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ir a fpractice but for an individual fellow._eswarch Award will be solicited up to Jan-_,ritten for each nomination. The letteraward might be granted and should _well as one copy of at least one but nong the carndidate's work. The empha-if a crtcal paper is in press, acopy'psprig letters are encouraged but not required. These lettersiraiation, who will then forward them to this office.ffinton, Administrative Assistant, Department of Research,krthwest Point Boulevard, Elk Grove Village, Illinois 60007,cf1 on Pediatric Research Selection Conunittee.wy pediatric depatent heads and other fellows of the Acade-idntl candlidates for this award.

Spontaneous reports in the post-marketing period suggestthat concomitant administration of clarithromycin and oralanticoagulants may potentiate the effects of the oral anticoag-ulants. Prothrombin times should be carefuilly monitoredwhile patients are receiving clarithromycin and oral anticoag-ulants simultaneously.Elevated digoxin serum concentrations in patients receiving

clarithromycin and digoxin concomitantly have also beenreported in post-marketing surveillance. Serum digoxin levelsshould be carefuilly monitored while patients are receivingdigoxin and clarithromycin simultaneously.The following drug interactions, other than increased serum

concentrations of carbamazepine and active acid metaboliteof terfenadine, have not been reported in clinical trials withclarithromycin; however, they have been observed with ery-thromycin products:Concuffent use of erythromycin and ergotamine or dihy-droergotamine has been associated in some patients withacute ergot toxicity characterized by severe peripheralvasospasm and dysesthesia.Erythromycin has been reported to decrease the clearance oftriazolam and, thus, may increase the pharmacologic effectof triazolam.

T'he use of erythromycin in patients concuffently takingdrugs metabolized by the cytochrome P450 system may beassociated with elevations in serum levels of these otherdrugs. There have been reports of interactions of ery-thromycin with carbamazepine, cyclosporine, hexobarbital,phenytoin, alfentanil, disopyramide, lovastatin, bromocrip-tine, valproate, terfenadine, and astemizole. Serum concen-trations of drugs metabolized by the cytochrome P450system should be monitored closely in patients concurrentlyreceiving erythromycin.

Carcinogenesis, Mutagenesis, Impairment of Fertility: T1hefollowing in vitro mutagenicity tests have been conductedwith clarithromycin: Salmonella/Mammalian MicrosomesTest, Bacterial Induced Mutation Frequency Test, In VitroChromosome Aberration Test, Rat Hepatocyte DNA Synthe-sis Assay, Mouse Lymphoma Assay, Mouse Dominant LethalStudy, and Mouse Micronucleus Test.All tests had negative results except the In Vitro Chromo-

some Abeffation Test which was weakly positive in one testand negative in another.In addition, a Bacterial Reverse-Mutation Test (Ames Test)

has been performed on clarithromycin metabolites with nega-tive results.Fertility and reproduction studies have shown that daily

doses of up to 160 mg/kg/day (1.3 times the recommendedmaximum human dose based on Mg/M2) to male and femalerats caused no adverse effects on the estrous cycle, fertility,parturition, or number and viability of offspring. Plasma lev-els in rats after 150 mg/kg/day were 2 times the human serumlevels.In the 150 mg/kg/day monkey studies, plasma levels were 3

times the human serum levels. When given orally at150 mg/kg/day (2.4 times the recommended maximumhuman dose based on Mg/M2), clarithromycin was shown toproduce embryonic loss in monkeys. This effect has beenattributed to marked maternal toxicity of the drug at this highdose.In rabbits, in utero fetal loss occuffed at an intravenous dose

of 33 Mg/M2, which is 17 times less than the maximum pro-posed human oral daily dose of 618 Mg/M2.Long-tenrm 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 andone with intravenous doses up to 160 mg/kg/day administeredduring the period of major organogenesis) and two in rabbitsat oral doses up to 125 mg/kg/day (approximately 2 times therecommended maximum human dose based on Mg/M2) orintravenous doses of 30 mg/kg/day administered during ges-tation days 6 to 18 failed to demonstrate any teratogenicityfrom clarithromycin. Two additional oral studies in a differ-ent rat strain at similar doses and similar conditions demon-strated a low incidence of cardiovascular anomalies at dosesof 150 mg/kg/day administered during gestation days 6 to 15.Plasma levels after 150 mg/kg/day were 2 times the humanserum levels. Four studies in mice revealed a variable inci-dence of cleft palate following oral doses of 1000 mg/kg/day(2 and 4 times the recommended maximum human dosebased on mg/M2, respectively) during gestation days 6 to 15.Cleft palate was also seen at 500 mg/kg/day. The1000 mg/kg/day exposure resulted in plasma levels 17 timesthe human serum levels. In monkeys, an oral dose of70 mg/kg/day (an approximate equidose of the recommendedmaximum human dose based on Mg/M2) produced fetalgrowth retardation at plasma levels that were2 times the human serum levels.There are no adequate and well-controlled studies in preg-

nant women. Clarithromycin should be used during preg-nancy only if the potential benefit justifies the potential riskto the fetus. (See WARNINGS.)Nursin AAthers It;is nt knw hthrcaihrmcni

excreted in human milk. Because many drugs are excreted inhuman milk, caution should be exercised when clar-ithromycin is administered to a nursing woman. It is knownthat clarithromycin is excreted in the milk of lactating animalsand 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 notadversely affected, despite data indicating higher drug levelsin mitk than in plasma.Pediatric Use: Safety and effectiveness of clarithromycin in

children under 6 months of age have not been established.Neonatal and juvenile animals tolerated clarithromycin in amanner similar to adult animals. Young animals were slightlymore intolerant to acute overdosage and to subtle reductionsin erythrocytes, platelets and leukocytes but were less sensi-tive 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 mgevery 12 hours, the maximum serum concentrations and areaunder the curves of clarithromycin and 14-OH clarithromycinwere increased compared to those achieved in healthy youngadults. These changes in pharmacokinetics parallel knownage-related decreases in renal function. In clinical trials,elderly patients did not have an increased incidence ofadverse events when compared to younger patients. Dosageadjustment should be considered in elderly patients withsevere renal impairnent.

ADVERSE REACTIONS:The majority of side effects observed in clinical trials were ofa mild and trasient nature. Fewer than 3% of adult patientsand fewer than 2% of pediatric patients discontinued therapybecause of drug-related side effects.The most frequently reported events in adults were diarrhea

(3%), nausea (3%), abnormal taste (3%), dyspepsia (2%),abdominal pain/discomfort (2%), and headache (2%). In pedi-atric patients, the most frequently reported events were diar-rhea (6%), vomiting (6%), abdominal pain (3%), rash (3%),and headache (2%). Most of these events were described asmild or moderate in severity. Of the reported adverse events,only I% was described as severe.In pneumonia studies conducted in adults comparing clar-

ithromycin to erythromycin base or erythromycin stearate,there were fewer adverse events involving the digestive sys-tem in clarithromycin-treated patients compared to ery-thromycin-treated patients (13% vs 32%; p