Prescription Drugs

CLINICAL PHARMACOLOGY Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the active antibiotic clindamycin. Clindamycin inhibits bacterial protein synthesis by binding to the 50S subunit of ribosomes. Clindamycin in vitro inhibits Propionibacterium acnes. Bacterial resistance may develop to clindamycin. Resistance to clindamycin may be associated with resistance to erythromycin. Also, cross-resistance has been demonstrated between clindamycin and lincomycin. Following multiple topical applications of clindamycin phosphate at a concentration equivalent to 10 mg 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. Microbiology Clindamycin is active against anaerobic gram-positive bacilli such as Corynebacteria but resistant subspecies of Clostridium may occur. Aerobic gram-negative bacteria are nearly all resistant to clindamycin. In-vitro susceptibility of P. acnes and related species to clindamycin is shown in Table 3. Table 3: In-vitro susceptibility of P. acnes and related species to clindamycin (Hoeffler et al, 1976) Species No. of strains Cumulative % of strains inhibited at MICs (mg/L) <0.02 0.04 0.1 0.2 0.4 P.acnes 38 - 34 87 95 100 P.granulosum 15 7 87 93 100 - P.avidum 16 - 56 69 81 100 C.minutissimum 3 - - - 100 - C.parvum 1 - - - 100 - Resistant strains of P. acnes (MIC ≥0.5mg/mL), reaching 48% in certain areas of the world, have been reported in recent years. Calculated clindamycin concentrations representing about of 600 mg/L in the epidermis have been reported following the topical application of clindamycin phosphate (see Pharmacology). Cross-resistance has been demonstrated between clindamycin and lincomycin. Cross resistance between clindamycin and erythromycin has also been identified. In one study involving human volunteers who used an alcoholic topical 1% clindamycin phosphate solution for eleven days, average P. acnes counts were reduced by 81%. Concurrent measurement of free fatty acid levels did not show significant changes over time. Pharmacology Topical clindamycin phosphate seems less prone to be systemically absorbed than clindamycin hydrochloride. In one study involving humans it was found that less than 1% of a 20 mg dose (1 mL b.i.d.; 0.25 mg/kg/day) of clindamycin phosphate was absorbed and peak serum levels of only 1.7 ng/mL were reached. The vehicle used in this study was unspecified. Clindamycin was not detected in urine samples from patients who used topical 1% clindamycin phosphate solution (50% v/v isopropyl alcohol) b.i.d. for eight weeks. If systemic absorption of clindamycin occurred, the amount excreted in urine was below the bioassay detectable limits of 0.25 ng/mL. Extracted comedones from twenty subjects treated for four weeks with topical 1% clindamycin phosphate solution (50% v/v isopropyl alcohol) were assayed for free clindamycin. Comedones in 18 subjects contained clindamycin. In those comedones, the mean clindamycin content was 0.60 μg/mg; corresponding to the mean epidermis clindamycin concentration of approximately 600 mg/L. Clindamycin concentrations in the mother, umbilical cord and neonate were assayed in 54 caesarean section human patients receiving perioperative clindamycin and gentamicin for prophylaxis. Each patient received 5.5 to 11.1 mg/kg of intravenous clindamycin. A half hour after the injection, the average level of clindamycin in the mother’s blood was around 5.5 mg/L and gradually declined over six to eight hours. About twenty minutes after the injection, the peak concentration of clindamycin in the venous blood of the umbilical cord was 3 mg/L. Neonatal venous blood concentrations of clindamycin during the first six hours of life were below 2 mg/L. Amniotic fluid samples obtained thirty and sixty minutes after injection showed no antibiotics. Toxicology Acute Animal Toxicity The systemic acute toxicity of clindamycin phosphate and clindamycin hydrochloride has been extensively studied in mice and rats. Results from these studies are summarized in Table 4. Table 4: Acute toxicity of clindamycin Species Treatment Route LD50 Observations Mouse (ICR line white Swiss, 20 g) Clindamycin HCl ip 361 mg/kg Depression and convulsions, death occurred 15 min to 4 days depending on the dose iv 245 mg/kg Depression and convulsions, death