Dosing and uses of Revlimid (lenalidomide)
Adult dosage forms and strengths
capsule
- 2.5mg
- 5mg
- 10mg
- 15mg
- 25mg
Myelodysplastic Syndromes
Indicated for transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities
10 mg PO qDay
Renal impairment (MDS)
- CrCl >60 mL/min: Dose adjustment not necessary
- CrCl 30-60 mL/min: 5 mg PO qDay
- CrCl <30 mL/min (nondialysis dependent): 2.5 mg PO qDay
- CrCl <30 mL/min (dialysis dependent): 2.5 mg PO qDay; on dialysis days, administer following dialysis
Dosage modifications (MDS)
Thrombocytopenia within 4 weeks at starting dose 10 mg/day (baseline ≥100,000/mcL)
- Falls to <50,000/mcL: Interrupt treatment
- Returns to ≥50,000/mcL: Resume at 5 mg/day
Thrombocytopenia within 4 weeks at starting dose 10 mg/day (baseline <100,000/mcL)
- Falls to 50% of baseline: Interrupt treatment
- If baseline ≥60,000/mcL and returns to ≥50,000/mcL: Resume at 5 mg/day
- If baseline <60,000/mcL and returns to ≥30,000/mcL: Resume at 5 mg/day
Thrombocytopenia after 4 weeks at starting dose 10 mg/day
- <30,000/mcL or <50,000/mcL with platelet transfusions: Interrupt treatment
- Return to ≥30,000/mcL (without hemostatic failure): Resume at 5 mg/day
Thrombocytopenia after 4 weeks at 5 mg/day
- <30,000/mcL or <50,000/mcL with platelet transfusions: Interrupt treatment
- Return to ≥30,000/mcL (without hemostatic failure): Resume at 2.5 mg/day
Neutropenia within 4 weeks at starting dose 10 mg/day (baseline ANC >1,000/mcL)
- Fall to <750/mcL: Interrupt treatment
- Return to ≥1,000/mcL: Resume at 5 mg/day
Neutropenia within 4 weeks at starting dose 10 mg/day (baseline ANC >1,000/mcL)
- Fall to <500/mcL: interrupt treatment
- Return to ≥500/mc/L: Resume at 5 mg/day
Neutropenia after 4 weeks at starting dose 10 mg/day
- <500/mcL for ≥7 days or with fever (≥38.5°C): Interrupt treatment
- Return to ≥500/mcL: Resume at 5 mg/day
Neutropenia after 4 weeks at dose 5 mg/day
- <500/mcL for ≥7 days or with fever (≥38.5°C): Interrupt treatment
- Return to ≥500/mcL: Resume at 2.5 mg/day
Other Grade 3-4 toxicities
- Interrupt treatment and resume at physicians discretion at next lower dose when toxicity has resolved to ≤Grade 2
Multiple Myeloma
Indicated in combination with dexamethasone for patients with Mm
25 mg PO qDay on Days 1-21 of 28-day cycle (used with dexamethasone)
Dexamethasone schedule
- 40 mg PO qDay on Days 1-4, 9-12, and 17-20 of each 28-day cycle for first 4 cycles, THEN
- 40 mg PO qDay on Days 1-4 every 28 days
- Age ≥75 yr: 20 mg PO qDay on Days 1, 8, 15, and 22 of each 28-day cycle
Renal impairment
- Follow same cycle, but decrease dose as listed below
- CrCl >50 mL/min: Dose adjustment not necessary
- Moderate (CrCl 30-50 mL/min): 10 mg PO qDay; consider escalating dose to 15 mg/day after 2 treatment cycles if 10 mg/day tolerated without dose-limiting toxicities
- Severe (CrCl <30 mL/min, nondialysis dependent): 15 mg PO every other day
- End-stage renal disease (CrCl <30 mL/min, dialysis dependent): 5 mg PO qDay; on dialysis days, administer following dialysis
Dosage modifications (MM)
Thrombocytopenia
- Platelets fall to <30,000/mcL: Interrupt treatment and following weekly CBC
- Returns to ≥30,000/mcL: Restart at next lower dose, but not <2.5 mg/day
- For each subsequent drop <30,000/mcL: Interrupt treatment, then when ≥30,000/mcL, resume at next lower dose, but not <2.5 mg/day
Neutropenia
- ANC falls to <1,000/mcL: Interrupt treatment, add G-CSF, follow CBC weekly
- ANC returns to ≥1,000/mcL and neutropenia is the only toxicity: Resume at 25 mg/day or inital starting dose
- ANC returns to ≥1,000/mcL with other toxicity: Resume at next lower dose, but <2.5 mg/day mg/day
- For each subsequent drop <1,000/mcL: Interrupt treatment, then when ≥1,000/mcL, resume at next lower dose, but not <2.5 mg/day
Other Grade 3-4 toxicities
- Interrupt treatment and resume at physicians discretion at next lower dose when toxicity has resolved to ≤Grade 2
Mantle Cell Lymphoma
Indicated for MCL in patients whose disease has relapsed or progressed after 2 prior therapies, 1 of which included bortezomiB
25 mg PO qDay on Days 1-21 of repeated 28-day cycles
Renal impairment (MCL)
- Follow same cycle, but decrease dose as listed below
- CrCl 30-60 mL/min: 10 mg PO qDay
- CrCl <30 mL/min: 15 mg PO q48hr
- ESRD: 5 mg PO qDay; on dialysis days, administer following dialysis
Dosage modifications (MCL)
Thrombocytopenia
- Falls to <50,000/mcL: Interrupt treatment
- Returns to ≥50,000/mcL: Resume at 5 mg/day less than previous dose; do not dose below 5 mg/day
Neutropenia
- ANC falls to <1,000/mcL for at least 7 days OR <1,000/mcL with fever (≥38.5°C) OR ANC <500/mcL: Interrupt treatment and follow weekly CBC
- Returns to ≥1,000/mcL: Resume at 5 mg/day less than previous dose; do not dose below 5 mg/day
Other Grade 3-4 toxicities
- Interrupt treatment and resume at physicians discretion at next lower dose when toxicity has resolved to ≤Grade 2
Dosing Considerations
Not indicated for and is not recommended for the treatment of patients with CLL outside of controlled clinical trials
Orphan Indications
Diffuse large-cell B lymphoma
Follicular lymphoma
