CLINDAMYCIN- clindamycin_injection, solution

CLINICAL PHARMACOLOGY
Biologically inactive clindamycin phosphate is converted to active clindamycin. By the end of short-term intravenous infusion, peak serum concentrations of active clindamycin are reached. After intramuscular injection of clindamycin phosphate, peak concentrations of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum concentration-time curves may be constructed from IV peak serum concentrations as given in Table 1 by application of elimination half-lives (see Excretion Serum concentrations of clindamycin can be maintained above the in vitro No significant concentrations of clindamycin are attained in the cerebrospinal fluid even in the presence of inflamed meninges. In vitro Biologically inactive clindamycin phosphate disappears from the serum with 6 minutes of the average elimination half-life; however, the average serum elimination half-life of active clindamycin is about 3 hours in adults and 2½ hours in pediatric patients. Patients with 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. Elderly Patients Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 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, the average elimination half-life is increased to approximately 4 hours (range 3. 1 h) in the elderly, compared to 3. 2 hours (range 2. 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 1 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 2 600 mg IV in 30 min q8h 10. 1 900 mg IV in 30 min q8h 14. 7 600 mg IM q12h * 9 Pediatric Patients (first dose) * 5 to 7 mg/kg IV in 1 hour 10 5 to 7 mg/kg IM 8 3 to 5 mg/kg IM 4 * 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 [see Indications and Usage (1) 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 The following in vitro 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 For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.
Distribution
Biologically inactive clindamycin phosphate is converted to active clindamycin. By the end of short-term intravenous infusion, peak serum concentrations of active clindamycin are reached. After intramuscular injection of clindamycin phosphate, peak concentrations of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum concentration-time curves may be constructed from IV peak serum concentrations as given in Table 1 by application of elimination half-lives (see Excretion Serum concentrations of clindamycin can be maintained above the in vitro No significant concentrations of clindamycin are attained in the cerebrospinal fluid even in the presence of inflamed meninges.
Metabolism
In vitro
Excretion
Biologically inactive clindamycin phosphate disappears from the serum with 6 minutes of the average elimination half-life; however, the average serum elimination half-life of active clindamycin is about 3 hours in adults and 2½ hours in pediatric patients.
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 [see Indications and Usage (1) 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 The following in vitro 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 For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Clindamycin Injection, USP is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Clindamycin Injection, USP 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 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. Clindamycin Injection, USP 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, E. faecalis Staphylococcus aureus. Skin and skin structure infections caused by Streptococcus pyogenes, Staphylococcus aureus 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 Enterococcus faecalis Bone and joint infections including acute hematogenous osteomyelitis caused by Staphylococcus aureus To reduce the development of drug-resistant bacteria and maintain the effectiveness of clindamycin injection, USP and other antibacterial drugs, clindamycin injection, USP 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.

If diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING Clindamycin phosphate Intramuscular administration should be used undiluted. Clindamycin phosphate Intravenous administration should be diluted Dilution for Intravenous use and Intravenous infusion rates Adults: Bacteroides fragilis Peptococcus Clostridium Clostridium perfringens 600 to 1,200 mg/day in 2, 3 or 4 equal doses. More severe infections, particularly those due to proven or suspected Bacteroides fragilis,Peptococcus Clostridium Clostridium perfringens 1,200 to 2,700 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 4,800 mg daily have been given intravenously to adults. See Dilution for Intravenous use and Intravenous Infusion Rates 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 intravenous infusion as follows: To maintain serum clindamycin levels Rapid infusion rate Maintenance infusion rate Above 4 mcg/mL Above 5 mcg/mL Above 6 mcg/mL 10 mg/min for 30 min 15 mg/min for 30 min 20 mg/min for 30 min 0. 75 mg/min 1 mg/min 1. 25 mg/min Neonates (less than 1 month): Pediatric patients 1 month of age to 16 years: 2 2 Parenteral therapy may be changed to clindamycin palmitate hydrochloride for oral solution or clindamycin hydrochloride capsules when the condition warrants and at the discretion of the physician. In cases of beta-hemolytic streptococcal infections, treatment should be continued for at least 10 days. Dilution for Intravenous use and Intravenous 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. Dose Diluent Time 300 mg 600 mg 900 mg 1,200 mg 50 mL 50 mL 50 to 100 mL 100 mL 10 min 20 min 30 min 40 min Administration of more than 1,200 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: 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www. gov/medwatch. Room Temperature: Refrigeration: 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: Frozen solutions should be thawed at room temperature and not refrozen.

Anaphylactic and Severe Hypersensitivity Reactions
Anaphylactic shock and anaphylactic reactions have been reported ( 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 ( 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.
ADVERSE REACTIONS
The following reactions have been reported with the use of clindamycin. Infections and Infestations: Clostridium difficile Gastrointestinal: WARNINGS WARNINGS Hypersensitivity Reactions: Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (see WARNINGS WARNINGS Skin and Mucous Membranes: Hypersensitivity Reactions Liver: Renal: Hematopoietic: Immune System: Local Reactions: Musculoskeletal: Cardiovascular: DOSAGE AND ADMINISTRATION

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

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 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.">Specific Populations
Patients with 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. Elderly Patients Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 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, the average elimination half-life is increased to approximately 4 hours (range 3.4 to 5.1 h) in the elderly, compared to 3.2 hours (range 2.1 to 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 1 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 2 600 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 to 7 mg/kg IV in 1 hour 10 5 to 7 mg/kg IM 8 3 to 5 mg/kg IM 4 *
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/m 2 2 Clindamycin injection 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 clindamycin injection 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 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.

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

Room Temperature: Refrigeration: 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: Frozen solutions should be thawed at room temperature and not refrozen.

WARNINGS
See BOXED WARNING Clostridium difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile Anaphylactic shock and anaphylactic reactions have been reported ( 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 ( 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. This product contains benzyl alcohol as a preservative. The preservative benzyl alcohol has been associated with serious adverse events, including the “gasping 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 “gasping 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-.
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/m 2
OVERDOSAGE
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 2,618 mg/kg. In the mice, convulsions and depression were observed. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum.
REFERENCES
Smith RB, Phillips JP: Evaluation of CLEOCIN HCl and CLEOCIN Phosphate in an Aged Population. Upjohn TR 8147-82-9122-021, December 1982. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India MAY 2018

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