Indications

  • REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL)
  • REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials
  • REVLIMID in combination with a rituximab product, is indicated for the treatment of adult patients with previously treated marginal zone lymphoma (MZL)
  • REVLIMID is only available through a restricted distribution program, REVLIMID REMS®
R² logo

REVLIMID + rituximab is a new combination immunotherapy approved for previously treated follicular lymphoma (FL) and marginal zone lymphoma (MZL)1

NCCN GUIDELINES® RECOMMENDATION:

Lenalidomide (REVLIMID) + rituximab is a preferred treatment option (Category 2A) recommended in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for second-line and subsequent therapy for patients with Grade 1-2 FL2

Clinical Data

Phase III AUGMENT Trial Overview

REVLIMID + rituximab (R²) VS RITUXIMAB IN RELAPSED/REFRACTORY FOLLICULAR AND MARGINAL ZONE LYMPHOMA1,3,4*

Learn about REVLIMID® (lenalidomide) and rituximab clinical trial design

ITT Patient Population

R² WAS STUDIED IN A BROAD RANGE OF PREVIOUSLY TREATED PATIENTS1,3,4

Baseline Characteristics of AUGMENT Patient Population (N=358):

  • Median Age: 63 years (range: 26-88)1,4
  • Ann Arbor Stage III-IV at enrollment: 73%3
  • FL Grade at diagnosis: Grade 1 (31%), Grade 2 (38%), Grade 3a (13%)3
  • FLIPI high-risk: 34%3
  • High tumor burden (GELF criteria): 51%3
  • Bulky disease*: 26%3
  • ECOG PS: 0 (68%); 1 (31%); 2 (1%)1

Prior Anti-lymphoma Treatments:

  • 51% of patients enrolled had received an anti-lymphoma therapy within the past 2 years3
  • 72% of patients had received a prior regimen that included both rituximab and chemotherapy3
  • No patients in either arm were rituximab refractory3

ITT Patient Population

R² SIGNIFICANTLY IMPROVED MEDIAN PFS VS RITUXIMAB1*

  • R² provided 39.4 months of median PFS vs 14.1 months with rituximab1
R² SIGNIFICANTLY IMPROVED MEDIAN PFS VS RITUXIMAB

Follicular Lymphoma Population

IN THE FL SUBGROUP, THE MEDIAN PFS WAS 39.4 MONTHS IN THE R² ARM AND 13.9 MONTHS WITH RITUXIMAB3*

Median PFS with REVLIMID® (lenalidomide) and rituximab in follicular lymphoma
  • Analysis Limitations: PFS in the FL subgroup is exploratory in nature and data should not be interpreted to determine a treatment difference between arms due to a higher possibility of a false positive3


Follicular Lymphoma Population

OVERALL SURVIVAL3*

  • Median OS has not been reached
Learn about REVLIMID® (lenalidomide) and rituximab
  • Analysis Limitations: OS was a secondary endpoint. These FL subgroup data are exploratory in nature and should not be interpreted to determine a treatment difference between arms due to a higher possibility of a false positive.


Safety

Established Safety Profile

  • Grade 3/4 neutropenia was reported in 50% of patients in the R² arm and 13% of patients in the rituximab arm1
    • All incidences of Grade 3/4 neutropenia in the R² arm recovered to Grade 1 or less, with a median time of 9 days3
  • Patients receiving R² had an incidence of febrile neutropenia of 3% vs <1% receiving rituximab1
  • 71% of patients receiving R² completed all 12 cycles of treatment vs 62% receiving rituximab/placebo3

Safety Population (N=356)

All Grade ARs, ≥20% of patients

All Adverse Reactions Grade 3/4 Adverse Reactions

(n=176)
Rituximab
(n=180)

(n=176)
Rituximab
(n=180)
Neutropeniad,e,f58%22%50%13%
Diarrheae,f31%23%2.8%0%
Constipation26%14%0%0%
Coughg24%19%<1%0%
Fatigue22%18%1.1%<1%
Rashe,h22%8%2.8%1.1%
Pyrexiad,e21%15%<1%1.7%
Leukopeniae,f20%9%7%1.7%
Prurituse,i20%5%1.1%0%



