Oforta

OFORTA- fludarabine phosphate tablet, film coated
sanofi-aventis U.S. LLC

WARNING: CNS TOXICITY, HEMOLYTIC ANEMIA, AND PULMONARY TOXICITY

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/m2 /day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m2 /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)]

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

2.1 Chronic Lymphocytic Leukemia (CLL)

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

The recommended adult dose of Oforta™ is 40 mg/m2 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):

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

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.

2.2 Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Neurotoxicity

Dose-dependent neurotoxicity has been observed with fludarabine phosphate. Dose levels approximately 4 times greater (96 mg/m2 /day for 5 days to 7 days) than the recommended intravenous dose (25 mg/m2 /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/m2 /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/m2 /day for 5 days per course) developed toxicity. In the pivotal clinical study conducted with Oforta™ administered at 40 mg/m2 , 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.

5.2 Bone Marrow Suppression

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.

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