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pentostatin injection, powder, lyophilized, for solution
----------Pentostatin for Injection
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.
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 C11H16N4O4 and a molecular weight of 268.27.
The chemical structure of pentostatin is:
Pentostatin is a white to off-white solid, freely soluble in distilled water.
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.
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/m2 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/m2, 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 (CrCl) in patients with creatinine clearance values ranging from 60 mL/min to 130 mL/min.1 Pentostatin half-life in patients with renal impairment (CrCl <50 mL/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CrCl >60 mL/min, n=14), about 6 hours.
The following table provides efficacy results for 4 groups (columns) of patients with hairy cell leukemia: patients who initially received pentostatin, patients who initially received alpha-interferon (IFN), and 2 different groups of patients who received pentostatin after proving to be refractory to, or intolerant of, IFN therapy. The first 2 groups represent treatment results from the SWOG 8691 study, a large multicenter study comparing pentostatin and IFN in untreated (frontline) patients with confirmed hairy cell leukemia. The third group represents evaluable patients from the SWOG study who crossed over to pentostatin after initially receiving IFN. The fourth group, labeled NCI Phase 2 studies, displays pooled results of 2 noncomparative studies (MD Anderson and CALGB), in which pentostatin was used to treat patients with confirmed IFN-refractory disease.
In the SWOG 8691 study, pentostatin was administered at a dose of 4 mg/m2 every 2 weeks. After 6 months of treatment, patients were evaluated for response. If a complete response was achieved, 2 additional doses of pentostatin were administered and then discontinued. If a partial response was achieved, pentostatin was continued for up to an additional 6 months. Pentostatin 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 pentostatin at a dose of 4 mg/m2 every other week for 3 months and responding patients received 3 additional months. CALGB patients received 4 mg/m2 of pentostatin 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/mm3, and granulocyte count to at least 1500/mm3. 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
bPatients either refractory to, or intolerant of, IFN
The results show that frontline patients treated with pentostatin achieved a significantly higher rate of response than those treated with IFN. The time to recovery of neutrophil and platelet counts was shorter with pentostatin treatment and the estimated duration of response was longer. The response rate in IFN-refractory patients treated with pentostatin was similar to that in pentostatin-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 pentostatin 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 pentostatin treatment.
In the Phase 3 SWOG study, 25 patients with hairy cell leukemia died during treatment or follow-up: 18 patients had last received pentostatin (3 of whom had crossed over from IFN), and 7 patients had last received IFN (1 of whom crossed over from pentostatin). 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 pentostatin group and 3 deaths in the IFN group. Additionally, infection contributed to the deaths of 3 patients in the pentostatin 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.
INDICATIONS AND USAGE
Pentostatin 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.
Pentostatin is contraindicated in patients who have demonstrated hypersensitivity to pentostatin.
See Boxed WARNING.
Patients with hairy cell leukemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to pentostatin 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 pentostatin 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 pentostatin 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 Category D
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 45 mg/m2) 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/m2). Teratogenic effects were observed at 0.75 mg/kg/day (4.5 mg/m2) 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/m2), on days 6 through 15 of gestation. Fetal malformations that were observed were an omphalocele at 0.05 mg/kg (0.3 mg/m2), gastroschisis at 0.75 mg/kg and 1 mg/kg (4.5 and 6 mg/m2), and a flexure defect of the hindlimbs at 0.75 mg/kg (4.5 mg/m2). Pentostatin was also shown to be teratogenic in mice when administered as a single 2 mg/kg (6 mg/m2) 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/m2); 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 pentostatin 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 pentostatin should be advised to avoid becoming pregnant.
Therapy with pentostatin requires regular patient observation and monitoring of hematologic parameters and blood chemistry values. If severe adverse reactions occur, the drug should be withheld (see DOSAGE AND ADMINISTRATION), and appropriate corrective measures should be taken according to the clinical judgment of the physician.
Pentostatin treatment should be withheld or discontinued in patients showing evidence of nervous system toxicity.
Information for patients
Patients should be advised of the signs and symptoms of adverse events associated with pentostatin therapy. (See ADVERSE REACTIONS.)
Prior to initialing therapy with pentostatin, renal function should be assessed with a serum creatinine and/or a creatinine clearance assay. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) Complete blood counts and serum creatinine should be performed before each dose of pentostatin and at other appropriate periods during therapy (see DOSAGE AND ADMINISTRATION). Severe neutropenia has been observed following the early courses of treatment with pentostatin and therefore frequent monitoring of complete blood counts is recommended during this time. If hematologic parameters do not improve with subsequent courses, patients should be evaluated for disease status, including a bone marrow examination. Periodic monitoring of the peripheral blood for hairy cells should be performed to assess the response to treatment.
In addition, bone marrow aspirates and biopsies may be required at 2 to 3 month intervals to assess the response to treatment.
Allopurinol and pentostatin are both associated with skin rashes. Based on clinical studies in 25 refractory patients who received both pentostatin and allopurinol, the combined use of pentostatin and allopurinol did not appear to produce a higher incidence of skin rashes than observed with pentostatin alone. There has been a report of one patient who received both drugs and experienced a hypersensitivity vasculitis that resulted in death. It was unclear whether this adverse event and subsequent death resulted from the drug combination.
Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and pentostatin may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.
The combined use of pentostatin and fludarabine phosphate is not recommended because it may be associated with an increased risk of fatal 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.
Carcinogenesis, mutagenesis, impairment of fertility
Carcinogenesis: No animal carcinogenicity studies have been conducted with pentostatin.
Mutagenesis: Pentostatin was nonmutagenic when tested in Salmonella typhimurium strains TA-98, TA-1535, TA-1537, and TA-1538. When tested with strain TA-100, a repeatable statistically significant response trend was observed with and without metabolic activation. The response was 2.1 to 2.2 fold higher than the background at 10 mg/plate, the maximum possible drug concentration. Formulated pentostatin was clastogenic in the in vivo mouse bone marrow micronucleus assay at 20, 120, and 240 mg/kg. Pentostatin was not mutagenic to V79 Chinese hamster lung cells at the HGPRT locus exposed 3 hours to concentrations of 1 to 3 mg/mL, with or without metabolic activation. Pentostatin did not significantly increase chromosomal aberrations in V79 Chinese hamster lung cells exposed 3 hours to 1 to 3 mg/mL in the presence or absence of metabolic activation.
Impairment 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.
Pregnancy Category D
It is not known whether pentostatin is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pentostatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of pentostatin to the mother.
Clinical studies of pentostatin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 studies and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with pentostatin (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (e.g., infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were assessed for severity were either mild or moderate, and diminished in frequency with continued therapy.
NR = Not Reported
aOccurring in more than 10% of patients, in any group, regardless of drug association
bIncludes only nausea with vomiting
cThese figures represent only unspecified infections. Refer to infection table.
dElevated liver enzymes and liver disorder for SWOG
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 pentostatin 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 pentostatin (8%) than for IFN (1%).
The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of pentostatin-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
Hemic and Lymphatic System—Agranulocytosis
Laboratory Deviations—Elevated Creatinine
Nervous System—Confusion, Dizziness, Insomnia, Paresthesia, Somnolence
Psychobiologic Function—Anxiety, Depression, Nervousness
Skin and Appendages—Skin Dry, Urticaria
The remaining adverse events which occurred in less than 3% of pentostatin-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, Glossilis, Ileus
Hemic and Lymphatic 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 pentostatin 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 pentostatin treatment, 4 during pentostatin crossover, 5 during initial IFN treatment, and 1 during both initial IFN treatment and pentostatin crossover. In the Phase 2 studies in IFN-refractory hairy cell leukemia, 11% of patients withdrew from treatment with pentostatin due to an adverse event.
No specific antidote for pentostatin overdose is known. Pentostatin administered at higher doses (20 to 50 mg/m2 in divided doses over 5 days) than recommended was associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity. In case of overdose, management would include general supportive measures through any period of toxicity that occurs.
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 pentostatin administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after pentostatin is given.
The recommended dosage of pentostatin for the treatment of hairy cell leukemia is 4 mg/m2 every other week. Pentostatin 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 pentostatin at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with pentostatin should be discontinued.
If the patient has achieved a partial response, pentostatin 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 pentostatin are recommended. Pentostatin 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 pentostatin 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.
Pentostatin 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 creatinine clearance determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (creatinine clearance <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 (creatinine clearances 50 to 60 mL/min) achieved complete response without unusual adverse events when treated with 2 mg/m2.
No dosage reduction is recommended at the start of therapy with pentostatin 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. Pentostatin should be temporarily withheld if the absolute neutrophil count falls during treatment below 200 cells/mm3 in a patient who had an initial neutrophil count greater than 500 cells/mm3 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 to the vial containing pentostatin 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. Pentostatin may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% dextrose injection or 0.9% sodium chloride injection. 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. Pentostatin solution when diluted for infusion with 5% dextrose injection or 0.9% sodium chloride injection does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL.
Pentostatin 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 pentostatin contains no preservatives.
Pentostatin for Injection is supplied as a sterile lyophilized white to off-white powder in single-dose vials containing 10 mg of pentostatin.
NDC 55390-244-01; individually boxed.
Storage: Store pentostatin vials under refrigerated storage conditions 2° to 8°C (36° to 46°F).
1. Malspeis L, et al. Clinical pharmacokinetics of 2'-Deoxycoformycin. Cancer Treatment Symposia 2:7-15, 1984.
2. Recommendations for the safe handling of parenteral antineoplastic drugs. NIH Publication 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402.
3. AMA Council Report. Guidelines for handling parenteral antineoplastics. JAMA 253:1590-2, 1985.
4. National Study Commission on Cytotoxic Exposure—Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, Sc.D., Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115.
5. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Australia 1:426-8, 1983.
6. Jones RB, et al. Safe handling of chemotherapeutic agents. A report from the Mount Sinai Medical Center CA. A Cancer Journal for Clinicians 33:258-63, 1983.
7. American Society of Hospital Pharmacists technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm 47:1033-49, 1990.
Revised: 05/2010 Bedford Laboratories
Reproduced with permission of U.S. National Library of Medicine
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