CLINDAMYCIN: 17,058 Adverse Event Reports & Safety Profile

DESCRIPTION CLEOCIN PHOSPHATE Sterile Solution in vials contains clindamycin phosphate, a water soluble ester of clindamycin and phosphoric acid. Each mL contains the equivalent of 150 mg clindamycin, 0.5 mg disodium edetate and 9.45 mg benzyl alcohol added as preservative in each mL. Clindamycin is a semisynthetic antibacterial drug produced by a 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. The chemical name of clindamycin phosphate is L- threo -α-D- galacto- Octopyranoside, methyl-7-chloro-6,7,8-trideoxy-6-[[(1-methyl-4-propyl-2-pyrrolidinyl)carbonyl] amino]-1-thio-, 2-(dihydrogen phosphate), (2 S-trans )-. The molecular formula is C 18 H 34 ClN 2 O 8 PS and the molecular weight is 504.96. The structural formula is represented below: CLEOCIN PHOSPHATE in the ADD-Vantage Vial is intended for intravenous use only after further dilution with appropriate volume of ADD-Vantage diluent base solution (see Directions for Use ) .

Cleocin Phosphate Iv

Solution in the GALAXY plastic container for intravenous use is composed of clindamycin phosphate equivalent to 300, 600 and 900 mg of clindamycin premixed with 5% dextrose as a sterile solution. Disodium edetate has been added at a concentration of 0.04 mg/mL. The pH has been adjusted with sodium hydroxide and/or hydrochloric acid. The plastic container is fabricated from a specially designed multilayer plastic, PL 2501. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

Chemical

Structure

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 <span class="opacity-50 text-xs">[see Indications and Usage (1.3 - 1.7) ]</span> .

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-associated pseudomembranous colitis, <span class="opacity-50 text-xs">[see Boxed Warning ]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

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.

4 CONTRAINDICATIONS

• History of hypersensitivity to clindamycin or other lincosamides ( 4.1 )
• History of regional enteritis, ulcerative colitis, or a history of Clostridioides difficile- associated diarrhea ( 4.2 , 5.1 )

4.1 Hypersensitivity Clindesse is contraindicated in individuals with a history of hypersensitivity to clindamycin or other lincosamides. Reported reactions to other formulations of clindamycin include rashes, urticaria, erythema multiforme, and anaphylactoid reactions <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

4.2 History of Bowel Disease Clindesse is contraindicated in patients with regional enteritis, ulcerative colitis, or a history of Clostridioides difficile -associated diarrhea.

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 &lt;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 &lt;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.

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 <span class="opacity-50 text-xs">[see Boxed Warning ]</span>.

5.2 Anaphylactic and Severe Hypersensitivity Reactions Anaphylactic shock and anaphylactic reactions have been reported <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span>.

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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5) ]</span> .

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.

PRECAUTIONS General Review of experience to date suggests that a subgroup of older patients with associated severe illness may tolerate diarrhea less well. When clindamycin is indicated in these patients, they should be carefully monitored for change in bowel frequency. Clindamycin hydrochloride should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis. Clindamycin hydrochloride should be prescribed with caution in atopic individuals. Indicated surgical procedures should be performed in conjunction with antibiotic therapy. The use of clindamycin hydrochloride occasionally results in overgrowth of nonsusceptible organisms—particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation. Clindamycin dosage modification 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.

The

75 mg and 150 mg capsules contain FD&C yellow no. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow no. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. Prescribing clindamycin hydrochloride 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. Due to the risk of esophagitis and esophageal ulcer, it is important to ensure adherence with administration guidance (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS ). Information for Patients Patients should be counseled that antibacterial drugs, including clindamycin hydrochloride capsules, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When clindamycin hydrochloride capsules are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by clindamycin hydrochloride capsules or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Advise patients that due to the risk of esophagitis and esophageal ulcer, it is important to adhere to the administration guidance for clindamycin hydrochloride capsules (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS ). Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 Laboratory Tests During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed.

Drug Interactions

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents. Clindamycin is metabolized predominantly by CYP3A4, and to a lesser extent by CYP3A5, to the major metabolite clindamycin sulfoxide and minor metabolite N-desmethylclindamycin. Therefore, inhibitors of CYP3A4 and CYP3A5 may increase plasma concentrations of clindamycin and inducers of these isoenzymes may reduce plasma concentrations of clindamycin. In the presence of strong CYP3A4 inhibitors, monitor for adverse reactions. In the presence of strong CYP3A4 inducers such as rifampicin, monitor for loss of effectiveness. In vitro studies indicate that clindamycin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2E1 or CYP2D6 and only moderately inhibits CYP3A4. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals have not been performed with clindamycin to evaluate carcinogenic potential. Genotoxicity tests performed included a rat micronucleus test and an Ames Salmonella reversion test. Both tests were negative. Fertility studies in rats treated orally with up to 300 mg/kg/day (approximately 1.6 times the highest recommended adult human dose based on mg/m 2 ) revealed no effects on fertility or mating ability. Pregnancy: Teratogenic effects In clinical trials with pregnant women, the systemic administration of clindamycin during the second and third trimesters, has not been associated with an increased frequency of congenital abnormalities. Clindamycin should be used during the first trimester of pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women during the first trimester of pregnancy. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600 mg/kg/day (3.2 and 1.6 times the highest recommended adult human dose based on mg/m 2 , respectively) or subcutaneous doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 times the highest recommended adult human dose based on mg/m 2 , respectively) revealed no evidence of teratogenicity.

Nursing Mothers

Limited published data based on breast milk sampling reports that clindamycin appears in human breast milk in the range of less than 0.5 to 3.8 mcg/mL. 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 breastfed 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 hydrochloride is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable.

Geriatric Use

Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridioides difficile ) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more severe. These patients should be carefully monitored for the development of diarrhea. Pharmacokinetic studies with clindamycin have shown no clinically important differences between young and elderly subjects with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

INTERACTIONS

• Concomitant use of topical medications with a strong drying effect can increase skin irritation. Use with caution. ( 7.1 )
• Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel should not be used in combination with erythromycin-containing products because of its clindamycin component. ( 7.2 )

7.1 Concomitant Topical Medication Concomitant topical medication, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol, astringents, spices or lime should be used with caution. When used with Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel, there may be increased skin irritation.

7.2 Erythromycin Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel should not be used in combination with erythromycin-containing products due to its clindamycin component. In vitro studies have shown antagonism between these two antimicrobials. The clinical significance of this in vitro antagonism is not known.

7.3 Neuromuscular Blocking Agents Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, Clindamycin Phosphate 1.2% and Tretinoin 0.025% Gel should be used with caution in patients receiving such agents.

It is a compound preparation. Each milliliter contains 10.0 mg of Clindamycin Hydrochloride (calculated as Clindamycin),

8.0 mg of Metronidazole.