WARNING
To reduce the development of drug-resistant bacteria and maintain the
effectiveness of clindamycin hydrochloride and other antibacterial drugs,
clindamycin hydrochloride should be used only to treat or prevent infections
that are proven or strongly suspected to be caused by bacteria.
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.
Because clindamycin 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. 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.
Diarrhea, colitis,
and pseudomembranous colitis have been observed to begin up to several weeks
following cessation of therapy with clindamycin.
DESCRIPTION
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.
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-α-D-
galacto-octopyranoside
monohydrochloride. The structural formula is represented below:
C18H33ClN2O5S•HCl
M.W. 461.45
Clindamycin hydrochloride capsules,
USP contain clindamycin hydrochloride equivalent to 150 mg or 300 mg of
clindamycin. Each capsule also contains the following inactive ingredients:
lactose monohydrate, corn starch, talc, and magnesium stearate. The empty hard
gelatin capsule shell consists of FD and C Blue No. 1, titanium dioxide, gelatin
and sodium lauryl sulphate. In addition 150 mg also contains yellow iron oxide.
The capsules are printed with edible ink containing black iron oxide and
shellac.
CLINICAL PHARMACOLOGY
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 2.5 mcg/mL was reached in 45 minutes; serum levels
averaged 1.51 mcg/mL at 3 hours and 0.7 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 clindamycin hydrochloride 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 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
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 function.
Microbiology
Clindamycin inhibits bacterial
protein synthesis by binding to the 50S subunit of the ribosome. It has activity
against Gram-positive aerobes and anaerobes as well as the Gram-negative
anaerobes. Clindamycin is bacteriostatic. Cross-resistance between clindamycin
and lincomycin is complete. Antagonism
in vitro has
been demonstrated between clindamycin and erythromycin.
Clindamycin has
been shown to be active against most of the isolates of the following
microorganisms, both
in vitro and in clinical
infections, as described in the
INDICATIONS AND USAGE section.
Gram-positive aerobes
Staphylococcus aureus (methicillin-susceptible
strains)
Streptococcus pneumoniae
(penicillin-susceptible strains)
Streptococcus
pyogenes
Anaerobes
Prevotella melaninogenica
Fusobacterium necrophorum
Fusobacterium nucleatum
Peptostreptococcus anaerobius
Clostridium perfringens
The following
in vitro data are available, but their clinical
significance is unknown. At least 90% of the following microorganisms exhibit an
in vitro minimum inhibitory concentration (MIC) less
than or equal to the susceptible breakpoint for clindamycin. However, the safety
and effectiveness of clindamycin in treating clinical infections due to these
microorganisms have not been established in adequate and well-controlled
clinical trials.
Gram-positive aerobes
Staphylococcus epidermidis
(methicillin-susceptible strains)
Streptococcus
agalactiae
Streptococcus anginosus
Streptococcus oralis
Streptococcus
mitis
Anaerobes
Prevotella intermedia
Prevotella
bivia
Propionibacterium acnes
Micromonas (“Peptostreptococcus”)
micros
Finegoldia (“Peptostreptococcus”) magna
Actinomyces
israelii
Clostridium clostridioforme
Eubacterium lentum
Susceptibility Testing Methods
NOTE: Susceptibility testing by dilution methods requires
the use of clindamycin susceptibility powder.
When available, the
results of
in vitro susceptibility tests should be
provided to the physician as periodic reports that describe the susceptibility
profile of nosocomial and community-acquired pathogens. These reports should aid
the physician in selecting the most effective antimicrobial.
Dilution
Techniques
Quantitative methods are used to determine antimicrobial
minimum inhibitory concentrations (MICs). These MICs provide estimates of the
susceptibility of bacteria to antimicrobial compounds. The MICs should be
determined using a standardized procedure. Standardized procedures are based on
a dilution method (broth and agar)
1,2,3 or equivalent
with standardized inoculum concentrations and standardized concentrations of
clindamycin powder. The MIC values should be interpreted according to the
criteria provided in Table 1.
Diffusion Techniques
Quantitative
methods that require the measurement of zone diameters also provide reproducible
estimates of the susceptibility of bacteria to antimicrobial compounds. One such
standardized procedure
2,3 requires the use of
standardized inoculum concentrations. This procedure uses paper disks
impregnated with 2 mcg of clindamycin to test the susceptibility of
microorganisms to clindamycin. The disk diffusion interpretive criteria are
provided in Table 1.
