Because clindamycin therapy has been asso- ciated with severe colitis which may end fatally, it should be reserved for serious infec- tions where less toxic antimicrobial agents are inappropriate, as described in the INDICA- TIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. Treatment with antibacterial agents alters the normal flora of the colon and may permit over- growth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis".

After the diagnosis of pseudomembranous colitis has been established, therapeutic mea- sures should be initiated. Mild cases of pseu- domembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to man- agement with fluids and electrolytes, protein supplementation, and treatment with an anti- bacterial drug clinically effective against C. dif- ficile colitis.

Diarrhea, colitis, and pseudomembranous colitis have been observed to begin up to sev- eral weeks following cessation of therapy with clindamycin.

DESCRIPTION

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.

CH3

Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.

Concentrations of clindamycin in the serum increased linearly with increased dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most indi- cated organisms for at least six hours following adminis- tration of the usually recommended doses. Clindamycin is widely distributed in body fluids and tissues (including bones). 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.

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.

No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges.

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, elimi- nation 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 function.

Microbiology: Clindamycin inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosome. It has activity against Gram-positive aerobes and anaer- obes as well as the Gram-negative anaerobes. Clinda- mycin is bacteriostatic. Cross-resistance between clin- damycin and lincomycin is complete. Antagonism in vitro has been demonstrated between clindamycin and erythromycin.

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 aerobes

Anaerobes

Prevotella melaninogenica Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus anaerobius Clostridium perfringens

The following in vitro data are available, but their clini- cal significance is unknown. At least 90% of the follow- ing microorganisms exhibit an in vitro minimum inhibi- tory concentration (MIC) less than or equal to the susceptible breakpoint for clindamycin. However, the safety and effectiveness of clindamycin in treating clini- cal infections due to these microorganisms have not been established in adequate and well-controlled clini- cal trials.

Gram-positive aerobes

dardized inoculum concentrations and standardized concentrations of clindamycin powder.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 also pro- vide reproducible estimates of the susceptibility of bac- teria to antimicrobial compounds. One such standard- ized procedure 2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of microorganisms to clindamycin. The disk diffusion interpretive criteria are provided in Table 1.

Table 1. Susceptibility Interpretive Criteria for Clindamycin

These interpretive standards for S. pneumoniae and other Strep- tococcus spp. are applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20 to 24 hours. These zone diameter interpretive standards are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and

incubated in 5% CO2 at 35degC for 20 to 24 hours. These interpretive criteria are for all anaerobic bacterial patho- gens; no organism specific interpretive criteria are available. NA=not applicable

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achiev- able. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorgan- ism is not fully susceptible to alternative, clinically feasi- ble 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, uncon- trolled technical factors from causing major discrepan- cies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the con- centrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard clin- damycin powder should provide the following range of

CH3 N

HCCl

CONHCH

organisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms

CH3CH2CH2

SCH3

HCl

Anaerobes

strains used for microbiological quality control are not clinically significant.

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-a-D- galacto-octopyranoside monohydrochloride.

CLINICAL PHARMACOLOGY

Human Pharmacology: 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 admin- istration 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.

Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function.

Micromonas ("Peptostreptococcus") micros Finegoldia ("Peptostreptococcus") magna Actinomyces israelii

SUSCEPTIBILITY TESTING METHODS:

NOTE:

Susceptibility testing by dilution methods requires the use of clindamycin susceptibility powder.

