WARNINGS
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT
WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE
THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING
THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL
HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE
EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT
IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED
PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED
IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES.
(See
PRECAUTIONS
, Pregnancy, Teratogenic Effects, Pregnancy Category
C.)
Pseudomembranous colitis has been reported with
nearly all antibacterial agents, including clarithromycin,
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 a 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 discontinuation of the drug 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 Clostridium difficile colitis.
For information about warnings of other drugs indicated
in combination with clarithromycin, refer to the
WARNINGS
section of their prescribing information.
PRECAUTIONS
General
Clarithromycin is principally excreted via the liver
and kidney. Clarithromycin may be administered without
dosage adjustment to patients with hepatic impairment
and normal renal function. However, in the presence of
severe renal impairment with or without coexisting hepatic
impairment, decreased dosage or prolonged dosing intervals
may be appropriate.
Clarithromycin in combination with ranitidine bismuth
citrate therapy is not recommended in patients with creatinine
clearance less than 25 ml/min. (See DOSAGE AND ADMINISTRATION.)
Clarithromycin in combination with ranitidine bismuth
citrate should not be used in patients with a history
of acute porphyria.
For information about precautions of other drugs indicated
in combination with clarithromycin, refer to the
PRECAUTIONS
section of their prescribing information.
Information for the Patient
Clarithromycin tablets and oral suspension can be taken
with or without food and can be taken with milk. Do NOT
refrigerate the suspension.
Carcinogenesis, Mutagenesis, and Impairment of
Fertility
The following in vitro mutagenicity tests have been conducted
with clarithromycin:
Salmonella/Mammalian
Microsomes Test.
Bacterial Induced Mutation
Frequency Test.
In Vitro Chromosome
Aberration Test.
Rat Hepatocyte DNA Synthesis
Assay.
Mouse Lymphoma Assay.
Mouse Dominant Lethal
Study.
Mouse Micronucleus Test.
All tests had negative results except the In Vitro Chromosome
Aberration Test which was weakly positive in one test
and negative in another.
In addition, a Bacterial Reverse-Mutation Test (Ames
Test) has been performed on clarithromycin metabolites
with negative results.
Fertility and reproduction studies have shown that daily
doses of up to 160 mg/kg/day (1.3 times the recommended
maximum human dose based on mg/m2) to male and female
rats caused no adverse effects on the estrous cycle, fertility,
parturition, or number and viability of offspring. Plasma
levels in rats after 150 mg/kg/day were 2 times the human
serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were
3 times the human serum levels. When given orally at 150
mg/kg/day (2.4 times the recommended maximum human dose
based on mg/m2), clarithromycin was shown to produce embryonic
loss in monkeys. This effect has been attributed to marked
maternal toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous
dose of 33 mg/m2, which is 17 times less than the maximum
proposed human oral daily dose of 618 mg/m2.
Long-term studies in animals have not been performed
to evaluate the carcinogenic potential of clarithromycin.
Pregnancy, Teratogenic Effects, Pregnancy Category
C
Four teratogenicity studies in rats (three with oral
doses and one with intravenous doses up to 160 mg/kg/day
administered during the period of major organogenesis)
and two in rabbits at oral doses up to 125 mg/kg/day (approximately
2 times the recommended maximum human dose based on mg/m2)
or intravenous doses of 30 mg/kg/day administered during
gestation days 6 to 18 failed to demonstrate any teratogenicity
from clarithromycin. Two additional oral studies in a
different rat strain at similar doses and similar conditions
demonstrated a low incidence of cardiovascular anomalies
at doses of 150 mg/kg/day administered during gestation
days 6 to 15. Plasma levels after 150 mg/kg/day were 2
times the human serum levels. Four studies in mice revealed
a variable incidence of cleft palate following oral doses
of 1000 mg/kg/day (2 and 4 times the recommended maximum
human dose based on mg/m2, respectively) during gestation
days 6 to 15. Cleft palate was also seen at 500 mg/kg/day.
The 1000 mg/kg/day exposure resulted in plasma levels
17 times the human serum levels. In monkeys, an oral dose
of 70 mg/kg/day (an approximate equidose of the recommended
maximum human dose based on mg/m2) produced fetal growth
retardation at plasma levels that were 2 times the human
serum levels.
There are no adequate and well-controlled studies in
pregnant women. Clarithromycin should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus. (See
WARNINGS
.)
Nursing Mothers
It is not known whether clarithromycin is excreted in
human milk. Because many drugs are excreted in human milk,
caution should be exercised when clarithromycin is administered
to a nursing woman. It is known that clarithromycin is
excreted in the milk of lactating animals and that other
drugs of this class are excreted in human milk. Preweaned
rats, exposed indirectly via consumption of milk from
dams treated with 150 mg/kg/day for 3 weeks, were not
adversely affected, despite data indicating higher drug
levels in milk than in plasma.
Pediatric Use
Safety and effectiveness of clarithromycin in children
under 6 months of age have not been established. The safety
of clarithromycin has not been studied in MAC patients
under the age of 20 months. Neonatal and juvenile animals
tolerated clarithromycin in a manner similar to adult
animals. Young animals were slightly more intolerant to
acute overdosage and to subtle reductions in erythrocytes,
platelets and leukocytes but were less sensitive to toxicity
in the liver, kidney, thymus, and genitalia.
Geriatric Use
In a steady-state study in which healthy elderly subjects
(age 65 to 81 years old) were given 500 mg every 12 hours,
the maximum serum concentrations and area under the curves
of clarithromycin and 14-OH clarithromycin were increased
compared to those achieved in healthy young adults. These
changes in pharmacokinetics parallel known age-related
decreases in renal function. In clinical trials, elderly
patients did not have an increased incidence of adverse
events when compared to younger patients. Dosage adjustment
should be considered in elderly patients with severe renal
impairment.
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