Clindamycin for Sepsis

INDICATIONS AND USAGE Clindamycin Phosphate in Sodium Chloride Injection contains clindamycin, a lincosamide antibacterial indicated for the treatment of the following in adult and pediatric patients for whom appropriate dosing with this formulation can be achieved: • Serious infections caused by susceptible anaerobic bacteria ( 1.1 ) • Infections Due to Susceptible Isolates of Streptococci, Pneumococci and Staphylococci. ( 1.2 ) • Lower Respiratory Tract Infections. ( 1.3 ) • Skin and Skin Structure Infections. ( 1.4 ) • Gynecological Infections. ( 1.5 ) • Intra-abdominal Infections. ( 1.6 ) • Septicemia. ( 1.7 ) • Bone and Joint Infections. ( 1.8 ) Limitation of use Since clindamycin does not diffuse adequately into the cerebrospinal fluid, Clindamycin Phosphate in Sodium Chloride Injection should not be used in the treatment of meningitis ( 1.9 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Clindamycin Phosphate in Sodium Chloride Injection and other antibacterial drugs, Clindamycin Phosphate in Sodium Chloride Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.10 ) 1.1 Infections Due to Susceptible Anaerobic Bacteria Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious infections caused by susceptible anaerobic bacteria in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved [see Indications and Usage (1.3 - 1.7) ] . 1.2 Infections Due to Susceptible Isolates of Streptococci, Pneumococci and Staphylococci Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious infections due to susceptible isolates of streptococci, pneumococci, and staphylococci in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 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 antibacterial drug-associated pseudomembranous colitis, [see Boxed Warning ] , before selecting clindamycin the physician should consider the nature of the infection and the suitability of less toxic alternatives (e.g., erythromycin). Bacteriologic studies should be performed to determine the causative organisms and their susceptibility to clindamycin. Indicated surgical procedures should be performed in conjunction with antibacterial therapy. 1.3 Lower Respiratory Tract Infections Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious lower respiratory tract infections including pneumonia, empyema, and lung abscess caused by susceptible isolates of anaerobes, Streptococcus pneumoniae , other streptococci (except E. faecalis ), and Staphylococcus aureus in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.4 Skin and Skin Structure Infections Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious skin and skin structure infections caused by susceptible isolates of Streptococcus pyogenes , Staphylococcus aureus , and anaerobes in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.5 Gynecological Infections Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious gynecological infections including endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection caused by susceptible anaerobes in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.6 Intra-abdominal Infections Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious intra-abdominal infections including peritonitis and intra-abdominal abscess caused by susceptible anaerobic organisms in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.7 Septicemia Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious septicemia caused by susceptible isolates of Staphylococcus aureus , streptococci (except Enterococcus faecalis ), and susceptible anaerobes in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.8 Bone and Joint Infections Clindamycin Phosphate in Sodium Chloride Injection is indicated for the treatment of serious bone and joint infections including acute hematogenous osteomyelitis caused by susceptible isolates of Staphylococcus aureus and as adjunctive therapy in the surgical treatment of chronic bone and joint infections due to susceptible organisms in adults and pediatric patients for whom appropriate dosing with this formulation can be achieved. 1.9 Limitations of Use Since clindamycin does not diffuse adequately into the cerebrospinal fluid, Clindamycin Phosphate in Sodium Chloride Injection should not be used in the treatment of meningitis [see Clinical Pharmacology (12.3) ] . 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Clindamycin Phosphate in Sodium Chloride Injection and other antibacterial drugs, Clindamycin Phosphate in Sodium Chloride Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION If diarrhea occurs during therapy, this antibacterial drug should be discontinued (see WARNING box ). Clindamycin phosphate IM administration should be used undiluted. Clindamycin phosphate IV administration should be diluted (see Dilution for IV use and IV infusion rates below). Adults: Parenteral (IM or IV Administration): Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis , Peptococcus species and Clostridium species other than Clostridium perfringens ): 600–1200 mg/day in 2, 3 or 4 equal doses. More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens : 1200–2700 mg/day in 2, 3 or 4 equal doses. For more serious infections, these doses may have to be increased. In life-threatening situations due to either aerobes or anaerobes these doses may be increased. Doses of as much as 4800 mg daily have been given intravenously to adults. See Dilution for IV use and IV Infusion Rates section below. Single intramuscular injections of greater than 600 mg are not recommended. Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows: Table 2: Serum Clindamycin Levels Maintained, Rapid Infusion Rate and Maintenance Infusion Rate 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 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. Clindamycin should be dosed based on total body weight regardless of obesity. As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m 2 /day for serious infections and 450 mg/m 2 /day for more severe infections. Parenteral therapy may be changed to oral CLEOCIN PEDIATRIC ® Flavored Granules (clindamycin palmitate hydrochloride) or CLEOCIN HCl ® Capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician. In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days. Pediatric Patients less than 1 month: The recommended dosage is 15 to 20 mg/kg/day in 3 to 4 equal doses. See Table 3 regarding the dosing regimen for pediatric patients with post-menstrual age (PMA) less than or equal to 32 weeks, or greater than 32 weeks to less than or equal to 40 weeks. Table 3: Dosing Regimens for Pediatric Patients with PMA less than or equal to 32 weeks, or greater than 32 weeks to less than or equal to 40 weeks PMA (weeks) Dose (mg/kg) Dosing Interval (hours) PMA: Post-Menstrual age Less than or equal to 32 5 8 Greater than or equal to 32 to less than or equal to 40 7 8 Dilution for IV use and IV Infusion Rates: The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL. Infusion rates should not exceed 30 mg per minute. The usual infusion dilutions and rates are as follows: Dose Diluent Time 300 mg 50 mL 10 min 600 mg 50 mL 20 min 900 mg 50–100 mL 30 min 1200 mg 100 mL 40 min Administration of more than 1200 mg in a single 1-hour infusion is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dilution and Compatibility: Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of CLEOCIN PHOSPHATE Sterile Solution (clindamycin phosphate) in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically. No incompatibility has been demonstrated with the antibacterial drugs cephalothin, kanamycin, gentamicin, penicillin or carbenicillin. The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate. The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions. Physico-Chemical Stability of Diluted Solutions of CLEOCIN PHOSPHATE Room Temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in glass bottles or Mini-Bag containers, demonstrated physical and chemical stability for at least 16 days at 25°C. Also, 18 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, in Mini-Bag containers, demonstrated physical and chemical stability for at least 16 days at 25°C. Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in glass bottles or Mini-Bag containers, demonstrated physical and chemical stability for at least 32 days at 4°C. IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible. Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in dextrose injection 5%, sodium chloride injection 0.9%, or Lactated Ringers Injection in Mini-Bag containers demonstrated physical and chemical stability for at least eight weeks at -10°C. Frozen solutions should be thawed at room temperature and not refrozen. DIRECTIONS FOR DISPENSING Pharmacy Bulk Package — Not for Direct Infusion The Pharmacy Bulk Package is for use in a Pharmacy Admixture Service only under a laminar flow hood. Entry into the vial should be made with a small diameter sterile transfer set or other small diameter sterile dispensing device, and contents dispensed in aliquots using aseptic technique. Multiple entries with a needle and syringe are not recommended. AFTER ENTRY USE ENTIRE CONTENTS OF VIAL PROMPTLY. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 24 HOURS AFTER INITIAL ENTRY. DIRECTIONS FOR USE CLEOCIN PHOSPHATE IV Solution in GALAXY Plastic Container Premixed CLEOCIN PHOSPHATE IV Solution is for intravenous administration using sterile equipment. Check for minute leaks prior to use by squeezing bag firmly. If leaks are found, discard solution as sterility may be impaired. Do not add supplementary medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use unless solution is clear and seal is intact. Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for Administration : 1. Suspend container from eyelet support. 2. Remove protector from outlet port at bottom of container. 3. Attach administration set. Refer to complete directions accompanying set. Preparation of CLEOCIN PHOSPHATE in ADD-Vantage System For IV Use Only. CLEOCIN PHOSPHATE 300 mg, 600 mg and 900 mg may be reconstituted in 50 mL (for 300 mg and 600 mg) or 100 mL (for 900 mg) of dextrose injection 5% or sodium chloride injection 0.9% in the ADD-diluent container. Refer to separate instructions for ADD-Vantage System.

