Lenalidomide

REVLIMID is a thalidomide analogue indicated for the treatment of adult patients with: • Multiple myeloma (MM), in combination with dexamethasone. • MM, as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT). • Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities. • Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. • Previously treated follicular lymphoma (FL), in combination with a rituximab product. • Previously treated marginal zone lymphoma (MZL), in combination with a rituximab product.

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes, follicular lymphoma and marginal zone lymphoma in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM.

• MM combination therapy: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. • MM maintenance therapy following auto-HSCT: 10 mg once daily continuously on Days 1-28 of repeated 28-day cycles. • MDS: 10 mg once daily. • MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. • FL or MZL: 20 mg once daily orally on Days 1-21 of repeated 28-day cycles for up to 12 cycles. • Renal impairment: Adjust starting dose based on the creatinine clearance value. • For concomitant therapy doses, see Full Prescribing Information.

• Pregnancy ( Boxed Warning, 4.1, 5.1, 8.1 ). • Demonstrated severe hypersensitivity to lenalidomide. Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide's structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.

Boxed warning (embryo-fetal toxicity, hematologic toxicity, and venous and arterial thromboembolism): Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with REVLIMID. • Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving REVLIMID. • Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue.

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: o Embryo-Fetal Toxicity o Hematologic Toxicity o Venous and Arterial Thromboembolism o Increased Mortality in Patients with CLL o Second Primary Malignancies o Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone o Hepatotoxicity o Severe Cutaneous Reactions o Tumor Lysis Syndrome o Tumor Flare Reactions o Impaired Stem Cell Mobilization o Thyroid Disorders o Early Mortality in Patients with MCL o Hypersensitivity • MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor.

• Digoxin: Monitor digoxin plasma levels periodically due to increased C max and AUC with concomitant REVLIMID therapy. • Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with REVLIMID may increase the risk of thrombosis.

Store at 20°C - 25°C (68°F - 77°F), excursions permitted to 15°C - 30°C (59°F - 86°F).