pulmonary toxicity (see warnings ). 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.

rally 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.

ll 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.

ions. refer to infection table. d elevated liver enzymes and liver disorder for swog percent of patients all adverse events a frontline, treated with nipent n=180 frontline, treated with ifn n=176 ifn-refractory, treated with nipent n=197 nausea and/or vomiting 63 22 53 b fever 46 59 42 rash 43 30 26 fatigue 42 55 29 leukopenia 22 15 60 pruritus 21 6 10 coughing/increased cough 20 15 17 myalgia 19 36 11 chills 19 34 11 headache 17 29 13 diarrhea 17 17 15 abdominal pain 16 15 4 anorexia 13 10 16 upper respiratory infection 13 8 16 asthenia 12 13 10 stomatitis 12 7 5 rhinitis 11 15 10 dyspnea 11 13 8 anemia 8 5 35 pain 8 19 20 pharyngitis 8 11 10 sweating/increased sweating 8 21 10 viral infection 8 17 nr infection 7 c 2 c 36 arthralgia 6 14 3 thrombocytopenia 6 6 32 skin disorder 4 5 17 allergic reaction 2 1 11 hepatic disorder/elevated liver function tests d 2 2 19 neurologic disorder, cns/cns toxicity 1 nr 11 lung disorder/disease nr 1 12 nausea nr nr 22 genitourinary disorder nr nr 15 the total incidence for all types of infections is considerably higher for both treatment groups in the swog 8691 study than is listed in the table above. an intent-to-treat analysis of infections found that 38% of patients treated with nipent and 34% of patients treated with ifn averaged 2.4 and 1.9 documented infections during treatment, respectively. the following table lists the different types of infections that were reported as adverse events during the initial phase of the swog study. there were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for nipent (8%) than for ifn (1%). percent of patients type of infection frontline, treated with nipent n=180 frontline, treated with ifn n=176 upper respiratory infection 13 8 rhinitis 11 15 herpes zoster 8 1 pharyngitis 8 11 viral infection 8 17 infection (unspecified) 7 2 sinusitis 6 4 cellulitis 6 3 bacterial infection 5 4 pneumonia 5 7 conjunctivitis 4 2 furunculosis 4 <1 herpes simplex 4 1 bronchitis 3 2 sepsis 3 2 urinary tract infection 3 3 abscess, skin 2 4 moniliasis, oral 2 <1 mycotic infection, skin <1 3 osteomyelitis 1 0 the drug relatedness of the adverse events listed below cannot be excluded. the following adverse events occurred in 3% to 10% of nipent-treated patients in the initial phase of the swog study: body as a whole —chest pain, death, face edema, peripheral edema cardiovascular system —hemorrhage, hypotension digestive system —dental abnormalities, dyspepsia, flatulence, gingivitis hematologic system —agranulocytosis laboratory deviations —elevated creatinine musculoskeletal system —arthralgia nervous system —confusion, dizziness, insomnia, paresthesia, somnolence psychobiologic function —anxiety, depression, nervousness respiratory system —asthma skin & appendages —skin dry, urticaria the remaining adverse events which occurred in less than 3% of nipent-treated patients during the initial phase of the swog study: body as a whole —flu-like symptoms, hangover effect, neoplasm cardiovascular system —angina pectoris, arrhythmia, a-v block, bradycardia, extrasystoles ventricular, heart arrest, heart failure, hypertension, pericardial effusion, phlebitis, pulmonary embolus, sinus arrest, tachycardia, thrombophlebitis deep, vasculitis digestive system —constipation, dysphagia, glossitis, ileus hematologic system —acute leukemia, anemia-hemolytic, aplastic anemia laboratory deviations —hypercalcemia, hyponatremia musculoskeletal system —arthritis, gout nervous system —amnesia, ataxia, convulsions, dreaming abnormal, dysarthria, encephalitis, hyperkinesia, meningism, neuralgia, neuritis, neuropathy, paralysis, syncope, twitching, vertigo psychobiologic function —decrease/loss libido, emotional lability, hallucination, hostility, neurosis, thinking abnormal respiratory system —bronchospasm, larynx edema skin and appendages —acne, alopecia, eczema, petechial rash, photosensitivity reaction special senses —amblyopia, deafness, earache, eyes dry, labyrinthitis, lacrimation disorder, nonreactive eye, photophobia, retinopathy, tinnitus, unusual taste, vision abnormal, watery eyes urogenital system —amenorrhea, breast lump, impotence, kidney function abnormal, nephropathy, renal failure, renal insufficiency, renal stone one patient with hairy cell leukemia treated with nipent during another clinical study developed unilateral uveitis with vision loss. nineteen (5%) patients withdrew from the phase 3 swog 8691 study because of adverse events; 9 during initial nipent treatment, 4 during nipent crossover, 5 during initial ifn treatment, and 1 during both initial ifn treatment and nipent crossover. in the phase 2 studies in ifn-refractory hairy cell leukemia, 11% of patients withdrew from treatment with nipent due to an adverse event. postmarketing experience the following adverse reactions have been identified during post-approval use of nipent. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. hematologic system —febrile neutropenia, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, autoimmune thrombocytopenia respiratory system —acute respiratory failure skin and appendages —exfoliative dermatitis

pulmonary toxicity (see warnings ). 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.