When available, the results of in vitro susceptibility tests should be provided to the physician as periodic reports that describe the susceptibility profile of nosoco- mial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentra- tions (MICs). These MICs provide estimates of the sus- ceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized proce- dure. Standardized procedures are based on a dilution method (broth and agar)1,2,3 or equivalent with stan-

Table 2. Acceptable Quality Control Ranges for Clindamycin to be Used in Validation of Susceptibility Test Results

Table 2. (continued)

NA = Not applicable This organism may be used for validation of susceptibility test results when testing Streptococcus spp. other than S. pneumoniae. This quality control range for S. pneumoniae is applicable only to tests performed by broth microdilution using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct colony suspension and incubated in ambient air at 35degC for 20 to 24 hours. This quality control zone diameter range is applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated with a direct colony suspension and incu-

bated in 5% CO2 at 35degC for 20 to 24 hours. ATCC (r) is a registered trademark of the American Type Culture Collection

Black
COMPOSITION ORDER # 22685	PRODUCT CLEOCIN HCL	COPY CODE # 810 570 928
CCS # 0225-01	NDC # 0009-0225-01	EDP # 692851	ITEM Insert
BOTTLE #	SIZE 10 x 10"	FOLDED SIZE 2.5 x 1"	DRAWING # PD2364
ADDITIONAL INFORMATION spine 4" from bottom	DATE 12/09/03	TYPESET BY KL/DHUFF

INDICATIONS AND USAGE

Clindamycin is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria.

Clindamycin is also indicated in the treatment of seri- ous 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 WARNING box, before selecting clin- damycin the physician should consider the nature of the infection and the suitability of less toxic alternatives (eg, erythromycin).

Anaerobes: Serious respiratory tract infections such as empyema, anaerobic pneumonitis and lung abscess; serious skin and soft tissue infections; septicemia; intra-abdominal infections such as peritonitis and intra-abdominal abscess (typically resulting from anaerobic organisms resident in the normal gastroin- testinal tract); infections of the female pelvis and geni- tal tract such as endometritis, nongonococcal tubo- ovarian abscess, pelvic cellulitis and postsurgical vaginal cuff infection.

Streptococci: Serious respiratory tract infections; seri- ous 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 deter-

mine 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 bacte- ria. 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.

CONTRAINDICATIONS

CLEOCIN HCl is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.

WARNINGS

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clin- damycin, and may range in severity from mild to life- threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic- associated colitis".

severe cases, consideration should be given to manage- ment with fluids and electrolytes, protein supplementa- tion, and treatment with an antibacterial drug clinically effective against C. difficile colitis.

A careful inquiry should be made concerning previous sensitivities to drugs and other allergens.

--Since clindamycin does not dif- fuse 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 sub- group 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.

Indicated surgical procedures should be performed in conjunction with antibiotic therapy.

The use of CLEOCIN HCl occasionally results in over- growth 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 neces- sary in patients with renal disease. In patients with mod- erate to severe liver disease, prolongation of clin- damycin 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 deter- minations 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 reac- tions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow no. 5 (tartrazine) sensitivity in the general popu- lation 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 prophylac- tic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resis- tant bacteria.

Information for Patients

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 pre- scribed 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 effec- tiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN HCl or other antibacte- rial drugs in the future.

Laboratory Tests

During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed.

Drug Interactions

Antagonism has been demonstrated between clin- damycin and erythromycin in vitro. Because of possible clinical significance, these two drugs should not be administered concurrently.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term studies in animals have not been per- formed with clindamycin to evaluate carcinogenic poten- tial. 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 rec- ommended adult human dose based on mg/m 2 ) revealed no effects on fertility or mating ability.

Pregnancy: Teratogenic effects

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 subcuta- neous doses of clindamycin up to 250 mg/kg/day (1.3

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduc- tion studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL.

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 suffi- cient 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 anti- biotics 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.

ADVERSE REACTIONS

The following reactions have been reported with the use of clindamycin.

Gastrointestinal: Abdominal pain, pseudomembranous colitis, esophagitis, nausea, vomiting and diarrhea (see WARNING box). The onset of pseudomembranous coli- tis symptoms may occur during or after antibacterial treatment (see WARNINGS).

Hypersensitivity Reactions:

Generalized mild to moder- ate morbilliform-like (maculopapular) skin rashes are the most frequently reported adverse reactions. Vesiculobullous rashes, as well as urticaria, have been observed during drug therapy. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, and a few cases of anaphylactoid reactions have also been reported.

