英文药名: Oforta(Fludarabine phosphate)

中文药名: 磷酸氟达拉滨片和注射剂

药品简介

赛诺菲安万特美国今天宣布，它已取得的权利，从生物技术公司Antisoma PLC的美国商业到Oforta（氟达拉滨磷化膜衣锭），一种口服B细胞慢性淋巴细胞白血病（CLL）的药物。 Oforta目前已被批准在美国作为第二线疗法来治疗B细胞慢性淋巴细胞白血病的成年人。

“我们非常高兴将我们现有的肿瘤Oforta组合，并认为它代表了一种为Sanofi - Aventis的美国激动人心的机会，说：”约翰哈灵顿，副总统和肿瘤业务部门的负责人赛诺菲安万特美国“赛诺菲安万特致力于确定和探索面临着严重的疾病，如白血病，患者带来了新的治疗方案的公司。这项协议进一步支持我们的努力，帮助我们的病人和补充疗法来治疗癌症提供强有力的遗产。“

Antisoma目前牌照的某些权利和拜耳先灵制药公司购买Oforta。作为这一交易的一部分，赛诺菲安万特，美国将获得这些协议。

Oforta是一种核苷类似物旨在防止通过抑制DNA合成癌细胞的分化。 Oforta获得加速审查，后来从2008年12月获得美国食品和药物管理局（FDA）批准用于治疗B细胞慢性淋巴细胞白血病的疾病并没有回应，或期间或之后，至少有一成年患者的标准治疗进展烷基化剂含有方案。 Oforta磷酸氟达拉滨是一种口服片剂。

Oforta表示为一成年患者的B细胞慢性淋巴细胞白血病的疾病并没有回应，或有进展过程中或治疗后，至少有一个标准的烷基化剂含有单药治疗方案。研究证明，如生存或缓解症状延长的临床利益没有得到执行。研究提供了直接比较的临床疗效和安全性磷酸氟达拉滨口服相对于静脉注射磷酸氟达拉滨没有被执行。最常见的不良反应包括骨髓抑制（白细胞减少，血小板减少和贫血），发烧和发冷，感染，恶心和呕吐。严重的机会性感染发生在磷酸氟达拉滨治疗慢性淋巴细胞白血病患者。

白血病是一种白血细胞和骨髓，它出现在老年群体为主（与白血病的大多数人至少50岁）生长缓慢的癌症。根据白血病和淋巴瘤协会，白血病是最常见的白血病 - 在2008年诊断出大约1.5万个新病例。估计有90,000人患有白血病今天。超过95例CLL的百分之所有有B -细胞的参与。

*注射用磷酸氟达拉滨
【成分】本品主要成分为磷酸氟达拉滨。

【药理毒理】
1.药效学本药系阿糖腺苷的2-氟，5-磷酸化衍生物。阿糖腺苷是一种合成的嘌呤类抗代谢药，虽然它是一种有效的抗病毒药，但由于它的低溶解度和腺嘌呤脱氨基酶的快速脱氨基作用，使体内抗肿瘤活性受到限制，因此可作为一种潜在的抗癌药。本药是在阿糖腺苷的嘌呤环第2位上以氟原子取代和第5’位上加上一个磷酸基而形成，提高了其溶解度，并可抵抗腺嘌呤脱氨基酶的脱氨基作用。本药在体内被血清磷酸酶去磷酸化成为2-氟-阿糖腺苷(9-β-D-阿拉伯呋喃糖-2-氟腺嘌呤)后，可被细胞摄取，然后被转化为有活性的三磷酸盐。该代谢产物是DNA合成的竞争性抑制剂。已有的数据表明，本药能抑制几种酶的活性，包括DNA聚合酶、核糖核酸还原酶、腺苷甲硫氨酸转移酶。曾有报道，本药对T细胞的作用强于B细胞；但是，临床治疗B细胞性恶性瘤有效。临床前研究显示，本药对和L白血病、CD乳腺癌、LX-1人类异种皮移植癌和其它动物及人类的肿瘤细胞有较强的抗肿瘤活性。在Ⅰ期试验时，本药的剂量限制性毒性反应是骨髓抑制，高剂量时可见神经毒性。本药治疗慢性淋巴细胞性白血病和非霍奇金淋巴瘤中的作用较强。
2.药动学用于慢性淋巴细胞性白血病时，静脉注射后7-21周可起效。口服给药1.1-1.2小时可达血药峰浓度，曲线下面积为1760-3016(ng·h)/ml；静脉给药曲线下面积为3060(ng·h)/ml；皮下给药曲线下面积为4.56(ng·h)/ml。多次静脉给药药效可维持65-91周；对非霍奇金淋巴瘤患者，多次给药药效可维持2-20个月。本药口服后生物利用度为54%-56%，皮下给药的生物利用度为静脉注射的1.05倍。本药分布半衰期为57分钟，分布容积为98L/m2。代谢产物为2-氟-阿糖腺苷(有活性)和2-氟-腺嘌呤-5-三磷酸盐。约40%经肾排泄，总体清除率为8.9L/(m2·h)。原型药物的清除半衰期为10.3-20小时。

【适应症】
用于B细胞性慢性淋巴细胞白血病(CLL)患者的治疗，这些患者至少接受过一个标准的包含烷化剂的方案的治疗，但在治疗期间或治疗后，病情并没有改善或仍持续进展。

