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.

CLINICAL PHARMACOLOGY Distribution Biologically inactive clindamycin phosphate is converted to active clindamycin. By the end of short-term intravenous infusion, peak serum levels of active clindamycin are reached. After intramuscular injection of clindamycin phosphate, peak levels of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum level curves may be constructed from IV peak serum levels as given in Table 1 by application of elimination half-lives (see Excretion). Serum levels of clindamycin can be maintained above the in vitro minimum inhibitory concentrations for most indicated organisms by administration of clindamycin phosphate every 8 to 12 hours in adults and every 6 to 8 hours in pediatric patients, or by continuous intravenous infusion. An equilibrium state is reached by the third dose. No significant levels of clindamycin are attained in the cerebrospinal fluid even in the presence of inflamed meninges. Metabolism In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly metabolized by Cytochrome P450 3A4 (CYP3A4), with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin. Excretion Biologically inactive clindamycin phosphate disappears rapidly from the serum; the average elimination half-life is 6 minutes; however, the serum elimination half-life of active clindamycin is about 3 hours in adults and 2. hours in pediatric patients. Special Populations Renal/Hepatic Impairment The elimination half-life of clindamycin is increased slightly in patients with markedly reduced renal or hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Dosage schedules need not be modified in the presence of mild or moderate renal or hepatic disease. Use In Elderly Pharmacokinetic studies in elderly volunteers (61-79 years) and younger adults (18-39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4-5.1 h) in the elderly, compared to 3.2 hours (range 2.1-4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function1. Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate. Table 1. Average Peak and Trough Serum Concentrations of Active Clindamycin After Dosing with Clindamycin Phosphate Dosage Regimen Peak mcg/mL Trough mcg/mL Healthy Adult Males (Post equilibrium) 600 mg IV in 30 min q6h 10.9 2.0 600 mg IV in 30 min q8h 10.8 1.1 900 mg IV in 30 min q8h 14.1 1.7 600 mg IM q12h* 9 Pediatric Patients (first dose)* 5-7 mg/kg IV in 1 hour 10 5-7 mg/kg IM 8 3-5 mg/kg IM 4 *Data in this group from patients being treated for infection. Microbiology Mechanism Of Action Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic. Resistance Resistance to clindamycin is most often caused by modification of specific bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete. Because the binding sites for these antibacterial drugs overlap, cross-resistance is sometimes observed among lincosamides, macrolides and streptogramin B.Macrolide-inducible resistance to clindamycin occurs in some isolates of macrolide-resistant bacteria. Macrolide-resistant isolates of staphylococci and beta-hemolytic streptococci should be screened for induction of clindamycin resistance using the D-zone test. Antimicrobial Activity Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section. Gram-Positive Bacteria Staphylococcus aureus (methicillin-susceptible strains) Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenes Anaerobic Bacteria Clostridium perfringens Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus anaerobius Prevotella melaninogenica At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 2. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials. Gram-Positive Bacteria Staphylococcus epidermidis (methicillin-susceptible strains) Streptococcus agalactiae Streptococcus anginosus Streptococcus mitis Streptococcus oralis Anaerobic Bacteria Actinomyces israelii Clostridium clostridioforme Eggerthella lenta Finegoldia (Peptostreptococcus) magna Micromonas (Peptostreptococcus) micros Prevotella bivia Prevotella intermedia Propionibacterium acnes Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 2. Diffusion Techniques Quantitative methods that require the measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method2,5. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of bacteria to clindamycin. The disk diffusion breakpoints are provided in Table 2. Anaerobic Techniques For anaerobic bacteria, the susceptibility to clindamycin can be determined by a standardized test method2,4. The MIC values obtained should be interpreted according to the criteria provided in Table 2. Table 2. Susceptibility Test Interpretive Criteria for Clindamycin Pathogen Susceptibility Interpretive Criteria Minimal Inhibitory Concentrations (MIC in mcg/mL) Disk Diffusion (Zone Diameters in mm) S I R S I R Staphylococcus spp. ≤0.5 1–2 ≥4 ≥21 15–20 ≤14 Streptococcus pneumoniae and other Streptococcus spp. ≤0.25 0.5 ≥1 ≥19 16–18 ≤15 Anaerobic Bacteria ≤2 4 ≥8 NA NA NA NA=not applicable A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test2,3,4,5. Standard clindamycin powder should provide the MIC ranges in Table 3. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved. Table 3. Acceptable Quality Control Ranges for Clindamycin QC Strain Acceptable Quality Control Ranges Minimum Inhibitory Concentration Range(mcg/mL) Disk Diffusion Range (Zone Diameters in mm) Enterococcus faecalis1 ATCC 29212 4-16 NA Staphylococcus aureus ATCC 29213 0.06-0.25 NA Staphylococcus aureus ATCC 25923 NA 24-30 Streptococcus pneumoniae ATCC 49619 0.03-0.12 19-25 Bacteroides fragilis ATCC 25285 0.5-2 NA Bacteroides thetaiotaomicron ATCC 29741 2-8 NA Clostridium difficile2 ATCC 700057 2-8 NA Eggerthella lenta ATCC 43055 0.06-0.25 NA 1. Enterococcus faecalis has been included in this table for quality control purposes only. 2. Quality control for C. difficile is performed using the agar dilution method only, all other obligate anaerobes may be tested by either broth microdilution or agar dilution methods. NA=Not applicable ATCC® is a registered trademark of the American Type Culture Collection REFERENCES 1. Smith RB, Phillips JP: Evaluation of CLEOCIN HCl and CLEOCIN Phosphate in an Aged Population. Upjohn TR 8147-82-9122-021, December 1982. 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 26th ed. CLSI supplement M100S. Wayne, PA: Clinical and Laboratory Standards Institute; 2016. 3. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10. Wayne, PA: Clinical and Laboratory Standards Institute; 2015. 4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Eighth Edition. CLSI document M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. 5. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Twelfth Edition. CLSI document M02-A12. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.

