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Information on Clindamycin Injection USP, its indications, contraindications, dosage, compatibility with other products, and potential adverse effects. It is essential for healthcare professionals and students in pharmacy, nursing, or medical fields.
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150 mg/mL clindamycin (as clindamycin phosphate) Sterile solution Antibiotic Sandoz Canada Inc. Date of Revision: May 1 5 , 201 9 1 10 rue de Lauzon Boucherville, QC, Canada J4B 1E Submission Control Number: 225904
Lower respiratory infections including pneumonia, empyema, and lung abscess when caused by anaerobes, Streptococcus pneumoniae , other streptococci (except Enterococcus faecalis ) and Staphylococcus aureus. Skin and skin structure infections including cellulitis, abscesses, and wound infections when caused by Streptococcus pyogenes , Staphylococcus aureus and anaerobes. Gynecological infections including endometritis, pelvic cellulitis, vaginal cuff infections, non- gonococcal tubo-ovarian abscess, salpingitis, and pelvic inflammatory disease when caused by susceptible anaerobes or Chlamydia trachomatis. Clindamycin should be given in conjunction with an antibiotic of appropriate gram negative aerobic spectrum. Intra-abdominal infections including peritonitis and abdominal abscess when caused by susceptible anaerobes. Clindamycin should be given in conjunction with an antibiotic of appropriate gram negative aerobic spectrum. Septicemia caused by Staphylococcus aureus , streptococci (except Enterococcus faecalis ) and susceptible anaerobes, where the bactericidal efficacy of clindamycin against the infecting organism has been determined in vitro at achievable serum levels. Bone and joint infections including osteomyelitis and septic arthritis when caused by sensitive strains of Staphylococcus aureus and anaerobes. Pneumocystis jiroveci pneumonia in patients with AIDS. Clindamycin in combination with primaquine may be used in patients who are intolerant to, or fail to respond to conventional therapy. Note: Clindamycin Injection USP is not indicated in the treatment of meningitis since it penetrates poorly into cerebrospinal fluid, even in the presence of inflamed meninges. Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin. Indicated surgical procedures and drainage should be performed in conjunction with antibiotic therapy. 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 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. Geriatrics (> 65 years of age):
Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. Pediatrics (birth up to 18 years of age): It is not known if use of clindamycin in the pediatric population is associated with differences in safety or effectiveness compared with adult patients. CONTRAINDICATIONS Clindamycin Injection USP (clindamycin phosphate) is contraindicated in patients with a known hypersensitivity to preparations containing clindamycin or lincomycin or to any ingredient in the formulation or component of the formulation. WARNINGS AND PRECAUTIONS General In patients with G- 6 - PD deficiency, the combination of clindamycin with primaquine may cause hemolytic reactions. Reference should also be made to the primaquine product monograph for other possible risk groups for other hematologic reactions (see ADVERSE REACTIONS). If patients should develop serious hematologic adverse effects, reducing the dosage regimen of primaquine and/or Clindamycin Injection USP should be considered (see DOSAGE and ADMINISTRATION). Clindamycin Injection USP (clindamycin phosphate) should be prescribed with caution in atopic individuals. Clindamycin Injection USP must be diluted for intravenous administration. It should not be injected undiluted as an intravenous bolus (see DOSAGE and ADMINISTRATION). The use of antibiotics occasionally results in overgrowth of nonsusceptible organisms, particularly yeasts. Should superinfections occur, appropriate measures should be taken as dictated by the clinical situation. Care should be exercised when treating patients with multiple medications (see DRUG INTERACTIONS). Gastrointestinal Clindamycin Injection USP should be prescribed with caution in patients with a history of gastrointestinal disease, particularly colitis, inflammatory bowel disease (including regional enteritis and ulcerative colitis), or a history of antibiotic-associated colitis (including pseudomembranous colitis).