occurred 1-2 min after dose. Rat (young adult TUC/SD, 175 g) Clindamycin HCl po 2618 mg/kg Death in 1 to 2 days after treatment. Rat (adult TUC/SD, 400 g) Clindamycin HCl sc 2618 mg/kg Death in 1 to 2 days after treatment. Rat (newborn TUC/SD, 6 g) Clindamycin HCl sc 245 mg/kg Rat (adult TUC/SD) Clindamycin phosphate sc >2000 mg/kg Rat (newborn TUC/SD) Clindamycin phosphate sc 179 mg/kg Chronic Animal Toxicity Chronic toxicity of clindamycin phosphate and clindamycin hydrochloride has been studied in a number of animal species. Results from these studies are summarized in Table 5. Table 5: Chronic toxicity of clindamycin Species Treatment Route Length Results 1. Chronic Toxicity Rat (Sprague - Dawley) n=10M Clindamycin phosphate 120 mg/kg once daily sc 6 days SUBCUTANEOUS TOLERANCE Body weight and food conversion were regarded as comparable to the control group. Normal haematology and necropsy. Rat (Sprague - Dawley) n=5M, 5F/ group Clindamycin phosphate 30, 60, 90 mg/kg once daily sc 1 month SUBCUTANEOUS TOLERANCE 30 mg/kg for 30 days produced low grade inflammatory changes and were accompanied by focal necrosis. No systemic effects. Dogs n=4/group Clindamycin phosphate 60, 120 mg/kg 6 days a week twice daily iv 1 month INTRAVENOUS TOLERANCE No drug related effects and no deviation among the hemogram, blood chemistry and urinalyses were observed. There was no difference in haemolysis between treated dogs and control dogs. In Heinz body formation or increased fragility of erythrocytes were observed in blood samples of treated animals. 2. Dermal Toxicity Rat n=10/group Clindamycin phosphate 3% aqueous solution, Dose: 50 to 72 mg/kg Topical, abraded and intact skin 22 days No skin changes, abrasions healed normally, females larger increase in body weight by 31.1% and 19.8% (abraded), haematology and organ weights normal. Syrian Hamster n= 7/ group Clindamycin HCl 0.1, 1, 10, 40 mg/day; 0.01 mg/day with and without 0.1% tretinoin Topical 2 weeks or less All hamsters given 40,10 and 1 mg died in less than 2 weeks, 50% mortality 0.1 mg, no mortality 0.01mg, mortality associated with clostridial toxin in cecal contents Pig n=6 (one group) Clindamycin HCl 3% Aq. solution, Dose: 7.33 to 10.26 mg/kg Topical 22 days No irritation 3. Photo toxicity Rats n=10M, 10F/group Clindamycin HCl 0, 30, 100, 300, 600 mg/kg/day; exposed to sunlight once for 2.75 hr po 8 months No photo toxic reactions, excessive exposure produced severe periorbital inflammation in all groups Teratology Teratological studies were not conducted with CLINDETS® (clindamycin phosphate pledget). Subcutaneous injections of clindamycin phosphate at 100 and 180 mg/kg/day (aqueous solution) on gestation days six through fifteen in ICR and CF1 mice and Sprague- Dawley rats had no detrimental effects on the litter weight, number of live and dead pups per litter and the number of resorptions per litter. Fetuses of rats and DV1 mice showed no sign of teratogenic activity as evidenced by examination for gross external, visceral and skeletal malformations. In fetus of ICR mice, a low incidence of cleft palate was observed. The incidence of cleft palate in the clindamycin phosphate treated litter was not significantly different from the incidence reported in the control litter. Bibliography Crawford, W.W., et al., Laboratory Induction and Clinical Occurrence of Combined Clindamycin and Erythromycin Resistance in Corynebacterium acnes, J. Invest. Dermatol. 1979;72:187-190. Guin, J.D., and W.L., Lummis Comedonal Levels of Free Clindamycin Following Topical Treatment with a 1% Solution of Clindamycin Phosphate, J. Am. Acad Dermatol. 1982;7:265-268. Guin, G.D., Topical Clindamycin: A Double-Blind Study Comparing Clindamycin Phosphate with Clindamycin Hydrochloride, Int. J. Dermatol. 1979;18:164-166. Kuhlman DS, Callen JP. A Comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris. Cutis 1986; Sept: 203-206. Leigh DA. Antibacterial Activity and Pharmacokinetics of Clindamycin. J Antimicrobial Chemotherapy 1981;7 Suppl A: 3-9. Parry, M.F. and C.K. Rha, Pseudo membraneous Colitis Caused by Topical Clindamycin Phosphate Arch Dermatol 1986;122:583-584. Weinstein, A.J., et al., Placental transfer of clindamycin and gentamicin in term pregnancy, AM.J. Obstet.Genecol.1976; 124: 688-69.