Chronic lymphocytic leukemia: In July 2013, the FDA halted clinical trials because of significant safety concerns; the ORIGIN trial (NCT00910910) showed higher rates of death in patients treated with lenalidomide compared to those treated with chlorambuciL
Orphan indication sponsor
- Celgene Corporation; 86 Morris Avenue; Summit, NJ 07901
Administration
Take at about the same time each day
Swallow capsule whole, do not chew or break open
May take with or without food
Monitor: CBC, Hgb, Hct, pregnancy testing, renal and hepatic function
Pediatric dosage forms and strengths
<18 years old: Safety and efficacy not established
Revlimid (lenalidomide) adverse (side) effects
>10%
Thrombocytopenia (62%)
Neutropenia (59%)
Diarrhea (48%)
Pruritus (42%)
Nausea (35%)
Rash (35%)
Fatigue (31%)
Constipation (24%)
Arthralgia (22%)
Back pain (21%)
Peripheral edema (21%)
Pyrexia (21%)
Dizziness (20%)
Headache (20%)
Cough (19%)
Muscle cramp (18%)
Dyspnea (17%)
URTI (15%)
Anemia (12%)
Pneumonia (12%)
UTI (11%)
1-10% (critical AEs)
Tumor flare reaction - MCL (10%)
Abdominal pain (8%)
Leukopenia (8%)
Myalgia (8%)
Pain (7%)
Bronchitis (6%)
Rhinitis (6%)
Febrile neutropenia (5%)
Peripheral neuropathy (5%)
Warnings
Black box warnings
Potential for human birth defects
- Analog of thalidomide, a known human teratogen that causes severe, life-threatening human birth defects
- Avoid during pregnancy; if taken during pregnancy, likely to cause birth defects or fetal death
RevAssist program
- Information about the RevAssist program can be obtained at https://www.revlimid.com or by calling the manufacturer's toll-free number (888) 423-5436
- Only available under special restricted distribution program called RevAssist; only health care providers and pharmacists registered with the program are able to prescribe and dispense the product; Only dispensed to patients who are registered and meet all the conditions of the RevAssist program
- Effective contraception must be used by patients for at least 4 weeks before beginning lenalidomide therapy, during therapy, during dose interruptions, and for 4 weeks following discontinuation of therapy; Reliable contraception is indicated, even if the patient has a history of infertility, unless infertility is because of hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months; 2 reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method; refer women of childbearing potential to a qualified provider of contraceptive methods, if needed
- Sexually mature women 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 are considered to be women of childbearing potential
- Before prescribing, women of childbearing potential should have 2 negative pregnancy test results (sensitivity of at least 50 milliunits/mL); Perform first pregnancy test within 10-14 days and the second test within 24 hr prior to prescribing; A prescription for a woman of childbearing potential must not be issued until negative pregnancy test results have been verified by the health care provider, and the pharmacist must verify a negative pregnancy test result with the prescriber before dispensing
- Male patients: Unknown whether drug is present in semen; therefore, men receiving this drug must always use latex condoms during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy
Pregnancy testing
- Once treatment has started and during dose interruptions, pregnancy testing for women of childbearing potential should occur weekly during the first 4 weeks of use and repeated q4week in women with regular menstrual cycles
- Irregular menstrual cycles: Pregnancy testing should occur q2week
- Missed period: Perform pregnancy testing and counseling if a patient misses her period or if any pregnancy test result or menstrual bleeding is abnormal; discontinue lenalidomide during this evaluation
- If pregnancy occurs, discontinue drug immediately
- Report any suspected fetal exposure to the Food and Drug Administration (FDA) via MedWatch at (800) 332-1088 and also to the manufacturer at (888) 423-5436
- Refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling
Patient education (females)
- Female patients: Use in women of childbearing potential is advised only when the patient meets all of the following conditions:
- 1) She understands the risks associated with the drug and can reliably carry out instructions
- 2) She is capable of complying with the contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the RevAssist program
- 3) She has received both oral and written warnings of the potential risks of taking lenalidomide during pregnancy and of exposing a fetus to this drug
- 4) She has received both oral and written warnings of the risk of possible contraception failure and of the need to use 2 reliable forms of contraception simultaneously, unless continuous abstinence from heterosexual sexual contact is the chosen method
- 5) Sexually mature women who have not undergone a hysterectomy, who have not been postmenopausal for at least 24 consecutive months (ie, who have had menses at some time in the preceding 24 consecutive months), or who have not had a bilateral oophorectomy are considered to be women of childbearing potential