【用法用量】
成人常规剂量静脉滴注一日25mg/m2，持续30分钟，连用5日。然后停药23日(即28日为1个疗程)。疗程取决于疗效及患者对药物的耐受性(一般至少需6个疗程)。肾功能不全时剂量对肾功能不全患者的剂量应作相应的调整。肌酐清除率为30-70ml/min时，剂量应减少50%，且应严密检测血液学改变以评价药物的毒性。若肌酐清除率小于30ml/min，应禁用本药。

[国外用法用量参考]
成人常规剂量静脉滴注一日25mg/m2，持续约30分钟，连用5日。28日后继续下1个疗程。用药剂量应根据血液或非血液毒性进行调整。建议在达到最佳治疗效果后，应再给药3个疗程。肾功能不全时剂量中度肾功能能损害[肌酐清除率为30-70ml/(min·1.73m的患者，用量应降低20%-50%；严重肾功能损害[肌酐清除率小于30ml/(min·1.73m)]的患者，不推荐使用本药。

【不良反应】
以下不良反应的发生频率(常见≥1%，不常见>；0.1%但<；1%)主要源于临床试验资料，而没有考虑与本药的因果关系。罕见的不良反应(低于0.1%)主要源于上市后的报道。
1.心血管系统可见水肿，罕见心衰和心律失常。
2.中枢神经系统
(1)常见周围神经病，少见精神混乱，罕见昏迷和焦虑不安。
(2)有研究发现，高剂量本药与严重的神经毒性(如失明、昏迷和死亡)相关。静脉内给药4倍于推荐剂量(一日96mg/m2，连用5-7日)后，36%的患者出现了严重的中枢神经系统毒性。而应用推荐剂量患者，严重的中枢神经系统症状(如昏迷和焦虑不安)罕见或(精神混乱)少见。
3.呼吸系统常见肺炎。
4.泌尿生殖系统罕见出血性膀胱炎的报道。
5.肝脏少见肝酶和胰腺相关酶的改变。
6.胃肠道
(1)常见胃肠异常(如恶心、呕吐、食欲缺乏、腹泻和胃炎)。
(2)有报道，本药不良反应主要是与血小板减少相关的消化道出血。
7.血液
(1)大多数患者可见血液学改变(如白细胞减少、血小板减少和贫血)。骨髓抑制可能是严重和有累积效应的。本药对减少T淋巴细胞数目长时间的影响可能导致机会感染危险性的增加[包括潜伏病毒的活化(如进行性多灶性脑白质病)。
(2)在实体瘤患者的Ⅰ期临床研究中发现，粒细胞数目降到最低的中位时间是13日(范围是3-25日)，血小板是16日(范围是2-32日)。大多数患者的基础造血功能有损伤，可能是基础疾病的原因或是以前用骨髓抑制药物的结果。
8.皮肤
(1)常见皮肤红斑。罕见Stevens－Johnson综合征或毒性表皮坏死(Lyells综合征)的报道。
(2)有患者在用药后，既往的皮肤癌病变出现可逆性的恶化或骤然爆发的报道。
9.眼常有视觉障碍的报道。罕见病例中会出现视神经炎、视神经病变和失明。
10.过敏反应少见因过敏所致的呼吸困难和咳嗽的反应(肺浸润、肺炎和肺间质纤维化)。
11.其它
(1)有出现肿瘤溶解综合征的报道，具体包括高尿酸血症、高磷酸血症、低钙血症、代谢性酸中毒、高钾血症、血尿、尿酸结晶尿和肾衰竭。腰疼和血尿可以是该综合征的首发症状。鉴于这种综合征在用药后的第1周就可出现，建议对高危人群应及早采取预防措施。
(2)有患者在用药后，出现致命的自身免疫现象(如自身免疫性溶血性贫血、自身免疫性血小板减少、血小板减少性紫癜、天疱疮、Evans综合征)的报道。大多数溶血性贫血的患者在再次接受本药治疗后，可出现症状的反复。此时应停药，输血(辐射后血液)并使用肾上腺皮质激素制剂进行治疗。

