Dalacin C Phosphate (Clindamycin Phosphate)

DALACIN® C PHOSPHATE

STERILE SOLUTION

Pharmacia & Upjohn

Clindamycin Phosphate

Antibiotic

Action And Clinical Pharmacology: Following parenteral administration, biologically inactive clindamycin phosphate is rapidly hydrolyzed in plasma to active clindamycin. Clindamycin exerts its antibacterial effect by binding to the 50 S ribosomal subunit of susceptible bacteria, causing a reduction in the rate of synthesis of nucleic acid, and cessation of protein synthesis.

Clindamycin is primarily bacteriostatic, but may be bactericidal at high concentrations. The mechanism of action of clindamycin in combination with primaquine P. carinii is not known.

Pharmacokinetics: Clindamycin is distributed into body fluids and tissues including bone, synovial fluid, bile and pleural fluid. Significant levels of clindamycin are not reached in cerebrospinal fluid even in the presence of inflamed meninges. Clindamycin readily crosses the placenta and is distributed into breast milk. The half-life of clindamycin phosphate is 3.5 to 4.5 hours. Approximately 10% of the microbiologically active form is excreted in the urine and about 4% in the feces. The remainder is excreted as biologically inactive metabolites.

Indications And Clinical Uses: For the treatment of serious infections due to susceptible anaerobic bacteria, such as Bacteroides species, Peptostreptococcus, anaerobic streptococci, Clostridium species and microaerophilic streptococci.

Also indicated for the treatment of serious infections due to susceptible strains of gram-positive aerobic bacteria (staphylococci, including penicillinase-producing staphylococci, streptococci and pneumococci) as well as in the treatment of C. trachomatis, when the patient is intolerant of, or the organism resistant to other appropriate antibiotics.

Because of the risk of antibiotic-associated pseudomembranous colitis as described in the Warnings section, before selecting clindamycin the physician should consider the nature of the infection and the suitability of alternative therapy.

Clindamycin phosphate is indicated for the treatment of the following serious infections when caused by susceptible strains of the designated organisms in the conditions listed below: Lower respiratory infections including pneumonia, empyema, and lung abscess when caused by anaerobes, S. pneumoniae, other streptococci (except E. faecalis) and S. aureus.

Skin and skin structure infections including cellulitis, abscesses, and wound infections when caused by S. pyogenes. S. aureus and anaerobes.

Gynecological infections including endometritis, pelvic cellulitis, vaginal cuff infections, nongonococcal tubo-ovarian abscess, salpingitis, and pelvic inflammatory disease when caused by susceptible anaerobes or C. 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 S. aureus, streptococci (except E. 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 S. aureus and anaerobes.

P. carinii 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 phosphate 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.

Contra-Indications: In patients with a known hypersensitivity to preparations containing clindamycin or lincomycin.

Manufacturers’ Warnings In Clinical States: Dalacin C Phosphate contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants.

Clindamycin has been associated with severe antibiotic-associated colitis. Severe colitis may be fatal if left untreated. If significant diarrhea occurs during therapy, this drug should be discontinued or, if necessary, continued only with close observation. It should be noted that diarrhea, colitis and pseudomembranous colitis have been observed to begin up to 1 month after discontinuation of medication. A relatively prolonged period of continuing observation is therefore recommended.

The diagnosis of colitis is usually made by recognition of the clinical symptoms. Colitis has a clinical spectrum from mild, watery diarrhea to severe, persistent diarrhea, leukocytosis, fever, severe abdominal cramps which may be associated with the passage of blood and mucus, and which, if allowed to progress, may produce peritonitis, shock and toxic megacolon.

If colitis is suspected, endoscopy is recommended. Endoscopic examination may reveal pseudomembranous colitis. Stool culture for C. difficile and stool assay for C. difficile toxin may be helpful diagnostically.

