Foscarnet (Foscarnet Sodium) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenicity studies were conducted in rats and mice at oral doses of 500 mg/kg/day and 250 mg/kg/day. Oral bioavailabilty in unfasted rodents is < 20%. No evidence of oncogenicity was reported at plasma drug levels equal to 1/3 and 1/5, respectively, of those in humans (at the maximum recommended human daily dose) as measured by the area-under-the-time/concentration curve (AUC).

Foscarnet sodium showed genotoxic effects in the BALB/3T3 in vitro transformation assay at concentrations greater than 0.5 mcg/mL and an increased frequency of chromosome aberrations in the sister chromatid exchange assay at 1000 mcg/mL. A high dose of foscarnet (350 mg/kg) caused an increase in micronucleated polychromatic erythrocytes in vivo in mice at doses that produced exposures (area under curve) comparable to that anticipated clinically.

Pregnancy:

Teratogenic Effect

Pregnancy, Category C: Foscarnet sodium did not adversely affect fertility and general reproductive performance in rats. The results of peri- and post-natal studies in rats were also negative. However, these studies used exposures that are inadequate to define the potential for impairment of fertility at human drug exposure levels.

Daily subcutaneous doses up to 75 mg/kg administered to female rats prior to and during mating, during gestation, and 21 days post-partum caused a slight increase (< 5%) in the number of skeletal anomalies compared with the control group. Daily subcutaneous doses up to 75 mg/kg administered to rabbits and 150 mg/kg administered to rats during gestation caused an increase in the frequency of skeletal anomalies/variations. On the basis of estimated drug exposure (as measured by AUC), the 150 mg/kg dose in rats and 75 mg/kg dose in rabbits were approximately one-eighth (rat) and one-third (rabbit) the estimated maximal daily human exposure. These studies are inadequate to define the potential teratogenicity at levels to which women will be exposed.

There are no adequate and well controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, foscarnet sodium injection should be used during pregnancy only if clearly needed.

OVERDOSAGE

In controlled clinical trials performed in the United States, overdosage with foscarnet sodium injection was reported in 10 out of 189 patients. All 10 patients experienced adverse events and all except one made a complete recovery. One patient died after receiving a total daily dose of 12.5 g for three days instead of the intended 10.9 g. The patient suffered a grand mal seizure and became comatose. Three days later the patient expired with the cause of death listed as respiratory/cardiac arrest. The other nine patients received doses ranging from 1.14 times to 8 times their recommended doses with an average of 4 times their recommended doses. Overall, three patients had seizures, three patients had renal function impairment, four patients had paresthesias either in limbs or periorally, and five patients had documented electrolyte disturbances

primarily involving calcium and phosphate.

Overdose (up to 20 times the recommended dose) has been reported in post-marketing use of foscarnet sodium. Some of these post-marketing reports were relative overdoses in that the dose of foscarnet sodium had not been adjusted in patients with a reduced renal function. The pattern of adverse events associated with a foscarnet sodium overdose is consistent with the known adverse event profile of the drug.

There is no specific antidote for foscarnet sodium overdose. Hemodialysis and hydration may be of benefit in reducing drug plasma levels in patients who receive an overdosage of foscarnet sodium, but the effectiveness of these interventions has not been evaluated. The patient should be observed for signs and symptoms of renal impairment and electrolyte imbalance. Medical treatment should be instituted if clinically warranted.

CONTRAINDICATIONS

Foscarnet sodium injection is contraindicated in patients with clinically significant hypersensitivity to foscarnet sodium.