Clindamycin Palmitate Hydrochloride

Although clindamycin palmitate HCl is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin.

Clindamycin has been shown to have in vitro activity against isolates of the following organisms:

Aerobic gram positive cocci, including:

•Staphylococcus aureus (penicillinase and non-penicillinase producing strains). When tested by in vitro methods some staphylococcal strains originally resistant to erythromycin rapidly develop resistance to clindamycin.

•Staphylococcus epidermidis (penicillinase and non-penicillinase producing strains). When tested by in vitro methods some staphylococcal strains originally resistant to erythromycin rapidly develop resistance to clindamycin.

•Streptococci (except Streptococcus faecalis)

•Pneumococci

Anaerobic gram negative bacilli, including:

•Bacteroides species (including Bacteroides fragilis group and Bacteroides melaninogenicus group)

•Fusobacterium species

Anaerobic gram positive nonsporeforming bacilli, including:

•Propionibacterium

•Eubacterium

•Actinomyces species

Anaerobic and microaerophilic gram positive cocci, including:

•Peptococcus species

•Peptostreptococcus species

•Microaerophilic streptococci

Clostridia: Clostridia are more resistant than most anaerobes to clindamycin.

Most Clostridium perfringens are susceptible, but other species, e.g., Clostridium sporogenes and

Most Clostridium perfringens are susceptible, but other species, e.g., Clostridium sporogenes and

Clostridium tertium are frequently resistant to clindamycin. Susceptibility testing should be done.

Cross resistance has been demonstrated between clindamycin and lincomycin.

Antagonism has been demonstrated between clindamycin and erythromycin.

Blood level studies comparing clindamycin palmitate HCl with clindamycin hydrochloride show that both drugs reach their peak active serum levels at the same time, indicating a rapid hydrolysis of the palmitate to the clindamycin.

Clindamycin is widely distributed in body fluids and tissues (including bones). Approximately 10% of the biological activity is excreted in the urine. The average serum half-life after doses of clindamycin palmitate HCl is approximately two hours in pediatric patients.

Serum half-life of clindamycin is increased slightly in patients with markedly reduced renal function. Hemodialysis and peritoneal dialysis are not effecting in removing clindamycin from the serum.

Serum level studies with clindamycin palmitate HCl in normal pediatric patients weighing 50 to 100 lbs given 2, 3 or 4 mg/kg every 6 hours (8, 12 or 16 mg/kg/day) demonstrated mean peak clindamycin serum levels of 1.24, 2.25 and 2.44 mcg/mL respectively, one hour after the first dose. By the fifth dose, the 6-hour serum concentration had reached equilibrium. Peak serum concentrations after this time would be about 2.46, 2.98 and 3.79 mcg/mL with doses of 8, 12 and 16 mg/kg/day, respectively.

Serum levels have been uniform and predictable from person to person and dose to dose. Multiple-dose studies in neonates and infants up to 6 months of age show that the drug does not accumulate in the serum and is excreted rapidly. Serum levels exceed the MICs for most indicated organisms for at least six hours following administration of the usually recommended doses of clindamycin palmitate HCl in adults and pediatric patients.

No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges.

Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate.

After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4 to 5.1 h) in the elderly compared to 3.2 hours (range 2.1 to 4.2 h) in younger adults; administration of clindamycin palmitate HCl resulted in a similar elimination half-life value of about 4.5 hours in elderly subjects. However, the extent of absorption is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function.

A standardized disk testing procedure is recommended for determining susceptibility of aerobic bacteria to clindamycin. A description is contained in the clindamycin palmitate HCl susceptibility disk insert. Using this method, the laboratory can designate isolates as resistant, intermediate, or susceptible.

Tube or agar dilution methods may be used for both anaerobic and aerobic bacteria. When the directions in the clindamycin palmitate HCl susceptibility powder insert are followed, an MIC (minimal inhibitory concentration) of 1.6 mcg/mL may be considered susceptible; MICs of 1.6 to 4.8 mcg/mL may be considered intermediate and MICs greater than 4.8 mcg/mL may be considered resistant.

Clindamycin palmitate HCl susceptibility disks 2 mcg. See package insert for use.

Clindamycin palmitate HCl susceptibility powder 20 mg. See package insert for use.

For anaerobic bacteria the minimal inhibitory concentration (MIC) of clindamycin can be determined by agar dilution and broth dilution (including microdilution) techniques. If MICs are not determined routinely, the disk broth method is recommended for routine use. THE KIRBY-BAUER DISK

DIFFUSION METHOD AND ITS INTERPRETIVE STANDARDS ARE NOT RECOMMENDED FOR ANAEROBES.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clindamycin palmitate HCl for oral solution, USP (pediatric) and other antibacterial drugs, clindamycin palmitate HCl for oral solution, USP (pediatric) 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.

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 palmitate HCl should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Clindamycin palmitate HCl should be prescribed with caution in atopic individuals.

Indicated surgical procedures should be performed in conjunction with antibiotic therapy.

The use of clindamycin palmitate HCl occasionally results in overgrowth of non-susceptible organisms particularly yeasts. Should superinfections occur, appropriate measures should be taken as indicated by the clinical situation.

Clindamycin dosage modification may not be 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.

Prescribing clindamycin palmitate HCl 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.

Patients should be counseled that antibacterial drugs including clindamycin palmitate HCl should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When clindamycin palmitate HCl is 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 palmitate HCl 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.

During prolonged therapy, periodic liver and kidney function tests and blood counts should be performed.

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.

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

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 300mg/kg/day (approximately 1.6 times the highest recommended adult human oral dose based on mg/m²) revealed no effects on fertility or mating ability.

Teratogenic Effects

Pregnancy Category B

Reproduction studies performed in rats and mice using oral doses of clindamycin up to 600mg/kg/day (3.2 and 1.6 times the highest recommended adult human oral dose based on mg/m², respectively) or subcutaneous doses of clindamycin up to 250mg/kg/day (1.3 and 0.7 times the highest recommended adult human oral dose based on mg/ m², respectively) revealed no evidence of teratogenicity.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed.

Clindamycin has been reported to appear in breast milk in the range of 0.7 to 3.8 mcg/mL.

When clindamycin palmitate HCl is administered to the pediatric population (birth to 16 years), appropriate monitoring of organ system functions is desirable.

Clinical studies of clindamycin did not include sufficient numbers of patients age 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experience indicates that antibiotic-associated colitis and diarrhea (due to Clostridium difficile) seen in association with most antibiotics occur more frequently in the elderly (>60 years) and may be more sever. These patients should be carefully monitored for the development of diarrhea.

Pharmacokinetic studies with clindamycin have shown no clinically important differences between young subjects (18 to 39 years) and elderly subjects (61 to 79 years) with normal hepatic function and normal (age-adjusted) renal function after oral or intravenous administration.

Generalized mild to moderate morbilliform-like (maculopapular) skin rashes are the most frequently reported adverse reactions. Vesiculobullous rashes, as well as urticaria, have been observed during drug therapy. Rare instances of erythema multiforme, some resembling Stevens-Johnson syndrome, and a few cases of anaphylactoid reactions have also been reported.

Skin and Mucous Membranes: Pruritus, vaginitis, and rare instances of exfoliative dermatitis have been reported. (See Hypersensitivity Reactions.)

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

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.

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 the foregoing.

Musculoskeletal: Rare instances of polyarthritis have been reported.