[国外不良反应参考]
1.心血管系统在临床试验(n=133)中，水肿发生率为8%-19%。
2.中枢神经系统
(1)在临床试验(n=133)中，可见虚弱无力(9%-65%)、感觉异常(4%-12%)；激动、精神混乱和昏迷也有报道。还有周围神经病变的报道和“垂腕症”的个案报道。
(2)有使用高剂量本药(一日100-150mg/m2，连用5-7日)，引起严重的迟发神经毒性的报道。表现为视野缺损、构音困难、感觉异常、虚弱无力及癫痫发作，甚至发展为双侧皮质盲、意识混乱、痉挛性瘫痪和昏迷。中枢神经系统进行性脱髓鞘可能是导致神经毒性反应的原因。
(3)在36位接受过至少1个疗程、一日剂量不超过96mg/m2、连用5-7日的患者中，有13位出现严重的中枢神经系统毒性，其中11位患者出现了视觉缺失。精神状态的恶化和进行性脑病也有发生。此13名患者全部死亡。
(4)有引起脑白质炎的报道。常见的症状有单侧轻偏瘫和共济失调，并有患者死亡的个案报道。
(5)有引起嗜睡和(或)疲倦的报道。
3.呼吸系统
(1)在临床试验(n=133)中，可见肺炎(16%-22%)、咳嗽(10%-44%)、呼吸困难(9%-22%)、鼻窦炎(不超过5%)、咽炎(不超过9%)及上呼吸道感染(2%-16%)。
(2)过敏时可见呼吸困难、咳嗽和间质性肺浸润。
(3)其它尚有急性呼吸窘迫综合征、呼吸窘迫、肺出血、肺纤维化和呼吸衰竭。
(4)有患者用药(一日25mg/m2，连用3日，一月1次)10个疗程后，出现了严重的呼吸系统合胞病毒(RSV)肺部感染的个案报道。
4.肌肉骨骼系统
(1)有出现肌无力的报道，但尚不清楚这是否为一种神经毒性的前驱症状。
(2)在临床试验(n=133)中，4%-16%的患者出现肌痛。
(3)有出现骨髓4维化的个案报道，但与本药的关系尚不明确。
5.泌尿生殖系统在临床试验(n=133)中，可见排尿困难(3%-4%)和感染(2%-15%)。极少有出现出血性膀胱炎的报道。
6.肝脏有联合使用环磷酰胺(首日1000mg/m2)和本药(20mg/m2，连用5日)3个疗程，治疗非霍奇金淋巴瘤，由于腺病毒感染而发生严重的爆发性肝功能衰竭的个案报道。
7.胃肠道
(1)在临床试验(n=133)中，可见恶心和(或)呕吐(31%-36%)、腹泻(13%-15%)、畏食(7%-34%)、口腔炎(低于9%)和胃肠道出血(3%-13%)。
(2)有引起假性肠梗阻的个案报道。
8.血液
(1)中性粒细胞减少症和血小板减少症是最常见不良反应，具有剂量限制性。少见淋巴细胞减少症和贫血症的报道。有本药引起全血血细胞减少(可持续2个月到1年)，并导致致死的报道。
(2)有引起自身免疫性贫血并致死的报道。多数患者再次用药时，会引起溶血复发。
(3)有引起嗜酸粒细胞增多症的报道。
(4)有引起嗜血细胞综合征，并导致患者死亡的个案报道。
(5)有引起骨髓纤维化的个案报道。
9.皮肤
(1)有患者静脉给药(25mg/m2，连用5日)后，出现副肿瘤性天疱疮[表现为结膜炎、水肿，四肢末端、颜面部和(或)躯干部表皮水疱]的报道。
(2)在临床试验(n=133)中，15%的患者可见皮疹。
10.眼
(1)在临床试验(n=133)中，3%-15%的患者出现视力障碍。
(2)有报道，本药(尤其是高剂量)导致的神经毒性综合征中，可见视力模糊、复视、畏光，甚至发展为失明。
11.其它
(1)在临床试验(n=133)中，出现了发热(69%)、寒战(11%-19%)、乏力(10%-38%)、感染(33%-44%)及疼痛(20%-22%)。
(2)有患者静脉给药后，先出现发热，然后出现肺炎的个案报道。
(3)有1例瓦尔登斯特伦巨球蛋白血症白人女性患者，用药6个月后，出现隐球菌性脑膜炎和颅内结核瘤的报道。
(4)有出现移植物抗宿主病、疱疹病毒感染的报道。
(5)对595例使用过本药的患者进行了平均时间长达7.4年的随访，其中23例出现继发的恶性肿瘤。继发肿瘤分别为肺癌(n=6)、霍奇金淋巴瘤(n=5)、结肠癌(n=4)、膀胱癌(n=2)、头颈部肿瘤(n=2)、肝癌(n=1)、白血病(n=1)、中枢神经系统肿瘤(n=10和肉瘤(n=1)。(6)据报道，在接受过本药治疗的患者中，曾出现过腰痛和血尿，这可能是肿瘤溶解综合征的症状。肿瘤溶解综合征可能包括了高尿酸血症、高磷血症、低钙血症、代谢性酸中毒、高钾血症、血尿、尿酸盐结晶和肾功能不全。

【禁忌】
1.禁忌症
(1)对本药过敏者(国外资料)。
(2)严重肾功能不全(肌酐清除率小于30ml/min)的患者。
(3)失代偿性溶血性贫血的患者。
(4)孕妇。
(5)哺乳期妇女。

2.慎用
(1)骨髓抑制者(国外资料)。
(2)肾功能不全者(国外资料)。
(3)有免疫缺陷的患者。
(4)有机会性感染病史的患者。
(5)肝功能不全者。
3.药物对儿童的影响儿童用药的安全性与有效性尚未确定。
4.药物对妊娠的影响国内资料中建议孕妇禁用本药，用药期间及停药后6个月内应避免怀孕；美国药品和食品管理局(FDA)对本药的妊娠安全性分级为D级。
5.药物对哺乳的影响尚不确定本药是否能分泌入乳汁，但在动物试验中，本药及其代谢产物可进入乳汁，因此，哺乳期妇女用药时应停止哺乳。
6.用药前后及用药时应当检查或监测治疗期间应定期(一周至少1次)监测全血细胞计数。

【注意事项】

药物-药物相互作用。
1.用药期间接种活疫苗(如轮状病毒疫苗)，可使免疫应答降低，导致患者被活疫苗感染。建议用药期间不应接种活疫苗。白血病缓解患者在结束化疗至少3个月后，方能接种活疫苗。
2.与喷司他丁合用，可增加发生严重肺毒性的风险。不推荐两药合用。
3.腺苷吸收抑制药(如双嘧达莫)可减弱本药的疗效。

