CLINDAMYCIN
DESCRIPTION:
WARNING
Clindamycin therapy has been associated
with severe colitis which may end fatally.
Therefore, 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. Studies
indicate a toxin(s) produced by clostridia
is one primary cause of antibiotic-
associated colitis. Cholestyramine and
colestipol resins have been shown to bind
the toxin In Vitro. See WARNINGS section.
The colitis is usually characterized by
severe, persistent diarrhea and severe
abdominal cramps and may be associated with
the passage of blood and mucus. Endoscopic
examination may reveal pseudomembranous
colitis. Stool culture for Clostridium
Difficile and stool assay for C. Difficile
toxin may be helpful diagnostically.
When significant diarrhea occurs, the drug
should be discontinued or, if necessary,
continued only with close observation of
the patient. Large bowel endoscopy has been
recommended.
Antiperistaltic agents such as opiates and
diphenoxylate with atropine may prolong
and/or worsen the condition. Vancomycin has
been found to be effective in the treatment
of antibiotic-associated pseudomembranous
colitis produced by Clostridium Difficile.
The usual adult dose is 500 milligrams to 2
grams of vancomycin orally per day in three
to four divided doses administered for 7 to
10 days. Cholestyramine or colestipol
resins bind vancomycin In Vitro. If both a
resin and vancomycin are to be administered
concurrently, it may be advisable to
separate the time of administration of each
drug.
Diarrhea, colitis, and pseudomembranous
colitis have been observed to begin up to
several weeks following cessation of
therapy with clindamycin.
Clindamycin hydrochloride is the hydrated hydrochloride salt of clindamycin.
Clindamycin is a semisynthetic antibiotic produced by a 7(S)-chloro-substitution
of the 7(R)-hydroxyl group of the parent compound lincomycin.
Dalacin Capsules contain clindamycin hydrochloride equivalent to 75 mg, 150
mg or 300 mg of clindamycin.
Inactive ingredients: 75 MG-corn starch, FD&C blue no. 1, FD&C yellow no. 5,
gelatin, lactose, magnesium stearate and talc; 150 MG-corn starch, FD&C blue no.
1, FD&C yellow no. 5, gelatin, lactose, magnesium stearate, talc and titanium
dioxide; 300 MG-corn starch, FD&C blue no. 1, gelatin, lactose, magnesium
stearate, talc and titanium dioxide.
The chemical name for clindamycin hydrochloride is Methyl 7-chloro-6,7, 8-
trideoxy-6-(1-methyl- TRANS-4-propyl-L- 2-pyrrolidinecarboxamido)-1-thio-L-
THREO- (alpha)-D-GALACTO-octopyranoside monohydrochloride.
ACTIONS/CLINICAL PHARMACOLOGY:
MICROBIOLOGY: Clindamycin has been shown to have In Vitro activity against
isolates of the following organisms: Aerobic Gram-Positive Cocci, including:
Staphylococcus Aureus
Staphylococcus Epidermidis
(Penicillinase And Nonpenicillinase 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, eg, 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.
HUMAN PHARMACOLOGY: Serum level studies with a 150 mg oral dose of clindamycin
hydrochloride in 24 normal adult volunteers showed that clindamycin was rapidly
absorbed after oral administration. An average peak serum level of 2.50 mcg/mL
was reached in 45 minutes; serum levels averaged 1.51 mcg/mL at 3 hours and 0.70
mcg/mL at 6 hours. Absorption of an oral dose is virtually complete (90%), and
the concomitant administration of food does not appreciably modify the serum
concentrations; serum levels have been uniform and predictable from person to
person and dose to dose. Serum level studies following multiple doses of CLEOCIN
HCl for up to 14 days show no evidence of accumulation or altered metabolism of
drug.
Serum half-life of clindamycin is increased slightly in patients with markedly
reduced renal function. Hemodialysis and peritoneal dialysis are not effective
in removing clindamycin from the serum.
Concentrations of clindamycin in the serum increased linearly with increased
dose. Serum levels exceed the MIC (minimum inhibitory concentration) for most
indicated organisms for at least six hours following administration of the
usually recommended doses. Clindamycin is widely distributed in body fluids and
tissues (including bones). The average biological half- life is 2.4 hours.
Approximately 10% of the bioactivity is excreted in the urine and 3.6% in the
feces; the remainder is excreted as bioinactive metabolites.
Doses of up to 2 grams of clindamycin per day for 14 days have been well
tolerated by healthy volunteers, except that the incidence of gastrointestinal
side effects is greater with the higher doses.