CLINICAL PHARMACOLOGY Human Pharmacology Absorption Serum level studies with a 150 mg oral dose of clindamycin hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly absorbed after oral administration. An average peak serum level of 2.50 mcg/mL was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.70 mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and the concomitant administration of food does not appreciably modify the serum concentrations; serum levels have been uniform and predictable from person to person and dose to dose. Serum level studies following multiple doses of CLEOCIN HCl for up to 14 days show no evidence of accumulation or altered metabolism of drug. Doses of up to 2 grams of clindamycin per day for 14 days have been well tolerated by healthy volunteers, except that the incidence of gastrointestinal side effects is greater with the higher doses. Distribution Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indicated organisms for at least six hours following administration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges. Excretion The average biological half-life is 2.4 hours. Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the feces; the remainder is excreted as bioinactive metabolites. Special Populations Renal Impairment Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Use in Elderly Pharmacokinetic studies in elderly volunteers (61-79 years) and younger adults (18-39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4-5.1 h) in the elderly compared to 3.2 hours (range 2.1 - 4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function1. Microbiology Mechanism of Action Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic. Resistance Resistance to clindamycin is most often caused by modification of specific bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete. Because the binding sites for these antibacterial drugs overlap, cross-resistance is sometimes observed among lincosamides, macrolides and streptogramin B. Macrolide-inducible resistance to clindamycin occurs in some isolates of macrolide-resistant bacteria. Macrolide-resistant isolates of staphylococci and beta-hemolytic streptococci should be screened for induction of clindamycin resistance using the D-zone test. Antimicrobial Activity Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section. Gram-positive Bacteria Staphylococcus aureus (methicillin-susceptible strains) Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenes Anaerobic Bacteria Clostridium perfringens Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus anaerobius Prevotella melaninogenica At least 90% of the microorganisms listed below exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the clindamycin susceptible MIC breakpoint for organisms of a similar type to those shown in Table 1. However, the efficacy of clindamycin in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials. Gram-positive Bacteria Staphylococcus epidermidis (methicillin-susceptible strains) Streptococcus agalactiae Streptococcus anginosus Streptococcus mitis Streptococcus oralis Anaerobic Bacteria Actinomyces israelii Clostridium clostridioforme Eggerthella lenta Finegoldia (Peptostreptococcus) magna Micromonas (Peptostreptococcus) micros Prevotella bivia Prevotella intermedia Propionibacterium acnes Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide cumulative in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method2,3 (broth and/or agar). The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques Quantitative methods that require the measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method2,5. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of bacteria to clindamycin. The disk diffusion breakpoints are provided in Table 1. Anaerobic Techniques For anaerobic bacteria, the susceptibility to clindamycin can be determined by a standardized test method2,4. The MIC values obtained should be interpreted according to the criteria provided in Table 1. Table 1: Susceptibility Test Interpretive Criteria for Clindamycin Pathogen Susceptibility Interpretive Criteria Minimal Inhibitory Concentrations (MIC in mcg/mL) Disk Diffusion (Zone Diameters in mm) S I R S I R Staphylococcus spp. ≤ 0.5 1-2 ≥ 4 ≥ 21 15-20 ≤ 14 Streptococcus pneumoniae and other Streptococcus spp. ≤ 0.25 0.5 ≥ 1 ≥ 19 16-18 ≤ 15 Anaerobic Bacteria ≤ 2 4 ≥ 8 NA NA NA NA=not applicable A report of Susceptible (S ) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.2,3,4,5 Standard clindamycin powder should provide the MIC ranges in Table 2. For the disk diffusion technique using the 2 mcg clindamycin disk the criteria provided in Table 2 should be achieved. Table 2: Acceptable Quality Control Ranges for Clindamycin QC Strain Acceptable Quality Control Ranges Minimum Inhibitory Concentration Range (mcg/mL) Disk Diffusion Range (Zone Diameters in mm) Enterococcus faecalis1 ATCC 29212 4-16 NA Staphylococcus aureus ATCC 29213 0.06-0.25 NA Staphylococcus aureus ATCC 25923 NA 24-30 Streptococcus pneumoniae ATCC 49619 0.03-0.12 19-25 Bacteroides fragilis ATCC 25285 0.5-2 NA Bacteroides thetaiotaomicron ATCC 29741 2-8 NA Clostridium difficile2 ATCC 700057 2-8 NA Eggerthella lenta ATCC 43055 0.06-0.25 NA 1Enterococcus faecalis has been included in this table for quality control purposes only. 2Quality control for C. difficile is performed using the agar dilution method only, all other obligate anaerobes may be tested by either broth microdilution or agar dilution methods. NA=Not applicable ATCC® is a registered trademark of the American Type Culture Collection REFERENCES 1. Smith RB, Phillips JP: Evaluation of CLEOCIN HCl and CLEOCIN Phosphate in an Aged Population. Upjohn TR 8147-82-9122-021, December 1982. 2. CLSI. Performance Standards for Antimicrobial Susceptibility Testing: 26th ed. CLSI supplement M100S. Wayne, PA: Clinical and Laboratory Standards Institute; 2016. 3. CLSI. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Tenth Edition. CLSI document M07-A10. Wayne, PA: Clinical and Laboratory Standards Institute; 2015. 4. CLSI. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard-Eighth Edition. CLSI document M11-A8. Wayne, PA: Clinical and Laboratory Standards Institute; 2012. 5. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Twelfth Edition. CLSI document M02-A12. Wayne, PA: Clinical and Laboratory Standards Institute; 2015.