【贮藏】室温(最高温度30℃)保存。

Severe neurologic effects, including blindness, coma, and death were observed in dose-ranging studies in patients with acute leukemia when fludarabine phosphate was administered at high doses. This severe central nervous system toxicity occurred in 36% of patients treated with doses approximately four times greater (96 mg/m/day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m/day). Similar severe central nervous system toxicity has been rarely (≤0.2%) reported in patients treated at doses in the range of the dose recommended for chronic lymphocytic leukemia. [See Warnings and Precautions (5.1) ] Periodic neurological assessments are recommended.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported after one or more cycles of treatment with fludarabine phosphate. Patients undergoing treatment with Oforta™ should be evaluated and closely monitored for hemolysis. [See Warnings and Precautions (5.2) ]

High incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL). Therefore, the use of Oforta™ in combination with pentostatin is not recommended [See Warnings and Precautions (5.3) ]

Oforta™ (fludarabine phosphate tablets) for oral use is indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia (CLL) whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Studies demonstrating clinical benefit such as prolongation of survival or relief of symptoms have not been performed. Studies providing a direct comparison of the clinical efficacy and safety of Oforta™ relative to intravenously administered fludarabine phosphate have not been performed.

The oral dose of Oforta™ is different than the intravenous fludarabine phosphate dose.

The recommended adult dose of Oforta™ is 40 mg/m administered by mouth daily for five consecutive days. Each 5-day course of treatment should commence every 28 days. Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs. Oforta™ can be taken either on an empty stomach or with food. The tablets have to be swallowed whole with water; they should not be chewed or broken.

The following table provides guidance for determining the number of tablets of Oforta™ to be administered based on body surface area (BSA):

A number of clinical settings may predispose to increased toxicity from Oforta™. These include advanced age, renal insufficiency, and bone marrow impairment. Such patients should be monitored closely for excessive toxicity and the dose modified accordingly. The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Oforta™ be administered following the achievement of a maximal response and then the drug should be discontinued.

TABLE 1: SUGGESTED NUMBER OF TABLETS TO BE ADMINISTERED

Body Surface Area (BSA)	Calculated Total Dose Equivalent to 40 mg/m2 BSA (rounded up or down to nearest 10 mg)	Total Number of Tablets
0.75 – 0.88	30 mg	3
0.89 – 1.13	40 mg	4
1.14 – 1.38	50 mg	5
1.39 – 1.63	60 mg	6
1.64 – 1.88	70 mg	7
1.89 – 2.13	80 mg	8
2.14 – 2.38	90 mg	9
2.39 – 2.50	100 mg	10

10 mg tablets that are capsule shaped and salmon pink in color, marked on one side with 'LN' in a regular hexagon.

None

Dose-dependent neurotoxicity has been observed with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m/day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m/day for 5 days) were associated with a syndrome characterized by delayed blindness, coma and death. Symptoms appeared from 21 days to 60 days following the last dose. Thirteen of 36 patients (36.1%) who received fludarabine phosphate intravenously at high doses (≥ 96 mg/m/day for 5 days to 7 days per course) developed severe neurotoxicity, while only one of 443 patients (0.2%) who received the drug intravenously at low doses (≤ 40 mg/m/day for 5 days per course) developed toxicity. In the pivotal clinical study conducted with Oforta™ administered at 40 mg/m, severe impairment of consciousness was reported in one patient. The effect of chronic administration of fludarabine phosphate on the central nervous system is unknown; however, patients have received the recommended dose for up to 15 courses of therapy. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

Severe bone marrow suppression, notably anemia, thrombocytopenia and neutropenia, has been reported in patients treated with fludarabine phosphate. In a study in adult solid tumor patients, the median time to nadir counts was 13 days (range, 3 days to 25 days) for granulocytes and 16 days (range, 2 days to 32 days) for platelets. Most patients had hematologic impairment at baseline either as a result of disease or as a result of prior myelosuppressive therapy. Cumulative myelosuppression may be seen. While chemotherapy-induced myelosuppression is often reversible, administration of Oforta™ requires careful hematologic monitoring.

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in adult patients. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients. One case of pancytopenia was reported in the pivotal clinical study conducted with Oforta™.

Instances of life-threatening and sometimes fatal autoimmune hemolytic anemia have been reported to occur after one or more cycles of treatment with fludarabine phosphate in patients with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test and who may or may not be in remission from their disease. Steroids may or may not be effective in controlling these hemolytic episodes. The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified. Patients undergoing treatment with Oforta™ should be evaluated and closely monitored for hemolysis.

A high incidence of fatal pulmonary toxicity was observed in a clinical investigation using fludarabine phosphate in combination with pentostatin (deoxycoformycin) for the treatment of refractory chronic lymphocytic leukemia (CLL) in adults. Therefore, the use of Oforta™ in combination with pentostatin is not recommended.

Of 133 adult patients with CLL who received intravenous fludarabine phosphate in two clinical trials, there were 29 fatalities during study. Approximately 50% of the fatalities were due to infection and 25% due to progressive disease. Of 183 adult patients with CLL that received Oforta™ in two clinical trials, there were 13 deaths. Approximately 50% of the deaths were due to progressive disease, while two patient deaths (15%) were attributed to infection. Monitor for signs and symptoms of infection.

Tumor lysis syndrome associated with fludarabine phosphate treatment has been reported in patients with CLL with large tumor burdens. Since Oforta™ can induce a response as early as the first week of treatment, precautions should be taken in those patients at risk of developing this complication.

Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of non-irradiated blood in fludarabine phosphate treated patients. Consideration should, therefore, be given to the use of irradiated blood products in those patients requiring transfusions while undergoing treatment with Oforta™.

Oforta™ must be administered cautiously in patients with renal impairment. Following dosing of the intravenous product, the total body clearance of 2-fluoro-ara-A has been shown to be directly correlated with creatinine clearance. Patients with mild to moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m) should have their Oforta™ dose reduced by 20% and be monitored closely. Patients with severe impairment of renal function (creatinine clearance < 30 mL/min/1.73 m) should have their Oforta™ dose reduced by 50% and be monitored closely.

Based on its mechanism of action, Oforta™ can cause fetal harm when administered to a pregnant woman. Fludarabine phosphate administered to rats and rabbits during organogenesis caused an increase in resorptions, skeletal and visceral malformation, and decreased fetal body weights. If Oforta™ is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. [see Use in Specific Populations (8.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Oforta™ in 159 patients exposed to the drug. Oforta™ was studied primarily in Study 1 in 78 patients with CLL who received prior therapy and in Study 2 in 81 patients with CLL who had not received prior therapy.

Based on experience with the intravenous and oral use of fludarabine phosphate, the most common adverse reactions include myelosuppression (neutropenia, thrombocytopenia and anemia), fever and chills, infection, and nausea and vomiting. Other commonly reported events include malaise, fatigue, anorexia, and weakness. Serious opportunistic infections have occurred in patients with CLL treated with fludarabine phosphate. The most frequently reported adverse reactions and those reactions which are more clearly related to the drug, as reported in clinical studies conducted with intravenous and oral fludarabine phosphate, are arranged below according to body system.

Hematopoietic Systems

Hematologic events (neutropenia, thrombocytopenia, and/or anemia) were reported in the majority of patients with CLL treated with fludarabine phosphate. During intravenous fludarabine phosphate treatment of 133 patients with CLL, the absolute neutrophil count decreased to less than 500/mm in 59% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 60%, and platelet count decreased from pretreatment values by at least 50% in 55%. Among 78 patients with B-CLL who were treated with Oforta™, the absolute neutrophil count decreased to less than 500/mm in 37% of patients, hemoglobin decreased from pretreatment values by at least 2 grams percent in 14%, and platelet count decreased from pretreatment values by at least 50% in 17% of patients. Myelosuppression may be severe, cumulative, and may affect multiple cell lines. Bone marrow fibrosis occurred in one CLL patient treated with fludarabine phosphate intravenously. In the pivotal oral fludarabine phosphate study (Study 1), there was one report of a non-fatal case of pancytopenia. Similarly, there was one case of non-fatal pancytopenia reported among the 133 patients with CLL treated with intravenous fludarabine phosphate.

Life-threatening and sometimes fatal autoimmune hemolytic anemias have been reported to occur in patients receiving fludarabine phosphate. [See Warnings and Precautions (5.2) ] The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process.

Metabolic

Tumor lysis syndrome has been reported in patients with CLL treated with fludarabine phosphate for injection. This complication may include hyperuricemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, hyperkalemia, hematuria, urate crystalluria, and renal failure. The onset of this syndrome may be heralded by flank pain and hematuria.

Nervous System

Objective weakness, agitation, confusion, visual disturbances, and coma have occurred in patients with CLL treated with fludarabine phosphate at the recommended dose. Peripheral neuropathy and one case of wrist-drop have been observed with intravenous administration of fludarabine phosphate. In Study 1 for Oforta™, there was one report of severe impairment of consciousness that presented concurrent with hemolytic anemia. This patient had enrolled in the study with pre-existing peripheral neurotoxicity. [See Warnings and Precautions (5.1) ]

Pulmonary System

Pneumonia, a frequent manifestation of infection in patients with CLL, was observed in two clinical trials conducted with intravenous fludarabine phosphate (16% and 22%) and in two clinical trials with Oforta™ (8% and 3%). Pulmonary hypersensitivity reactions to fludarabine phosphate characterized by dyspnea, cough and interstitial pulmonary infiltrate have been observed. In Study 1 conducted with Oforta™, severe pulmonary toxicity was reported in 5 of 78 patients, often in conjunction with respiratory or pulmonary infections and hence not regarded as isolated drug related pulmonary toxicity.

Gastrointestinal System

Gastrointestinal disturbances such as nausea and vomiting, anorexia, diarrhea, stomatitis and gastrointestinal bleeding have been reported in patients treated with fludarabine phosphate. Nausea and vomiting occurred in up to 38% of patients following treatment with Oforta™ in the clinical trials.

Cardiovascular

Edema has been frequently reported. One patient developed a pericardial effusion possibly related to treatment with Oforta™. No other severe cardiovascular events were considered to be drug related.

Genitourinary System

Hemorrhagic cystitis has been reported in patients treated intravenously with fludarabine phosphate.

Skin

Skin toxicity, consisting primarily of skin rashes, has been reported in patients treated with oral and intravenous fludarabine phosphate.

Data in Table 2 are derived from the 159 patients with CLL who received Oforta™ in Study 1 and Study 2.