PrCLINDETS® clindamycin solution in pledget 1% w/v (as clindamycin phosphate) DESCRIPTION Drug Substance Proper name: Clindamycin phosphate Chemical name: Methyl 7-chloro-6,7,8-trideoxy-6-(1-methyl-trans-4-propyl-L-2- pyrrolidinecarboxamido)-1-thio-L-threo--D-galacto-octopyranoside 2-(dihydrogen phosphate) Structural formula: Molecular formula: C18H34ClN2O8PS Molecular weight: 504.96 Clindamycin is a white to off-white, odourless or almost odourless, hygroscopic, crystalline powder with a bitter taste, soluble in water (1 in 2.5); slightly soluble in dehydrated alcohol and very slightly soluble in acetone. 1.2 g of clindamycin phosphate is approximately equivalent to 1 g of clindamycin base. Clindamycin phosphate has a melting point of 208E to 212EC and a pH of 3.5 - 4.5 (1% in water). Composition CLINDETS® contains clindamycin phosphate USP at a concentration equivalent to 1% w/v clindamycin in a vehicle of isopropyl alcohol, propylene glycol, and purified water. Each CLINDETS® pledget applicator is composed of viscose, polyolefin and nylon, and contains approximately 1 mL of clindamycin phosphate topical solution.

INDICATIONS CLINDETS® (clindamycin phosphate pledget) is indicated in the treatment of moderate acne vulgaris. DOSAGE AND ADMINISTRATION CLINDETS® (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. CLINDETS® 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. HOW SUPPLIED Dosage Forms And Strengths Box of 60 individual pledgets. Each CLINDETS® pledget applicator contains approximately 1 mL of 1% w/v clindamycin (as phosphate) topical solution. Stability And Storage Recommendations Store between 15°C and 25°C. Do not freeze. Contents are flammable. Keep away from fire, flame or heat. Do not leave CLINDETS® in direct sunlight. Keep out of the sight and reach of children. GlaxoSmithKline Inc. 7333 Mississauga Road, Mississauga, Ontario L5N 6L4. Revised: 2014.

PATIENT INFORMATION PrCLINDETS® clindamycin solution in pledget 1% w/v (as clindamycin phosphate) This leaflet is designed specifically for consumers. This leaflet is a summary and will not tell you everything about CLINDETS®. Contact your doctor or pharmacist if you have any questions about the drug. ABOUT THIS MEDICATION What the medication is used for: CLINDETS® is a prescription medication used on the skin to treat moderate acne in adults and adolescents 13 years and older. The safety and effectiveness of CLINDETS® in children under the age of 13 are not known. What it does: CLINDETS® contains the active ingredient clindamycin, which interferes with bacterial growth, thereby reducing the bacteria associated with acne. This is how CLINDETS® helps to improve your acne condition. When it should not be used: Do not use CLINDETS® if you currently have or have had a history of: An allergy (hypersensitivity) to clindamycin, lincomycin or any of the other ingredients in CLINDETS® (see What the important nonmedicinal ingredients are). Inflammation of the small intestine (regional enteritis). Inflammation of the large intestine (colitis), which may be due to the presence of ulcers (ulcerative colitis) or associated with the use of antibiotics. Inflammatory bowel disease or antibiotic-associated colitis (severe, prolonged or bloody diarrhea following antibiotic use). What the medicinal ingredient is: Clindamycin as clindamycin phosphate USP. What the important nonmedicinal ingredients are: Isopropyl alcohol, propylene glycol and purified water. What dosage forms it comes in: Topical medicated pads. WARNINGS AND PRECAUTIONS CLINDETS® is for external use only. Keep CLINDETS® away from your eyes, inside the nose, mouth, lips, other mucous membranes or areas of broken skin. If contact occurs, flush areas with large amounts of cool tap water for at least 5 minutes. If discomfort persists, consult your doctor. Do not use any other acne medications, or other topical medications, unless your doctor instructs you to do so. If you have recently taken or used other clindamycin or erythromycin-containing medicines, there is an increased chance that CLINDETS® will not work as well as it should. BEFORE you use CLINDETS® talk to your doctor or pharmacist if you: Are pregnant or