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REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM). REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

Dose Modifications for Adverse Events
in NSCT NDMM

The following select adverse events were among the most frequently reported (≥20%) in clinical trials of combinations with REVLIMID. Dose modifications are recommended in patients with these adverse events.1

For a complete list of the most frequently reported adverse events, please click here.

AE Reference Cards

Neutropenia Rash Fatigue Diarrhea

Neutropenia

Changes in dosing for neutropenia during REVLIMID in NSCT NDMM are based on decreases in absolute neutrophil count (ANC).

Neutropenia: How to Dose Modify REVLIMID
in NSCT NDMM1

No dose adjustments required for ANC ≥1000/mcL

REVLIMID dose modifications for Grade 3/4 hematologic toxicities in patients with NSCT NDMM*
When ANC <1000/mcL Interrupt REVLIMID treatment, follow CBC weekly
Return to ANC ≥1000/mcL If neutropenia is the only toxicity, resume REVLIMID at 25 mg daily or initial starting dose
If other toxicity, resume REVLIMID at next lower dose
Do not dose below 2.5 mg daily
For each subsequent drop
to ANC <1000/mcL
Interrupt REVLIMID treatment
Return to ANC ≥1000/mcL Resume REVLIMID at next lower dose
Do not dose below 2.5 mg daily
REVLIMID dose modifications for Grade 3/4 hematologic toxicities in patients with NSCT NDMM*
When ANC <1000/mcL Interrupt REVLIMID treatment, follow CBC weekly
Return to ANC ≥1000/mcL If neutropenia is the only toxicity, resume REVLIMID at 25 mg daily or initial starting dose If other toxicity, resume REVLIMID at next lower dose
Do not dose below 2.5 mg daily
For each subsequent drop to ANC <1000/mcL Interrupt REVLIMID treatment
Return to ANC ≥500/mcL Resume REVLIMID at next lower dose
Do not dose below 2.5 mg daily

Downloads

AE Reference Card

Neutropenia AE Reference Card

Get a dose modification card
for neutropenia.

Download
Dose Modifications: Patient Profiles

Dose Modifications: Patient Profiles

Read case studies about modifying
patient dosage based on adverse events.

Download

*The FIRST Trial enrolled 1,623 patients with NDMM who did not receive a stem cell transplant.

See full reference list.

Rash

Interruption or discontinuation of REVLIMID is recommended in the presence of Grade 3 rash.
For Grade 4 rash, permanently discontinue treatment with REVLIMID.

Rash: How to Dose Modify REVLIMID

Dose modifications for non-hematologic adverse events

REVLIMID dose modifications based on rash grade in patients with MM1
Grade 1 No dose adjustment required
Grade 2
Grade 3 Hold treatment and restart at the physician’s discretion at next lower dose when toxicity
has resolved to Grade 2 or below
Grade 4 Permanently discontinue REVLIMID
REVLIMID dose modifications based on rash grade in patients with MM1
Grade 1 No dose adjustment required
Grade 2 No dose adjustment required
Grade 3 Hold treatment and restart at the physician’s discretion at next lower dose when toxicity has resolved to Grade 2 or below
Grade 4 Permanently discontinue REVLIMID

Downloads

AE Reference Card

Rash AE
Reference Card

Get a dose modification card
for rash.

Download
Dose Modifications: Patient Profiles

Dose Modifications:
Patient Profiles

Read case studies about modifying
patient dosage based on adverse events.

Download

For more information, please refer to the American Cancer Society website.

See full reference list.

Fatigue

Hold treatment and restart at next lower dose for Grade 3/4 fatigue.

FATIGUE: How to Dose Modify REVLIMID

Dose modifications for non-hematologic adverse events

REVLIMID dose modifications based on fatigue grade in patients with MM1,12
Grade 1: Mild fatigue over baseline No dose adjustment required
Grade 2: Moderate or causing difficulty
performing some ADL
Grade 3: Severe fatigue interfering with ADL Hold treatment and restart at the physician's discretion at next lower dose
when toxicity has resolved to Grade 2 or below
Grade 4: Disabling
REVLIMID dose modifications based on fatigue grade in patients with MM1,12
Grade 1: Mild fatigue over baseline No dose adjustment required
Grade 2: Moderate or causing difficulty performing some ADL No dose adjustment required
Grade 3: Severe fatigue interfering with ADL Hold treatment and restart at the physician's discretion at next lower dose when toxicity has resolved to Grade 2 or below
Grade 4: Disabling Hold treatment and restart at the physician's discretion at next lower dose when toxicity has resolved to Grade 2 or below

The severity of AEs was graded by CTCAE v3.0 in the FIRST Trial and Maintenance Study 1. Maintenance Study 2 used the WHO toxicity criteria to grade adverse events.*

Downloads

AE Reference Card

Fatigue AE
Reference Card

Get a dose modification card for fatigue.

Download
Dose Modifications: Patient Profiles

Dose Modifications:
Patient Profiles

Read case studies about modifying
patient dosage based on adverse events.

Download

For patients who are auto-HSCT eligible, hematopoietic stem cell mobilization should occur within 4 cycles of receiving REVLIMID-containing therapy.
For more information, please refer to the American Cancer Society website.

See full reference list.

Diarrhea

Hold treatment and restart at next lower dose for Grade 3/4 diarrhea.