TABLE 2: Incidence (≥5%) of Non-Hematologic Adverse Reactions in Patients with CLL Treated with Oforta™

ADVERSE REACTIONS	Study 1 (N=78) %	Study 2 (N=81) %
ANY ADVERSE REACTION	82	89
BODY AS A WHOLE	59	77
FEVER	26	11
INFECTION	12	17
PAIN	5	19
FLU SYNDROME	8	5
DIAPHORESIS	8	0
NEUROLOGICAL	19	41
WEAKNESS/FATIGUE (ASTHENIA)	13	31
SWEATING INCREASED	0	14
HEADACHE	9	9
PULMONARY	37	53
COUGH	21	0
COUGH INCREASED	0	6
PNEUMONIA	8	3
DYSPNEA	1	5
SINUSITIS	1	5
UPPER RESPIRATORY INFECTION	9	14
RHINITIS	3	11
BRONCHITIS	6	9
METABOLIC AND NUTRITIONAL	3	31
WEIGHT DECREASED	1	6
LACTIC DEHYDROGENASE INCREASED	0	6
PERIPHERAL EDEMA	0	7
GASTROINTESTINAL	41	28
NAUSEA	5	1
DIARRHEA	6	5
ANOREXIA	19	0
ABDOMINAL PAIN	8	10
CUTANEOUS	22	25
RASH	5	4
SKIN DISORDER	0	6
HERPES SIMPLEX	8	7
GENITOURINARY	8	14
URINARY TRACT INFECTION	4	5
CARDIOVASCULAR	14	17
CHEST PAIN	0	5
MUSCULOSKELETAL	10	19
BACK PAIN	4	9

The following adverse reactions have been identified during post approval use of Oforta™. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possibly to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hematopoietic Systems

Several instances of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported in post-marketing surveillance. The duration of clinically significant cytopenia in the reported cases has ranged from approximately 2 months to approximately 1 year. These episodes have occurred both in previously treated or untreated patients.

Nervous System

In post-marketing experience, cases of progressive multifocal leukoencephalopathy have been reported. Most cases had a fatal outcome. Many of these cases were confounded by prior and/or concurrent chemotherapy. The median time to onset was approximately one year.

Pulmonary System

In post-marketing experience, cases of severe pulmonary toxicity have been observed with fludarabine phosphate use which resulted in acute respiratory distress syndrome, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, and respiratory failure. After exclusion of an infectious origin, some patients experienced symptom improvement with corticosteroids.

The use of Oforta™ in combination with pentostatin is not recommended due to the risk of severe pulmonary toxicity. [See Warnings and Precautions (5.6) ]

"Pregnancy Category D. See 'Warnings and Precautions' section."

Based on its mechanism of action, Oforta™ can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of fludarabine phosphate in pregnant women. Fludarabine phosphate was embryolethal and teratogenic in both rats and rabbits. If Oforta™ is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy.

In rats, repeated intravenous doses of fludarabine phosphate at 1.5 times and 4.5 times the recommended human oral dose (40 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 1.5 times the human oral dose, and was limited to slight body weight decreases at 4.5 times the human oral dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 2.4 times the human oral dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (≥ 0.3 times the human oral dose).

It is not known whether Oforta™ is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions including tumorigenicity in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

Of 78 previously treated patients with B-CLL treated with Oforta™ 50% were ≥ age 65 and 3% were ≥ age 75. The response rate was generally lower among patients age 65 and older. Among previously treated patients (Study 1) age 65 and older, the overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 41%. The safety profile among younger and older patients on study was similar. Other reported clinical experience has not identified differences in responses or safety between older and younger patients.

In patients receiving intravenous fludarabine phosphate, the total body clearance of the metabolite 2-fluoro-ara-adenine (2F-ara-A) correlated with the creatinine clearance, indicating the importance of the renal excretion pathway for the elimination of the drug. Renal clearance represented approximately 40% of the total body clearance. Patients with mild to moderate renal impairment (30 to 70 mL/min/1.73 m) receiving 20% reduced fludarabine phosphate dose had a similar exposure compared to patients with normal renal function receiving the recommended dose (AUC; 21 nM∙h/mL versus 20 nM∙h/mL). Two patients with severe renal impairment (< 30 mL/min/1.73 m) receiving 40% reduced fludarabine phosphate dose had a 40% increase in exposure compared to patients with normal renal function receiving the recommended dose. The mean total body clearance was 172 mL/min for patients with normal renal function, 124 mL/min for patients with mild to moderately impaired renal function, and 71 mL/min for the two patients with severe renal impairment.

High doses of fludarabine phosphate [See Indications and Usage (1.1) and Warnings and Precautions (5.1) ] have been associated with an irreversible central nervous system toxicity characterized by delayed blindness, coma and death. High doses are also associated with severe thrombocytopenia and neutropenia due to bone marrow suppression. There is no known specific antidote for fludarabine phosphate overdosage. Treatment consists of drug discontinuation and supportive therapy. In Study 2, two patients ingested an overdose of 20% to 33% of Oforta™. No serious side effects were reported.

The chemical name for fludarabine phosphate is 9H-Purin-6-amine,2-fluoro-9-(5-O-phosphono-β-D-arabinofuranosyl)(2-fluoro-ara-AMP). The molecular formula of fludarabine phosphate is CHFNOP (MW 365.2) and the structure is provided in Figure 1

Oforta™ (fludarabine phosphate tablets) for oral administration contain fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-beta -D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. Each tablet contains 10 mg of the active ingredient fludarabine phosphate. The tablet core consists of microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172).