evealed 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.

airment of fertility: no fertility studies have been conducted in animals; however, in a 5-day intravenous toxicity study in dogs, mild seminiferous tubular degeneration was observed with doses of 1 and 4 mg/kg. the possible adverse effects on fertility in humans have not been determined.

d for response. if a complete response was achieved, 2 additional doses of nipent were administered and then discontinued. if a partial response was achieved, nipent was continued for up to an additional 6 months. nipent was discontinued for stable disease after 6 months or progressive disease after 2 months of therapy. ifn was administered 3 million units subcutaneously 3 times per week. patients who achieved a complete or partial response after 6 months of treatment continued on ifn for another 6 months. ifn was discontinued if patients did not achieve a complete or partial response after 6 months of initial treatment or progressed after 2 months. this study allowed crossover of patients intolerant of, or refractory to, initial treatment. interferon-refractory patients enrolled into the md anderson study received nipent at a dose of 4 mg/m 2 every other week for 3 months and responding patients received 3 additional months. calgb patients received 4 mg/m 2 of nipent every other week for 3 months and responding patients were treated monthly for up to 9 additional months. almost all patients had a ps of 0 to 2 in the phase 2 and 3 studies. for each study, a complete response (cr) required clearing of the peripheral blood and bone marrow of all hairy cells, normalization of organomegaly and lymphadenopathy by physical examination, and recovery of hemoglobin to at least 12 g/dl, platelet count to at least 100,000/mm 3 , and granulocyte count to at least 1500/mm 3 . a partial response (pr) required that the percentage of hairy cells in the blood and bone marrow decrease by more than 50%, enlarged organs and lymph nodes decrease by more than 50% by physical examination, and hematologic parameters had to meet the same criteria as for complete response. the table below reports the response rate for 2 groups of patients: (1) evaluable, i.e., patients who could be evaluated for response and (2) intent-to-treat, i.e., patients diagnosed with hairy cell leukemia. nr = not reached by kaplan-meier method; anc = absolute neutrophil count. a evaluable patients b patients either refractory to, or intolerant of, ifn c kaplan-meier estimate frontline ifn-refractory a parameter evaluable nipent n = 138 evaluable ifn n=130 swog 8691 b crossover n=79 nci phase 2 studies n=44 response rates (%) evaluable cr 84 18 85 58 pr 6 24 4 28 intent-to-treat n=170 n=170 cr 68 14 pr 5 18 median time to response (months) cr 6.6 11.5 6.0 4.2 pr 4.0 6.2 5.8 — median duration of response (months) cr nr 8.3 nr >7.7 c (calgb) >15.2 c (mda) pr nr 15.2 nr — % estimated to be in response after 24 months cr 76 16 85 — pr 50 21 — — median time to recovery (days) anc (1500/mm 3 ) 70 106 — — platelets (100,000/mm 3 ) 22 36 — — the results show that frontline patients treated with nipent achieved a significantly higher rate of response than those treated with ifn. the time to recovery of neutrophil and platelet counts was shorter with nipent treatment and the estimated duration of response was longer. the response rate in ifn-refractory patients treated with nipent was similar to that in nipent-treated frontline patients. at a median follow-up duration of 46 months, there was no statistically significant difference in survival between hairy cell leukemia patients initially treated with nipent and those initially treated with ifn. however, no definite conclusions regarding survival can be made from these results because they are complicated by the fact that the majority of ifn patients crossed over to nipent treatment. in the phase 3 swog study, 25 patients with hairy cell leukemia died during treatment or follow-up: 18 patients had last received nipent (3 of whom had crossed over from ifn), and 7 patients had last received ifn (1 of whom crossed over from nipent). eleven of the 25 deaths occurred within 60 days of the last dose of treatment. of these, hairy cell leukemia was cited by the investigators as a contributory cause for 1 death in the nipent group and 3 deaths in the ifn group. additionally, infection contributed to the deaths of 3 patients in the nipent group and 2 patients in the ifn group. approximately 4% of hairy cell leukemia patients, in each arm, died more than 60 days after the last dose of either treatment and there was no outstanding cause of death among these patients.