pentostatin 10 MG Injection

INDICATIONS AND USAGE NIPENT is indicated as single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.

DOSAGE AND ADMINISTRATION It is recommended that patients receive hydration with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent before NIPENT administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after NIPENT is given. The recommended dosage of NIPENT for the treatment of hairy cell leukemia is 4 mg/m 2 every other week. NIPENT may be administered intravenously by bolus injection or diluted in a larger volume and given over 20 to 30 minutes (See Preparation of Intravenous Solution ). Higher doses are not recommended. No extravasation injuries were reported in clinical studies. The optimal duration of treatment has not been determined. In the absence of major toxicity and with observed continuing improvement, the patient should be treated until a complete response has been achieved. Although not established as required, the administration of two additional doses has been recommended following the achievement of a complete response. All patients receiving NIPENT at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with NIPENT should be discontinued. If the patient has achieved a partial response, NIPENT treatment should be continued in an effort to achieve a complete response. At any time thereafter that a complete response is achieved, two additional doses of NIPENT are recommended. NIPENT treatment should then be stopped. If the best response to treatment at the end of 12 months is a partial response, it is recommended that treatment with NIPENT be stopped. Withholding or discontinuation of individual doses may be needed when severe adverse reactions occur. Drug treatment should be withheld in patients with severe rash, and withheld or discontinued in patients showing evidence of nervous system toxicity. NIPENT treatment should be withheld in patients with active infection occurring during the treatment but may be resumed when the infection is controlled. Patients who have elevated serum creatinine should have their dose withheld and a CL cr determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (CL cr <60 mL/min). Patients with impaired renal function should be treated only when the potential benefit justifies the potential risk. Two patients with impaired renal function (CL cr 50 to 60 mL/min) achieved complete response without unusual adverse events when treated with 2 mg/m 2 . No dosage reduction is recommended at the start of therapy with NIPENT in patients with anemia, neutropenia, or thrombocytopenia. In addition, dosage reductions are not recommended during treatment in patients with anemia and thrombocytopenia if patients can be otherwise supported hematologically. NIPENT should be temporarily withheld if the absolute neutrophil count falls during treatment below 200 cells/mm 3 in a patient who had an initial neutrophil count greater than 500 cells/mm 3 and may be resumed when the count returns to predose levels. Preparation of Intravenous Solution 1. Procedures for proper handling and disposal of anticancer drugs should be followed. Several guidelines on this subject have been published. 2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Spills and wastes should be treated with a 5% sodium hypochlorite solution prior to disposal. 2. Protective clothing including polyethylene gloves must be worn. 3. Transfer 5 mL of Sterile Water for Injection USP to the vial containing NIPENT and mix thoroughly to obtain complete dissolution of a solution yielding 2 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. 4. NIPENT may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP. Dilution of the entire contents of a reconstituted vial with 25 mL or 50 mL provides a pentostatin concentration of 0.33 mg/mL or 0.18 mg/mL, respectively, for the diluted solutions. 5. NIPENT solution when diluted for infusion with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL. Stability NIPENT vials are stable at refrigerated storage temperature 2° to 8° C (36° to 46°F) for the period stated on the package. Vials reconstituted or reconstituted and further diluted as directed may be stored at room temperature and ambient light but should be used within 8 hours because NIPENT contains no preservatives.

WARNINGS See Boxed Warning . Patients with hairy cell leukemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to NIPENT treatment have in some cases developed worsening of their condition leading to death, whereas others have achieved complete response. Patients with infection should be treated only when the potential benefit of treatment justifies the potential risk to the patient. Efforts should be made to control the infection before treatment is initiated or resumed. In patients with progressive hairy cell leukemia, the initial courses of NIPENT treatment were associated with worsening of neutropenia. Therefore, frequent monitoring of complete blood counts during this time is necessary. If severe neutropenia continues beyond the initial cycles, patients should be evaluated for disease status, including a bone marrow examination. Elevations in liver function tests occurred during treatment with NIPENT and were generally reversible. Renal toxicity was observed at higher doses in early studies; however, in patients treated at the recommended dose, elevations in serum creatinine were usually minor and reversible. There were some patients who began treatment with normal renal function who had evidence of mild to moderate toxicity at a final assessment (See DOSAGE AND ADMINISTRATION ). Rashes, occasionally severe, were commonly reported and may worsen with continued treatment. Withholding of treatment may be required (See DOSAGE AND ADMINISTRATION ). Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant. Pregnancy Pentostatin can cause fetal harm when administered to a pregnant woman. Pentostatin was administered intravenously at doses of 0, 0.01, 0.1, or 0.75 mg/kg/day (0, 0.06, 0.6, and 4.5 mg/m 2 ) to pregnant rats on days 6 through 15 of gestation. Drug-related maternal toxicity occurred at doses of 0.1 and 0.75 mg/kg/day (0.6 and 4.5 mg/m 2 ). Teratogenic effects were observed at 0.75 mg/kg/day (4.5 mg/m 2 ) manifested by increased incidence of various skeletal malformations. In a dose range-finding study, pentostatin was administered intravenously to rats at doses of 0, 0.05, 0.1, 0.5, 0.75, or 1 mg/kg/day (0, 0.3, 0.6, 3, 4.5, 6 mg/m 2 ), on days 6 through 15 of gestation. Fetal malformations that were observed were an omphalocele at 0.05 mg/kg (0.3 mg/m 2 ), gastroschisis at 0.75 mg/kg and 1 mg/kg (4.5 and 6 mg/m 2 ), and a flexure defect of the hindlimbs at 0.75 mg/kg (4.5 mg/m 2 ). Pentostatin was also shown to be teratogenic in mice when administered as a single 2 mg/kg (6 mg/m 2 ) intraperitoneal injection on day 7 of gestation. Pentostatin was not teratogenic in rabbits when administered intravenously on days 6 through 18 of gestation at doses of 0, 0.005, 0.01, or 0.02 mg/kg/day (0, 0.015, 0.03, or 0.06 mg/m 2 ); however maternal toxicity, abortions, early deliveries, and deaths occurred in all drug-treated groups. There are no adequate and well-controlled studies in pregnant women. If NIPENT is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential receiving NIPENT should be advised to avoid becoming pregnant.

CONTRAINDICATIONS NIPENT is contraindicated: In patients who have demonstrated hypersensitivity to NIPENT.

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 having 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. Pharmacokinetics/Drug Metabolism A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration. In man, following a single-dose of 4 mg/m 2 of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes, the mean terminal half-life was 5.7 hours, the mean plasma clearance was 68 mL/min/m 2 , and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%. A positive correlation was observed between pentostatin clearance and creatinine clearance (CL cr ) in patients with CL cr values ranging from 60 mL/min to 130 mL/min. 1 Pentostatin half-life in patients with renal impairment (CL cr <50 mL/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CL cr >60 mL/min, n=14), about 6 hours.