PENTOSTATIN- pentostatin injection, powder, lyophilized, for solution
Bedford Laboratories
Rx ONLY
WARNING
Pentostatin for Injection should be administered under the supervision of a physician qualified and experienced in the use of cancer chemotherapeutic agents. The use of higher doses than those specified (see DOSAGE AND ADMINISTRATION) is not recommended. Dose-limiting severe renal, liver, pulmonary, and CNS toxicities occurred in Phase 1 studies that used pentostatin at higher doses (20 to 50 mg/m2 in divided doses over 5 days) than recommended.
In a clinical investigation in patients with refractory chronic lymphocytic leukemia using pentostatin at the recommended dose in combination with fludarabine phosphate, 4 of 6 patients entered in the study had severe or fatal pulmonary toxicity. The use of pentostatin in combination with fludarabine phosphate is not recommended.
DESCRIPTION
Pentostatin for Injection is supplied as a sterile, apyrogenic, lyophilized powder in single-dose vials for intravenous administration. Each vial contains 10 mg of pentostatin and 50 mg of mannitol. The pH of the final product is maintained between 7.0 and 8.5 by addition of sodium hydroxide or hydrochloric acid.
Pentostatin, also known as 2′-deoxycoformycin (DCF), is a potent inhibitor of the enzyme adenosine deaminase. Pentostatin is known chemically as (R)-3-(2-deoxy-β-D -erythro -pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d ][1,3]diazepin-8-ol, with a molecular formula of C11 H16 N4 O4 and a molecular weight of 268.27.
Pentostatin is a white to off-white solid, freely soluble in distilled water.
CLINICAL PHARMACOLOGY
Mechanism of Action
Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase (ADA). The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells and T-cell malignancies higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity, and this is believed to be due to elevated intracellular levels of dATP which can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. In addition to elevated dATP, these mechanisms may also contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin's antitumor effect, however, in hairy cell leukemia is not known.