WARNINGS AND PRECAUTIONS • Anaphylactic shock, anaphylactic reactions and severe hypersensitivity reactions have been reported. Discontinue treatment if such reactions occur. ( 5.2 ) • Cases with acute kidney injury (AKI) have been reported during treatment with clindamycin. Consider renal function monitoring, particularly in certain patients (e.g., those with pre-existing renal dysfunction). Discontinue treatment, if AKI occurs and no other etiology is identified. ( 5.3 ) • Elderly patients with associated severe illness may have a greater risk of developing adverse reactions from diarrhea. Monitor these patients carefully for change in bowel frequency. ( 5.4 ) • Avoid use of Clindamycin Phosphate in Sodium Chloride Injection in individuals with a history of gastrointestinal disease, particularly colitis. ( 5.5 ) • Avoid use of Clindamycin Phosphate in Sodium Chloride Injection in atopic individuals. ( 5.6 ) • During prolonged therapy, perform periodic liver and kidney function tests and blood counts. ( 5.7 ) • The use of Clindamycin Phosphate in Sodium Chloride Injection may result in overgrowth of nonsusceptible organisms-particularly yeasts. Take appropriate measures, if this occurs. ( 5.8 ) 5.1 Clostridioides difficile -Associated Diarrhea Clostridioides difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clindamycin Phosphate in Sodium Chloride Injection, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated [see Boxed Warning ]. 5.2 Anaphylactic and Severe Hypersensitivity Reactions Anaphylactic shock and anaphylactic reactions have been reported [see Adverse Reactions (6) ]. Severe hypersensitivity reactions, including acute myocardial ischemia with or without myocardial infarction, and severe skin reactions such as toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), some with fatal outcome, have been reported [see Adverse Reactions (6) ]. 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. 5.3 Nephrotoxicity Clindamycin is potentially nephrotoxic and cases with acute kidney injury have been reported. Consider monitoring of renal function particularly in patients with pre-existing renal dysfunction or those taking concomitant nephrotoxic drugs. In case of acute kidney injury, discontinue Clindamycin Phosphate in Sodium Chloride Injection when no other etiology is identified [see Adverse Reactions (6) ]. 5.4 Diarrhea in Elderly Patients with Associated Severe Illness Elderly patients with associated severe illness may have a greater risk of developing adverse reactions from diarrhea. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency [see Use in Specific Populations (8.5) ] . 5.5 Use in Patients with Gastrointestinal Disease Clindamycin Phosphate in Sodium Chloride Injection products should be avoided in individuals with a history of gastrointestinal disease, particularly colitis. 5.6 Use in Atopic Individuals Clindamycin Phosphate in Sodium Chloride Injection should be avoided in atopic individuals. 5.7 Laboratory Tests: Monitoring to Assess Safety During prolonged therapy periodic liver and kidney function tests and blood counts should be performed. Clindamycin dosage modification is not necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of clindamycin half-life has been found. However, it was postulated from studies that when given every eight hours, accumulation should rarely occur. Therefore, dosage modification in patients with liver disease may not be necessary. However, periodic liver enzyme determinations should be made when treating patients with severe liver disease. 5.8 Overgrowth of Nonsusceptible Organisms The use of Clindamycin Phosphate in Sodium Chloride Injection may result in overgrowth of nonsusceptible organisms-particularly yeasts. If such infections occur, appropriate measures should be taken as indicated by the clinical situation. 5.9 Development of Drug-Resistant Bacteria Prescribing Clindamycin Phosphate in Sodium Chloride Injection 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.

DRUG INTERACTIONS • Neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. ( 7.1 ) • Monitor for adverse reactions when strong CYP3A4 and/or CYP3A5 inhibitors are coadministered with clindamycin. ( 7.2 ) • In the presence of strong CYP3A4 and/or CYP3A5 inducers such as rifampicin, monitor for loss of effectiveness. ( 7.3 ) 7.1 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be avoided in patients receiving such agents. 7.2 Inhibitors of CYP3A4 and CYP3A5 Inhibitors of CYP3A4 and/or CYP3A5 may increase plasma concentrations of clindamycin [ see Clinical Pharmacology (12.3) ]. Monitor for adverse reactions when strong CYP3A4 and/or CYP3A5 inhibitors are coadministered with clindamycin. 7.3 Inducers of CYP3A4 and CYP3A5 Inducers of CYP3A4 and/or CYP3A5 may reduce plasma concentrations of clindamycin. In the presence of strong CYP3A4 and/or CYP3A5 inducers such as rifampicin, monitor for loss of effectiveness.

