Revlimid Drug Information

Recommended Dosage for Multiple Myeloma REVLIMID Combination Therapy The recommended starting dose of REVLIMID is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced.

Treatment should be continued until disease progression or unacceptable toxicity. In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy.

Table 1: Dose Adjustments for Hematologic Toxicities for MM REVLIMID Maintenance Therapy Following Auto-HSCT Following auto-HSCT, initiate REVLIMID maintenance therapy after adequate hematologic recovery (ANC at least 1,000/mcL and/or platelet counts at least 75,000/mcL). The recommended starting dose of REVLIMID is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

Table 2: Dose Adjustments for Hematologic Toxicities for MM

Recommended Dosage for Myelodysplastic Syndromes

Treatment is continued or modified based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MDS Treatment Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows: Platelet counts If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows: If thrombocytopenia develops during treatment at 5 mg daily in MDS Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows: Absolute Neutrophil counts (ANC) If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows: If neutropenia develops during treatment at 5 mg daily in MDS

Recommended Dosage for Mantle Cell Lymphoma

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. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID. Platelet counts Thrombocytopenia during treatment in MCL

Recommended Dosage for Follicular Lymphoma or Marginal Zone Lymphoma 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.

Platelet counts Thrombocytopenia during treatment in FL or MZL Neutropenia during treatment in FL or MZL

Dosage Modifications for Non-Hematologic Adverse Reactions

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.

Recommended Dosage for Patients with Renal Impairment

The recommendations for dosing patients with renal impairment are shown in the following table. REVLIMID Maintenance Therapy Following Auto-HSCT for MM and for MCL and MDS: Base subsequent REVLIMID dose increase or decrease on individual patient treatment tolerance. REVLIMID Combination Therapy for FL or for MZL: For patients with CLcr of 30 to 60 mL/min, after 2 cycles, the REVLIMID dose may be increased to 15 mg orally if the patient has tolerated therapy.

Administration

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.

Clinical Trials Experience

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. Newly Diagnosed MM – REVLIMID Combination Therapy: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of REVLIMID with low dose dexamethasone (Rd) given for 2 different durations of time i.e., until progressive disease or for up to eighteen 28-day cycles or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia.

The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of REVLIMID were infection events (28.8%); overall, the median time to the first dose interruption of REVLIMID was 7 weeks. The most common adverse reactions leading to dose reduction of REVLIMID in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of REVLIMID was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of REVLIMID were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous. Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms* 0 Newly Diagnosed MM - REVLIMID Maintenance Therapy Following Auto-HSCT: Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity. As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID arm were still on treatment at the same cut-off date The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In general, the most frequently reported adverse reactions (more than 20% in the REVLIMID arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia.

The most frequently reported Grade 3 or 4 reactions (more than 20% in the REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm. For REVLIMID, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only).

The most common adverse reaction leading to dose reduction of REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). Table 5 summarizes the adverse reactions reported for the REVLIMID and placebo maintenance treatment arms. Table 5: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the REVLIMID Vs Placebo Arms* Note: Adverse Events (AEs) are coded to Body System /Adverse Reaction using MedDRA v15.1.

A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent AEs in at least 5% of patients in the REVLIMID Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. b All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. c All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study @ - ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 ): Pneumonias Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia,: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis 0 After At Least One Prior Therapy for MM: Data were evaluated from 703 patients in two studies who received at least one dose of REVLIMID/dexamethasone (353 patients) or placebo/dexamethasone (350 patients). Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups. This should be taken into consideration when comparing frequency of adverse reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone. Venous and Arterial Thromboembolism VTE and ATE are increased in patients treated with REVLIMID.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of REVLIMID treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms.

Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group.

Other Adverse Reactions: After At Least One Prior Therapy for MM In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported: Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia Cardiac disorders: bradycardia, myocardial infarction, angina pectoris Endocrine disorders: hirsutism Eye disorders: blindness, ocular hypertension Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia General disorders and administration site conditions: malaise Investigations: liver function tests abnormal, alanine aminotransferase increased Nervous system disorders: cerebral ischemia Psychiatric disorders: mood swings, hallucination, loss of libido Reproductive system and breast disorders: erectile dysfunction Respiratory, thoracic and mediastinal disorders: cough, hoarseness Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation Myelodysplastic Syndromes: A total of 148 patients received at least 1 dose of 10 mg REVLIMID in the del 5q MDS clinical study. At least one adverse reaction was reported in all of the 148 patients who were treated with the 10 mg starting dose of REVLIMID. The most frequently reported adverse reactions were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Table 9 summarizes the adverse reactions that were reported in ≥ 5% of the REVLIMID treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. In the single-arm studies conducted, it is often not possible to distinguish adverse reactions that are drug-related and those that reflect the patient's underlying disease.

Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-six patients (57%) underwent at least one dose interruption due to adverse reactions, and 51 patients (38%) underwent at least one dose reduction due to adverse reactions. Twenty-six patients (19%) discontinued treatment due to adverse reactions.

Cardiac disorder: Cardiac failure Ear and labyrinth disorders: Vertigo General disorders and administration site conditions: Chills Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy Psychiatric disorders: Insomnia Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse reactions not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Blood and lymphatic system disorders: Neutropenia Cardiac disorder: Myocardial infarction (including acute MI), supraventricular tachycardia Infections and infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism Follicular Lymphoma or Marginal Zone Lymphoma The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N=176) and MAGNIFY (N=222). Subjects with active HIV, hepatitis B or C were not eligible.

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving REVLIMID/rituximab in AUGMENT and 29% in MAGNIFY.

The most frequent serious adverse reaction that occurred in ≥ 2.5% of patients in the REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was neutropenia (4.8%).

A patient with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse reaction. 1 All treatment-emergent AEs in at least 5% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 2 All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). 3 All serious treatment-emergent AEs in at least 1% of patients in the REVLIMID + rituximab group and at least 1% higher frequency (%) than the rituximab + placebo group (control arm). $ Serious ADR reported. @ - adverse reactions in which at least one resulted in a fatal outcome. % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). *Adverse Reactions for combined ADR terms (based on relevant TEAE PTs ): a "Thromboembolic events" combined term includes the following PTs: pulmonary embolism, deep vein thrombosis, cerebrovascular accident, embolism, and thrombosis. b "Cough" combined AE term includes the following PTs: cough and productive cough. Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure Endocrine disorders: Hypothyroidism, hyperthyroidism Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests Immune system disorders: Angioedema, anaphylaxis, acute graft-versus-host disease (following allogeneic hematopoietic transplant), solid organ transplant rejection Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML) Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

Digoxin

When digoxin was co-administered with multiple doses of REVLIMID (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 REVLIMID.

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 REVLIMID.

Warfarin Co-administration of multiple doses of REVLIMID (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 REVLIMID 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.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the REMS Call Center at 1-888-423-5436.

Risk Summary Based on the mechanism of action and findings from animal studies, REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats.

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. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring.

As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20-40% of the maternal C max. Following a single oral dose to pregnant rats, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues.

These data indicated that lenalidomide crossed the placenta.

Pediatric Use Safety and effectiveness have not been established in pediatric patients.

Severe Hypersensitivity Reactions REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.

There is no specific experience in the management of REVLIMID overdose in patients with MM, MDS, MCL, FL, or MZL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs.

In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.