Mild cases showing minimal mucosal changes may respond to simple drug discontinuance. Moderate to severe cases, including those showing ulceration or pseudomembrane formation should be managed with fluid, electrolyte, and protein supplementation as indicated. Corticoid retention enemas and systemic corticoids may be of help in persistent cases. Anticholinergics and antiperistaltic agents may worsen colitis. Other causes of colitis should be considered.

Studies indicate a toxin(s) produced by C. difficile is the primary cause of antibiotic-associated colitis and that toxigenic Clostridium is usually sensitive in vitro to vancomycin. When 125 mg to 500 mg of vancomycin was administered orally 4 times a day for 5 to 10 days, there was a rapid observed disappearance of the toxin from fecal samples and a coincidental recovery from the diarrhea.

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.

Precautions: General: Clindamycin phosphate should be prescribed with caution in atopic individuals and in individuals with a history of gastrointestinal disease particularly colitis.

Clindamycin phosphate does not diffuse adequately into cerebrospinal fluid and thus should not be used in the treatment of meningitis.

Clindamycin phosphate must be diluted for i.v. administration. It should not be injected undiluted as an i.v. bolus (see Dosage).

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.

Periodic liver and kidney function tests and blood counts should be performed during prolonged therapy.

Clindamycin phosphate dose modification is not necessary in patients with renal disease. In patients with moderate to severe liver disease, prolongation of the half-life of clindamycin has been found, but a pharmacokinetic study has shown that, when given every 8 hours, accumulation of clindamycin should rarely occur. Therefore, dosage reduction in liver disease is not generally considered necessary.

Geriatrics: Experience has demonstrated that antibiotic-associated colitis may occur more frequently and with increased severity among elderly (>60 years) and debilitated patients.

Pregnancy: Reproduction studies have been performed in rats and mice using s.c. 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 fetus due to clindamycin. In 1 mouse strain, cleft palates were observed in treated fetuses; this response was not produced in other mouse strains or in other species, and therefore may be a strain specific effect.

Safety for use in pregnancy has not been established.

Lactation: Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 µg/mL at doses of 150 mg orally to 600 mg i.v. Because of the potential for adverse reactions in neonates, a decision should be made whether to discontinue nursing or to not administer clindamycin after taking into account the importance of the drug to the mother.

Drug Interactions: Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Because of a possible clinical significance, the two drugs should not be administered concurrently.

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.

Adverse Reactions: Gastrointestinal: abdominal pain, nausea, vomiting and diarrhea, colitis (see Warnings). An unpleasant or metallic taste has occasionally been reported after i.v. administration of higher doses of clindamycin phosphate.

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 reactions. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. A few cases of anaphylactoid reactions have been reported.

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

Skin and Mucous Membranes: Pruritus, vaginitis and rare instances of exfoliative and vesiculobullous dermatitis have been reported.

Hematopoietic: Transient neutropenia (leukopenia) and eosinophilia have been reported. Reports of agranulocytosis and thrombocytopenia have been made. No direct etiologic relationship to concurrent clindamycin therapy could be made in any of these instances. However, in clindamycin/primaquine combination studies, serious hematologic toxicities (grade III, grade IV neutropenia or anemia, platelet counts
Cardiovascular: Rare instances of cardiopulmonary arrest and hypotension have been reported following too rapid i.v. administration (see Dosage).

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

Musculoskeletal: Rare instances of polyarthritis have been reported.

Local Reactions: Local irritation, pain, abscess formation have been seen with i.m. injection. Thrombophlebitis has been reported with i.v. injection. These reactions can be minimized by deep i.m. injection and avoidance of indwelling i.v. catheters.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Reported cases of overdosage have occurred very infrequently. The majority of these reports have involved infants and young children ranging in age from 1 day to 3 years. In this age group, doses as high as 2.4 g have been used i.v. in 36 hours without observation of adverse reactions. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. No specific antidote is known.

Dosage And Administration: Note: If diarrhea occurs during treatment, this antibiotic should be discontinued (see Warnings).