planning to become pregnant. If you are pregnant, or think you could be, or if you are planning to become pregnant, do not take CLINDETS® without checking with your doctor. Are breast-feeding or plan to breast-feed. It is not known whether the ingredients of CLINDETS® can pass into breast milk. If you are breastfeeding, check with your doctor before you use CLINDETS®. If used during breast-feeding, do not apply CLINDETS® to the breast area to avoid accidental ingestion by the infant. During the first weeks of treatment, you may experience peeling and reddening. These symptoms will normally subside if treatment is temporarily interrupted and restarted after your symptoms have settled. Avoid alcohol based solutions (e.g., after shave lotions) as they have a drying effect and may irritate your skin. FLAMMABLE: Due to the flammable nature of CLINDETS®, you should avoid smoking or being near an open flame while you are applying CLINDETS®, and immediately after you have used it. INTERACTIONS WITH THIS MEDICATION Know the medicines you take. Keep a list of them and tell your doctor / pharmacist about all the medicines and skin products you use. Tell your doctor especially if you are taking or using any of the following medicines: Neuromuscular blocking agents (medicines used as muscle relaxants when you are given an anaesthetic) – as CLINDETS® has been shown to increase their activity. Erythromycin – as it should not be used at the same time as CLINDETS®. Other acne or skin preparations including peeling agents (e.g., sulfur, resorcinol, salicylic acid) and abrasive agents as concomitant use with CLINDETS® may increase side effects such as skin irritation. PROPER USE OF THIS MEDICATION CLINDETS® should only be applied to your skin. CLINDETS® should be used for the entire treatment period as instructed by your doctor even if your acne symptoms begin improving after a few days. Stopping your treatment too soon may result in the return of your acne condition. Do not expect to see immediate improvement of your acne. Be patient and apply your medication as your doctor has directed. Six to eight weeks may be required before improvement is seen. If you do not see improvement after using CLINDETS® for 6-8 weeks, or if your acne becomes worse, contact your doctor. CLINDETS® consists of a small pad which is medicated with a 1% concentration of clindamycin. The pad also contains alcohol and is enclosed within an aluminum foil, which you must open just before use. Instructions for applying CLINDETS®: CLINDETS® contains alcohol. Wait 30 minutes after shaving before applying CLINDETS® as the alcohol may irritate freshly shaving skin. Before you apply CLINDETS®, wash the affected skin gently with a mild, non-irritating cleanser, rinse with warm water, and pat dry. Gently apply CLINDETS® to lightly cover the entire affected area of your skin (face) with a thin layer. Avoid eyes, nostrils, mouth, lips, other mucous membranes or areas of broken skin. Wash your hands with soap and water after applying CLINDETS®. Discard CLINDETS® after use. Do not use if the seal is broken. Apply CLINDETS® in the morning and at night or as directed by your doctor. Remember: CLINDETS® has been prescribed by your doctor for you alone; do not allow other people to use it, even if they have the same condition that you have, as it may not be suitable for them. Overdose: In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms. If you apply too much CLINDETS®, wash carefully off and seek medical advice. If you do accidentally swallow CLINDETS®, rinse your mouth immediately with water and seek medical advice. You may get symptoms similar to when you take antibiotics by mouth (an upset stomach). This product contains a significant amount of isopropyl alcohol and should be considered in case of accidental oral ingestion. SIDE EFFECTS AND WHAT TO DO ABOUT THEM During the first weeks of using CLINDETS®, you may notice some skin irritation such as rash (including redness, small red bumps), dryness, itching, oiliness, swelling, irritation, stinging, tingling or numbness, burning or peeling. These symptoms will normally subside if treatment is temporarily interrupted and restarted after your