IMPORTANT SAFETY INFORMATION FOR REVLIMID & POMALYST
WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS & ARTERIAL THROMBOEMBOLISM
EMBRYO-FETAL TOXICITY: REVLIMID & POMALYST are thalidomide analogues and are contraindicated in pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting treatment and use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping treatment. To avoid embryo-fetal exposure, REVLIMID and POMALYST are only available through their respective restricted distribution program REVLIMID REMS® and POMALYST REMS®.
Information about the REVLIMID REMS and POMALYST REMS programs is available at www.celgeneriskmanagement.com or by calling 1-888-423-5436.
HEMATOLOGIC TOXICITY: 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 & POMALYST have demonstrated a significantly increased risk of deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke in patients with MM. Thromboprophylaxis is recommended and the choice of regimen should be based on assessment of the patient’s underlying risk factors. 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.
Pregnancy: See Boxed WARNINGS. REVLIMID & POMALYST can cause fetal harm when administered to a pregnant female and are contraindicated in females who are pregnant. If the patient becomes pregnant while taking REVLIMID or POMALYST, the patient should be apprised of the potential risk to the fetus.
Severe Hypersensitivity Reactions: REVLIMID & POMALYST are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis) to lenalidomide, pomalidomide, or any of the excipients.
REVLIMID & POMALYST WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity & Females of Reproductive Potential: See Boxed WARNINGS. Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID or POMALYST.
Males: REVLIMID & POMALYST are 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 or POMALYST even if they have undergone a successful vasectomy. This protective measure must be followed for up to 4 weeks after discontinuing REVLIMID or POMALYST. Males must not donate sperm while taking REVLIMID or POMALYST.
Blood Donation: Patients must not donate blood during treatment with REVLIMID or POMALYST and for 4 weeks following discontinuation of the drug, as the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID or POMALYST.
REMS Program: See Boxed WARNINGS. Prescribers and pharmacies must be certified with the respective REVLIMID or POMALYST REMS program by enrolling and complying with the REMS requirements; pharmacies must only dispense to patients who are authorized to receive REVLIMID or POMALYST. 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.
- Further information about the POMALYST or REVLIMID REMS program is available at www.CelgeneRiskManagement.com or by telephone at 1-888-423-5436.
Hematologic Toxicity: REVLIMID & POMALYST can cause significant neutropenia and thrombocytopenia. Neutropenia, anemia, and thrombocytopenia were the most frequently reported Grade 3 or 4 adverse reactions in patients taking REVLIMID & POMALYST in clinical trials. Patients may require dose interruption and/or modification. For REVLIMID, monitor patients with neutropenia for signs of infection and advise patients to observe for bleeding or bruising, especially with use of concomitant medications that may increase risk of bleeding. Monitor complete blood counts (CBC) every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days thereafter. For POMALYST, monitor CBC weekly for the first 8 weeks and monthly thereafter.
Venous & Arterial Thromboembolism: See Boxed WARNINGS. Venous thromboembolic events (DVT and PE) and arterial thromboses (myocardial infarction [MI] and stroke [CVA]) are increased in patients treated with REVLIMID or POMALYST. Thromboprophylaxis is recommended and the regimen should be based on the patient’s underlying risks. 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). Erythropoietin-stimulating agents (ESAs) and estrogens may further increase the risk of thrombosis when used with REVLIMID and their use should be based on a benefit-risk decision.
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. In patients taking REVLIMID, monitor for the development of SPM and take into account both the potential benefit of REVLIMID and risk of SPM when considering treatment. In patients receiving POMALYST as an investigational therapy outside of MM, cases of AML have been reported.
Increased Mortality With Pembrolizumab: In clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue (REVLIMID or POMALYST) 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, have occurred in patients treated with REVLIMID + dexamethasone and POMALYST. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with POMALYST. Monitor liver function tests monthly for POMALYST, and periodically for REVLIMID. Stop REVLIMID or POMALYST upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.
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 with REVLIMID & POMALYST. These reactions can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. Consider REVLIMID & POMALYST interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue REVLIMID & POMALYST for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.
Tumor Lysis Syndrome (TLS): TLS may occur in patients treated with REVLIMID or POMALYST. Fatal instances of TLS have been reported during treatment with REVLIMID. Closely monitor patients at risk and take appropriate preventive approaches.
Hypersensitivity: Hypersensitivity including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID & POMALYST have been reported. Permanently discontinue REVLIMID & POMALYST for angioedema or anaphylaxis.
REVLIMID WARNINGS AND PRECAUTIONS (CONTINUED)
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.