Skin and Mucous Membranes: Pruritus, vaginitis, 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 dysfunc- tion as evidenced by azotemia, oliguria, and/or protein- uria has been observed in rare instances.

Hematopoietic:

Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agran- ulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the foregoing.

Musculoskeletal:

Rare instances of polyarthritis have been reported.

OVERDOSAGE

Significant mortality was observed in mice at an intra- venous dose of 855 mg/kg and in rats at an oral or sub- cutaneous 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.

DOSAGE AND ADMINISTRATION

If significant diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box).

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 usu- ally treated with CLEOCIN PHOSPHATE (r) Sterile Solution. However, in clinically appropriate circum- stances, the physician may elect to initiate treatment or continue treatment with CLEOCIN HCI Capsules.

In cases of b-hemolytic streptococcal infections, treat- ment should continue for at least 10 days.

HOW SUPPLIED

CLEOCIN HCl Capsules are available in the following strengths, colors and sizes:

mg Green

mg Light Blue and Green

mg Light Blue

Store at controlled room temperature 20deg to 25deg C (68deg to 77deg F) [see USP].

ANIMAL TOXICOLOGY

One year oral toxicity studies in Spartan Sprague- Dawley rats and beagle dogs at dose levels up to 300 mg/kg/day (approximately 1.6 and 5.4 times the highest recommended adult human dose based on mg/m2, respectively) have shown clindamycin to be well toler- ated. No appreciable difference in pathological findings has been observed between groups of animals treated with clindamycin and comparable control groups. Rats receiving clindamycin hydrochloride at 600 mg/kg/day (approximately 3.2 times the highest recommended adult human dose based on mg/m2) for 6 months toler- ated the drug well; however, dogs dosed at this level (approximately 10.8 times the highest recommended adult human dose based on mg/m2) vomited, would not eat, and lost weight.

REFERENCES

Black
COMPOSITION ORDER # 22685	PRODUCT CLEOCIN HCL	COPY CODE # 810 570 928
CCS # 0225-01	NDC # 0009-0225-01	EDP # 692851	ITEM Insert
BOTTLE #	SIZE 10 x 10"	FOLDED SIZE 2.5 x 1"	DRAWING # PD2364
ADDITIONAL INFORMATION spine 4" from bottom	DATE 12/09/03	TYPESET BY KL/DHUFF

To reduce the development of drug-resistant bacteria and main- tain the effectiveness of CLEOCIN PHOSPHATE and other antibac- terial drugs, CLEOCIN PHOSPHATE should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clindamycin, and may range in severity from mild to life-threatening. There- fore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administra- tion of antibacterial agents.

Because clindamycin 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 non- bacterial infections such as most upper respiratory tract infec- tions. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis". therapy with clindamycin.

CLEOCIN PHOSPHATE Sterile Solution in vials contains clin- damycin phosphate, a water soluble ester of clindamycin and phos- phoric acid. Each mL contains the equivalent of 150 mg clin- damycin, 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-a-D- galacto-Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-[ [ (1- methyl-4-propyl-2-pyrrolidinyl) carbonyl] amino]-1-thio-, 2-(dihy- drogen phosphate), (2S-trans)-.

The molecular formula is C18H34CIN208PS and the molecular weight is 504.96. The structural formula is represented below:

ADD-Vantage Vial is intended for intravenous use only after further dilution with appropriate volume of ADD-Vantage diluent base solution.

CLEOCIN PHOSPHATE IV Solution in the Galaxy(r) plastic container for intravenous use is composed of clindamycin phos- phate equivalent to 300, 600 and 900 mg of clindamycin premixed with 5% dextrose as a sterile solu- tion. 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 mul- tilayer plastic, PL 2501. Solutions in contact with the plastic con- tainer 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.