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.

CLEOCIN PHOSPHATE® (clindamycin) Injection WARNING Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN PHOSPHATE 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. Because CLEOCIN PHOSPHATE therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. 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. DESCRIPTION CLEOCIN PHOSPHATE Sterile Solution in vials contains clindamycin phosphate, a water soluble ester of clindamycin and phosphoric acid. Each mL contains the equivalent of 150 mg clindamycin, 0.5 mg disodium edetate and 9.45 mg benzyl alcohol added as preservative in each mL. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. The chemical name of clindamycin phosphate is L-threo-α-D-galacto-Octopyranoside, methyl-7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl] amino]-1-thio-, 2-(dihydrogen phosphate), (2S-trans)-. The molecular formula is C18H34CIN208PS and the molecular weight is 504.96. The structural formula is represented below: CLEOCIN PHOSPHATE in the ADD-Vantage Vial is intended for intravenous use only after further dilution with appropriate volume of ADD-Vantage diluent base solution (see Directions For Use). CLEOCIN PHOSPHATE IV Solution in the GALAXY plastic container for intravenous use is composed of clindamycin phosphate equivalent to 300, 600 and 900 mg of clindamycin premixed with 5% dextrose as a sterile solution. Disodium edetate has been added at a concentration of 0.04 mg/mL. The pH has been adjusted with sodium hydroxide and/or hydrochloric acid. The plastic container is fabricated from a specially designed multilayer plastic, PL 2501. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