Tumor Flare Reaction (TFR): Serious tumor flare reactions have occurred during investigational use of REVLIMID for CLL and lymphoma. Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL.
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).
POMALYST WARNINGS AND PRECAUTIONS (CONTINUED)
Dizziness & Confusional State: In patients taking POMALYST in clinical trials, 14% experienced dizziness (1% Grade 3 or 4) and 7% a confusional state (3% Grade 3 or 4). Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice.
Neuropathy: In patients taking POMALYST in clinical trials, 18% experienced neuropathy (2% Grade 3 in one trial) and 12% peripheral neuropathy.
REVLIMID - Multiple Myeloma
- In Newly Diagnosed: 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.
The most common adverse reactions reported in ≥20% (Arm Rd Continuous): diarrhea (45%), anemia (44%), neutropenia (35%), fatigue (33%), back pain (32%), asthenia (28%), insomnia (28%), rash (26%), decreased appetite (23%), cough (23%), dyspnea (22%), pyrexia (21%), abdominal pain (20%), muscle spasms (20%), and thrombocytopenia (20%).
Maintenance Therapy Post Auto-HSCT: The most frequently reported Grade 3 or 4 reactions in ≥20% (REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions of lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.
The most frequently reported adverse reactions in ≥20% (REVLIMID arm) across both maintenance studies (Study 1, Study 2) were neutropenia (79%, 61%), thrombocytopenia (72%, 24%), leukopenia (23%, 32%), anemia (21%, 9%), upper respiratory tract infection (27%, 11%), bronchitis (4%, 47%), nasopharyngitis (2%, 35%), cough (10%, 27%), gastroenteritis (0%, 23%), diarrhea (54%, 39%), rash (32%, 8%), fatigue (23%, 11%), asthenia (0%, 30%), muscle spasm (0%, 33%), and pyrexia (8%, 20%).
After at Least One Prior Therapy: The most common adverse reactions reported in ≥20% (REVLIMID/dex vs dex/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (27% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), and weight decreased (20% vs 15%).
The most common adverse reactions for POMALYST (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia.
In the phase III trial, nearly all patients treated with POMALYST + low-dose dex experienced at least one adverse reaction (99%). Adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥2% higher than control) included neutropenia (51%), fatigue and asthenia (47%), upper respiratory tract infection (31%), thrombocytopenia (30%), pyrexia (27%), dyspnea (25%), diarrhea (22%), constipation (22%), back pain (20%), cough (20%), pneumonia (19%), bone pain (18%), edema peripheral (17%), peripheral neuropathy (17%), muscle spasms (15%), and nausea (15%). Grade 3 or 4 adverse reactions (≥15% in the POMALYST + low-dose dex arm and ≥1% higher than control) included neutropenia (48%), thrombocytopenia (22%), and pneumonia (16%).
REVLIMID: Periodically monitor digoxin plasma levels due to increased Cmax and AUC with concomitant REVLIMID therapy. Patients taking concomitant therapies such as ESAs 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.
POMALYST: Avoid concomitant use with strong inhibitors of CYP1A2. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce POMALYST dose to 2 mg.
USE IN SPECIFIC POPULATIONS
REVLIMID & POMALYST
Pregnancy: See Boxed WARNINGS for REVLIMID & POMALYST. 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 are REVLIMID and POMALYST pregnancy exposure registries that monitor pregnancy outcomes in females exposed to REVLIMID or POMALYST during pregnancy as well as female partners of male patients who are exposed to REVLIMID or POMALYST. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure of the drug 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 pomalidomide or lenalidomide in human milk, the effects of POMALYST or REVLIMID on the breastfed child, or the effects of POMALYST or REVLIMID on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST or REVLIMID, advise women not to breastfeed during treatment.
Pediatric Use: Safety and effectiveness of REVLIMID or POMALYST have not been established in pediatric patients.
- Renal Impairment: Adjust the starting dose of REVLIMID based on the creatinine clearance value and for patients on dialysis.
- Geriatric Use: No dose adjustment is required for POMALYST based on age. Patients >65 years of age were more likely than patients ≤65 years of age to experience pneumonia.
- Renal Impairment: For patients with severe renal impairment requiring dialysis, reduce the recommended dosage to 3 mg orally daily. Take dose of POMALYST following hemodialysis on hemodialysis days.
- Hepatic Impairment: In patients with mild to moderate hepatic impairment, reduce POMALYST dosage to 3 mg orally daily and to 2 mg orally daily in patients with severe hepatic impairment.
- Smoking Tobacco: Advise patients that smoking may reduce the efficacy of POMALYST. Cigarette smoking reduces pomalidomide AUC due to CYP1A2 induction.