Diarrhea: How to Dose Modify REVLIMID

Dose modifications for non-hematologic adverse events

REVLIMID dose modifications based on diarrhea grade in patients with MM1,12
Grade 1: Increase of <4 stools per day over baseline; mild increase in
ostomy output compared to baseline
No dose adjustment required
Grade 2: Increase of 4-6 stools per day over baseline; IV fluids
indicated <24 hours; moderate increase in ostomy output compared
to baseline; not interfering with ADL
Grade 3: Increase of ≥7 stools per day over baseline; incontinence;
IV fluids ≥24 hours; hospitalization; severe increase in ostomy output
compared to baseline; interfering with ADL
Hold treatment and restart at the physician’s discretion at next
lower dose when toxicity has resolved to Grade 2 or below
Grade 4: Life-threatening consequences (eg, hemodynamic collapse)
REVLIMID dose modifications based on diarrhea grade in patients with MM1,12
Grade 1: Increase of <4 stools per day over baseline; mild increase in ostomy output compared to baseline No dose adjustment required
Grade 2: Increase of 4-6 stools per day over baseline; IV fluids indicated <24 hours; moderate increase in ostomy output compared to baseline; not interfering with ADL No dose adjustment required
Grade 3: Increase of ≥7 stools per day over baseline; incontinence; IV fluids ≥24 hours; hospitalization; severe increase in ostomy output compared to baseline; interfering with ADL Hold treatment and restart at the physician’s discretion at next lower dose when toxicity has resolved to Grade 2 or below
Grade 4: Life-threatening consequences (eg, hemodynamic collapse) Hold treatment and restart at the physician’s discretion at next lower dose when toxicity has resolved to Grade 2 or below

The severity of AEs was graded by CTCAE v3.0 in the FIRST Trial and Maintenance Study 1. Maintenance Study 2 used the WHO toxicity criteria to grade adverse events.*

Downloads

AE Reference Card

Diarrhea AE
Reference Card

Get a dose modification card
for diarrhea.

Download
Dose Modifications: Patient Profiles

Dose Modifications:
Patient Profiles

Read case studies about modifying
patient dosage based on adverse events.

Download

For more information, please refer to the American Cancer Society website.

ADL, activities of daily living; AE, adverse event; ANC, absolute neutrophil count; auto-HSCT, autologous hematopoietic stem cell transplantation; CBC, complete blood count; CTCAE, Common Terminology Criteria for Adverse Events; FIRST, Frontline Investigation of REVLIMID + dexamethasone versus Standard Thalidomide; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; NSCT, non-stem cell transplant; WHO, World Health Organization.

More information about dosing with REVLIMID, including renal dosing.

INDICATIONS

REVLIMID® (lenalidomide) in combination with dexamethasone (dex) is indicated for the treatment of adult patients with multiple myeloma (MM). REVLIMID is indicated as maintenance therapy in adult patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT). REVLIMID is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

 

INDICATION FOR REVLIMID + DEXAMETHASONE + DARATUMUMAB (DRd)

DRd is indicated for the treatment of adult patients with newly diagnosed MM who are ineligible for an autologous stem cell transplant. Information about DRd does not appear in the REVLIMID full Prescribing Information. Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalexhcp.com.

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.

 

CONTRAINDICATIONS FOR DARATUMUMAB

Daratumumab is contraindicated in patients with a history of severe hypersensitivity (eg, anaphylactic reactions) to daratumumab or any of the components of the formulation.

 

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: See Boxed WARNINGS.

  • Females of Reproductive PotentialSee 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 a dose interruption and/or dose reduction. MM: Monitor complete blood counts in patients taking REVLIMID + dexamethasone or REVLIMID as maintenance therapy, every 7 days for the first 2 cycles, on days 1 and 15 of cycle 3, and every 28 days 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. Erythropoietin-stimulating agents (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: 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. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS.

 

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).

 

Hypersensitivity: Hypersensitivity including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for these reactions.

 

WARNINGS AND PRECAUTIONS FOR DARATUMUMAB

  • Infusion reactions: Interrupt daratumumab infusion for infusion reactions of any severity. Permanently discontinue the infusion in case of anaphylactic reactions or life-threatening infusion reactions and institute appropriate emergency care.
  • Interference with cross-matching and red blood cell antibody screening: Type and screen patients prior to starting treatment. Inform blood banks that a patient has received daratumumab.
  • Neutropenia: Monitor complete blood cell counts periodically during treatment. Monitor patients with neutropenia for signs of infection. Dose delay may be required to allow recovery of neutrophils.
  • Thrombocytopenia: Monitor complete blood cell counts periodically during treatment. Dose delay may be required to allow recovery of platelets.
  • Interference With Determination of Complete Response: Daratumumab can interfere with the determination of complete response and of disease progression in some patients with IgG kappa myeloma protein.

 

ADVERSE REACTIONS

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%).

 

ADVERSE REACTIONS: DRd

  • The most frequent (≥20%) adverse reactions (DRd arm) were: infusion reactions (41%), diarrhea (57%), constipation (41%), nausea (32%), peripheral edema (41%), fatigue (40%), back pain (34%), asthenia (32%), pyrexia (23%), upper respiratory tract infection (52%), bronchitis (29%), pneumonia (26%), decreased appetite (22%), muscle spasms (29%), peripheral sensory neuropathy (24%), dyspnea (32%), and cough (30%).
  • Grade 3 or 4 hematology laboratory abnormalities (DRd arm) included: neutropenia (56%), lymphopenia (52%), leukopenia (35%), anemia (13%), thrombocytopenia (9%).

DRUG INTERACTIONS

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.

 

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, a Bristol Myers Squibb company, 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 for patients on dialysis.

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

Please see the daratumumab full Prescribing Information and Important Safety Information at www.darzalexhcp.com.