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Revlimid (Lenalidomide) - Warnings and Precautions

 
 



POTENTIAL FOR HUMAN BIRTH DEFECTS

WARNING: POTENTIAL FOR HUMAN BIRTH DEFECTS

LENALIDOMIDE IS AN ANALOGUE OF THALIDOMIDE. THALIDOMIDE IS A KNOWN HUMAN TERATOGEN THAT CAUSES SEVERE LIFE-THREATENING HUMAN BIRTH DEFECTS. IF LENALIDOMIDE IS TAKEN DURING PREGNANCY, IT MAY CAUSE BIRTH DEFECTS OR DEATH TO AN UNBORN BABY. FEMALES SHOULD BE ADVISED TO AVOID PREGNANCY WHILE TAKING REVLIMID® (lenalidomide).

Special Prescribing Requirements

BECAUSE OF THIS POTENTIAL TOXICITY AND TO AVOID FETAL EXPOSURE TO REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) IS ONLY AVAILABLE UNDER A SPECIAL RESTRICTED DISTRIBUTION PROGRAM. THIS PROGRAM IS CALLED "RevAssist®". UNDER THIS PROGRAM, ONLY PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE PROGRAM CAN PRESCRIBE AND DISPENSE THE PRODUCT. IN ADDITION, REVLIMID® (lenalidomide) MUST ONLY BE DISPENSED TO PATIENTS WHO ARE REGISTERED AND MEET ALL THE CONDITIONS OF THE RevAssist® PROGRAM.

PLEASE SEE THE FOLLOWING INFORMATION FOR PRESCRIBERS, FEMALE PATIENTS, AND MALE PATIENTS ABOUT THIS RESTRICTED DISTRIBUTION PROGRAM.

RevAssist® PROGRAM DESCRIPTION

Prescribers

REVLIMID® (lenalidomide) can be prescribed only by licensed prescribers who are registered in the RevAssist® program and understand the potential risk of teratogenicity if lenalidomide is used during pregnancy.

Effective contraception must be used by female patients of childbearing potential for at least 4 weeks before beginning REVLIMID® (lenalidomide) therapy, during REVLIMID® (lenalidomide) therapy, during dose interruptions and for 4 weeks following discontinuation of REVLIMID® (lenalidomide) therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential.

Before prescribing REVLIMID® (lenalidomide), females of childbearing potential should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The first test should be performed within 10–14 days, and the second test within 24 hours prior to prescribing REVLIMID® (lenalidomide). A prescription for REVLIMID® (lenalidomide) for a female of childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.

Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID® (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy.

Once treatment has started and during dose interruptions, pregnancy testing for females of childbearing potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding. REVLIMID® (lenalidomide) treatment must be discontinued during this evaluation.

Pregnancy test results should be verified by the prescriber and the pharmacist prior to dispensing any prescription.

If pregnancy does occur during REVLIMID® (lenalidomide) treatment, REVLIMID® (lenalidomide) must be discontinued immediately.

Any suspected fetal exposure to REVLIMID® (lenalidomide) should be reported to the FDA via the MedWatch number at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Female Patients

REVLIMID® (lenalidomide) should be used in females of childbearing potential only when the patient MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is unable to become pregnant while on lenalidomide therapy):

  • she understands and can reliably carry out instructions.
  • she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the RevAssist® program.
  • she has received and understands both oral and written warnings of the potential risks of taking lenalidomide during pregnancy and of exposing a fetus to the drug.
  • she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously, unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months), or had a bilateral oophorectomy are considered to be females of childbearing potential.
  • she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks after discontinuation of lenalidomide therapy.
  • she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL, within 10-14 days and 24 hours prior to beginning therapy.
  • if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.

Male Patients

REVLIMID® (lenalidomide) should be used in sexually active males when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:

  • he understands and can reliably carry out instructions.
  • he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the RevAssist® program.
  • he has received and understands both oral and written warnings of the potential risks of taking lenalidomide and exposing a fetus to the drug.
  • he has received both oral and written warnings of the risk of possible contraception failure and that it is unknown whether lenalidomide is present in semen. He has been instructed that he must always use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy.
  • he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy. Females of childbearing potential are considered to be sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months).
  • if the patient is between 12 and 18 years of age, his parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.

HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA)

This drug is associated with 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)

DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM

This drug has demonstrated a significantly increased risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

You can get the information about REVLIMID® (lenalidomide) and the RevAssist® program on the internet at www.REVLIMID.com or by calling the manufacturer’s toll free number 1-888-423-5436.

 

WARNINGS

Pregnancy Category X: (See BOXED WARNINGS and CONTRAINDICATIONS)

REVLIMID® (lenalidomide) is an analogue of thalidomide. Thalidomide is a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates 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. The teratogenic effect of lenalidomide in humans cannot be ruled out. REVLIMID® (lenalidomide) may cause fetal harm when administered to a pregnant female. Females of childbearing potential should be advised to avoid pregnancy while on REVLIMID® (lenalidomide). Two effective contraceptive methods should be used during therapy, during therapy interruptions and for at least 4 weeks after completing therapy.

There are no adequate and well-controlled studies in pregnant females.

Because of this potential toxicity and to avoid fetal exposure to REVLIMID® (lenalidomide), REVLIMID® (lenalidomide) is only available under a special restricted distribution program. This program is called RevAssist®.