No significant levels of clindamycin are attained in the cerebrospinal fluid,
even in the presence of inflamed meninges.
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,
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 (REF. 1).
INDICATIONS AND USAGE:
Clindamycin is indicated in the treatment of serious infections caused by
susceptible anaerobic bacteria.
Clindamycin 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 colitis, as described in the WARNING box, before selecting clindamycin
the physician should consider the nature of the infection and the suitability of
less toxic alternatives (eg, erythromycin).
ANAEROBES: Serious respiratory tract infections such as empyema, anaerobic
pneumonitis and lung abscess; serious skin and soft tissue infections;
septicemia; intra-abdominal infections such as peritonitis and intra-abdominal
abscess (typically resulting from anaerobic organisms resident in the normal
gastrointestinal tract); infections of the female pelvis and genital tract such
as endometritis, nongonococcal tubo-ovarian abscess, pelvic cellulitis and
postsurgical vaginal cuff infection.
STREPTOCOCCI: Serious respiratory tract infections; serious skin and soft tissue
infections.
STAPHYLOCOCCI: Serious respiratory tract infections; serious skin and soft
tissue infections.
PNEUMOCOCCI: Serious respiratory tract infections.
Bacteriologic studies should be performed to determine the causative organisms
and their susceptibility to clindamycin.
In Vitro SUSCEPTIBILITY TESTING: A standardized disk testing procedure(*) is
recommended for determining susceptibility of aerobic bacteria to clindamycin. A
description is contained in the CLEOCIN(R) 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 CLEOCIN(R) Susceptibility Powder
insert are followed, an MIC 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.
*Bauer AW, Kirby WMM, Sherris JC, et al: Antibiotic susceptibility testing by a
standardized single disc method. Am J Clin Pathol 45:493-496, 1966. Standardized
disc susceptibility test. Federal Register 37:20527-29, 1972. CLEOCIN
Susceptibility Disks 2 mcg. See package insert for use.
DALACINSusceptibility 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.
CONTRAINDICATIONS:
Dalacin is contraindicated in individuals with a history of hypersensitivity
to preparations containing clindamycin or lincomycin.
WARNINGS:
WARNING
Clindamycin therapy has been associated
with severe colitis which may end fatally.
Therefore, 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. Studies
indicate a toxin(s) produced by clostridia
is one primary cause of antibiotic-
associated colitis. Cholestyramine and
colestipol resins have been shown to bind
the toxin In Vitro. See WARNINGS section.
The colitis is usually characterized by
severe, persistent diarrhea and severe
abdominal cramps and may be associated with
the passage of blood and mucus. Endoscopic
examination may reveal pseudomembranous
colitis. Stool culture for Clostridium
Difficile and stool assay for C. Difficile
toxin may be helpful diagnostically.
When significant diarrhea occurs, the drug
should be discontinued or, if necessary,
continued only with close observation of
the patient. Large bowel endoscopy has been
recommended.
Antiperistaltic agents such as opiates and
diphenoxylate with atropine may prolong
and/or worsen the condition. Vancomycin has
been found to be effective in the treatment
of antibiotic-associated pseudomembranous
colitis produced by Clostridium Difficile.
The usual adult dose is 500 milligrams to 2
grams of vancomycin orally per day in three
to four divided doses administered for 7 to
10 days. Cholestyramine or colestipol
resins bind vancomycin In Vitro. If both a
resin and vancomycin are to be administered
concurrently, it may be advisable to
separate the time of administration of each
drug.
Diarrhea, colitis, and pseudomembranous
colitis have been observed to begin up to
several weeks following cessation of
therapy with clindamycin.
PSEUDOMEMBRANOUS COLITIS HAS BEEN REPORTED WITH NEARLY ALL ANTIBACTERIAL AGENTS,
INCLUDING CLINDAMYCIN, AND MAY RANGE IN SEVERITY FROM MILD TO LIFE-THREATENING.
THEREFORE, IT IS IMPORTANT TO CONSIDER THIS DIAGNOSIS IN PATIENTS WHO PRESENT
WITH DIARRHEA SUBSEQUENT TO THE ADMINISTRATION OF ANTIBACTERIAL AGENTS.
Treatment with antibacterial agents alters the normal flora of the colon and may
permit overgrowth of clostridia. Studies indicate that a toxin produced by
Clostridium Difficile is one primary cause of "antibiotic-associated colitis".