Prescribing Clindamycin Injection USP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria. Special Populations Pregnant Women: There are no adequate and well-controlled studies in pregnant women. Safety for use in pregnancy has not been established. Clindamycin should not be used in pregnancy unless clearly needed and unless the expected benefits to the mother outweigh any potential risks to the fetus. Clindamycin crosses the placenta in humans. After multiple doses, amniotic fluid concentrations were approximately 30% of maternal blood concentrations. Clindamycin was widely distributed in fetal tissues with the highest concentration found in liver. Clindamycin Injection USP multidose formulation contains benzyl alcohol. The preservative benzyl alcohol can cross the placenta (see WARNINGS AND PRECAUTIONS). Reproduction studies have been performed in rats and mice using subcutaneous and oral doses of clindamycin ranging from 20 to 600 mg/kg/day and have revealed no evidence of impaired fertility or harm to the foetus due to clindamycin except at doses that caused maternal toxicity. In one mouse strain, cleft palates were observed in treated foetuses; this response was not produced in other mouse strains or in other species, and therefore may be a strain specific effect. Oral and subcutaneous reproductive toxicity studies in rats and rabbits revealed no evidence of impaired fertility or harm to the fetus due to clindamycin, except at doses that caused maternal toxicity. Animal reproduction studies are not always predictive of human response. Nursing Women: Clindamycin has been reported to appear in human breast milk in the range of 0.7 to 3.8 mcg/mL at doses of 150 mg orally to 600 mg intravenously. Because of the potential for serious adverse reactions in nursing infants, clindamycin should not be administered to nursing mothers. Pediatrics Benzyl Alcohol Toxicity Clindamycin Injection USP multidose formulation contains benzyl alcohol. The preservative benzyl alcohol has been associated with serious adverse events, including the "gasping syndrome" and death in pediatric patients. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis and gasping respirations) has been reported in preterm and low birth weight newborns. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia and cardiovascular collapse. 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 hepatic and renal capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When Clindamycin Injection USP is administered to the pediatric population (birth to 16 years) appropriate monitoring of organ system functions is desirable. Geriatrics (>60 years of age): Experience has demonstrated that antibiotic-associated colitis may occur more frequently and with increased severity among elderly (> 60 years) and debilitated patients. These patients should be carefully monitored for the development of diarrhea. Monitoring and Laboratory Tests Periodic liver and kidney function tests and blood counts should be performed during prolonged therapy when treating patients with severe liver disease. Routine blood examinations should be done during therapy with primaquine to monitor potential hematologic toxicities. Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate. ADVERSE REACTIONS Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Adverse drug reaction frequencies for the three clindamycin formulations (clindamycin capsules, clindamycin granules for oral solution and clindamycin injection) are based on the clinical data sources from the original drug submission and on the total number of patients enrolled in the clinical trials (N=1787). Adverse drug reactions that were considered causally related to clindamycin and observed in ≥ 1% of patients are presented below in Table 1. They are listed according to MedDRA system organ class. Table 1. Adverse Drug Reactions Occurring in ≥ 1% of Patients treated with clindamycin within the Original Clinical Trials
Immune system disorders: Generalized mild to moderate morbilliform-like skin rashes, anaphylactic shock, anaphylactoid reactions, anaphylactic reactions, hypersensitivity, and drug reaction with eosinophilia and systemic symptoms (DRESS). Infections and infestations: Clostridium difficile colitis Musculoskeletal: Polyarthritis Renal and urinary disorders: Renal dysfunction as evidenced by azotemia, oliguria and/or proteinuria Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), erythema multiforme, dermatitis exfoliative, dermatitis bullous, dermatitis vesiculobullous, rash morbilliform, vaginal infection, vaginitis, acute generalized exanthematous pustulosis (AGEP), angioedema. Vascular disorders: Thrombophlebitis has been seen with rapid intravenous administration (see DOSAGE AND ADMINISTRATION). DRUG INTERACTIONS Overview Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent CYP3A5, to the major metabolite clindamycin sulfoxide and minor metabolite, N-desmethylclindamycin. Therefore inhibitors of CYP3A4 and CYP3A5 may reduce clindamycin clearance and inducers of these isoenzymes may increase clindamycin clearance. In the presence of strong CYP3A4 inducers such as rifampin, 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. Therefore, clinically important interactions between clindamycin and coadministered drugs metabolized by these CYP enzymes are unlikely. Clindamycin has been shown to have neuromuscular blocking properties and potential antagonism with erythromycin and aminoglycosides (see Table 2). In a clindamycin/primaquine combination study, serious hematologic toxicity has been observed, but the contribution of clindamycin, if any, is unknown (see ADVERSE REACTIONS). For other physicochemical interactions, please see to compatibility / incompatibility information in section DOSAGE AND ADMINISTRATION. Drug-Drug Interactions The drugs listed in the table below are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction. Table 2. Established or Potential Drug-Drug Interactions Proper name Ref Effect Clinical comment Neuromuscular blocking agents CS Clindamycin has been shown to have Use with caution in patients receiving these
Proper name Ref Effect Clinical comment Examples include: atracurium, doxacurium, pancuronium, vecuronium neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. agents concurrently. aminoglycosides T Clindamycin is reported to antagonize bactericidal activity of aminoglycosides in vitro. In vivo antagonism has not been demonstrated. erythromycin T Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Clindamycin and erythromycin may compete for the same protein binding site in bacteria. Due to possible clinical significance the two drugs should not be administered concurrently. Inhibitors of CYP3A4, CYP3A T Clearance of clindamycin may be reduced. Inducers of CYP3A4, CYP3A T Clearance of clindamycin may be increased. Monitor for loss of effectiveness. Strong inducers of CYP3A4 such as rifampin CS and CT Rifampin appears to dramatically decrease the serum clindamycin concentration. Serum clindamycin levels and effectiveness should be carefully monitored. A clinically relevant effect of clindamycin on rifampin concentrations is not expected. Legend : CS = Case Study; CT = Clinical Trial; T = Theoretical Drug-Food Interactions Interactions with food have not been established. Drug-Herb Interactions Efficacy of clindamycin should be closely monitored in patients using concomitant St. John’s Wort, a CYP3A4 inducer.
