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Amonafide


Pronunciation

 (a MON a fide)


Synonyms

 Amonafide Hydrochloride; Benzisoquinolinedione; BIDA; M-FA-142; Nafidimide; NSC-308847


Generic Available

 No


Use - Unlabeled/Investigational

 Has shown some activity against breast, prostate, renal cell, ovarian, pancreatic, and nonsmall cell lung cancers


Contraindications

 Hypersensitivity to amonafide or any component of the formulation; pregnancy


Warnings/Precautions

 Amonafide should be used cautiously in bone marrow transplant patients and patients with existing bone marrow suppression, hepatic dysfunction, arrhythmias, conduction problems, congestive heart failure, or seizures or other neurological disorders. Amonafide toxicity, particularly hematologic, correlates with the patient's acetylator status. If possible, determination of acetylator type (fast vs slow) should be considered prior to beginning therapy.


Adverse Reactions

>10%:

Gastrointestinal: Nausea and vomiting (mild)

Hematologic: Granulocytopenia, possibly dose-limiting; nadir occurs at days 12-15, recovery by day 21

1% to 10%:

Cardiovascular: Chest pain

Central nervous system: Dizziness, fatigue, headache

Dermatologic: Skin rash, exfoliative dermatitis, alopecia

Local: Inflammatory reactions

Otic: Tinnitus

Neuromuscular & skeletal: Myoclonic jerking, weakness

<1%: CHF, hypotension, taste alteration, thrombocytopenia


Stability

 Store intact vials under refrigeration at 2°C to 8°C (36°F to 46°F). Vials may be reconstituted with SWFI or 0.9% sodium chloride. Reconstituted vials and solutions of 0.25 mg/mL for infusion are stable for up to 14 days at room temperature or under refrigeration.


Compatibility

 Incompatible: Dextrose solutions


Mechanism of Action

 Amonafide acts as a DNA intercalator, stabilizing DNA to thermal denaturation and producing single-strand DNA breaks.


Pharmacodynamics/Kinetics

Distribution: Vd: 370-530 L/m 2

Protein binding: High

Half-life:

Elimination: 3.5-11 hours

Terminal: 3-6 hours

Metabolism: Hepatic, primarily by oxidation and N-acetylation. N-acetylamonafide (active) and amonafide-N'-oxide are the major metabolites. Clearance depends on whether the patient is a fast or slow acetylator. Fast acetylators may experience greater toxicity from the drug.

Excretion: Urine (3% to 22% as unchanged drug)


Dosage

 Adults (refer to individual protocols):

Breast cancer: 800 mg/m 2 over 3 hours every 28 days

Renal cell, ovarian, pancreatic cancer: Up to 450 mg/m 2 over 1 hour on days 1-5 every 21 days

Nonsmall cell lung cancer: 1600 mg/m 2 by continuous infusion over 24 hours every 21 days

Dosage adjustment in hepatic impairment: May be required but specific guidelines have not been established.


Administration

 May be administered by short (1-3 hours) infusion or continuous 24-hour infusion.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause dizziness and sedation


Mental Health: Effects on Psychiatric Treatment

 Granulocytopenia is common; use caution with clozapine; monitor


Oncology: Emetic Potential

 Moderate (30% to 60%)


Oncology: Vesicant

 No


Dosage Forms

 Powder for injection, lyophilized: 500 mg


References

Kornek G, Raderer M, Depisch D, et al, "Amonafide as First-Line Chemotherapy for Metastatic Breast Cancer," Eur J Cancer , 1994, 30A(3):398-400.

Kreis W, Chan K, Budman DR, et al, "Clinical Pharmacokinetics of Amonafide (NSC-308847) in 62 Patients," Cancer Invest , 1996, 14(4):320-7.

Leaf AN, Neuberg D, Schwartz EL, et al, "An ECOG Phase II Study of Amonafide in Unresectable or Recurrent Carcinoma of the Head and Neck (PB390). Eastern Cooperative Oncology Group," Invest New Drugs , 1997, 15(2):165-72.

Marshall ME, Blumenstein B, Crawford ED, et al, "Phase II Trial of Amonafide for the Treatment of Advanced, Hormonally Refractory Carcinoma of the Prostate," Am J Clin Oncol , 1994, 17(6):514-5.

Ratain MJ, Rosner G, Allen SL, et al, "Population Pharmacodynamic Study of Amonafide: A Cancer and Leukemia Group B Study," J Clin Oncol , 1995, 13(3):741-7.


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