Lenalidomide has been shown to have an embryocidal effect in rabbits at a dose of 50 mg/kg (approximately 120 times the human dose of 10 mg based on body surface area).

An embryo-fetal development study in rats revealed no teratogenic effects at the highest dose of 500 mg/kg (approximately 600 times the human dose of 10 mg based on body surface area). At 100, 300 or 500 mg/kg/day there was minimal maternal toxicity that included slight, transient, reduction in mean body weight gain and food intake. However this animal model may not adequately address the full spectrum of the potential embryo-fetal developmental effects of lenalidomide.

A pre- and post-natal development study in rats revealed few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 600 times the human dose of 10 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.

The structural similarity of lenalidomide to thalidomide, a known human teratogen, as well as malformations seen in the offspring of female monkeys administered lenalidomide during pregnancy, suggests a potential risk to the developing fetus.

HEMATOLOGIC TOXICITY (NEUTROPENIA AND THROMBOCYTOPENIA):

This drug is associated with significant neutropenia and thrombocytopenia.

Eighty percent of patients with del 5q MDS had to have a dose delay or reduction during the major study for the indication. 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. 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). 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)

In the pooled multiple myeloma studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID® (lenalidomide) and dexamethasone than in patients treated with dexamethasone alone. (See ADVERSE REACTIONS: Table 7.) Patients on therapy should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients may require dose interruption and/or dose reduction. (See DOSAGE AND ADMINISTRATION)

DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM:

This drug has demonstrated a significantly increased risk of DVT and PE in patients with multiple myeloma who were treated with REVLIMID® (lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID® (lenalidomide) may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. (See ADVERSE REACTIONS: Table 7)

PRECAUTIONS

Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 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® (lenalidomide). REVLIMID® (lenalidomide) interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID® (lenalidomide) must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions.

Tumor Lysis Syndrome

Lenalidomide has antineoplastic activity and therefore the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Information for Patients

Patients should be counseled on lenalidomide’s potential risk of teratogenicity due to its structural similarity to thalidomide and data from an embryofetal development study showing treatment with lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. Patients may only acquire a prescription for REVLIMID® (lenalidomide) therapy through a controlled distribution program (RevAssist®) through contracted pharmacies. Female patients of childbearing potential will be educated and counseled on the requirements of the RevAssist® program and the precautions to be taken to preclude fetal exposure to REVLIMID® (lenalidomide). Patients should become familiar with the REVLIMID® (lenalidomide) RevAssist® educational materials and Patient Medication Guide, and direct any questions to their physician or pharmacist prior to starting REVLIMID® (lenalidomide) therapy.

Laboratory Tests

The MDS clinical study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm3, platelet counts ≥ 50,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2.0 mg/dL . A complete blood cell count (CBC), including white blood cell count with differential, platelet count, hemoglobin, and hematocrit should be performed weekly for the first 8 weeks of REVLIMID® (lenalidomide) treatment and monthly thereafter to monitor for cytopenias.

The multiple myeloma Studies 1 and 2 enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm3, platelet counts ≥ 75,000/mm3, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2.0 mg/dL. A CBC should be performed every two weeks for the first three months and at least monthly thereafter to monitor for cytopenias.

Drug Interactions

Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID® (lenalidomide) is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions in man.

Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R- and S-warfarin. Co-administration of single 25-mg dose warfarin had no effect on the pharmacokinetics of total lenalidomide. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant lenalidomide administration.

When digoxin was co-administered with lenalidomide the digoxin AUC was not significantly different, however, the digoxin Cmax was increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of lenalidomide.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity: Carcinogenicity studies with lenalidomide have not been conducted.

Mutagenesis: Lenalidomide did not induce mutation in the Ames test, chromosome aberrations in cultured human peripheral blood lymphocytes, or mutation at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

Fertility: A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 600 times the human dose of 10 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

Pregnancy

Pregnancy Category X: (See BOXED WARNINGS and CONTRAINDICATIONS)

Because of the structural similarity to thalidomide, a known human teratogen, and the data from an embryofetal development study showing treatment with lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, REVLIMID® (lenalidomide) is contraindicated in females who are or may become pregnant and who are not using the two required types of birth control or who are not continually abstaining from reproductive heterosexual sexual intercourse. REVLIMID® (lenalidomide) should not be used by females who are pregnant or who could become pregnant while taking the drug. If pregnancy does occur during treatment, the drug should be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID® (lenalidomide) should be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

Use in Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 have not been established.

Geriatric Use

REVLIMID® (lenalidomide) has been used in del 5q MDS clinical trials in patients up to 95 years of age.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

REVLIMID® (lenalidomide) has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age.


Of the 692 MM patients enrolled in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID® (lenalidomide)/dexamethasone and placebo/dexamethasone groups. Of the 346 patients who received REVLIMID® (lenalidomide)/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience diarrhea, fatigue, pulmonary embolism, and syncope following use of REVLIMID® (lenalidomide). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Renal Impairment

Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID® (lenalidomide) are recommended to provide appropriate drug exposure in patients with moderate or severe (CLcr < 60 mL/min) renal impairment and in patients on dialysis. See DOSAGE AND ADMINISTRATION.

Page last updated: 2009-04-15

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