REVLIMID in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma (MM).

REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is indicated for the treatment of adult 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.

REVLIMID is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL).

REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL).

REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.

The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

The recommended starting dose of REVLIMID is 20 mg orally once daily on Days 1-21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab-product. Refer to Section 14.4 for specific rituximab dosing from the AUGMENT trial. For dose adjustments due to toxicity with rituximab, refer to the product prescribing information.

For non-hematologic Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to Grade 2 or below.

Permanently discontinue REVLIMID for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.9, 5.15)].

The recommendations for dosing patients with renal impairment are shown in the following table [see Clinical Pharmacology (12.3)].

Advise patients to take REVLIMID orally at about the same time each day, either with or without food. Advise patients to swallow REVLIMID capsules whole with water and not to open, break, or chew them.

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 [see Boxed Warning]. 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 [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1, 8.3)].

REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.9, 5.15)].

REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy.

REVLIMID is only available through the Lenalidomide REMS program [see Warnings and Precautions (5.2)].

Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Lenalidomide REMS program.

Required components of the Lenalidomide REMS program include the following:

• Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3)] and males must comply with contraception requirements [see Use in Specific Populations (8.3)].
• Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements.

Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-888-423-5436.

REVLIMID can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and Administration (2.1, 2.2, 2.3)].

Monitor complete blood counts (CBC) in patients taking REVLIMID in combination with dexamethasone or as REVLIMID maintenance therapy for MM every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required [see Dosage and Administration (2.1)]. In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of REVLIMID-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of REVLIMID-treated patients [see Adverse Reactions (6.1)].

Monitor complete blood counts (CBC) in patients taking REVLIMID for MDS weekly for the first 8 weeks and at least monthly thereafter. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days) [see Boxed Warning and Dosage and Administration (2.2)].

Monitor complete blood counts (CBC) in patients taking REVLIMID for MCL weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

Monitor complete blood counts (CBC) in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the AUGMENT and MAGNIFY trials, Grade 3 or 4 neutropenia was reported in 50% and 33%, respectively, of patients in the REVLIMID/rituximab arm. Grade 3 or 4 thrombocytopenia was reported in 2% and 8%, respectively, of patients in the REVLIMID/rituximab arm [see Adverse Reactions (6.1)].

Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with REVLIMID.

A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) [see Boxed Warning and Adverse Reactions (6.1)].

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with REVLIMID and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) [see Adverse Reactions (6.1)].

Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed MM who were treated with REVLIMID and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms.

In the AUGMENT trial, the incidence of VTE (including DVT and PE) in FL or MZL patients was 3.4% in the REVLIMID/rituximab arm [see Adverse Reactions (6.1)]. In the AUGMENT trial, the incidence of ATE (including MI) in FL or MZL patients was 0.6% in the REVLIMID/rituximab arm [see Adverse Reactions (6.1)].

Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient's underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving REVLIMID [see Drug Interactions (7.2)].

In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor second primary malignancies (SPM) notably AML and MDS have been observed. An increase in hematologic SPM including AML and MDS occurred in 5.3% of patients with NDMM receiving REVLIMID in combination with oral melphalan compared with 1.3% of patients receiving melphalan without REVLIMID. The frequency of AML and MDS cases in patients with NDMM treated with REVLIMID in combination with dexamethasone without melphalan was 0.4%.

In patients receiving REVLIMID maintenance therapy following high dose intravenous melphalan and auto-HSCT, hematologic SPM occurred in 7.5% of patients compared to 3.3% in patients receiving placebo. The incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8% in patients receiving placebo with a median follow-up of 91.5 months. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving REVLIMID maintenance, compared to 2.6% in the placebo arm.

In patients with relapsed or refractory MM treated with REVLIMID/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving REVLIMID/dexamethasone, compared to 0.6% in the dexamethasone alone arm.

Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID.

In the AUGMENT trial with FL or MZL patients receiving REVLIMID/rituximab therapy, hematologic plus solid tumor SPMs, notably AML, have been observed. In the AUGMENT trial, hematologic SPM of AML occurred in 0.6% of patients with FL or MZL receiving REVLIMID/rituximab therapy. The incidence of hematologic plus solid tumor SPMs (excluding nonmelanoma skin cancers) was 1.7% in the REVLIMID/rituximab arm with a median follow-up of 29.8 months (range 0.5 to 51.3 months) [see Adverse Reactions (6.1)]. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID.

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5)].

Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Monitor patients at risk closely and take appropriate preventive approaches. In the AUGMENT trial in FL or MZL patients, TLS occurred in 2 patients (1.1%) in the REVLIMID/rituximab arm. TLS occurred in 1 patient (0.5%) in the MAGNIFY trial during the REVLIMID/rituximab induction period; the event was a serious, Grade 3 adverse reaction.

Tumor flare reaction (TFR), including fatal reactions, have occurred during investigational use of REVLIMID for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare reaction may mimic progression of disease (PD).

In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in Cycle 1 and one patient developed TFR again in Cycle 11. In the AUGMENT trial in FL or MZL patients, TFR was reported in 19/176 (10.8%) of patients in REVLIMID with rituximab arm; one patient in the REVLIMID/rituximab arm experienced a Grade 3 TFR. In the MAGNIFY trial, 9/222 (4.1%) of patients experienced TFR; all reports were Grade 1 or 2 in severity and 1 event was considered as serious. In a separate MCL phase 2 trial, one case of TFR resulted in a fatal outcome.

REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician's discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with REVLIMID has been reported. In patients who are auto-HSCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

Both hypothyroidism and hyperthyroidism have been reported [see Adverse Reactions (6.2)]. Measure thyroid function before start of REVLIMID treatment and during therapy.

In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. On exploratory multivariate analysis, risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥ 10 x 10⁹/L).

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for angioedema and anaphylaxis [see Dosage and Administration (2.2)].

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.