Table 1. Susceptibility Interpretive Criteria for Clindamycin
Pathogen | Susceptibility Interpretive
Criteria |
Minimal Inhibitory
Concentrations (MIC in mcg/mL) | Disk Diffusion (Zone
Diameters in mm) |
| S | I | R | S | I | R |
Staphylococcus
spp.
| ≤0.5
| 1-2
| ≥4
| ≥21
| 15-20
| ≤14
|
Streptococcus
pneumoniae and other Streptococcus
spp.
| ≤0.25a
| 0.5
| ≥1
| ≥19b
| 16-18
| ≤15
|
Anaerobic Bacteriac
| ≤2
| 4
| ≥8
| NA
| NA
| NA
|
a These
interpretive standards for
S. pneumoniae and other
Streptococcus spp. are applicable only to tests
performed by broth microdilution using cation-adjusted Mueller-Hinton broth with
2 to 5% lysed horse blood inoculated with a direct colony suspension and
incubated in ambient air at 35°C for 20 to 24 hours.
b
These zone diameter interpretive standards are applicable only to tests
performed using Mueller-Hinton agar supplemented with 5% sheep blood inoculated
with a direct colony suspension and incubated in 5% CO
2
at 35°C for 20 to 24 hours.
c These interpretive
criteria are for all anaerobic bacterial pathogens; no organism specific
interpretive criteria are available.
NA=Not applicable
A report of
“Susceptible” indicates that the pathogen is likely to be inhibited if the
antimicrobial compound in the blood reaches the concentrations usually
achievable. A report of “Intermediate” indicates that the result should be
considered equivocal, and, if the microorganism is not fully susceptible to
alternative, clinically feasible drugs, the test should be repeated. This
category implies possible clinical applicability in body sites where the drug is
physiologically concentrated or in situations where high dosage of drug can be
used. This category also provides a buffer zone that prevents small,
uncontrolled technical factors from causing major discrepancies in
interpretation. A report of “Resistant” indicates that the pathogen is not
likely to be inhibited if the antimicrobial compound in the blood reaches the
concentrations usually achievable; other therapy should be
selected.
Quality Control
Standardized susceptibility test
procedures require the use of quality control microorganisms to control the
technical aspects of the test procedures. Standard clindamycin powder should
provide the following range of values noted in Table 2.
NOTE:
Quality control microorganisms are specific strains of organisms with
intrinsic biological properties relating to resistance mechanisms and their
genetic expression within bacteria; the specific strains used for
microbiological quality control are not clinically significant.
Table 2. Acceptable Quality Control Ranges for Clindamycin to be Used
in Validation of Susceptibility Test Results
QC Strain | Acceptable Quality Control
Ranges |
Minimum Inhibitory Concentrations (MIC in
mcg/mL) | Disk Diffusion (Zone Diameters in
mm) |
When Testing Aerobic
Pathogens
|
|
|
Staphylococcus
aureus ATCC 29213
| 0.06–0.25
| NA
|
Staphylococcus
aureus ATCC 25923
| NA
| 24–30
|
Streptococcus
pneumoniae ATCC 49619d
| 0.03–0.12e
| 19–25f
|
When Testing Strict
Anaerobes
|
|
|
Bacteroides
fragilis ATCC 25285
| 0.5–2
| NA
|
Bacteroides
thetaiotaomicron ATCC 29741
| 2–8
| NA
|
Eubacterium lentum
ATCC 43055
| 0.06–0.25
|
NA
|
NA=Not applicable
d This organism may be used for validation of susceptibility
test results when testing
Streptococcus spp. other
than
S. pneumoniae.
e This
quality control range for
S. pneumoniae is applicable
only to tests performed by broth microdilution using cation-adjusted
Mueller-Hinton broth with 2 to 5% lysed horse blood inoculated with a direct
colony suspension and incubated in ambient air at 35°C for 20 to 24
hours.
f This quality control zone diameter range is
applicable only to tests performed using Mueller-Hinton agar supplemented with
5% sheep blood inoculated with a direct colony suspension and incubated in 5%
CO
2 at 35°C for 20 to 24 hours.
ATCC
® is a registered trademark of the American Type Culture
Collection
INDICATIONS AND USAGE
Clindamycin
hydrochloride capsules are indicated in the treatment of serious infections
caused by susceptible anaerobic
INDICATIONS AND USAGE
Clindamycin hydrochloride capsules are indicated in the treatment of serious
infections caused by susceptible anaerobic bacteria.
Clindamycin
hydrochloride capsules 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 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 (e.g., 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 tuboovarian 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.