Dosing

FIXED-DURATION DOSING

R² is administered for 12 cycles

  • R² should be administered for 12 cycles or until unacceptable toxicity1
    • REVLIMID 20 mg/day: 12 cycles1
    • Rituximab 375 mg/m2: 5 cycles
  • In the AUGMENT trial, 71% of patients receiving R² completed all 12 cycles of treatment3

Cycle 1

Revlimid® (lenalidomide) with rituximab administered - Cycle 1

Cycles 2-5

Revlimid® (lenalidomide) with rituximab administered - Cycles 2 through 5

Cycles 6-12

Revlimid® (lenalidomide) with rituximab administered - Cycles 6 through 12

Dose Modifications May Help Patients Stay on Therapy1

Renal Impairment

STARTING DOSE MODIFICATIONS FOR RENAL IMPAIRMENT1

Renal Function (Cockcroft-Gault): Starting Dose in REVLIMID Combination Therapy for FL:
CrCI 30 to 60 mL/min 10 mg once daily.
CrCI <30 mL/min
(not requiring dialysis)
5 mg once daily.
CrCI below 30 mL/min
(requiring dialysis)
5 mg once daily. On dialysis days, administer the dose following dialysis.

CrCI, creatinine clearance rate; FL, follicular lymphoma.

Neutropenia

DOSE MODIFICATIONS FOR GRADE 3/4 NEUTROPENIA1

When Neutrophils: Recommended Course:
Fall below 1000/mcL for at least 7 days
OR
Fall below 1000/mcL with anassociated temperature ≥38.5°C
OR
Fall below 500/mcL
Interrupt REVLIMIDtreatment and follow CBC weekly.
Return to at least 1000/mcL If patient starting dose was 20 mg daily, resume REVLIMID at5 mg less than previous dose. Do not dose below 5 mg daily.

If patient starting dose was 10 mg daily, resume at 5 mgless than previous dose. Do not dose below 2.5 mg daily.

CBC, complete blood count.

Thrombocytopenia

DOSE MODIFICATIONS FOR GRADE 3/4 THROMBOCYTOPENIA1

When Platelets: Recommended Course
Fall below 50,000/mcL Interrupt REVLIMIDtreatment and follow CBC weekly.
Return to at least 50,000/mcL If patient starting dose was 20 mg daily, resume REVLIMID at5 mg less than previous dose. Do not dose below 5 mg daily.

If patient starting dose was 10 mg daily, resume at 5 mgless than previous dose. Do not dose below 2.5 mg daily.

CBC, complete blood count.

A single source for access

Celgene Patient Support® provides:

  • A single Celgene Patient Support® Specialist assigned to help patients in your geographic area
  • Assistance if you have questions regarding patient insurance coverage for REVLIMID
  • Information about financial assistance for REVLIMID

REVLIMID REMS®


REVLIMID® (lenalidomide) is only available through a restricted distribution program, REVLIMID REMS®

To avoid embryo-fetal exposure, REVLIMID is only available through a restricted distribution program called the REVLIMID Risk Evaluation and Mitigation Strategy (REMS) program. The REVLIMID REMS® program requires prescribers and pharmacies to be certified and patients to enroll and comply with all of the program requirements.

To enroll you and your patients, receive more information, and download forms related to the REVLIMID REMS® program, please visit www.CelgeneRiskManagement.com or call 1-888-423-5436.


Important Safety Information

Important Safety Information

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. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS® program.

Information about the REVLIMID REMS® program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)
REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q MDS 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 MDS 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.

Venous and Arterial Thromboembolism
REVLIMID 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 MM who were treated with REVLIMID 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.