- 6) She acknowledges, in writing, her understanding of these warnings and of the need for using 2 reliable methods of contraception for 4 weeks prior to initiating therapy, during therapy, during dose interruptions, and for 4 weeks after discontinuing therapy
- 7) She has had 2 negative pregnancy test results with a sensitivity of at least 50 milliunits/mL within 10-14 days and 24 hr prior to beginning therapy
- 8) If the patient is between 12-18 years of age, her parent or legal guardian must have read this material and agreed to ensure compliance
Patient education (males)
- Male patients: Use in sexually active men is advised only when the patient meets all of the following conditions:
- 1) He understands the risks associated with the drug and can reliably carry out instructions
- 2) 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
- 3) He has received and understands both oral and written warnings of the potential risks of taking lenalidomide and of exposing a fetus to the drug
- 4) 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
- 5) He has been instructed that he must always use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy
- 6) He acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with women of childbearing potential, even if he has undergone a successful vasectomy; women of childbearing potential are considered to be sexually mature women who have not undergone a hysterectomy, have not had a bilateral oophorectomy, or who have not been postmenopausal for at least 24 consecutive months (ie, who have had menses at any time in the preceding 24 consecutive months)
- 7) If the patient is between 12-18 years of age, his parent or legal guardian must have read this material and agreed to ensure compliance
Hematologic toxicity (neutropenia and thrombocytopenia)
- Associated with significant neutropenia and thrombocytopenia
- 80% of patients with deletion 5q myelodysplastic syndromes (MDS) had to have a dose delay/reduction during the major study; 34% had to have a 2nd dose delay/reduction
- Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study
- Patients on therapy for MM should have CBC monitored weekly for the first 2 cycles, on Days 1 and 15 of Cycle 3, and 4 weeks thereafter; reduce dose when necessary
- Patients may require dose interruption and/or reduction
- Patients may require use of blood product support and/or growth factors
Venous and arterial thrombosis
- 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 with dexamethasone
- Anti-thrombotic prophylaxis is recommended
Contraindications
Pregnancy; sexually active women of childbearing potential not using 2 forms of contraception
Demonstrated hypersensitivity (eg, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis)
Cautions
Also see Black box warnings for details regarding teratogenicity, pregnancy testing and patient education, RevAssist program, hematologic toxicities, and thromboses
Obtainable only through RevAssist program and can be prescribed only by physicians registered in the program
Any suspected fetal exposure should be reported to FDA via MedWatch telephone number at 1-800-FDA-1088 & also to Celgene Corp at 1-888-423-5436
Potential teratogen: women of childbearing potential should use 2 forms of contraception or abstain from heterosexual intercourse; males should use latex condoms
Avoid pregnancy
Discontinue if pregnancy occurs
Risk of hematologic toxicity
Increased risk of DVT, PE, MI, and stroke (see Black box warnings)
Renal impairment
Increased mortality in patients with chronic lymphocytic leukemia observed in a study using single-agent lenalidomide
Fatal tumor lysis syndrome reported
Tumor flare reaction (TFR) has occurred during investigational use for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash; tumor flare may mimic progression of disease; may continue treatment if grade 1 or 2 TFR (treat with corticosteroids, NSAIDs, and/or narcotic analgesics), hold treatment for grade 3 or 4 TFR until resolves to ≤Grade 1
Hepatic failure, including fatalities occurred with lenalidomide in combination with dexamethasone
Increased risk for second primary malignancies: Patients treated with lenalidomide (with melphalan and stem cell transplantation) had higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide
Angioedema and serious dermatologic reactions
- Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) reported
- Patients with prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide
- Consider interrupting or discontinuing for Grade 2-3 skin rash
- 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
Pregnancy and lactation
Pregnancy category: X
Lactation: discontinue drug or do not nurse
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Revlimid (lenalidomide)
Mechanism of action
Thalidomide analog; immunomodulatory and antiangiogenic; inhibits secretion of proinflammatory cytokines; enhances cell-mediated immunity by stimulating proliferation of anti-CD3 stimulated T cells
Pharmacokinetics
Half-life: 3 hr
Peak plasma time: 0.5-6 hr
Protein bound: 30%
Excretion: urine (82%)
Dialyzable: No