symptoms have settled. Other side effects that have been reported include headache diarrhea and nausea. If you experience symptoms such as severe diarrhea (bloody or watery) with or without fever, abdominal pain, or tenderness, you may have Clostridium difficile colitis (bowel inflammation). If this occurs, stop taking CLINDETS® and contact a healthcare professional immediately. SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM Symptom / effect Talk with your doctor or pharmacist Stop taking drug and call your doctor or pharmacist Only if severe In all cases Rare Severe allergic reaction: raised and itchy rash (hives), swelling of face or lips, causing difficulty in breathing. Rare Inflammation of intestines, colitis: abdominal or stomach cramps, severe pain, bloating, severe or prolonged watery diarrhea which may be bloody, nausea or vomiting. HOW TO STORE IT Store between 15°C and 25°C. Do not freeze. Contents are flammable. Keep CLINDETS® away from all sources of fire, flame and heat. Do not leave CLINDETS® in direct sunlight. Keep your medicine in a safe place, out of the sight and reach of children. REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: $ Report online at www.healthcanada.gc.ca/medeffect $ Call toll-free at 1-866-234-2345 $ Complete a Canada Vigilance Reporting Form and: Fax toll-free to 1-866-678-6789, or Mail to: Canada Vigilance Program Health Canada Postal Locator 0701E Ottawa, Ontario K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect. NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

OVERDOSE For management of a suspected drug overdose, contact your regional Poison Control Centre. Symptoms Topically applied clindamycin phosphate from CLINDETS® 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 CLINDETS®, the use of the pledgets should be discontinued for several days before resuming therapy (see WARNINGS). CLINDETS® 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 CLINDETS® 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). CONTRAINDICATIONS CLINDETS® (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. CLINDETS® 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).

SIDE EFFECTS Clinical Trial Adverse Drug Reactions The safety was assessed in 150 acne vulgaris patients from a placebo-controlled study in which CLINDETS® 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 CLINDETS® Clinical Trial Local Tolerance* Signs and Symptoms Treatment Number of Patients with Worsening Score Week 2 n/N (%) Week 5 n/N (%) Week 8 n/N (%) Week 11 n/N(%) General disorders and administrative site conditions Erythema CLINDETS® 1/73 (1.4) 2/72 (2.8) 0 0 Vehicle 1/72 (1.4) 2/70 (2.9) 0 0 Peeling CLINDETS® 2/73 (2.7) 2/72 (2.8) 1/73 (1.4) 0 Vehicle 1/72 (1.4) 3/70 (4.3) 0 0 Burning CLINDETS® 4/73 (5.5) 1/72 (1.4) 2/73 (2.7) 1/73 (1.4) Vehicle 4/72 (5.6) 4/70 (5.7) 0 0 * Change from Baseline of Signs and Symptoms| 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 CLINDETS® Clinical Trial Adverse Drug Reaction CLINDETS® % N=75 Vehicle % N=75 Nervous system disorders Paresthesia - 1.3 Headache 1.3 - Gastrointestinal disorders Diarrhea 1.3 1.3 Nausea 1.3 - 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). DRUG INTERACTIONS Clindamycin and erythromycin have been shown to be antagonistic in vitro. Systemic clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.

WARNINGS Skin FOR EXTERNAL USE ONLY. NOT FOR OPHTHALMIC USE. CLINDETS® (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 CLINDETS ®, 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 CLINDETS®, patients should avoid smoking or being near an open flame during application and immediately after use. Use In Pregnancy The safety of CLINDETS® 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 CLINDETS® (clindamycin phosphate pledget) and it is not known whether CLINDETS® can cause fetal harm when administered to pregnant women or can affect reproduction capacity. CLINDETS® 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 CLINDETS® 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 CLINDETS®. 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 CLINDETS® 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.