CONTRAINDICATIONS

Pregnancy: REVLIMID can cause fetal harm when administered to a pregnant female and 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 the fetus

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

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS

  • Females of Reproductive Potential: See Boxed WARNINGS
  • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm
  • Blood Donation: Patients must not donate blood during treatment with REVLIMID 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 REVLIMID

REVLIMID REMS® Program: See Boxed WARNINGS: Prescribers and pharmacies must be certified with the REVLIMID REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID. Patients must sign a Patient-Physician Agreement Form and comply with REMS requirements; 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

Hematologic Toxicity: 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 medications that may increase risk of bleeding. Patients may require dose interruption and/or dose reduction. 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

Venous and Arterial Thromboembolism: See Boxed WARNINGS: Venous thromboembolic events (DVT and PE) and arterial thromboses (MI and CVA) are increased in patients treated with REVLIMID. 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 and the regimen should be based on the patient’s underlying risks. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision

Increased Mortality in Patients with CLL: In a clinical trial in the first-line treatment of patients with CLL, single-agent REVLIMID therapy increased the risk of death as compared to single-agent chlorambucil. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure, occurred more frequently in the REVLIMID arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials

Second Primary Malignancies (SPM): In clinical trials in patients with MM receiving REVLIMID and in patients with FL or MZL receiving REVLIMID + rituximab therapy, an increase of hematologic plus solid tumor SPM, notably AML, have been observed. In patients with MM, MDS was also observed. Monitor patients for the development of SPM. Take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment

Increased Mortality With Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone 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

Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with REVLIMID + dexamethasone. 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 Hypersensitivity Reactions: 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. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID 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

Tumor Lysis Syndrome (TLS): Fatal instances of TLS have been reported during treatment with REVLIMID. The patients at risk of TLS are those with high tumor burden prior to treatment. Closely monitor patients at risk and take appropriate preventive approaches

Tumor Flare Reaction (TFR): TFR has occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL or MZL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1. REVLIMID may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion

Impaired Stem Cell Mobilization: A decrease in the number of CD34+ cells collected after treatment (>4 cycles) with REVLIMID has been reported. Consider early referral to transplant center to optimize timing of the stem cell collection

Thyroid Disorders: Both hypothyroidism and hyperthyroidism have been reported. Measure thyroid function before starting REVLIMID treatment and during therapy

Early Mortality in Patients with MCL: 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. Risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (≥10 x 109/L)

ADVERSE REACTIONS

Follicular Lymphoma/Marginal Zone Lymphoma

  • Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID + rituximab across both trials. Fatal adverse reactions (1 each) included: cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. The most frequent serious adverse reaction that occurred in the REVLIMID/rituximab arm was febrile neutropenia (3.0%)
  • Grade 3 and 4 adverse reactions reported in ≥5% of patients treated in the FL/MZL trial with REVLIMID + rituximab were: neutropenia (50%) and leukopenia (7%)
  • Adverse reactions reported in ≥15% of patients with FL/MZL treated with REVLIMID + rituximab were: neutropenia (58%), diarrhea (31%), constipation (26%), cough (24%), fatigue (22%), rash (22%), pyrexia (21%), leukopenia (20%), pruritus (20%), upper respiratory tract infections (18%), abdominal pain (18%), anemia (16%), headache (15%), thrombocytopenia (15%)

DRUG INTERACTIONS

Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis. 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

USE IN SPECIFIC POPULATIONS

  • PREGNANCY: See Boxed WARNINGS: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. There is a REVLIMID 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 Celgene Corporation at 1-888-423-5436
  • LACTATION: There is no information regarding the presence of lenalidomide in human milk, the effects of REVLIMID on the breastfed infant, or the effects of REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from REVLIMID, advise female patients not to breastfeed during treatment with REVLIMID
  • RENAL IMPAIRMENT: Adjust the starting dose of REVLIMID based on creatinine clearance value and in patients on dialysis

Please see full Prescribing Information, including Boxed WARNINGS, for REVLIMID.

Please see the rituximab full Prescribing Information for Important Safety Information at www.rituxan.com.