Find Lowest Prices on CLEOCIN HCl® (clindamycin hydrochloride) capsules, USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of CLEOCIN HCl and other antibacterial drugs, CLEOCIN HCl should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. WARNING Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN HCl 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. difficle. Because CLEOCIN HCl therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. 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. DESCRIPTION Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin. Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. CLEOCIN HCl Capsules contain clindamycin hydrochloride equivalent to 75 mg, 150 mg, or 300 mg of clindamycin. Inactive ingredients: 75 mg - corn starch, FD&C blue no. 1, FD&C yellow no. 5, gelatin, lactose, magnesium stearate, and talc; 150 mg - corn starch, FD&C blue no. 1, FD&C yellow no. 5, gelatin, lactose, magnesium stearate, talc and titanium dioxide; 300 mg - corn starch, FD&C blue no. 1, gelatin, lactose, magnesium stearate, talc, and titanium dioxide. The structural formula is represented below: The chemical name for clindamycin hydrochloride is Methyl 7-chloro-6,7,8-trideoxy-6­(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)-1-thio-L-threo-α-D-galacto­octopyranoside monohydrochloride.

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.

INDICATIONS CLEOCIN PHOSPHATE products are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. CLEOCIN PHOSPHATE products are also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Its use should be reserved for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate. Because of the risk of antibiotic-associated pseudomembranous colitis, as described in the BOXED WARNING, before selecting clindamycin the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin). Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. CLEOCIN PHOSPHATE is indicated in the treatment of serious infections caused by susceptible strains of the designated organisms in the conditions listed below: Lower respiratory tract infections including pneumonia, empyema, and lung abscess caused by anaerobes, Streptococcus pneumoniae, other streptococci (except E. faecalis), and Staphylococcus aureus. Skin and skin structure infections caused by Streptococcus pyogenes, Staphylococcus aureus, and anaerobes. Gynecological infections including endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection caused by susceptible anaerobes. Intra-abdominal infections including peritonitis and intra-abdominal abscess caused by susceptible anaerobic organisms. Septicemia caused by Staphylococcus aureus, streptococci (except Enterococcus faecalis), and susceptible anaerobes. Bone and joint infections including acute hematogenous osteomyelitis caused by Staphylococcus aureus and as adjunctive therapy in the surgical treatment of chronic bone and joint infections due to susceptible organisms. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CLEOCIN PHOSPHATE and other antibacterial drugs, CLEOCIN PHOSPHATE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. DOSAGE AND ADMINISTRATION If diarrhea occurs during therapy, this antibiotic should be discontinued (see BOX WARNING). Clindamycin phosphate IM administration should be used undiluted. Clindamycin phosphate IV administration should be diluted (see Dilution for IV use and IV infusion rates below). Adults Parenteral (IM or IV Administration): Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600.1200 mg/day in 2, 3 or 4 equal doses. More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1200.2700 mg/day in 2, 3 or 4 equal doses. For more serious infections, these doses may have to be increased. In life-threatening situations due to either aerobes or anaerobes these doses may be increased. Doses of as much as 4800 mg daily have been given intravenously to adults. See Dilution for IV use and IV Infusion Rates section below. Single intramuscular injections of greater than 600 mg are not recommended. Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows: To maintain serum clindamycin levels Rapid infusion rate Maintenance infusion rate Above 4 mcg/mL 10 mg/min for 30 min 0.75 mg/min Above 5 mcg/mL 15 mg/min for 30 min 1.00 mg/min Above 6 mcg/mL 20 mg/min for 30 min 1.25 mg/min Neonates (Less Than 1 Month) 15 to 20 mg/kg/day in 3 to 4 equal doses. The lower dosage may be adequate for small prematures. Pediatric Patients 1 Month Of Age To 16 Years Parenteral (IM or IV) Administration: 20 to 40 mg/kg/day in 3 or 4 equal doses. The higher doses would be used for more severe infections. As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m2/day for serious infections and 450 mg/m2/day for more severe infections. Parenteral therapy may be changed to oral CLEOCIN PEDIATRICR® Flavored Granules (clindamycin palmitate hydrochloride) or CLEOCIN HClR® Capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician. In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days. Dilution for IV use and IV Infusion Rates: The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL. Infusion rates should not exceed 30 mg per minute. The usual infusion dilutions and rates are as follows: Dose Diluent Time 300 mg 50 mL 10 min 600 mg 50 mL 20 min 900 mg 50-100 mL 30 min 1200 mg 100 mL 40 min Administration of more than 1200 mg in a single 1-hour infusion is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dilution And Compatibility Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of CLEOCIN PHOSPHATE Sterile Solution (clindamycin phosphate) in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically. No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin. The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate. The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions. For current information regarding compatibilities of clindamycin phosphate under specific conditions, please contact the Medical and Drug Information Unit, Pharmacia & Upjohn Company (Division of Pfizer Inc). Physico-Chemical Stability Of Diluted Solutions Of CLEOCIN PHOSPHATE Room Temperature 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C. Also, 18 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C. Refrigeration 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C. IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible. Frozen 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at -10°C. Frozen solutions should be thawed at room temperature and not refrozen. Directions For Dispensing Pharmacy Bulk Package Not for Direct Infusion The Pharmacy Bulk Package is for use in a Pharmacy Admixture Service only under a laminar flow hood. Entry into the vial should be made with a small diameter sterile transfer set or other small diameter sterile dispensing device, and contents dispensed in aliquots using aseptic technique. Multiple entries with a needle and syringe are not recommended. AFTER ENTRY USE ENTIRE CONTENTS OF VIAL PROMPTLY. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 24 HOURS AFTER INITIAL ENTRY. Directions For Use Cleocin Phosphate IV Solution In Galaxy Plastic Container Premixed CLEOCIN PHOSPHATE IV Solution is for intravenous administration using sterile equipment. Check for minute leaks prior to use by squeezing bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not add supplementary medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use unless solution is clear and seal is intact. Caution Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation For Administration Suspend container from eyelet support. Remove protector from outlet port at bottom of container. Attach administration set. Refer to complete directions accompanying set. Preparation of CLEOCIN PHOSPHATE in ADD-Vantage System –.For IV Use Only. CLEOCIN PHOSPHATE 300 mg, 600 mg and 900 mg may be reconstituted in 50 mL (for 300 mg and 600 mg) or 100 mL (for 900 mg) of dextrose injection 5% or sodium chloride injection 0.9% in the ADD-diluent container. Refer to separate instructions for ADD-Vantage System. HOW SUPPLIED Each mL of CLEOCIN PHOSPHATE Sterile Solution contains clindamycin phosphate equivalent to 150 mg clindamycin, 0.5 mg disodium edetate, 9.45 mg benzyl alcohol added as preservative. When necessary, pH is adjusted with sodium hydroxide and/or hydrochloric acid. CLEOCIN PHOSPHATE is available in the following packages: 25-2 mL vials NDC 0009-0870-26 25-4 mL vials NDC 0009-0775-26 25-6 mL vials NDC 0009-0902-18 5-60 mL Pharmacy Bulk Package NDC 0009-0728-09 CLEOCIN PHOSPHATE is supplied in ADD-Vantage vials as follows: NDC Vial Size Total Clindamycin Phosphate/vial 0009-6582-01 25-2 mL Vials 300 mg 0009-3124-03 25-4 mL Vials 600 mg 0009-3447-03 25-6 mL Vials 900 mg Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. CLEOCIN PHOSPHATE IV Solution in GALAXY plastic containers is a sterile solution of clindamycin phosphate with 5% dextrose. The single dose GALAXY plastic containers are available as follows: 24-300 mg/50 mL containers NDC 0009-3381-02 24-600 mg/50 mL containers NDC 0009-3375-02 24-900 mg/50 mL containers NDC 0009-3382-02 Exposure of pharmaceutical products to heat should be minimized. It is recommended that GALAXY plastic containers be stored at room temperature (25°C). Avoid temperatures above 30°C. Distributed by: Pfizer, Pharmacia&Upjohn Co, Division Of Pfizer Inc, New York, NY 10017. Revised: 2017