Biologically inactive clindamycin phosphate is rapidly converted to active clindamycin. By the end of short-term intravenous infusion, peak serum levels of active clindamycin are reached. Biologically inactive clindamycin phosphate disappears rapidly from the serum; the average elimi- nation half-life is 6 minutes; however, the serum elimination half-life

of active clindamycin is about 3 hours in adults and 21/2 hours in pediatric patients. 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 con- structed from IV peak serum levels as given in Table 1 by applica- tion of elimination half-lives listed above. 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. brospinal fluid even in the presence of inflamed meninges. 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, vol-

Table 1. Average Peak and Trough Serum Concentrations of Active Clindamycin After Dosing with Clindamycin Phosphate

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

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: Clindamycin inhibits bacterial protein synthesis by binding to the 50S subunit of the ribosome. It has activity against Gram-positive aerobes and anaerobes as well as the Gram-nega- tive anaerobes. Clindamycin is bacteriostatic. Cross-resistance between clindamycin and lincomycin is complete. Antagonism in vitro has been demonstrated between clindamycin and ery- thromycin. Clindamycin has been shown to be active against most of the iso- lates of the following microorganisms, both in vitro and in clinical infections, as described in the INDICATIONS AND USAGE section. Gram-positive aerobes

Staphylococcus aureus (methicillin-susceptible strains) Streptococcus pneumoniae (penicillin-susceptible strains) Streptococcus pyogenes

Prevotella melaninogenica Fusobacterium necrophorum Fusobacterium nucleatum Peptostreptococcus anaerobius Clostridium perfringens

The following in vitro data are available, but their clinical signifi- cance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for clindamycin. However, the safety and effectiveness of clindamycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Streptococcus agalactiae Streptococcus anginosus Streptococcus oralis Streptococcus mitis

Micromonas ("Peptostreptococcus") micros Finegoldia ("Peptostreptococcus") magna Actinomyces israelii

Susceptibility testing by dilution methods requires the use of clindamycin susceptibility powder.

When available, the results of in vitro susceptibility tests should be provided 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 the most effective antimicrobial. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimi- crobial compounds. The MICs should be determined using a stan- dardized procedure. Standardized procedures are based on a dilu- tion method (broth and agar)1,2,3 or equivalent with standardized inoculum concentrations and standardized concentrations of clin- damycin powder. The MIC values should be interpreted according to the criteria provided in Table 2. Diffusion Techniques: Quantitative methods that require the mea- surement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 requires the use of standardized inocu- lum concentrations. This procedure uses paper disks impregnated with 2 mcg of clindamycin to test the susceptibility of microorgan- isms to clindamycin. The disk diffusion interpretive criteria are pro- vided in Table 2. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indi- cates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically fea- sible drugs, the test should be repeated. This category implies pos- sible clinical applicability in body sites where the drug is physio- logically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that pre- vents small, uncontrolled technical factors from causing major dis- crepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial com- pound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard clindamycin powder should provide the following range of values noted in Table 3. NOTE: Quality control microorganisms are specific strains of organisms with intrin- sic biological properties relating to resistance mechanisms and their genetic expression within bacteria; the specific strains used for microbiological quality control are not clinically significant.

incubated in 5% CO2 at 35degC for 20 to 24 hours. These interpretive criteria are for all anaerobic bacterial pathogens; no organism specific interpretive criteria are avail- able. NA=not applicable

Table 3. Acceptable Quality Control Ranges for Clindamycin to be Used in Validation of Susceptibility

incubated in 5% CO2 at 35degC for 20 to 24 hours. ATCC(r) is a registered trademark of the American Type Culture Collection

CLEOCIN PHOSPHATE products are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. CLEOCIN PHOSPHATE products are also indicated in the treat- ment of serious infections due to susceptible strains of strepto- cocci, 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 WARNING box, before selecting clindamycin the physician should consider the nature of the infection and the suit- ability 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 organ- isms 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 pyo- genes, 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-abdom- inal 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 infec- tions due to susceptible organisms. To reduce the development of drug-resistant bacteria and main- Cleocin Phosphate

tain the effectiveness of CLEOCIN PHOSPHATE and other antibac- terial 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.

