<p><strong>Lenalidomide REMS Program</strong>: Because of the embryo-fetal risk, Lenalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Lenalidomide REMS<br />
program. Required components of the Lenalidomide REMS program include the following:</p>

<ul>
	<li>Prescribers must be certified with the Lenalidomide REMS program by enrolling and complying with the REMS requirements.</li>
	<li>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 and males must comply with contraception requirements.</li>
	<li>Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive Lenalidomide and comply with REMS requirements.</li>
</ul>

<p><strong>Hematologic Toxicity</strong>: Lenalidomide 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 Lenalidomide should have their complete blood counts assessed periodically as described below. Monitor complete blood counts (CBC) in patients taking Lenalidomide in combination with Dexamethasone or as Lenalidomide 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. Monitor complete blood counts (CBC) in patients taking Lenalidomide for MDS weekly for the first 8 weeks and at least monthly thereafter. Monitor complete blood counts (CBC) in patients taking Lenalidomide 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. Monitor complete blood counts (CBC) in patients taking Lenalidomide for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 24, and then monthly thereafter. Patients may require dose interruption and/or dose reduction.<br />
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<strong>Venous and Arterial Thromboembolism</strong>: Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with Lenalidomide. 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). Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient&rsquo;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 Lenalidomide.<br />
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<strong>Increased Mortality in Patients with CLL</strong>: Lenalidomide is not indicated and not recommended for use in CLL outside of controlled clinical trials.<br />
<br />
<strong>Second Primary Malignancies</strong>: Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of Lenalidomide and the risk of second primary malignancies when considering treatment with Lenalidomide.<br />
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<strong>Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone</strong>: 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.<br />
<br />
<strong>Hepatotoxicity</strong>: Hepatic failure, including fatal cases, has occurred in patients treated with Lenalidomide in combination with Dexamethasone. 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 Lenalidomide upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.<br />
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<strong>Severe Cutaneous Reactions Including Hypersensitivity Reactions</strong>: Angioedema and 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 Lenalidomide. Lenalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Lenalidomide must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected and should not be resumed following discontinuation for these reactions.<br />
<br />
<strong>Tumor Lysis Syndrome</strong>: Monitor patients at risk closely and take appropriate preventive approaches. Tumor Flare Reaction: Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. Tumor flare reaction may mimic the progression of disease (PD).<br />
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<strong>Impaired Stem Cell Mobilization</strong>: A decrease in the number of CD34+ cells collected after treatment (&gt;4 cycles) with Lenalidomide 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 Lenalidomide-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 GCSF with a CXCR4 inhibitor may be considered.<br />
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<strong>Thyroid Disorders</strong>: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before the start of Lenalidomide treatment and during therapy.</p>