Dosage and route of administration should be determined by the severity of the infection, the condition of the patient and the susceptibility of the causative microorganisms.

In cases of b-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

Adults (I.M. or I.V. Administration): The usual daily adult dosage for infections of the intra-abdominal area, female pelvis, and other complicated or serious infections is 2 400 to 2 700 mg given in 2, 3 or 4 equal doses. Less complicated infections may respond to lower doses such as 1 200 to 1 800 mg/day administered in 3 or 4 equal doses.

Doses of up to 4 800 mg daily have been used without adverse effects. Single i.m. doses of greater than 600 mg are not recommended.

Pelvic Inflammatory Disease: 900 mg (i.v.) every 8 hours plus an antibiotic with appropriate gram-negative aerobic spectrum administered i.v. Treatment with i.v. drugs should continue for at least 48 hours after the patient demonstrates significant clinical improvement. Then continue with appropriate oral therapy to complete 10 to 14 days total therapy.

P. carinii pneumonia in patients with AIDS: 600 to 900 mg (i.v.) every 6 hours or 900 mg (i.v.) every 8 hours in combination with oral daily dose of 15 to 30 mg of primaquine. Alternatively, clindamycin HCl 300 to 450 mg may be given orally every 6 hours in combination with 15 to 30 mg of primaquine for 21 days. If patients should develop serious hemotologic adverse effects, reducing the dosage regimen of primaquine and/or clindamycin phosphate should be considered.

Children over 1 month of age (I.M. or I.V. Administration): 20 to 40 mg/kg/day in 3 or 4 equal doses. The higher doses would be used for more severe infections.

Neonates under 1 month of age (I.M. or I.V. Administration): 10 to 20 mg/kg/day in 3 or 4 equal doses. The lower dosage may be adequate for small prematures.

Note: Clindamycin phosphate injections should be administered with caution to newborn infants less than 30 days of age. This product contains benzyl alcohol which has been associated with a fatal gasping syndrome in infants.

Dilution and Infusion Rates: Clindamycin phosphate must be diluted prior to i.v. administration (see Preparation for I.V. Use for a listing of infusion solutions).

Administration of more than 1 200 mg in a single 1-hour infusion is not recommended.

Parenteral Products: All parenteral products should be visually inspected for heaviness, particulate matter, discoloration and leakage prior to administration.

Preparation for I.V. Use: Clindamycin phosphate was found to be compatible over a period of 24 hours when 4 mL (600 mg) of clindamycin phosphate was diluted in 1 000 mL of the following commonly used infusion solutions: Sodium chloride injection, Dextrose 5% in water, Dextrose 5% in saline, Dextrose 5% in Ringer’s Solution, Dextrose 5% in half-strength saline plus 40 mEq potassium chloride, Dextrose 2 1/2% in Lactated Ringer’s Solution (Hartmann’s Solution).

Compatibility with Other Products: Clindamycin phosphate was not stable when added to Dextrose 5% in water plus vitamins. Although clindamycin phosphate is compatible with Dextrose 5% in water, it is not recommended that clindamycin phosphate 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 phosphate and gentamicin sulfate prior to dilution. Rather, dilute one drug or the other, agitate the solution and then add the second antibiotic.

Availability And Storage: Each mL of sterile solution contains: clindamycin phosphate equivalent to 150 mg of clindamycin base, benzyl alcohol 9 mg, disodium edetate 0.5 mg and water for injection q.s. When necessary, the pH is adjusted with sodium hydroxide and/or hydrochloric acid to maintain a pH range of 5.5 to 7.0. Vials of 2, 4 and 6 mL. Pharmacy bulk vials of 60 mL. The availability of the pharmacy bulk vial is limited to hospitals with a pharmacy based i.v. admixture program. The pharmacy bulk vial is intended for single puncture, multiple dispensing for i.v. use only.

DALACIN® C PHOSPHATE STERILE SOLUTION Pharmacia & Upjohn Clindamycin Phosphate Antibiotic

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