Fludarabine phosphate (2F-ara-AMP) is a synthetic purine nucleotide antimetabolite agent. Upon administration, 2F-ara-AMP is rapidly dephosphorylated in the plasma to 2F-ara-A, which then enters into the cell. Intracellularly, 2F-ara-A is converted to the 5'-triphosphate, 2-fluoro-ara-ATP (2F-ara-ATP). 2F-ara-ATP competes with deoxyadenosine triphosphate for incorporation into DNA. Once incorporated into DNA, 2F-ara-ATP functions as a DNA chain terminator, inhibits DNA polymerase alpha, gamma, and delta, and inhibits ribonucleoside diphosphate reductase. 2F-ara-A also inhibits DNA primase and DNA ligase I. The mechanism of action of this antimetabolite is not completely characterized and may be multi-faceted.

Cardiac Electrophysiology

In a randomized, uncontrolled, open-label, parallel study, patients with B-cell CLL were administered a single dose of Oforta™ 40 mg/m (n = 42) or intravenous fludarabine phosphate 25 mg/m (n=14). The maximum increase in the baseline-corrected mean change in QTcI (individual-corrected QT interval) following treatment with Oforta™ was less than 10 milliseconds.

Studies with the intravenous product have demonstrated that fludarabine phosphate is converted to the active metabolite, 2F-ara-A. Clinical pharmacology studies have focused on 2F-ara-A pharmacokinetics.

Following administration of the intravenous product, systemic plasma clearance of 2F-ara-A is approximately 117 mL/min to 145 mL/min. After five daily 30 minute intravenous infusions of 25 mg 2F-ara- AMP/m to cancer patients, trough concentrations of 2F-ara-A increased by a factor of about 2. The terminal half-life of 2F-ara-A was approximately 20 hours. Plasma protein binding of 2F-ara-A was approximately 19% to 29%. A correlation was noted between the degree of absolute granulocyte count nadir and increased area under the concentration x time curve (AUC).

2F-ara-A exhibits dose proportional increases in AUC and Cmax after single oral doses of 50 mg, 70 mg or 90 mg of 2F-ara-AMP. Cmax of 2F-ara-A occurs 1 hour to 2 hours after single or multiple oral doses and is approximately 20 % to 30 % of the maximum plasma concentrations produced at the end of a 30 minute intravenous infusion of the same dose. The absolute oral bioavailability of 2F-ara-A is 50 – 65% following single and repeated doses of Oforta™. Similar systemic exposure (AUC) was observed after a single 40 mg/m Oforta™ and a single 25 mg/m fludarabine phosphate intravenous dose. The terminal half-life of 2F-ara-A was similar to that following intravenous administration; approximately 20 hours. The Cmax, AUC and terminal half-life of 2F-ara-A are unaffected when administered with a high fat meal, although Tmax is slightly delayed from 1.3 hours to 2.2 hours.

Following intravenous administration, renal clearance of 2F-ara-A represents approximately 40% of the total body clearance of fludarabine phosphate, and total body clearance is inversely correlated with serum creatinine and creatinine clearance. In two patients with median creatinine clearance of 22 mL/min/1.73 m, 2F-ara-A clearance was reduced by 56%. Dosage adjustment based on creatinine clearance is recommended as follows:

Reduce dose by 20% in patients with mild to moderate renal impairment (creatinine clearance 30 to 70 mL/min/1.73 m). [See Warnings and Precautions (5.7) ]

Reduce dose by 50% in patients with severe renal impairment (creatinine clearance < 30 mL/min/1.73 m). [See Warnings and Precautions (5.7) ]

No animal carcinogenicity studies with Oforta™ have been conducted.

Oforta™ is a clastogen.

Fludarabine phosphate was clastogenic in vitro to Chinese hamster ovary cells (chromosome aberration assay) in the presence of metabolic activation and induced sister chromatid exchanges both in the presence and absence of metabolic activation. In addition, fludarabine phosphate was clastogenic in vivo (mouse micronucleus assay) but was not mutagenic to germ cells (dominant lethal test in male mice). Fludarabine phosphate was not mutagenic to bacteria (Ames test) or mammalian cells either in the presence or absence of metabolic activation.

Studies in mice, rats and dogs have demonstrated dose-related adverse effects on the male reproductive system. Observations consisted of a decrease in mean testicular weights in mice and rats with a trend toward decreased testicular weights in dogs and degeneration and necrosis of spermatogenic epithelium of the testes in mice, rats and dogs.

Study 1, a single-arm, open-label study of Oforta™ was conducted in 78 adult patients with CLL refractory to at least one prior standard alkylating-agent containing regimen. In this multicenter study patients were treated with Oforta™ at a dose of 40 mg/m daily for 5 days every 28 days. The patient population median age was 64.5 years and consisted of 72% males and 28% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.9%), Stage I (20.5%), Stage II (32.1%), Stage III (11.5%), and Stage IV (32.1%). The mean number of treatment cycles was 5.1 with a mean daily dose of Oforta™ of 38 mg/m. The overall objective response, according to standardized response criteria developed by the National Cancer Institute CLL Working Group (NCI criteria), was 51%, including 18% complete responses and 33% partial responses. The overall response rate, according to standardized criteria developed by the International Workshop on CLL (IWCLL criteria), was 46%, including 21% complete responses and 26% partial responses. Data on duration of response was not collected.

