LENALIDOMIDE Drug Interactions: What You Need to Know

INTERACTIONS

• Digoxin: Monitor digoxin plasma levels periodically due to increased C max and AUC with concomitant lenalidomide capsule therapy ( 7.1 ).
• Concomitant use of erythropoietin stimulating agents or estrogen containing therapies with lenalidomide capsules may increase the risk of thrombosis ( 7.2 ).

7.1 Digoxin When digoxin was co-administered with multiple doses of lenalidomide capsules (10 mg/day) the digoxin C max and AUC inf were increased by 14%. Periodically monitor digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, during administration of lenalidomide capsules.

7.2 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving lenalidomide capsules <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span> .

7.3 Warfarin Co-administration of multiple doses of lenalidomide capsules (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant lenalidomide capsule administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.

Drug

Interactions Co-administration of a single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide capsules (25 mg). Co-administration of lenalidomide capsules (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the C max or AUC of lenalidomide. Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg) with lenalidomide capsules (25 mg) did not significantly alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of temsirolimus). In vitro studies demonstrated that lenalidomide capsules are a substrate of P-glycoprotein (P-gp). Lenalidomide capsules are not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Lenalidomide is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.

4 CONTRAINDICATIONS

• Pregnancy ( Boxed Warning , 4.1 , 5.1 , 8.1 ).
• Demonstrated severe hypersensitivity to lenalidomide ( 4.2 , 5.9 , 5.15 ).

4.1 Pregnancy Lenalidomide capsules 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 <span class="opacity-50 text-xs">[see Boxed Warning ]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) , Use in Special Populations (8.1 , 8.3) ]</span> .

4.2 Severe Hypersensitivity Reactions Lenalidomide capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9 , 5.15) ]</span> .

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use lenalidomide capsules 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. In females of reproductive potential, obtain 2 negative pregnancy tests before starting lenalidomide capsules treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide capsules treatment [ see Warnings and Precautions ( 5.1 ), and Medication Guide ( 17 ) ] . To avoid embryo-fetal exposure to lenalidomide, lenalidomide capsules are only available through a restricted distribution program, the Lenalidomide REMS program ( 5.2 ). Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the manufacturer’s toll-free number 1-866-604-3268.

Hematologic

Toxicity (Neutropenia and Thrombocytopenia) Lenalidomide capsules can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction.

Grade

3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration ( 2.2 )] . Venous and Arterial Thromboembolism Lenalidomide capsule has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma who were treated with lenalidomide capsules and dexamethasone therapy. Monitor for and advise patients about signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Thromboprophylaxis is recommended and the choice of regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions ( 5.4 )] . WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception ( 5.1 ). Lenalidomide capsules are available only through a restricted distribution program, called the Lenalidomide REMS program ( 5.2 , 17 ). HEMATOLOGIC TOXICITY . Lenalidomide capsules can cause significant neutropenia and thrombocytopenia ( 5.3 ).

Venous And Arterial Thromboembolism

Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as risk of myocardial infarction and stroke in patients with multiple myeloma receiving lenalidomide capsules with dexamethasone. Anti-thrombotic prophylaxis is recommended ( 5.4 ).

5 WARNINGS AND PRECAUTIONS Increased Mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with lenalidomide capsules ( 5.5 ).

Second Primary

Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving lenalidomide ( 5.6 ).

Increased

Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.7 ). Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop lenalidomide capsules and evaluate if hepatotoxicity is suspected ( 5.8 ).

Severe Cutaneous

Reactions: Discontinue lenalidomide capsules for severe reactions ( 5.9 ). Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.10 ). Tumor flare reaction: Serious tumor flare reactions, including fatal reactions, have occurred during investigational use of lenalidomide for chronic lymphocytic leukemia and lymphoma ( 5.11 ).

Impaired Stem

Cell mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with lenalidomide has been reported. Consider early referral to transplant center ( 5.12 ). Early mortality in MCL: Higher rate of early deaths have occurred in patients with MCL ( 5.14 ). Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue lenalidomide capsules for angioedema and anaphylaxis ( 5.15 ).

5.1 Embryo-Fetal Toxicity Lenalidomide 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. Lenalidomide capsules are only available through the Lenalidomide REMS program <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning lenalidomide capsules therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with lenalidomide capsules, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide capsules therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing lenalidomide capsules therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> .

Males

Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide capsules and for up to 4 weeks after discontinuing lenalidomide capsules, even if they have undergone a successful vasectomy. Male patients taking lenalidomide capsules must not donate sperm and for up to 4 weeks after discontinuing lenalidomide capsules [see Use in Specific Populations ( 8.3 )] .

Blood Donation

Patients must not donate blood during treatment with lenalidomide capsules and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to lenalidomide.

5.2 Lenalidomide REMS Program Because of the embryo-fetal risk [ see Warnings and Precautions ( 5.1 ) ] , lenalidomide capsules are 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> and males must comply with contraception requirements <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> . Pharmacies must be certified with the Lenalidomide REMS program, must only dispense to patients who are authorized to receive lenalidomide capsules and comply with REMS requirements. Further information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by telephone at 1-866-604-3268.

5.3 Hematologic Toxicity 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 capsules should have their complete blood counts assessed periodically as described below <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 , 2.2 , 2.3 )]</span> . Monitor complete blood counts (CBC) in patients taking lenalidomide capsules in combination with dexamethasone or as lenalidomide capsule 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of lenalidomide-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of lenalidomide-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor complete blood counts (CBC) in patients taking lenalidomide capsules 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 lenalidomide capsule 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 lenalidomide capsule 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 lenalidomide capsule/rituximab arm.

Grade

3 or 4 thrombocytopenia was reported in 2% and 8%, respectively, of patients in the lenalidomide capsule/rituximab arm [see Adverse Reactions ( 6.1 )] .

5.4 Venous and Arterial Thromboembolism Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with lenalidomide capsules. 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 lenalidomide 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) <span class="opacity-50 text-xs">[see Boxed Warning and Adverse Reactions ( 6.1 )]</span> . 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 lenalidomide 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) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 lenalidomide 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 lenalidomide capsule/rituximab arm <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In the AUGMENT trial, the incidence of ATE (including MI) in FL or MZL patients was 0.6% in the lenalidomide capsule/rituximab arm <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 lenalidomide capsules <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span>.

5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent lenalidomide 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 lenalidomide 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 lenalidomide treatment arm. Lenalidomide capsules are not indicated and not recommended for use in CLL outside of controlled clinical trials.

5.6 Second Primary Malignancies In clinical trials in patients with MM receiving lenalidomide, 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 lenalidomide in combination with oral melphalan compared with 1.3% of patients receiving melphalan without lenalidomide. The frequency of AML and MDS cases in patients with NDMM treated with lenalidomide in combination with dexamethasone without melphalan was 0.4%. In patients receiving lenalidomide capsule 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 lenalidomide maintenance, compared to 2.6% in the placebo arm. In patients with relapsed or refractory MM treated with lenalidomide/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 lenalidomide/dexamethasone, compared to 0.6% in the dexamethasone alone arm. Patients who received lenalidomide-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration lenalidomide-containing arms. 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 capsules. In the AUGMENT trial with FL or MZL patients receiving lenalidomide capsule/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 lenalidomide capsule/rituximab therapy. The incidence of hematologic plus solid tumor SPMs (excluding nonmelanoma skin cancers) was 1.7% in the lenalidomide capsule/rituximab arm with a median follow-up of 29.8 months (range 0.5 to 51.3 months) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of lenalidomide capsule and the risk of second primary malignancies when considering treatment with lenalidomide capsule.

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone 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.

5.8 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide 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 lenalidomide capsules upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.9 Severe Cutaneous Reactions 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 capsules. Consider lenalidomide capsules interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue lenalidomide capsules for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

5.10 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. 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 lenalidomide capsule/rituximab arm. TLS occurred in 1 patient (0.5%) in the MAGNIFY trial during the lenalidomide capsule/rituximab induction period; the event was a serious, Grade 3 adverse reaction.

5.11 Tumor Flare Reaction Tumor flare reaction (TFR), including fatal reactions, have occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Lenalidomide capsules are 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 lenalidomide capsule with rituximab arm; one patient in the lenalidomide capsule/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. Lenalidomide 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 lenalidomide 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.

5.12 Impaired Stem Cell Mobilization 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 capsules-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.

5.13 Thyroid Disorders Both hypothyroidism and hyperthyroidism have been reported <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Measure thyroid function before start of lenalidomide capsules treatment and during therapy.

5.14 Early Mortality in Patients with MCL In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the lenalidomide capsule 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 10 9 /L).

5.15 Hypersensitivity Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to lenalidomide capsules has been reported. Permanently discontinue lenalidomide capsules for angioedema and anaphylaxis <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .