【中文品名】喷司他汀 【药效类别】抗肿瘤药>抗代谢剂 【通用药名】PENTOSTATIN 【中文别名】喷司他丁、脱氧助间型霉素 【英文别名】2'-Deoxycoformycin、Covidarabine、Deoxycoformycin、Nipent 【别　　名】Coforin, YK-176 【化学名称】 Imidazo[4,5-d][1,3]diazepin-8-ol, 3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,4,7,8-tetrahydro-, (R)- 【CA登记号】[53910-25-1] 【结 构 式】 【分 子 式】C11H16N4O4 【分 子 量】268.27 【收录药典】 【开发单位】Yamasa Corporation 【首次上市】1996年，日本 【性　　状】 【用　　途】腺嘌呤脱氨酶抑制药，用于治疗成年T细胞白血病和毛细胞白血病。 【药理药动】 本品是一种腺苷脱氨酶(ADA)的强抑制剂。类淋巴系统的组织中ADA活性高，急性淋巴细胞性白血病和髓细胞性白血病患者的淋巴母细胞和髓母细胞中ADA活性增高。本品在体外与ADA的结合亲和力高，并能抑制动物和人慢性髓细胞白血病患者髓细胞中的酶活性。对急性淋巴母细胞性白血病患者静注本品0.1～1mg/kg时，本品的剂量与抑制淋巴母细胞的ADA活性相关。静注本品后，随着ADA的活性被抑制，细胞的脱氧腺苷三磷酸(dATP)水平增高。dATP通过抑制核糖核苷酸还原酶阻断DNA合成。本品还能抑制RNA合成和增强对DNA的损伤。本品除具有上述对淋巴细胞及其细胞的直接毒性作用外，还具有免疫抑制作用，且能增强其他受腺苷脱氨酶代谢的抗肿瘤药的作用。本品对毛细胞白血病的确切作用机制尚不清楚。 【药动学】 静注本品0.25.1mg/kg后约1小时其血药平均浓度为2～6μmol/L。 本品能够穿过血脑屏障，静注后2～4小时脑脊液中药物浓度为血药浓度的10％～12％。在终末期和稳态下平均表观分布容积各有42.4和36.9L。患者静注本品5～30mg／平方米后，在第1天尿中可回收剂量的50％～82％。在另一研究中24小时内回收到的原形药物或能抑制ADA活性的化合物约为给药量的96％。本品的血浆消除半减期为3～9.6小时。 【适 应 症】 适用于治疗干扰素难治的毛细胞白血病。 【用法用量】 用于包括对α-干扰素治疗无效的毛细胞白血病，推荐剂量为每2周静注4mg／平方米，如无毒性表现，治疗应继续到完全缓解。 [制剂与规格]注射剂每瓶10mg。 【不良反应】 常见的不良反应是骨髓抑制及肾毒性。 本品的主要限制剂量毒性是中性白细胞缺乏，16％～25％是严重缺乏；其中25％～70％是威胁生命性的。 用本品治疗的肿瘤患者，感染发生率为8％～58％。毛细胞白血病机会感染发生率3％～6％，常为致死性的感染。 其他不良反应有恶心和呕吐(36％～87％)和轻～中等程度皮疹(6％～67％)。此外，尚见倦乏、头痛、不适和抑郁。本品还可引起短暂的轻、中度的肝、肾功能不良。 特别通知：产品已到货，敬请患者抓紧购买； 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 C11H16N4O4 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. 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/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. CLINICAL STUDIES 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. FRONTLINE IFN-REFRACTORYa Parameter Evaluable Pentostatin N =138 Evaluable IFN N=130 SWOG 8691b 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 4.2 PR 4 6.2 5.8 — Median Duration of Response (months) CR NR 8.3 NR >7.7c (CALGB ) >15.2c (MCA) 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/mm3) 70 106 — — Platelets (100,000/mm3) 22 36 — — NR = Not reached by Kaplan-Meier method; ANC = Absolute neutrophil count aEvaluable patients bPatients either refractory to, or intolerant of, IFN cKaplan-Meier estimate 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. CONTRAINDICATIONS Pentostatin is contraindicated in patients who have demonstrated hypersensitivity to pentostatin. 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 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. PRECAUTIONS General 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.) Laboratory tests 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. Interactions Drug interactions 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 Teratogenic effects Pregnancy Category D (See WARNINGS.) Nursing mothers 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. Pediatric use Safety and effectiveness in children or adolescents have not been established. Geriatric use 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. ADVERSE REACTIONS 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. Percent of Patients All Adverse Eventsa Frontline, TreatedWith Pentostatin N=180 Frontline, TreatedWith IFN N=176 IFN-Refractory, Treated With Pentostatin N=197 Nausea and/or Vomiting 63 22 53b 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 7c 2c 36 Arthralgia 6 14 3 Thrombocytopenia 6 6 32 Skin Disorder 4 5 17 Allergic Reaction 2 1 11 Hepatic Disorder/Elevated Liver Function Testsd 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 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%). Percent of Patients Type of Infection Frontline, Treated With Pentostatin 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 6 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 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 Musculoskeletal System—Arthralgia Nervous System—Confusion, Dizziness, Insomnia, Paresthesia, Somnolence Psychobiologic Function—Anxiety, Depression, Nervousness Respiratory System—Asthma 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. OVERDOSAGE 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. Stability 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. HOW SUPPLIED 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). REFERENCES 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. Manufactured by: Manufactured for: Ben Venue Laboratories, Inc. Bedford Laboratories™ Bedford, OH 44146 Bedford, OH 44146 August 2006 PTST-P00 コホリン静注用７．５ｍｇ 一般名 ペントスタチン（Pentostatin） 慣用名 ２’－デオキシコホルマイシン、DCF 化学名 （R）－3（2－deoxy－β－D－erythro－pento－furanosyl）－3,6,7,8－tetrahydroimidazo［4,5－d］［1,3］diazepin－8－ol 分子式 C11H16N4O4 分子量 268.27 構造式 性状 ペントスタチンは、白色～淡黄白色の結晶又は結晶性の粉末で、においはない。 水に溶けやすく、メタノール又はエタノールに溶けにくく、エーテルにほとんど溶けない。 融点 約198℃（分解 組成 性状 コホリン静注用7.5mgは、白色～淡黄白色の粉末で、添付溶解液で用時溶解して用いる注射剤である。 pH コホリン静注用 効能又は効果 効能又は効果/用法及び用量 下記疾患の自覚的並びに他覚的症状の緩解 (1) 成人Ｔ細胞白血病リンパ腫 (2) ヘアリーセル白血病 成人Ｔ細胞白血病リンパ腫の場合 通常、ペントスタチンとして４～５mg/m2（体表面積）を１週間間隔で４回静脈内投与する。この方法を１クールとし、２～３クール繰り返す。 ヘアリーセル白血病の場合 通常、ペントスタチンとして４～５mg/m2を１～２週間に１回静脈内投与する。 いずれの場合にも、腎障害がある場合には、クレアチニンクリアランスを測定し、５９～４０ｍＬ/分の場合には２～４mg/m2に、３９～２５ｍＬ/分の場合には１～３mg/m2に減量し、それぞれ低用量から始めて安全性を確認しながら慎重に投与する。 注射液の調製方法 本剤１バイアルに添付の溶解液７．５ｍＬを注入して溶解する。 使用上の注意 慎重投与 （次の患者には慎重に投与すること） 1. 肝障害のある患者 ［肝障害が増悪するおそれがある。］ 2. 腎障害のある患者（クレアチニンクリアランスが59～25mL/分の患者） ［腎障害が増悪するおそれがある。］ 3. 心機能異常のある患者 ［心機能異常が増悪するおそれがある。］ 4. 感染症を合併している患者 ［免疫抑制作用により、感染症が増悪するおそれがある。］ 5. アロプリノール投与中の患者 ［「相互作用」の項参照］ 6. 高齢者 ［「高齢者への投与」の項参照］ 重要な基本的注意 1. 腎障害、肝障害等の副作用が起こることがあるので、適宜臨床検査（血液検査、腎機能・肝機能検査等）を行うなど、患者の状態を観察すること。異常が認められた場合には減量、休薬等適切な処置を行うこと。 2. 感染症の発現又は増悪に十分注意すること。 3. 免疫抑制作用が起こることがあるので十分注意すること。 4. 腎障害の患者（2例、うち1例は高カルシウム血症）で溶血性尿毒症症候群（HUS：Hemolytic Uremic Syndrome）又は腎不全で死亡した症例が報告されているので、頻回に臨床検査を行うなど、患者の状態を十分に観察すること。異常が認められた場合には減量、休薬等適切な処置を行うこと。 なお、高カルシウム血症の患者では腎機能が低下しているおそれがあり、本剤の排泄が遅れる可能性があるので、高カルシウム血症の治療を行った後、本剤を投与すること。 5. 食欲不振、嘔気・嘔吐等の消化器症状があらわれることがあるので、患者の状態を十分に観察し、適切な処置を行うこと。7.5mgは、1バイアル中に次の成分を含有する。   有効成分 副作用 副作用等発現状況の概要 総症例359例（承認時56例、使用成績調査303例） における副作用及び臨床検査値異常の発現率は60.4％であり、主なものは、白血球数減少（19.5％）、食欲不振（12.8％）、発熱（12.5％）、嘔吐（11.4％）、倦怠感（8.4％）、血小板数減少（7.8％）、悪心（7.5％）、アラニン・アミノトランスフェラーゼ増加（7.2％）、アスパラギン酸アミノトランスフェラーゼ増加（6.1％）、貧血（4.2％）であった。〔再審査終了時〕 重大な副作用 1. 重篤な腎障害 腎障害の患者で溶血性尿毒症症候群（HUS：Hemolytic Uremic Syndrome）又は腎不全で死亡した症例が報告されているので、頻回に臨床検査を行うなど、患者の状態を十分に観察すること。異常が認められた場合には減量、休薬等の適切な処置を行うこと。 2. 骨髄抑制 （頻度不明） 汎血球減少、白血球減少（顆粒球減少、好中球減少、リンパ球減少）、血小板減少、貧血があらわれる又は増悪することがあるので、頻回に血液検査を行うなど観察を十分に行い、異常が認められた場合には、投与間隔の延長、減量、休薬等の適切な処置を行うこと。 その他の副作用 1. 心臓 （５％未満） 頻脈、心電図異常 2. 肝臓 （５％以上） 肝障害（AST(GOT)、ALT(GPT)、Al-P、LDH、総ビリルビン上昇等） 3. 腎臓 （５％以上） 腎障害（クレアチニン上昇、クレアチニンクリアランス低下、BUN上昇、蛋白尿等） 4. 消化器 （５％以上） 食欲不振、嘔気・嘔吐 5. 消化器 （５％未満） 下痢、腹痛、口内炎 6. 皮膚 （５％未満） 紅斑そう痒、紅斑性皮疹、皮膚炎、アレルギー性皮疹 7. 血液 （５％以上） 白血球減少、血小板減少、貧血 8. 呼吸器 （５％未満） 咳嗽、PaO2減少 9. 精神神経系 （５％未満） 意識障害、頭痛 10. 抵抗機構 （５％未満） 感染症（帯状疱疹、肺炎、腹膜炎） 11. その他 （５％以上） 全身倦怠感、発熱 12. その他 （５％未満） 結膜炎、筋肉痛、背部痛、腹水、CRP上昇 その他の副作用の注意 以上のような症状があらわれた場合には、減量・休薬等の適切な処置を行うこと。 高齢者への投与 本剤は、主として腎臓から排泄されるため、高齢者では腎機能が低下していることが考えられ、高い血中濃度が持続するおそれがあるので、減量又は投与間隔をあけるなど慎重に投与すること。 妊婦、産婦、授乳婦等への投与 1. 妊婦又は妊娠している可能性のある婦人には投与しないこと。 ［動物実験（マウス）で催奇形性作用、胚・胎児毒性がみられている6）,7）。］ 2. 授乳婦に投与する場合には授乳を中止させること。 ［動物実験（マウス）で乳汁中への移行が認められている。］ 小児等への投与 低出生体重児、新生児、乳児、幼児又は小児に対する安全性は確立していない。 適用上の注意 1. 投与経路 静脈内注射にのみ使用すること。 2. 調製後 調製した注射液は速やかに使用し、残液は廃棄すること。 3. 投与時 (1) 本剤はｐＨ６以下では安定性が低下するので、点滴静注の場合は、調製後2時間以内に投与すること。 (2) 本剤の尿中への排泄を促進するため、投与前後にそれぞれ500～1000mLの輸液を行うことが望ましい。 薬物動態 1. 血中濃度 成人T細胞白血病リンパ腫（ATL）及びその他の悪性腫瘍患者15例に本剤の3～7mg/m2を静脈内投与した場合、二相性の減衰を示し、α相の半減期は7～10分、β相の半減期は3～4時間であった。 包装 7.5mg　1バイアル（溶解液7.5mL添付）