INDICATIONS Clindamycin is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Clindamycin is also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. Its use should be reserved for penicillin-allergic patients or other patients for whom, in the judgment of the physician, a penicillin is inappropriate. Because of the risk of colitis, as described in the BOXED WARNING, before selecting clindamycin, the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin). Anaerobes Serious respiratory tract infections such as empyema, anaerobic pneumonitis, and lung abscess; serious skin and soft tissue infections; septicemia; intra­abdominal infections such as peritonitis and intra-abdominal abscess (typically resulting from anaerobic organisms resident in the normal gastrointestinal tract); infections of the female pelvis and genital tract such as endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection. Streptococci Serious respiratory tract infections; serious skin and soft tissue infections. Staphylococci Serious respiratory tract infections; serious skin and soft tissue infections. Pneumococci Serious respiratory tract infections. Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CLEOCIN HCl and other antibacterial drugs, CLEOCIN HCl should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. DOSAGE AND ADMINISTRATION If significant diarrhea occurs during therapy, this antibiotic should be discontinued (see BOXED WARNING). Adults Serious infections - 150 to 300 mg every 6 hours. More severe infections – 300 to 450 mg every 6 hours. Pediatric Patients: Serious infections - 8 to 16 mg/kg/day (4 to 8 mg/lb/day) divided into three or four equal doses. More severe infections - 16 to 20 mg/kg/day (8 to 10 mg/lb/day) divided into three or four equal doses. To avoid the possibility of esophageal irritation, CLEOCIN HCl Capsules should be taken with a full glass of water. Serious infections due to anaerobic bacteria are usually treated with CLEOCIN PHOSPHATE® Sterile Solution. However, in clinically appropriate circumstances, the physician may elect to initiate treatment or continue treatment with CLEOCIN HCl Capsules. In cases of β-hemolytic streptococcal infections, treatment should continue for at least 10 days. HOW SUPPLIED CLEOCIN HCl Capsules are available in the following strengths, colors and sizes: 75 mg Green Bottles of 100 NDC 0009-0331-02 150 mg Light Blue and Green Bottles of 100 NDC 0009-0225-02 Unit dose package of 100 NDC 0009-0225-03 300 mg Light Blue Bottles of 100 NDC 0009-0395-14 Unit dose package of 100 NDC 0009-0395-02 Store at controlled room temperature 20° to 25° C (68° to 77° F) [see USP]. Distributed by; Pharmacia & Upjohn Co, Division of Pfizer Inc., NY, NY 10017. Revised July 2016

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.

PATIENT INFORMATION Patients should be counseled that antibacterial drugs including CLEOCIN PHOSPHATE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CLEOCIN PHOSPHATE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN PHOSPHATE or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. INSTRUCTIONS FOR USE FOR ADD-VANTAGE SYSTEM.FOR IV USE ONLY CLEOCIN PHOSPHATE® Clindamycin Sterile Solution for Injection, USP in ADD-Vantage® Vial To Open Diluent Container: Peel overwrap from the corner and remove container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. To Assemble Vial and Flexible Diluent Container: (Use Aseptic Technique) Remove the protective covers from the top of the vial and the vial port on the diluent container as follows: To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (SEE FIGURE 1.), then pull straight up to remove the cap. (SEE FIGURE 2.) NOTE: Once the breakaway cap has been removed, DO NOT ACCESS VIAL WITH SYRINGE. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (SEE FIGURE 3.) Screw the vial into the vial port until it will go no farther. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click. (SEE FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once the vial is seated, do not attempt to remove it. (SEE FIGURE 4.) Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly. Label appropriately. To Prepare Admixture: Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (SEE FIGURE 5.) Pull the inner cap from the drug vial. (SEE FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix. Mix container contents thoroughly and use within the specified time. Preparation for Administration: (Use Aseptic Technique) Confirm the activation and admixture of vial contents. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired. Close flow control clamp of administration set. Remove cover from outlet port at bottom of container. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger. Squeeze and release drip chamber to establish proper fluid level in chamber. Open flow control clamp and clear air from set. Close clamp. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture. Regulate rate of administration with flow control clamp. WARNING: Do not use flexible container in series connections.

