Amifostine

Possible synergy of amifostine with antihypertensive drugs.

Decrease in serum calcium concentrations is a known pharmacological effect of amifostine. At the recommended doses, clinically significant hypocalcemia was reported in 1% of patients in the randomized head and neck cancer study, and not reported in the ovarian cancer study.

Pregnancy Category C.

Amifostine has been shown to be embryotoxic in rabbits at doses of 50 mg/kg, approximately sixty percent of the recommended dose in humans on a body surface area basis. There are no adequate and well-controlled studies in pregnant women. Amifostine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

No information is available on the excretion of amifostine or its metabolites into human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, it is recommended that breast feeding be discontinued if the mother is treated with amifostine.

No long term animal studies have been performed to evaluate the carcinogenic potential of amifostine.

Amifostine was negative in the Ames test and in the mouse micronucleus test. The free thiol metabolite was positive in the Ames test with S9 microsomal fraction in the TA1535 Salmonella typhimurium strain and at the TK locus in the mouse L5178Y cell assay. The metabolite was negative in the mouse micronucleus test and negative for clastogenicity in human lymphocytes.

In the randomized study of patients with ovarian cancer given amifostine at a dose of 910 mg/m² prior to chemotherapy, transient hypotension was observed in 62% of patients treated. The mean time of onset was 14 minutes into the 15-minute period of amifostine infusion, and the mean duration was 6 minutes. In some cases, the infusion had to be prematurely terminated due to a more pronounced drop in systolic blood pressure. In general, the blood pressure returned to normal within 5-15 minutes. Fewer than 3% of patients discontinued amifostine due to blood pressure reductions. In the randomized study of patients with head and neck cancer given amifostine at a dose of 200 mg/m² prior to radiotherapy, hypotension was observed in 15% of patients treated.

Hypotension that requires interruption of the amifostine infusion should be treated with fluid infusion and postural management of the patient (supine or Trendelenburg position). If the blood pressure returns to normal within 5 minutes and the patient is asymptomatic, the infusion may be restarted, so that the full dose of amifostine can be administered.

Short term, reversible loss of consciousness has been reported rarely. Blood pressure reductions during amifostine administration have not been reported to cause long term CNS, cardiovascular or renal sequelae, but clinical studies performed to date have not evaluated the safety of amifostine in elderly patients or in patients with preexisting cardiovascular or cerebrovascular conditions.

Nausea and/or vomiting occur frequently after amifostine infusion and may be severe. In the ovarian cancer randomized study, the incidence of severe nausea/vomiting on day 1 of cyclophosphamide cisplatin chemotherapy was 10% in patients who did not receive amifostine, and 19% in patients who did receive amifostine. In the randomized study of patients with head and neck cancer, the incidence of severe nausea/vomiting was 8% in patients who received amifostine and 1% in patients who did not receive amifostine.

Other effects which have been described during or following amifostine infusion are flushing/feeling of warmth, chills/feeling of coldness, fever, dizziness, somnolence, hiccups and sneezing. These effects have not generally precluded the completion of therapy.

Decrease in serum calcium concentrations is a known pharmacological effect of amifostine. At the recommended doses, clinically significant hypocalcemia has occurred rarely (<1%).

Allergic reactions have been reported with the use of amifostine. The majority of cases presented with the following symptoms: hypotension, fever, chills/rigors, dyspnea, skin rashes and urticaria. Other skin reactions including erythema multiforme, and in rare cases Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported. There have been rare reports of anaphylactoid reactions including hypoxia, laryngeal edema, chest tightness, and possible cardiac arrest.

There have been rare reports of seizures in patients receiving amifostine.

The following table contains a summary of the more common adverse events from the two approved doses of amifostine.

Incidence of Common Adverse Events in Patients Receiving Amifostine:

^a According to protocol-defined criteria. WR-1: requiring interruption of infusion; WR-38: drop of >20mm Hg.

In the randomized study of patients with head and neck cancer, 17% (26/150) discontinued amifostine due to adverse events. All but one of these patients continued to receive radiation treatment until completion.