FDA Approval for Lenalidomide
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On June 29, 2006, the U.S. Food and Drug Administration granted approval to lenalidomide oral capsules (Revlimid®, made by Celgene Corporation) for use in combination with dexamethasone in patients with multiple myeloma who have received one prior therapy. Lenalidomide is available under a special restricted distribution program, called RevAssistSM (described below).
Efficacy and safety were demonstrated in two randomized, double-blind, multicenter, multinational, placebo-controlled studies comparing the combination of lenalidomide plus oral pulse dexamethasone versus dexamethasone alone in patients with multiple myeloma who had received at least one prior therapy.
Lenalidomide was administered at a starting dose of 25 mg/day orally as a single 25 mg capsule on days 1-21 of repeated 28-day cycles. Dexamethasone was administered orally at a dose of 40 mg/day on days 1-4, 9-12, and 17-20 of each 28-day cycle for the first four cycles and then 40 mg/day orally on days 1-4 every 28 days in both treatment arms of both studies.
Data were evaluated from 692 patients in the two studies, 341 patients in Study 1 and 351 patients in Study 2. The primary endpoint of time-to-progression (TTP) was evaluated in a prespecified interim analysis in each study. In Study 1, median TTP was 37.1 weeks in the lenalidomide/dexamethasone arm compared to 19.9 weeks with dexamethasone alone (HR=0.356; 95 percent CI [0.257, 0.494]; p < 0.0001). In Study 2, median TTP was not reached in the lenalidomide/dexamethasone arm compared to 20 weeks in the dexamethasone alone arm (HR=0.392; 95 percent CI [0.274, 0.562]; p < 0.0001).
Safety data were evaluated from 691 patients in the two studies. Grade 3 and 4 neutropenia, thrombocytopenia, leukopenia, lymphopenia, febrile neutropenia, deep vein thrombosis, pulmonary embolism, atrial fibrillation, constipation, diarrhea, fatigue, pneumonia, hypokalemia, hypocalcemia, muscle weakness, neuropathy and depression were reported in a greater proportion of patients treated with the combination of lenalidomide and dexamethasone compared to dexamethasone alone.
Thrombotic or thromboembolic events, including deep vein thrombosis, pulmonary embolism, thrombosis, and intracranial venous sinus thrombosis were reported more frequently in patients treated with the combination of lenalidomide plus dexamethasone (12 percent) compared to dexamethasone alone (4 percent) in the pooled analyses.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. It is unknown whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with lenalidomide may reduce the potential for venous thromboembolic events. The decision to prescribe prophylactic measures should be considered carefully after an assessment of an individual patient’s underlying risk factors.
Patients with renal impairment were excluded from the studies. Because lenalidomide is primarily excreted by the kidney, renal function should be carefully monitored.
Females should be advised to avoid pregnancy while taking lenalidomide. Lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe life-threatening human birth defects. Reproductive toxicity studies are ongoing to assess lenalidomide’s potential teratogenicity.
To avoid fetal exposure, lenalidomide is only available under a special restricted distribution program called RevAssist. Under this program, only prescribers and pharmacists registered with the program can prescribe and dispense the product. Patients enrolled in the program to receive the drug must agree to comply with the requirements of the RevAssist program. For more information, go to the RevAssist Web site or call the Celgene Customer Care Center toll-free at 1-888-423-5436.
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On December 27, 2005, the U.S. Food and Drug Administration granted Subpart H approval (restricted distribution) to lenalidomide oral capsules (Revlimid®, made by Celgene Corp.) for use in patients with transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Lenalidomide will be available only under a special restricted distribution program, RevAssistSM, similar to the S.T.E.P.S.® program instituted for Thalomid®. (See the FDA press release.)
Safety and efficacy were demonstrated in one single-arm, multicenter clinical trial of 148 patients. This multicenter trial enrolled patients with transfusion-dependent anemia secondary to low or intermediate-1 risk MDS associated with deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Patients must have required ≥ two units of red blood cells (RBC) transfused within the eight weeks prior to study treatment.
The primary endpoint was RBC transfusion independence response (an eight-week or longer transfusion-free period). Lenalidomide was administered at 10 mg daily or 10 mg x 21 days in a 28-day cycle. Dose delays and reductions to 5 mg daily and 5 mg every other day were allowed. Patients who developed neutropenia were permitted to receive granulocyte colony-stimulating factors.
RBC transfusion independence response was observed in 67 percent (99/148) of patients in the trial. The median RBC transfusion response duration was 44 weeks (range of 0 to > 67 weeks). Ninety percent of responding patients demonstrated evidence of response within three months after initiating lenalidomide.
One-hundred percent of patients reported at least one adverse event; 89 percent (131/148) experienced at least one grade 3/4 adverse event. The most frequently reported were thrombocytopenia (62 percent) and neutropenia (59 percent). Grade 3/4 thrombocytopenia or neutropenia was observed in 50 percent and 53 percent, respectively. Other common adverse events were diarrhea (49 percent), pruritis (42 percent), rash (36 percent), and fatigue (31 percent).
Eighty percent required a dose delay and/or reduction for toxicity during the study. Thirty-four percent required a second dose delay/reduction. Dose adjustment recommendations for neutropenia and thrombocytopenia are provided in product labeling. Patients should have complete blood counts monitored weekly for the initial eight weeks and at least monthly thereafter.
Thromboembolic events were rare in the lenalidomide studies in MDS patients with deletion 5q cytogenetic abnormalities. However, in recently reported trials conducted in multiple myeloma, a significantly increased risk of deep venous thrombosis and pulmonary embolism was observed in patients treated with lenalidomide combination therapy. The role of prophylactic anticoagulation and/or antiplatelet therapy with lenalidomide has not been adequately assessed. Any prophylactic measures should be prescribed after a careful assessment of individual risk factors.
Patients with serum creatinine above 2.5 mg/dl were excluded from the studies. Because lenalidomide is predominately excreted by the kidney, renal function should be carefully monitored.
Females should be advised to avoid pregnancy while taking lenalidomide. Lenalidomide is an analogue of thalidomide, a known human teratogen that causes severe human birth defects. Additional reproductive toxicity studies will be performed to assess any potential lenalidomide teratogenicity. Only prescribers and pharmacists registered under the RevAssistSM program can prescribe or dispense lenalidomide. Patients must agree to comply with the RevAssistSM program requirements.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.