PATIENT INFORMATION Patients should be counseled that antibacterial drugs, including CLEOCIN HCl, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CLEOCIN HCl is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN HCl or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

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).

OVERDOSE Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg. In the mice, convulsions and depression were observed. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. CONTRAINDICATIONS This drug is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.

OVERDOSE Significant mortality was observed in mice at an intravenous dose of 855 mg/kg and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg. In the mice, convulsions and depression were observed. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. CONTRAINDICATIONS CLEOCIN HCl is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.

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.

SIDE EFFECTS The following reactions have been reported with the use of clindamycin. Infections and Infestations: Clostridium difficile colitis Gastrointestinal: Antibiotic-associated colitis (see WARNINGS), pseudomembranous colitis, abdominal pain, nausea, and vomiting. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). An unpleasant or metallic taste has been reported after intravenous administration of the higher doses of clindamycin phosphate. Hypersensitivity Reactions: Maculopapular 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. Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (see WARNINGS). Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. Anaphylactic shock, anaphylactic reaction and hypersensitivity have also been reported (see WARNINGS). Skin and Mucous Membranes: Pruritus, vaginitis, angioedema and rare instances of exfoliative dermatitis have been reported (see Hypersensitivity Reactions). Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy. 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. Hematopoietic: Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agranulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing. Immune System: Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported. Local Reactions: Injection site irritation, pain, induration and sterile abscess have been reported after intramuscular injection and thrombophlebitis after intravenous infusion. Reactions can be minimized or avoided by giving deep intramuscular injections and avoiding prolonged use of indwelling intravenous catheters. Musculoskeletal: Polyarthritis cases have been reported. Cardiovascular: Cardiopulmonary arrest and hypotension have been reported following too rapid intravenous administration (see DOSAGE AND ADMINISTRATION). DRUG INTERACTIONS 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. Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent by CYP3A5, to the major metabolite clindamycin sulfoxide and minor metabolite N-desmethylclindamycin. Therefore inhibitors of CYP3A4 and CYP3A5 may increase plasma concentrations of clindamycin and inducers of these isoenzymes may reduce plasma concentrations of clindamycin. In the presence of strong CYP3A4 inhibitors, monitor for adverse reactions. In the presence of strong CYP3A4 inducers such as rifampicin, monitor for loss of effectiveness. In vitro studies indicate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP2D6 and only moderately inhibits CYP3A4. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, the two drugs should not be administered concurrently.

SIDE EFFECTS The following reactions have been reported with the use of clindamycin. Infections and Infestations: Clostridium difficile colitis Gastrointestinal: Abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting, and diarrhea (see BOXED WARNING). The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS). Esophageal ulcer has been reported. An unpleasant or metallic taste has been reported after oral administration. Hypersensitivity Reactions: Generalized mild to moderate morbilliform-like (maculopapular) skin rashes are the most frequently reported adverse reactions. Vesiculobullous rashes, as well as urticaria, have been observed during drug therapy. Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (See WARNINGS). Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, anaphylactic shock, anaphylactic reaction and hypersensitivity have also been reported. Skin and Mucous Membranes: Pruritus, vaginitis, angioedema and rare instances of exfoliative dermatitis have been reported. (See Hypersensitivity Reactions.) Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy. 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. Hematopoietic: Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agranulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing. Immune System: Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported. Musculoskeletal: Cases of polyarthritis have been reported. DRUG INTERACTIONS 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. Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

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.