To
reduce the development of drug-resistant bacteria and maintain the effectiveness
of clindamycin hydrochloride and other antibacterial drugs, clindamycin
hydrochloride 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
Clindamycin hydrochloride capsules are contraindicated in individuals with a
history of hypersensitivity to preparations containing clindamycin or
lincomycin.
WARNINGS
See
WARNING box.
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.
Clindamycin hydrochloride should be prescribed with caution
in individuals with a history of gastrointestinal disease, particularly
colitis.
Clindamycin hydrochloride should be prescribed with caution in
atopic individuals.
Indicated surgical procedures should be performed in
conjunction with antibiotic therapy.
The use of clindamycin
hydrochloride 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.
Prescribing clindamycin
hydrochloride 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.
Information for Patients
Patients should be counseled that antibacterial drugs including clindamycin
hydrochloride should only be used to treat bacterial infections. They do not
treat viral infections (e.g., the common cold). When clindamycin hydrochloride
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 hydrochloride or other antibacterial
drugs in the future.
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 Salmonella reversion test. Both tests were
negative.
Fertility studies in rats treated orally with up to 300
mg/kg/day (approximately 1.6 times the highest recommended adult human dose
based on mg/m
2) revealed no effects on fertility or
mating ability.
Pregnancy
Teratogenic effects
Pregnancy Category
B
Reproduction studies performed in rats and mice using oral doses of
clindamycin up to 600 mg/kg/day (3.2 and 1.6 times the highest recommended adult
human dose based on mg/m
2, respectively) or subcutaneous
doses of clindamycin up to 250 mg/kg/day (1.3 and 0.7 times the highest
recommended adult human dose based on mg/m
2,
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.
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 clindamycin hydrochloride 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.
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.
OVERDOSAGE
Significant mortality was observed in mice at an intravenous dose of 855 mg/kg
and in rats at an oral or subcutaneous dose of approximately 2618 mg/kg. In the
mice, convulsions and depression were observed.
Hemodialysis and
peritoneal dialysis are not effective in removing clindamycin from the
serum.
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, clindamycin hydrochloride capsules should
be taken with a full glass of water.
Serious infections due to anaerobic
bacteria are usually treated with clindamycin phosphate injection. However, in
clinically appropriate circumstances, the physician may elect to initiate
treatment or continue treatment with clindamycin hydrochloride
capsules.
In cases of β-hemolytic streptococcal infections, treatment
should continue for at least 10 days.
HOW SUPPLIED
Clindamycin hydrochloride capsules are available in the following
strengths, colors and sizes:
150 mg Turquoise blue opaque cap and light green body
printed with “RX692” on cap and body in black ink.
NDC 67296-0315-3 Bottles of 40
Store at 20 - 25° C (68 - 77° F). (See USP Controlled Room Temperature).
One year oral toxicity studies in Spartan Sprague-Dawley rats and beagle dogs at
dose levels up to 300 mg/kg/day (approximately 1.6 and 5.4 times the highest
recommended adult human dose based on mg/m
2,
respectively) have shown clindamycin to be well tolerated. No appreciable
difference in pathological findings has been observed between groups of animals
treated with clindamycin and comparable control groups. Rats receiving
clindamycin hydrochloride at 600 mg/kg/day (approximately 3.2 times the highest
recommended adult human dose based on mg/m
2) for 6 months
tolerated the drug well; however, dogs dosed at this level (approximately 10.8
times the highest recommended adult human dose based on mg/m
2) vomited, would not eat, and lost weight.
REFERENCES
- NCCLS. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria
that Grow Aerobically; Approved Standard-5th ed. NCCLS document M7-A5, 2000.
NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898.
- NCCLS. Performance Standards for Antimicrobial Susceptibility Testing: 13th
Informational Supplement. NCCLS document M100-S13 (M2 and M7), 2003. NCCLS,
940 West Valley Road, Suite 1400, Wayne, PA 19087-1898.
- NCCLS. Methods for Antimicrobial Susceptibility Testing of Anaerobic
Bacteria 5th ed. Approved Standard. NCCLS document M11-A5, 2001. NCCLS, 940 West
Valley Road, Suite 1400, Wayne, PA 19087-1898.
- NCCLS. Performance Standards for Antimicrobial Disk Susceptibility Tests;
Approved Standard-8th ed. NCCLS document M2-A8 (ISBN 1-56238-393-0), 2003.
NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898.
Manufactured for:
Ranbaxy Pharmaceuticals Inc.
Jacksonville, FL 32257 USA
by: Ohm Laboratories Inc.
North Brunswick, NJ 08902 USA
November 2006
RedPharm Drug Inc.