After the diagnosis of pseudomembranous colitis has been established,
therapeutic measures should be initiated. Mild cases of pseudomembranous colitis
usually respond to drug discontinuation alone. In moderate to severe cases,
consideration should be given to management with fluids and electrolytes,
protein supplementation, and treatment with an antibacterial drug clinically
effective against C. Difficile colitis.
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.
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.
Dalacin should be prescribed with caution in individuals with a history of
gastrointestinal disease, particularly colitis.
Dalacin should be prescribed with caution in atopic individuals.
Indicated surgical procedures should be performed in conjunction with antibiotic
therapy.
The use of Dalacin 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 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.
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.
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.
Antagonism has been demonstrated between clindamycin and erythromycin In Vitro.
Because of possible clinical significance, these two drugs should not be
administered concurrently.
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 test. Both tests were negative. Fertility studies
in rats treated orally with up to 300 mg/kg/day (31 times the human exposure
based on mg/m(squared)) revealed no effects on fertility or mating ability.
PREGNANCY: TERATOGENIC EFFECTS
Pregnancy category B
Reproduction studies have been performed in rats and mice using oral and
parenteral doses of clindamycin up to 600 mg/kg/day (4.5 and 2.3 times,
respectively, the maximum human exposure based on mg/m(squared)) and have
revealed no evidence of harm to the fetus due to clindamycin. In one mouse
strain, cleft palates were observed in treated fetuses; this outcome was not
produced in other mouse strains or in other species and is, therefore,
considered to be a strain specific effect.
There are, however, no adequate and well- controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
NURSING MOTHERS
Clindamycin has been reported to appear in breast milk in the range of 0.7 to
3.8 mcg/mL.
PEDIATRIC USE
When Dalacin 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 CLOSTRIDIUM 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.
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.
Antagonism has been demonstrated between clindamycin and erythromycin In Vitro.
Because of possible clinical significance, these two drugs should not be
administered concurrently.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The following reactions have been reported with the use of clindamycin.
GASTROINTESTINAL: Abdominal pain, pseudomembranous colitis, esophagitis, nausea,
vomiting and diarrhea (see WARNING box). The onset of pseudomembranous colitis
symptoms may occur during or after antibacterial treatment (see WARNINGS).
HYPERSENSITIVITY REACTIONS: 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.
DOSAGE AND ADMINISTRATION:
If significant diarrhea occurs during therapy, this antibiotic should be
discontinued (see WARNING box).
ADULTS: SERIOUS INFECTIONS-150 to 300 mg every 6 hours. MORE SEVERE INFECTIONS-
300 to 450 mg every 6 hours. PEDIATRIC PATIENTS: SERIOUS INFECTIONS-8 to 16
mg/kg/day (4 to 8 mg/lb/day) divided into three or four equal doses. MORE SEVERE
INFECTIONS-16 to 20 mg/kg/day (8 to 10 mg/lb/day) divided into three or four
equal doses.
To avoid the possibility of esophageal irritation, Dalacin Capsules should
be taken with a full glass of water.
Serious infections due to anaerobic bacteria are usually treated with CLEOCIN
PHOSPHATE(R) Sterile Solution. However, in clinically appropriate circumstances,
the physician may elect to initiate treatment or continue treatment with CLEOCIN
HCl Capsules.
In cases of (beta)-hemolytic streptococcal infections, treatment should continue
for at least 10 days.
TOXICOLOGY
Animal toxicity studies showed the following:
LD50 I.P. Administration-Mouse
361 mg/kg
LD50 I.V. Administration-Mouse
245 mg/kg
LD50 Oral Administration-Rat
2,618 mg/kg
One year oral toxicity studies in Spartan Sprague-Dawley rats and Beagle dogs at
levels of 30, 100, and 300 mg/kg/day (3 grams/day per dog) have shown CLEOCIN
HCl to be well tolerated. No appreciable difference in pathological findings has
been obtained in groups of animals treated with Dalacin from comparable
control groups. Rats receiving clindamycin hydrochloride at 600 mg/kg/day for
six months tolerated the drug well; however, dogs dosed at this level vomited,
would not eat and lost weight.
CAUTION: Federal law prohibits dispensing without prescription.
Made in Canada for
Pharmacia & Upjohn Company
Kalamazoo, MI 49001, USA
By Global Pharm Inc.
Don Mills, Ontario M3B 1Y6
Canada
Revised April 1997 810 570 621
691015
REFERENCES:
1. Smith RB, Phillips JP: Evaluation of Dalacin and DALACINPhosphate in an
Aged Population. Upjohn TR 8147-82-9122-021, December 1982.
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