WARNINGS See BOX WARNING. Clostridium Difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN PHOSPHATE, 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. Anaphylactic And Severe Hypersensitivity Reactions Anaphylactic shock and anaphylactic reactions have been reported (see ADVERSE REACTIONS). Severe hypersensitivity reactions, including severe skin reactions such as toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS), some with fatal outcome, have been reported(see ADVERSE REACTIONS). In case of such an anaphylactic or severe hypersensitivity reaction, discontinue treatment permanently and institute appropriate therapy. A careful inquiry should be made concerning previous sensitivities to drugs and other allergens. Benzyl Alcohol Toxicity In Pediatric Patients (“Gasping Syndrome”) This product contains benzyl alcohol as a preservative. The preservative benzyl alcohol has been associated with serious adverse events, including the “ggasping syndrome”, and death in pediatric patients. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “asping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys’ capacity to detoxify the chemical. Premature and low birth weight infants may be more likely to develop toxicity. Usage In Meningitis Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis. PRECAUTIONS General Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. CLEOCIN PHOSPHATE products should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. CLEOCIN PHOSPHATE should be prescribed with caution in atopic individuals. Certain infections may require incision and drainage or other indicated surgical procedures in addition to antibiotic therapy. The use of CLEOCIN PHOSPHATE may result in overgrowth of nonsusceptible organisms-particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. CLEOCIN PHOSPHATE should not be injected intravenously undiluted as a bolus, but should be infused over at least 10-60 minutes as directed in the DOSAGE AND ADMINISTRATIONsection. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease. Prescribing CLEOCIN PHOSPHATE in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients Patients should be counseled that antibacterial drugs including CLEOCIN PHOSPHATE should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When CLEOCIN PHOSPHATE is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN PHOSPHATE or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Laboratory Tests During prolonged therapy periodic liver and kidney function tests and blood counts should be performed. 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 Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.1 times the highest recommended adult human dose based on mg/m2) revealed no effects on fertility or mating ability. 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. Clindamycin should be used during the first trimester of pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (2.1 and 1.1 times the highest recommended adult human dose based on mg/m2, respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (0.9 and 0.5 times the highest recommended adult human dose based on mg/m2 , respectively) revealed no evidence of teratogenicity. CLEOCIN PHOSPHATE Sterile Solution contains benzyl alcohol. Benzyl alcohol can cross the placenta. see WARNINGS. Nursing Mothers Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL at dosages of 150 mg orally to 600 mg intravenously. 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 When CLEOCIN PHOSPHATE Sterile Solution is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable. Usage In Newborns And Infants This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "Gasping Syndrome" in premature infants. see WARNINGS. The potential for the toxic effect in the pediatric population from chemicals that may leach from the single dose premixed IV preparation in plastic has not been evaluated. see WARNINGS. Geriatric Use Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

WARNINGS See BOXED WARNING Clostridium Difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN HCl, 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. Anaphylactic And Severe Hypersensitivity Reactions Anaphylactic shock and anaphylactic reactions have been reported (see ADVERSE REACTIONS). Severe hypersensitivity reactions, including severe skin reactions such as toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS), some with fatal outcome, have been reported (see ADVERSE REACTIONS). In case of such an anaphylactic or severe hypersensitivity reaction, discontinue treatment permanently and institute appropriate therapy. A careful inquiry should be made concerning previous sensitivities to drugs and other allergens. Usage In Meningitis Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis. PRECAUTIONS General Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. CLEOCIN HCl should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. CLEOCIN HCl should be prescribed with caution in atopic individuals. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. The use of CLEOCIN HCl occasionally results in overgrowth of nonsusceptible organisms—particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Clindamycin dosage modification may not be necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease. The 75 mg and 150 mg capsules contain FD&C yellow no. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow no. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Prescribing CLEOCIN HCl in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Laboratory Tests During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed. 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 Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.6 times the highest recommended adult human dose based on mg/m²) revealed no effects on fertility or mating ability. Pregnancy Teratogenic Effects Pregnancy Category B 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. Clindamycin should be used during the first trimester of pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (3.2 and 1.6 times the highest recommended adult human dose based on mg/m², respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 times the highest recommended adult human dose based on mg/m², respectively) revealed no evidence of teratogenicity. Nursing Mothers Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL. Because of the potential for serious adverse reactions in nursing infants, clindamycin should not be taken by nursing mothers. Pediatric Use When CLEOCIN HCl is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable. Geriatric Use Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly ( > 60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.