In Study 2, a supportive single-arm, open-label study, Oforta™ was administered to 81 previously untreated patients with B-CLL. In this multicenter study each patient was treated with Oforta™ at a dose of 40 mg/m daily for 5 days every 28 days. The patient population median age was 64.0 years and consisted of 63% males and 37% females. Ninety-nine percent of the patients were Caucasian. The Rai stage for patients entering the study was: Stage 0 (3.7%), Stage I (37.0%), Stage II (37.0%), Stage III (9.9%), and Stage IV (12.3%). The mean number of treatment cycles was 5.9 with a mean daily dose per patient of 71 mg to 74 mg. The overall responses rate, according to NCI criteria, was 80%, including 12% complete responses and 68% partial responses. The overall response rate, according to IWCLL criteria, was 72%, including 37% complete responses and 35% partial responses. The median duration of response was 22.9 months.

Study 3 was a supportive randomized controlled open label study in patients with previously untreated B-CLL that included fludarabine phosphate monotherapy and fludarabine phosphate combination therapy arms. In this study 107 evaluable patients received Oforta™ 40mg/m orally daily for 5 days every 28 days. The overall response rate according to modified NCI criteria was 74% and the CR plus nodular PR rate was 41%.

HOW SUPPLIED

Oforta™ is supplied in 10 milligram tablets that are film-coated, capsule shaped, salmon pink in color, and marked on one side with 'LN' in a regular hexagon. Each film-coated tablet contains 10 mg fludarabine phosphate. The tablets are supplied in blisters, each blister strip containing 5 tablets. Packages of 15 and 20 tablets are available in child-resistant containers.

NDC 0024-5820-15: 15 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 3 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton.

NDC0024-5820-20: 20 - 10 milligram film-coated tablets per container. Each film-coated tablet is packaged in an individual blister package; 5 tablets per blister strip; 4 blister strips packaged in a plastic bottle with a child-resistant container closure; each bottle is packaged in an individual chip-board carton.

STORAGE

Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP controlled room temperature].

HANDLING AND DISPOSAL

Procedures for proper handling and disposal should be considered. Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published. Caution should be exercised in the handling of Oforta™. Push tablets through foil to open. Do not remove tablets from individual blisters until immediately prior to taking or administering each scheduled dose. Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes.

Inform patients that Oforta™ decreases blood cell counts such as white blood cells, platelets, and red blood cells. Thus, it is important that periodic assessment of their blood count be performed to detect the development of neutropenia, thrombocytopenia and anemia. [See Warnings and Precautions (5.2) ]

Instruct patients to notify their physician promptly if fever or other signs of infection such as chills, cough, or burning pain on urination occurs while on therapy. [See Warnings and Precautions (5.4) ]

Women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy. Oforta™ may cause fetal harm when administered to a pregnant woman. [See Warnings and Precautions (5.9) ]

Instruct patients that caution should be exercised in the handling of Oforta™. Do not crush tablets. Avoid exposure by direct contact of the skin or mucous membranes or by inhalation. If contact occurs, wash thoroughly with soap and water or wash the eyes immediately with gently flowing water for at least 15 minutes. Consult healthcare provider in case of a skin reaction or if the drug gets in the eyes. Ask your healthcare provider or pharmacist for directions about how to safely dispose of Oforta™.

Manufactured for: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807

©2009

OFORTA™ (oh-FORT-tuh)

(oral fludarabine phosphate tablets)

Read this Patient Information leaflet before you start taking OFORTA™ and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What Is OFORTA™?

OFORTA™(oral fludarabine phosphate tablets) is a prescription anticancer medicine that slows or stops the growth of cancer cells in adults with chronic lymphocytic leukemia (CLL). OFORTA™ also stops or slows the growth of some healthy cells. This can cause side effects that you should know about and report to your healthcare provider.

OFORTA™ has not been studied in children.

What is the most important information I should know about OFORTA™?

On rare occasions people taking OFORTA™ can have life-threatening symptoms. If you:

What should I tell my healthcare provider before taking OFORTA™?

Before taking OFORTA™, tell your healthcare provider about all of your medical conditions, including if you:

Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Using OFORTA™ with certain other medicines may affect each other. Using OFORTA™ with other medicines may cause serious side effects.

Know the medicines you take. Keep a list of them with you to show your healthcare provider.

How should I take OFORTA™?

What should I avoid while taking OFORTA™?

What are the possible side effects of OFORTA™?

See "What is the most important information I should know about OFORTA™?"

OFORTA™ may cause serious side effects, including:

OFORTA™ may cause other side effects, including:

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of OFORTA™. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How should I store and throw away OFORTA™?

Keep OFORTA™ and all medicines out of the reach of children.

General information about OFORTA™

Medicines are sometimes prescribed for conditions that are not mentioned in patient information. Do not use OFORTA™ for a condition for which it was not prescribed. Do not give OFORTA™ to other people, even if they have the same symptoms you have. It may harm them.

This patient information leaflet summarizes the most important information about OFORTA™. For more information about OFORTA™, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about OFORTA™ that is written for health professionals. For more information call 1-800-633-1610.

What are the ingredients in OFORTA™?

Active ingredients: fludarabine phosphateInactive ingredients: microcrystalline cellulose, lactose monohydrate, colloidal anhydrous silicon dioxide, croscarmellose sodium and magnesium stearate. The film-coat contains hypromellose, talc, titanium dioxide (E171) and ferric oxide pigment (red/E172, yellow/E172).