|
TOXICOLOGY
Acute, Subchronic, and Chronic Toxicity
Studies were conducted in mice, rats, dogs and/or monkeys with
clarithromycin administered orally. The duration of administration ranged
from a single oral dose to repeated daily oral administration for six
consecutive months.
In acute mouse and rat studies, one rat, but no mice, died following a
single gavage of 5 g/kg body weight. The median lethal dose, therefore, was
greater than 5 g/kg, the highest feasible dose for administration. No
adverse effects were attributed to clarithromycin in primates exposed to 100
mg/kg/day for 14 consecutive days or to 35 mg/kg/day for one month.
Similarly, no adverse effects were seen in rats exposed to 75 mg/kg/day for
one month, to 35 mg/kg/day for three months, or to 8 mg/kg/day for six
months. Dogs were more sensitive to clarithromycin, tolerating 50 mg/kg/day
for 14 days, 10 mg/kg/day for one and three months, and 4 mg/kg/day for six
months without adverse effects.
The major clinical signs at toxic doses in
these studies described above included emesis, weakness, reduced food
consumption and reduced weight gain, salivation, dehydration, and
hyperactivity. Two of ten monkeys receiving 400 mg/kg/day died on treatment
day eight; yellow discolored feces were passed on a few isolated occasions
by some surviving monkeys given a dose of 400 mg/kg/day for 28 days.
The
primary target organ at toxic dosages in all species was the liver. The
development of hepatotoxicity in all species was detectable by early
elevation of serum concentrations of alkaline phosphatase, alanine and
aspartate aminotransferase, gamma-glutamyl transferase, and/or lactic
dehydrogenase. Discontinuation of the drug generally resulted in a return to
or toward normal concentrations of these specific parameters.
Additional tissues less commonly
affected in the various studies included the stomach. thymus and other
lymphoid tissues, and the kidneys. Conjunctival injection and lacrimation,
following near therapeutic dosages, occurred in dogs only. At a massive
dosage of 400 mg/kg/day, some dogs and monkeys developed corneal opacities
and/or edema.
Fertility, Reproduction, and Teratogenicity
Fertility and reproduction studies have shown daily dosages of 150 to 160
mg/kg/day to male and female rats caused no adverse effects on the estrous
cycle, fertility, parturition, and number and viability of offspring. Two teratogenicity studies in both Wistar (p.o.) and Sprague-Dawley (p.o, and
i.v.) rats, one study in New Zealand White rabbits and one study in
cynomolgus monkeys failed to demonstrate any teratogenicity from
clarithromycin. Only in one additional study in Sprague-Dawley rats at
similar doses and essentially similar conditions did a very low,
statistically insignificant incidence (approximately 6%) of cardiovascular
anomalies occur. These anomalies appeared to be due to spontaneous
expression of genetic changes within the colony. Two studies in mice also
revealed a variable incidence of cleft pal at (3 to 30%) following doses of
70 times the upper range of the usual daily human clinical dose (500 mg
b.i.d.), but not at 35 times the maximal daily human clinical dose,
suggesting maternal and fetal toxicity but not teratogenicity.
Clarithromycin has been shown to produce embryonic loss in monkeys when
administered at approximately ten times the upper range of the usual daily
human dose (500 mg b.i.d.), starting at gestation day 20. This effect has
been attributed to maternal toxicity of the drug at very high doses. An
additional study in pregnant monkeys at dosages of approximately 2.5 to 5
times the maximal intended daily dosage produced no unique hazard to the
conceptus.
A dominant lethal test in mice given 1000 mg/kg/day (approximately 70 times
the maximal human daily clinical dose) was clearly negative for any
mutagenic activity, and, in a Segment I study of rats treated with up to 500
mg/kg/day (approximately 35 times the maximal daily human clinical dose) for
80 days, no evidence of functional impairment of male fertility due to this
long-term exposure to these very high Closet of clarithromycin was
exhibited.
Mutagenicity
Studies to evaluate the mutagenic potential of clarithromycin were performed
using both nonactivated and rat-liver-microsome-activated test systems (Ames
Test). Results of these studies provided no evidence of mutagenic potential
at drug concentrations of 25 mcg/Petri plate or less. At a concentration of
50 mop the drug was toxic for all strains tested.
INDICATIONS
Treatment of infections caused by pathogens sensitive to Clarithromycin.
Infection of nose-pharynx tract (tonsillitis, pharyngitis) and of paranasal
sinuses. Infections of lower respiratory tract: bronchitis, bacterial
pneumonia and atypical pneumonia. Skin infections: impetigo, erysipelas,
folliculitis, furunculosis and septic wounds.
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with known hypersensitivity to
macrolide antibiotic drugs. Concomitant administration of clarithromycin and
any of the following drugs is contraindicated: astemizole cisapride,
pimozide, terfenadine and ergotamine or dihydroergotamine (see
PRECAUTIONS - Drug Interactions).
WARNING
The physician should not prescribe clarithromycin to pregnant women without
carefully weighing the benefits against risk, particularly during the first
three months of pregnancy.
Pseudomembranous colitis has been reported with nearly all antibacterial
agents, including macrolides and may range in severity from mild to
life-threatening.
1
2
3
4
5
|