This drug is contraindicated in individuals with a history of hyper- sensitivity to preparations containing clindamycin or lincomycin.

See WARNING box. "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been estab- lished, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementa- tion, and treatment with an antibacterial drug clinically effective against C. difficile colitis. A careful inquiry should be made concerning previous sensitivi- ties to drugs and other allergens. This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "Gasping Syndrome" in premature infants. (See PRECAUTIONS-Pediatric Use.)

-- Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

SERIOUS ANAPHYLACTOID REACTIONS REQUIRE IMMEDI- ATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN Cleocin Phosphate

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 imme- diate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CLEOCIN PHOS- PHATE or other antibacterial drugs in the future.

During prolonged therapy periodic liver and kidney function tests and blood counts should be performed.

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, the two drugs should not be administered concurrently. Carcinogenesis, Mutagenesis, Impairment of Fertility Long term studies in animals have not been performed with clin- damycin to evaluate carcinogenic potential. Genotoxicity tests per- formed 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 category B 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, respec- tively) 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 terato- genicity. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

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. Because of the potential for adverse reactions due to clindamycin in neonates (see Pediatric Use), the decision to dis- continue the drug should be made, taking into account the impor- tance of the drug to the mother.

Hemodialysis and peritoneal dialysis are not effective in remov- ing clindamycin from the serum.

If diarrhea occurs during therapy, this antibiotic should be dis- continued (see WARNING box).

Serious infections: 600-1200 mg/day in 2, 3 or 4 equal doses. More severe infections: 1200-2700 mg/day in 2, 3 or 4 equal doses. In life-threatening situations due to either aerobes or anaer- obes these doses may be increased. Doses of as much as 4800 mg daily have been given intravenously to adults. See Dilution and 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 Maintenance clindamycin levels Rapid infusion rate 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

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 alter- native 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 infec- tions. Parenteral therapy may be changed to oral CLEOCIN PEDI- ATRIC(r) Flavored Granules (clindamycin palmitate hydrochloride) or CLEOCIN HCl(r) Capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician. In cases of b-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

Dilution and Infusion Rates: Clindamycin phosphate must be diluted prior to IV administration. The concentration of clin- damycin in diluent for infusion should not exceed 18 mg per mL. Infusion rates should not exceed 30 mg per minute.

for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use unless solution is clear and seal is intact.

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 of CLEOCIN PHOSPHATE in ADD-Vantage System -- For IV Use Only. CLEOCIN PHOSPHATE 600 mg and 900 mg may be reconstituted in 50 mL or 100 mL, respectively, of Dextrose Injection 5% or Sodium Chloride Injection 0.9% in the ADD-diluent container. Refer to separate instructions for ADD- Vantage++ System.

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 0009-0902-11 1-60 mL Pharmacy Bulk Package NDC 0009-0728-05 CLEOCIN PHOSPHATE is supplied in ADD-Vantage vials as follows:

0009-3124-03 25-4 mL vials 600 mg 50 mL 0009-3447-03 25-6 mL vials 900 mg 100 mL Store at controlled room temperature 20deg to 25degC (68deg to 77degF) [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. When CLEOCIN PHOSPHATE Sterile Solution is administered to It is recommended that Galaxy plastic containers be stored at room AND INTRAVENOUS CORTICOSTEROIDS SHOULD ALSO BE ADMINISTERED AS INDICATED.

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 cau- tion in individuals with a history of gastrointestinal disease, partic- ularly colitis. CLEOCIN PHOSPHATE should be prescribed with caution in atopic individuals. Certain infections may require incision and drainage or other indi- cated surgical procedures in addition to antibiotic therapy. The use of CLEOCIN PHOSPHATE may result in overgrowth of nonsusceptible organisms -- particularly yeasts. Should superin- fections occur, appropriate measures should be taken as indicated by the clinical situation. 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.