Neonates under one month of age (IM or IV Administration) 10 - 20 mg/kg/day in 3 or 4 equal doses. The lower dosage may be adequate for small prematures. Table 3. IM or IV Administration in Neonates Weight Age Dose Route < 2 kg 0 - 7 days 5 mg/kg q12h IV < 2 kg 8 - 30 days 5 mg/kg q8h IV ≥ 2 kg 0 - 7 days 5 mg/kg q8h IV ≥ 2 kg 8 - 30 days 5 mg/kg q6h IV NOTE: Clindamycin Injection USP multidose formulation should be administered with caution to newborn infants less than 30 days of age. This product contains benzyl alcohol which has been associated with the fatal “gasping syndrome” in newborn infants. Preterm and low-birth weight infants may be more likely to develop toxicity (see WARNINGS AND PRECAUTIONS). Administration Injection site irritation can be minimized by deep IM injection and avoidance of indwelling intravenous catheters. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. IM Administration Clindamycin Injection USP should be used undiluted. IV Administration Clindamycin Injection USP should be diluted. Dilution for IV use and Infusion Rates Clindamycin Injection USP must be diluted prior to intravenous administration (see Compatibility with other products for a listing of infusion solutions). The concentration in diluent for infusion should not exceed 18 mg/mL. Infusion rates should NOT EXCEED 30 MG PER MINUTE as indicated below: Table 4. Dilution and infusion rates Dose (mg) Diluent (mL) Time (minutes) 300 50 10 600 50 20 900 100 30 1200 100 45 Administration of more than 1200 mg in a single 1-hour infusion is not recommended. Alternatively, the drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:
Table 5. Infusion rates per clindamycin levels 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. Compatibility with other products Clindamycin was found to be compatible over a period of 24 hours when 4 mL (600 mg) of clindamycin was diluted with 1000 mL of the following commonly used infusion solutions; Sodium chloride 0.9% Dextrose 5% in water Clindamycin phosphate was not stable when added to Dextrose 5% in water plus vitamins. Although Clindamycin Injection USP is compatible with Dextrose 5% in water, it is not recommended that Clindamycin Injection USP be mixed with any infusion solutions containing B vitamins. Clindamycin phosphate has been shown to be compatible with gentamicin sulfate, tobramycin sulfate and amikacin sulfate. However, a precipitate has been observed when clindamycin and gentamicin are drawn undiluted into the same syringe before subsequent dilution. This precipitate appears to be a zinc-clindamycin complex which results from the zinc content of some gentamicin products. The particle size of the insoluble material is very small and disappears when the admixture is shaken. To avoid this problem, do not mix clindamycin and gentamicin sulfate prior to dilution. Rather, dilute one drug or the other, agitate the solution and then add the second antibiotic. Incompatibility with other products When combined with clindamycin in an infusion solution, ampicillin, phenytoin sodium, barbiturates, aminophyllin, calcium gluconate, magnesium sulfate, ceftriaxone sodium, and ciprofloxacin are each physically incompatible with clindamycin phosphate. Missed Dose: If a dose is missed, it should be taken as soon as remembered unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose. OVERDOSAGE Reported cases of overdosage with clindamycin phosphate have occurred very infrequently. The majority of these reports have involved infants and young children ranging in age from one day to three years. In this age group, doses as high as 2.4 grams have been used intravenously in 36 hours without observation of adverse reactions. Cardiorespiratory arrest and hypotension have been seen with rapid intravenous administration. Hemodialysis and peritoneal dialysis are not effective in
