Cleocin Phosphate - Clindamycin Phosphate injection, Solution prescribing information
WARNING
Clostridioides difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CLEOCIN PHOSPHATE 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 CLEOCIN PHOSPHATE 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.
INDICATIONS AND USAGE
CLEOCIN PHOSPHATE products are indicated in the treatment of serious infections caused by susceptible anaerobic bacteria.
CLEOCIN PHOSPHATE products are 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.
CLEOCIN PHOSPHATE 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 CLEOCIN PHOSPHATE and other antibacterial drugs, CLEOCIN PHOSPHATE 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 antibiotic 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:
| 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.
| 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 antibiotics 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, 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, 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.
CONTRAINDICATIONS
This drug is contraindicated in individuals with a history of hypersensitivity to preparations containing clindamycin or lincomycin.
ADVERSE REACTIONS
The following reactions have been reported with the use of clindamycin.
Infections and Infestations: Clostridioides difficile colitis
Gastrointestinal: Antibiotic-associated colitis (see WARNINGS ), pseudomembranous colitis, abdominal pain, nausea, and vomiting. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment (see WARNINGS ). An unpleasant or metallic taste has been reported after intravenous administration of the 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 of all adverse reactions.
Severe skin reactions such as Toxic Epidermal Necrolysis, some with fatal outcome, have been reported (see WARNINGS ). Cases of Acute Generalized Exanthematous Pustulosis (AGEP), erythema multiforme, some resembling Stevens-Johnson syndrome, have been associated with clindamycin. Anaphylactic shock, anaphylactic reaction and hypersensitivity have also been reported (see WARNINGS ).
Skin and Mucous Membranes: Pruritus, vaginitis, angioedema 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: Acute kidney injury (see WARNINGS ).
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.
Immune System: Drug reaction with eosinophilia and systemic symptoms (DRESS) cases have been reported.
Local Reactions: Injection site irritation, pain, induration and sterile abscess have been reported after intramuscular injection and thrombophlebitis after intravenous infusion. Reactions can be minimized or avoided by giving deep intramuscular injections and avoiding prolonged use of indwelling intravenous catheters.
Musculoskeletal: Polyarthritis cases have been reported.
Cardiovascular: Cardiopulmonary arrest and hypotension have been reported following too rapid intravenous administration (see DOSAGE AND ADMINISTRATION ).
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.
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 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), (2 S-trans )-.
The molecular formula is C 18 H 34 CIN 2 0 8 PS and the molecular weight is 504.96.
The structural formula is represented below:
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 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 do not need to be modified in patients with renal or hepatic disease.
Geriatric Patients
Pharmacokinetic studies in elderly volunteers (61–79 years) and younger adults (18–39 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 4.0 hours (range 3.4–5.1 h) in the elderly, compared to 3.2 hours (range 2.1–4.2 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 function 1 .
Pharmacokinetics in Pediatric Patients with PMA ≤32 weeks, or >32 to ≤40 weeks
Systemic clearance (CL) in premature infants increases with increases in body weight (kg) and post-menstrual age (PMA). The dosing regimens for pediatric patients ≤32 weeks PMA (5 mg/kg) and >32 to ≤40 weeks PMA (7 mg/kg), both administered intravenously every 8 hours, achieve exposures comparable to therapeutic exposures in adults (weighing 70 kg) administered clindamycin 600 mg every 8 hours (Table 1).
| Age | Adult (70 kg) | PMA ≤32 weeks | PMA>32 – ≤40 weeks |
|---|---|---|---|
| PMA: post-menstrual age; AUC ss,0–8 hour : area under the concentration-time curve during a dosing interval at steady state; C max,ss : maximum drug concentration at steady state; C min,ss : minimum or trough drug concentration at steady state. | |||
Dose (every 8 hours) | 600 mg | 5 mg/kg | 7 mg/kg |
AUC ss,0–8 hour (mcg∙h/mL) | 50.5 (30.95) | 52.5 (17.0) | 55.9 (23.55) |
C max,ss (mcg/mL) | 12.0 (3.49) | 9.0 (2.02) | 10.5 (2.79) |
C min,ss (mcg/mL) | 3.1 (3.34) | 4.6 (2.00) | 4.4 (2.77) |
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
- Cutibacterium 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 .
HOW SUPPLIED
Each mL of CLEOCIN PHOSPHATE Sterile Solution contains clindamycin phosphate equivalent to 150 mg clindamycin, 0.5 mg disodium edetate; 9.45 mg benzyl alcohol added as preservative. When necessary, pH is adjusted with sodium hydroxide and/or hydrochloric acid. CLEOCIN PHOSPHATE is available in the following packages:
25–2 mL vials | NDC 0009-3051-02 |
25–4 mL vials | NDC 0009-4073-04 |
25–6 mL vials | NDC 0009-5095-06 |
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].
Mechanism of Action
Clindamycin inhibits bacterial protein synthesis by binding to the 23S RNA of the 50S subunit of the ribosome. Clindamycin is bacteriostatic.