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 bac- terial infection, patients should be told that although it is common to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable.

This product contains benzyl alcohol as a preservative. Benzyl alcohol has been associated with a fatal "Gasping Syndrome" in premature infants. The potential for the toxic effect in the pediatric population from chemicals that may leach from the single dose premixed IV prepa- ration in plastic has not been evaluated.

Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond dif- ferently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibi- otics 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 clini- cally important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

The following reactions have been reported with the use of clin- damycin. Gastrointestinal: Antibiotic-associated colitis (see WARNINGS), pseudomembranous colitis, abdominal pain, nausea, and vomiting. The onset of pseudomembranous colitis symptoms may occur dur- ing or after antibacterial treatment (see WARNINGS). An unpleas- ant or metallic taste occasionally has been reported after intra- venous administration of the higher doses of clindamycin phosphate.

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. Rare instances of erythema mul- tiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. A few cases of anaphylactoid reac- tions have been reported. If a hypersensitivity reaction occurs, the drug should be discontinued. The usual agents (epinephrine, corti- costeroids, antihistamines) should be available for emergency treatment of serious reactions.

Skin and Mucous Membranes: Pruritus, vaginitis, and rare instances of exfoliative dermatitis have been reported (see Hypersensitivity Reactions).

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

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

Transient neutropenia (leukopenia) and eosino- philia have been reported. Reports of agranulocytosis and throm- bocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of the fore- going.

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.

Cardiovascular: Rare instances of cardiopulmonary arrest and hypotension have been reported following too rapid intravenous administration. (See DOSAGE AND ADMINISTRATION section.)

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 depres- sion were observed. 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 partic- ulate 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 demon- strated no inactivation or incompatibility with the use of CLEOCIN PHOSPHATE Sterile Solution (clindamycin phosphate) in IV solu- tions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usu- ally used clinically. No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or car- benicillin. 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.

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, demon- strated physical and chemical stability for at least 16 days at 25degC. Also, 18 mg/mL (equivalent to clindamycin base) in dextrose injec- tion 5%, in minibags, demonstrated physical and chemical sta- bility for at least 16 days at 25degC. 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, demon- strated physical and chemical stability for at least 32 days at 4degC. IMPORTANT: This chemical stability information in no way indi- cates 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 -10degC. Frozen solutions should be thawed at room temperature and not refrozen.

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 CON- TENTS OF VIAL PROMPTLY. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 24 HOURS AFTER INITIAL ENTRY.

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 temperature (25degC). Avoid temperatures above 30degC.

One year oral toxicity studies in Spartan Sprague-Dawley rats and beagle dogs at dose levels up to 300 mg/kg/day (approximately 1.1 and 3.6 times the highest recommended adult human dose based on mg/m2, respectively) have shown clindamycin to be well tolerated. No appreciable difference in pathological findings has been observed between groups of animals treated with clindamycin and comparable control groups. Rats receiving clindamycin hydrochloride at 600 mg/kg/day (approximately 2.1 times the high- est recommended adult human dose based on mg/m2) for 6 months tolerated the drug well; however, dogs dosed at this level (approx- imately 7.2 times the highest recommended adult human dose based on mg/m2) vomited, would not eat, and lost weight. Pharmacia & Upjohn Company A subsidiary of Pharmacia Corporation 810 020 241B Kalamazoo, MI 49001, USA 692843 Revised October 2003 0775-26

ADD-Vantage is a registered trademark of Abbott Laboratories. CLEOCIN PHOSPHATE IV Solution in the Galaxy plastic contain- ers is manufactured for Pharmacia & Upjohn Company by Baxter Healthcare Corporation, Deerfield, IL 60015.

Galaxy is a trademark of Baxter International, Inc. and is regis- tered in the US Patent Office.