ADVERSE REACTIONS Clinical trials Non-pregnant Women In clinical trials involving non-pregnant women, 1.8% of 600 patients who received treatment with clindamycin phosphate vaginal cream 2% for 3 days and 2.7% of 1325 patients who received treatment for 7 days discontinued therapy due to drug-related adverse events. Medical events judged to be related, probably related, possibly related, or of unknown relationship to vaginally administered clindamycin phosphate vaginal cream 2%, were reported for 20.7% of the patients receiving treatment for 3 days and 21.3% of the patients receiving treatment for 7 days. Events occurring in ≥1% of patients receiving clindamycin phosphate vaginal cream 2% are shown in Table 1 . TABLE 1 – Events Occurring in ≥1% of Non-pregnant Patients Receiving Clindamycin Phosphate Vaginal Cream 2% Event Clindamycin Phosphate Vaginal Cream 2% 3 Day n=600 7 Day n=1325 Urogenital Vaginal moniliasis 7.7 10.4 Vulvovaginitis 6.0 4.4 Vulvovaginal disorder 3.2 5.3 Trichomonal vaginitis 0 1.3 Body as a Whole Moniliasis (body) 1.3 0.2 Other events occurring in <1% of the clindamycin vaginal cream 2% groups include: Urogenital system : vaginal discharge, metrorrhagia, urinary tract infection, endometriosis, menstrual disorder, vaginitis/vaginal infection, and vaginal pain. Body as a whole: localized abdominal pain, generalized abdominal pain, abdominal cramps, halitosis, headache, bacterial infection, inflammatory swelling, allergic reaction, and fungal infection. Digestive system: nausea, vomiting, constipation, dyspepsia, flatulence, diarrhea, and gastrointestinal disorder. Endocrine system : hyperthyroidism. Central nervous system: dizziness and vertigo. Respiratory system: epistaxis. Skin: pruritus (non-application site), moniliasis, rash, maculopapular rash, erythema, and urticaria. Special senses: taste perversion. Pregnant Women In a clinical trial involving pregnant women during the second trimester, 1.7% of 180 patients who received treatment for 7 days discontinued therapy due to drug-related adverse events. Medical events judged to be related, probably related, possibly related, or of unknown relationship to vaginally administered clindamycin phosphate vaginal cream 2%, were reported for 22.8% of pregnant patients. Events occurring in ≥1% of patients receiving either clindamycin phosphate vaginal cream 2% or placebo are shown in Table 2 . TABLE 2 - Events Occurring in ≥1% of Pregnant Patients Receiving Clindamycin Phosphate Vaginal Cream 2% or Placebo Event Clindamycin Phosphate Vaginal Cream 2% Placebo 7 DAY n=180 7 Day n=184 Urogenital Vaginal moniliasis 13.3 7.1 Vulvovaginal disorder 6.7 7.1 Abnormal labor 1.1 0.5 Body as a Whole Fungal infection 1.7 0 Skin Pruritus, non-application site 1.1 0 Other events occurring in <1% of the clindamycin vaginal cream 2% group include: Urogenital system: dysuria, metrorrhagia, vaginal pain, and trichomonal vaginitis. Body as a whole: upper respiratory infection. Skin: pruritus (topical application site) and erythema. Post-marketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In the post-marketing period, there have been case reports of pseudomembranous colitis with the use of clindamycin phosphate vaginal cream. Other clindamycin formulations Clindamycin vaginal cream affords minimal peak serum levels and systemic exposure (AUCs) of clindamycin compared to 100 mg oral clindamycin dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral clindamycin, the possibility of these and other reactions cannot be excluded presently. Data from well-controlled trials directly comparing clindamycin administered orally to clindamycin administered vaginally are not available. The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of clindamycin: Infections and Infestations: Clostridioides difficile coliti s Gastrointestinal: Abdominal pain, esophagitis, nausea, vomiting, diarrhea and pseudomembranous colitis. (See WARNINGS. ) Hematopoietic: Transient neutropenia (leukopenia), eosinophilia, agranulocytosis, and thrombocytopenia have been reported. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of these reports. Hypersensitivity Reactions : Maculopapular rash and urticaria have been observed during drug therapy. Generalized mild to moderate morbilliform-like skin rashes are the most frequently reported of all adverse reactions. Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. A few cases of anaphylactoid reactions have been reported. If a hypersensitivity reaction occurs, the drug should be discontinued. Liver: Jaundice and abnormalities in liver function tests have been observed during clindamycin therapy. Musculoskeletal : Cases of polyarthritis have been reported. Renal: Acute kidney injury Immune System : Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported.