surface lipid percentages, quantitative bacterial counts, and clinical response were assessed every two weeks. A significant reduction (88%) in the percentage of free fatty acids in the surface lipids was seen in the clindamycin-treated group and not in the vehicle-treated group. Free fatty acids on the skin surface have been decreased from approximately 14% to 2% following application of clindamycin solution in a hydroalcoholic base to 9 patients (average age 22.3 years) with acne vulgaris. There was no significant change in the surface microflora. Despite the short duration of treatment, objective clinical improvement was seen in three of nine treated patients, while none was observed in the placebo-treated patients.

Pharmacotherapeutic group: Anti-infectives for treatment of acne, ATC Code: DA10AF01.

Microbiology

Clindamycin is a lincosamide antibiotic that inhibits bacterial protein synthesis. It binds to the 50S ribosomal subunit and affects both ribosome assembly and the translation process. Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Clindamycin has been shown to have in vitro activity against isolates of the following organisms:

Anaerobic gram positive nonsporeforming bacilli, including:

- Propionibacterium acnes.

EUCAST has established susceptibility interpretive criteria for gram-negative and gram-positive anaerobes (with the exception of C. difficile): susceptible, ≤4 mg/L; resistant, >4 mg/L.

In a U.S. surveillance study, clindamycin MICs were ≤4 mg/L for 97% of P. acnes isolates tested.

In some bacterial species, cross resistance has been demonstrated in vitro among lincosamides, macrolides, and streptogramins B.

Clinical efficacy and safety

P. acnes produces an extracellular lipase that hydrolyses sebum triglycerides to glycerol, used by the organism as a growth substrate, and free fatty acids, which have pro-inflammatory and comedogenic properties. A double-blind study had been conducted to examine the effect of topical 1% clindamycin hydrochloride hydrate in a hydroalcoholic vehicle as compared to the effect of the vehicle alone. Fourteen patients applied clindamycin or vehicle alone twice daily for eight weeks. Free fatty acid surface lipid percentages, quantitative bacterial counts, and clinical response were assessed every two weeks. A significant reduction (88%) in the percentage of free fatty acids in the surface lipids was seen in the clindamycin-treated group and not in the vehicle-treated group. Free fatty acids on the skin surface have been decreased from approximately 14% to 2% following application of clindamycin solution in a hydroalcoholic base to 9 patients (average age 22.3 years) with acne vulgaris. There was no significant change in the surface microflora. Despite the short duration of treatment, objective clinical improvement was seen in three of nine treated patients, while none was observed in the placebo-treated patients.

Pharmacodynamics of Clindamycin/Benzoyl Peroxide Mylan Foam is unknown.

General characteristics of active substance

Following parenteral administration, the biologically inactive clindamycin phosphate is hydrolysed to clindamycin. When the equivalent of 300 mg of clindamycin is injected intramuscularly, a mean peak plasma concentration of 6 microgram/ml is achieved within three hours; 600 mg gives a peak concentration of 9 microgram/ml. In children, peak concentration may be reached within one hour. When the same doses are infused intravenously, peak concentrations of 7 and 10 micrograms per ml respectively are achieved by the end of infusion.

Clindamycin is widely distributed in body fluids and tissues including bone, but it does not reach the cerebrospinal fluid in significant concentrations. It diffuses across the placenta into the foetal circulation and appears in breast milk. High concentrations occur in bile. It accumulates in leucocytes and macrophages. Over 90% of clindamycin in the circulation is bound to plasma proteins. The half-life is 2 to 3 hours, although this may be prolonged in pre-term neonates and patients with severe renal impairment.

Clindamycin undergoes metabolism, to the active N-demethyl and sulphoxide metabolites and also some inactive metabolites. About 10% of the drug is excreted in the urine as active drug or metabolites and about 4% in the faeces; the remainder is excreted as inactive metabolites. Excretion is slow and takes place over several days. It is not effectively removed from the blood by dialysis.

Characteristics in patients

General characteristics of active substance

Following parenteral administration, the biologically inactive clindamycin phosphate is hydrolysed to clindamycin. When the equivalent of 300mg of clindamycin is injected intramuscularly, a mean peak plasma concentration of 6 microgram/ml is achieved within three hours; 600mg gives a peak concentration of 9 microgram/ml. In children, peak concentration may be reached within one hour. When the same doses are infused intravenously, peak concentrations of 7 and 10 micrograms per ml respectively are achieved by the end of infusion.

Clindamycin is widely distributed in body fluids and tissues, including bone, but it does not reach the cerebrospinal fluid in significant concentrations. It diffuses across the placenta into the foetal circulation and appears in breast milk. High concentrations occur in bile. It accumulates in leucocytes and macrophages. Over 90% of clindamycin in the circulation is bound to plasma proteins. The half-life is 2 to 3 hours, although this may be prolonged in pre-term neonates and patients with severe renal impairment.

Clindamycin undergoes metabolism, to the active N-demethyl and sulphoxide metabolites and also some inactive metabolites. About 10% of the drug is excreted in the urine as active drug or metabolites and about 4% in the faeces; the remainder is excreted as inactive metabolites. Excretion is slow and takes place over several days. It is not effectively removed from the blood by dialysis.

Characteristics in patients

No special characteristics."Special warnings and special precautions for use" for further information.

Following multiple topical applications of Clindamycin/Benzoyl Peroxide Mylan at a concentration equivalent to 10 mg clindamycin per mL in an isopropyl alcohol and water solution, very low levels of clindamycin are present in the serum (0-3 ng/mL) and less than 0.2% of the dose is recovered in urine as clindamycin.

Clindamycin concentrations has been demonstrated in comedones from acne patients. The mean (±SD) concentration of clindamycin in extracted comedones after application of clindamycin topical solution for 4 weeks was 0.60±0.11 mcg.

Older people

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

Following multiple topical applications of clindamycin phosphate at a concentration equivalent to 10 mg clindamycin per mL in an isopropyl alcohol and water solution, very low levels of clindamycin are present in the serum (0-3 ng/mL) and less than 0.2% of the dose is recovered in urine as clindamycin.

Clindamycin concentrations has been demonstrated in comedones from acne patients. The mean (±SD) concentration of clindamycin in extracted comedones after application of clindamycin topical solution for 4 weeks was 0.60±0.11 mcg.

Older people

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

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/Benzoyl Peroxide Mylan 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 Cmax and AUC(0-12) were 23% and 9% lower, respectively, for Clindamycin/Benzoyl Peroxide Mylan Foam than for the clindamycin gel, 1%.

Following multiple applications of Clindamycin/Benzoyl Peroxide Mylan Foam, less than 0.024% of the total dose was excreted unchanged in the urine over 12 hours on Day 5.

Following a single intravaginal application of Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) cream to 20 healthy women, the mean (range) AUC0-inf and Cmax estimates were 175 (38.6 to 541) ng/mL·hr and 6.6 (0.8 to 39) ng/mL, respectively. The mean Cmax of clindamycin for Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate) was approximately 0.3%, 0.1%, and 7.6% of that observed after the administration of a 150 mg Cleocin oral capsule (2.5 mcg/mL), a 600 mg Cleocin intravenous injection (10.9 mcg/mL), and a single dose of 100 mg of Cleocin Vaginal Cream (86.5 ng/mL), respectively. The peak serum concentration of clindamycin was attained approximately 20 hours post dosing for Clindamycin/Benzoyl Peroxide Mylan (clindamycin phosphate).