Bone IM 600 mg every 8 hours 1.44 mcg/g Bone IV 600 mg every 8 hours 0.75 mcg/g Bone Marrow IM 600 mg every 8 hours 10.83 mcg/g Bile IV 300 mg every 6 hours 2.70 mcg/g Synovial Fluid IM 300 mg every 8 hours 4.87 mcg/mL Synovial Fluid IM 150 mg every 12 hours 15.6 mcg/mL Pleural Fluid IV 450 mg every 8 hours 3.65 mcg/mL Table 7. Average Peak Serum Concentrations after Dosing with Clindamycin Phosphate Clindamycin Phosphate Dosage Regimen Clindamycin mcg/mL Clindamycin Phosphate mcg/mL Healthy Adult Male ( Post Equilibrium ) 300 mg IV in 10 min., q8h 7 15 600 mg IV in 20 min., q8h 10 23 900 mg IV in 30 min., q12h 11 29 1200 mg IV in 45 min., q12h 14 49 300 mg IM q8h 6 3 600 mg IM q12h* 9 3 Children (first dose)* 5 - 7 mg/kg IV in 1 hour 10 3 - 5 mg/kg IM 4 5 - 7 mg/kg IM 8
Renal Impairment Four patients with impaired renal function had a mean serum elimination half-life of 3.0 hours (range 1.7 to 5.6 hours) (see DETAILED PHARMACOLOGY). STORAGE AND STABILITY Store Clindamycin Injection USP at controlled room temperature (15 to 30 C). When diluted as recommended, Clindamycin Injection USP is compatible for 24 hours. SPECIAL HANDLING INSTRUCTIONS There are no special handling instructions. DOSAGE FORMS, COMPOSITION AND PACKAGING Composition Preservative-free Formulation: Each mL of Clindamycin Injection USP (clindamycin phosphate) contains clindamycin (as phosphate) 150 mg, disodium edetate 0.5 mg, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection. Multidose Formulation (benzyl alcohol-preserved) : Each mL of Clindamycin Injection USP (clindamycin phosphate) contains clindamycin (as phosphate) 150 mg, benzyl alcohol 0.9% as preservative, disodium edetate 0.5 mg, sodium hydroxide and/or hydrochloric acid to adjust pH and water for injection. Availability of Dosage forms Clindamycin Injection USP is available as a preservative-free and a benzyl alcohol-preserved Multidose Formulation as follows: Preservative-free Formulation:
Drug Substance Proper Name: Clindamycin phosphate Chemical Name: 1) 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), (2 S - trans );
The authorized indications were based on safety and efficacy clinical trials which were conducted with clindamycin phosphate. DETAILED PHARMACOLOGY Absorption and Excretion in Normal Human Volunteers Clindamycin phosphate is essentially inactive as the phosphate ester. Chemical or enzymatic hydrolysis of clindamycin phosphate is necessary to obtain the antibiotic activity of the clindamycin base. When tested with commercial human serum, clindamycin at a concentration of 1 mcg/mL of clindamycin free base is 92.8% protein bound. Intramuscular: Serum levels and urinary excretion of clindamycin and clindamycin phosphate were measured after the single administration of 300 mg (2 mL) base equivalent of clindamycin phosphate and multiple dose administration (300 mg every 8 hours for 14 days). The results are shown in Table 8. Table 8. Mean serum levels in mcg/mL of free clindamycin and clindamycin phosphate after 1st^ and 43rd^ IM dose of 300 mg (2 mL) of clindamycin phosphate Hours after Injection 1 st^ Injection 43 rd^ Injection 0.5 1 1.5 2 3 4 7.5 0 7. Free clindamycin
Clindamycin phosphate
The apparent half-life of clindamycin phosphate is 3.5 to 4.5 hours. Bioavailability of clindamycin from its phosphate was estimated to be greater than 75%, based on urinary excretion of free clindamycin bioactivity (0 to 12 hours). During the multiple dose studies (300 mg every 8 hours for 14 days), there was no evidence of drug accumulation or enzyme induction. Intravenous: Determination of serum levels of clindamycin and clindamycin phosphate after intravenous infusion of 300 to 1200 mg free base equivalents of clindamycin phosphate indicated that the concentrations of free clindamycin and intact phosphate were approximately equivalent during rapid infusion (see Table 9). The mean half-life of free clindamycin given by intravenous infusion is 2.28 hours for a 300 mg dose, 2.94 hours for a 600 mg dose, 3.27 hours for a 900 mg dose and 3.07 hours for a 1200 mg dose. During maintenance infusion, free clindamycin (3.6 to 6.9 mcg/mL) was the predominant species in circulation. Over the total infusion period (0 to 8 hours) clindamycin and clindamycin phosphate were excreted in the urine in amounts up to 12.3% and 5.1% respectively, of the administered
