Clindamycin in 5 Percent Dextrose: Package Insert and Label Information

CLINDAMYCIN IN 5 PERCENT DEXTROSE- clindamycin injection, solution
Civica, Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Clindamycin in 5% Dextrose Injection and other antibacterial drugs, Clindamycin in 5% Dextrose Injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Clindamycin in 5% Dextrose Injection in the Cryovac Plastic Container is a Sterile Solution for Intravenous Use Only

WARNING

Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clindamycin in 5% Dextrose 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.

Because Clindamycin in 5% Dextrose Injection therapy has been associated with severe colitis which may end fatally, it should be reserved for serious infections where less toxic antimicrobial agents are inappropriate, as described in the INDICATIONS AND USAGE section. It should not be used in patients with nonbacterial infections such as most upper respiratory tract infections. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

DESCRIPTION

Clindamycin in 5% Dextrose Injection in the Cryovac plastic container for intravenous use is composed of clindamycin phosphate equivalent to 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. Clindamycin is a semisynthetic antibiotic 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), (2S-trans)-.

The molecular formula is C18 H34 CIN2 08 PS and the molecular weight is 504.97.

The structural formula is represented below:

Structure formula
(click image for full-size original)

The plastic container is fabricated from a specially designed multilayer plastic, M312A material. 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.

CLINICAL PHARMACOLOGY

Distribution

Biologically inactive clindamycin phosphate is converted to active clindamycin. By the end of short-term intravenous infusion, peak serum concentrations of active clindamycin are reached.

After intramuscular injection of clindamycin phosphate, peak concentrations of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum concentration-time curves may be constructed from IV peak serum concentrations as given in Table 1 by application of elimination half-lives (see Excretion).

Serum concentrations of clindamycin can be maintained above the in vitro minimum inhibitory concentrations for most indicated organisms by administration of clindamycin phosphate every 8 to 12 hours in adults and every 6 to 8 hours in pediatric patients, or by continuous intravenous infusion. An equilibrium state is reached by the third dose.

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

Metabolism

In vitro studies in human liver and intestinal microsomes indicated that clindamycin is predominantly metabolized by Cytochrome P450 3A4 (CYP3A4), with minor contribution from CYP3A5, to form clindamycin sulfoxide and a minor metabolite, N-desmethylclindamycin.

Excretion

Biologically inactive clindamycin phosphate disappears from the serum with 6 minutes of the average elimination half-life; however, the average serum elimination half-life of active clindamycin is about 3 hours in adults and 2½ hours in pediatric patients.

Specific Populations

Patients with Renal/Hepatic Impairment

The elimination half-life of clindamycin is increased slightly in patients with markedly reduced renal or hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Dosage schedules need not be modified in the presence of mild or moderate renal or hepatic disease.

Elderly Patients

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, the average elimination half-life is increased to approximately 4 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. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function1.

Table 1. Average Peak and Trough Serum Concentrations of Active Clindamycin After Dosing with Clindamycin Phosphate
Dosage Regimen Peak
mcg/mL
Trough
mcg/mL
*
Data in this group from patients being treated for infection.

Healthy Adult Males (Post equilibrium)

600 mg IV in 30 min q6h

10.9

2

600 mg IV in 30 min q8h

10.8

1.1

900 mg IV in 30 min q8h

14.1

1.7

Pediatric Patients (first dose) *

5 to 7 mg/kg IV in 1 hour

10

Obese Pediatric Patients Aged 2 to Less than 18 Years and Obese Adults Aged 18 to 20 Years

An analysis of pharmacokinetic data in obese pediatric patients aged 2 to less than 18 years and obese adults aged 18 to 20 years demonstrated that clindamycin clearance and volume of distribution, normalized by total body weight, are comparable regardless of obesity.

Microbiology

Mechanism of Action

Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic.

Resistance

Resistance to clindamycin is most often caused by modification of specific bases of the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete. Because the binding sites for these antibacterial drugs overlap, cross-resistance is sometimes observed among lincosamides, macrolides and streptogramin B. Macrolide-inducible resistance to clindamycin occurs in some isolates of macrolide-resistant bacteria. Macrolide-resistant isolates of staphylococci and beta-hemolytic streptococci should be screened for induction of clindamycin resistance using the D-zone test.

Antimicrobial Activity

Clindamycin has been shown to be active against most of the isolates of the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE]:

Gram-positive Bacteria

Staphylococcus aureus
(methicillin-susceptible strains)
Streptococcus pneumoniae
(penicillin-susceptible strains)
Streptococcus pyogenes

Anaerobic Bacteria

Clostridium perfringens
Fusobacterium necrophorum
Fusobacterium nucleatum
Peptostreptococcus anaerobius
Prevotella melaninogenica

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for clindamycin against isolates of a similar genus or organism group. However, the efficacy of clindamycin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus epidermidis
(methicillin-susceptible strains)
Streptococcus agalactiae
Streptococcus anginosus
Streptococcus mitis
Streptococcus oralis

Anaerobic Bacteria

Actinomyces israelii
Clostridium clostridioforme
Eggerthella lenta
Finegoldia (Peptostreptococcus) magna
Micromonas (Peptostreptococcus) micros
Prevotella bivia
Prevotella intermedia
Propionibacterium acnes

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

INDICATIONS AND USAGE

Clindamycin in 5% Dextrose Injection is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria.

Clindamycin in 5% Dextrose Injection is also indicated in the treatment of serious infections due to susceptible strains of streptococci, pneumococci, and staphylococci. 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 antibiotic-associated pseudomembranous colitis, as described in the 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 antibiotic therapy.

Clindamycin in 5% Dextrose Injection is indicated in the treatment of serious infections caused by susceptible strains of the designated organisms in the conditions listed below:

Lower respiratory tract infections including pneumonia, empyema, and lung abscess caused by anaerobes, Streptococcus pneumoniae , other streptococci (except E. faecalis), and Staphylococcus aureus.

Skin and skin structure infections caused by Streptococcus pyogenes, Staphylococcus aureus , and anaerobes.

Gynecological infections including endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis, and postsurgical vaginal cuff infection caused by susceptible anaerobes.

Intra-abdominal infections including peritonitis and intra-abdominal abscess caused by susceptible anaerobic organisms.

Septicemia caused by Staphylococcus aureus , streptococci (except Enterococcus faecalis), and susceptible anaerobes.

Bone and joint infections including acute hematogenous osteomyelitis caused by Staphylococcus aureus and as adjunctive therapy in the surgical treatment of chronic bone and joint infections due to susceptible organisms.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Clindamycin in 5% Dextrose Injection and other antibacterial drugs, Clindamycin in 5% Dextrose 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.

CONTRAINDICATIONS

This drug is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.

WARNINGS

See BOXED WARNING.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Clindamycin in 5% Dextrose 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 strains 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 antibiotic 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 antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile , and surgical evaluation should be instituted as clinically indicated.

Anaphylactic and Severe Hypersensitivity Reactions

Anaphylactic shock and anaphylactic reactions have been reported (see ADVERSE REACTIONS).

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 (see ADVERSE REACTIONS).

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.

Usage in Meningitis

Since clindamycin does not diffuse adequately into the cerebrospinal fluid, the drug should not be used in the treatment of meningitis.

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