Usual Adult Dose for Multiple Myeloma

In combination with dexamethasone:
25 mg orally once a day on Days 1 to 21 of repeated 28-day cycles until disease progression or unacceptable toxicity

Maintenance therapy following auto-HSCT:
10 mg once a day continuously (Days 1 to 28 of repeated 28-day cycles) for 3 cycles, then increase to 15 mg once a day if tolerated until disease progression or unacceptable toxicity

Comments:

• For patients who are not eligible for auto-HSCT, therapy should continue until disease progression or unacceptable toxicity.
• For patients who are eligible for auto-HSCT, hematopoietic stem cell mobilization should occur within 4 cycles.
• Following auto-HSCT, initiate maintenance therapy after adequate hematologic recovery (ANC 1000/mcL or more AND/OR platelet count 75,000/mcL or more).
• Consult the manufacturer product information for dexamethasone dosing recommendations.

Uses:

• In combination with dexamethasone for multiple myeloma (MM)
• Maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT)

Usual Adult Dose for Myelodysplastic Disease

10 mg orally once a day; therapy is continued or modified based upon clinical and laboratory findings until disease progression or unacceptable toxicity

Use: Treatment of transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities

Usual Adult Dose for Lymphoma

FOLLICULAR LYMPHOMA OR MARGINAL ZONE LYMPHOMA:
20 mg orally once a day on Days 1 through 21 of repeated 28-day cycles for up to 12 cycles in combination with a rituximab-product

MANTLE CELL LYMPHOMA:
25 mg orally once a day on Days 1 to 21 of repeated 28-day cycles until disease progression or unacceptable toxicity; treatment is continued, modified, or discontinued based upon clinical and laboratory findings

Uses:

• For the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after 2 prior therapies, onw1 of which included bortezomib

Use: In combination with a rituximab product for the treatment of previously treated follicular lymphoma (FL)

• In combination with a rituximab product for the treatment of previously treated marginal zone lymphoma (MZL)

Renal Dose Adjustments

DOSE ADJUSTMENTS IN COMBINATION THERAPY IN MULTIPLE MYELOMA (MM) AND MANTLE CELL LYMPHOMA (MCL):

• CrCl greater than 60 mL/min: No adjustment recommended.
• CrCl 30 to 60 mL/min: 10 mg once a day; consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose without dose-limiting toxicity.
• CrCl less than 30 mL/min (not requiring dialysis): 15 mg every other day
• CrCl below 30 mL/min (requiring dialysis): 5 mg once daily; on dialysis days, administer the dose following dialysis.

DOSE ADJUSTMENTS IN COMBINATION THERAPY IN FOLLICULAR LYMPHOMA (FL) AND MARGINAL ZONE LYMPHOMA (MZL):

• CrCl greater than 60 mL/min: No adjustment recommended.
• CrCl 30 to 60 mL/min: 10 mg once a day; after 2 cycles, the dose may be increased to 15 mg daily if the patient has tolerated therapy.
• CrCl less than 30 mL/min (not requiring dialysis): 5 mg once daily
• CrCl below 30 mL/min (requiring dialysis): 5 mg once daily; on dialysis days, administer the dose following dialysis.

DOSE ADJUSTMENTS IN maintenance therapy following auto-HSCT for multiple myeloma (MM) and MYELODYSPLASTIC SYNDROMES (MDS):

• CrCl greater than 60 mL/min: No adjustment recommended.
• CrCl 30 to 60 mL/min: 2.5 mg once daily; base subsequent dose increases or decrease on individual patient tolerance.
• CrCl less than 30 mL/min (not requiring dialysis): 2.5 mg once a day; base subsequent dose increases or decrease on individual patient tolerance.
• CrCl below 30 mL/min (requiring dialysis): 2.5 mg once daily; base subsequent dose increases or decrease on individual patient tolerance; on dialysis days administer the dose following dialysis.

Liver Dose Adjustments

Mild hepatic impairment (total bilirubin greater than 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN): No adjustment recommended.
Moderate to severe hepatic impairment: Data not available

Dose Adjustments

DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES FOR MULTIPLE MYELOMA (MM):
NEUTROPENIA IN MM:
When neutrophils:

• Fall to less than 1000/mcL: Interrupt therapy and follow CBC weekly.
• Return to 1000/mcL or more AND neutropenia is only toxicity: Resume therapy at 25 mg/day or initial starting dose.
• Return to 1000/mcL or more AND if other toxicity: Resume therapy at next lower dose; do not dose below 2.5 mg/day.
• Each subsequent drop below 1000/mcL: Interrupt therapy.
• Each subsequent return to 1000/mcL or More: Resume therapy at next lower dose; do not dose below 2.5 mg/day.

THROMBOCYTOPENIA IN MM:
When platelets:

• Fall to less than 30,000/mcL: Interrupt therapy and follow CBC weekly.
• Return to 30,000/mcL or more: Resume therapy at next lower dose; do not dose below 2.5 mg/day.
• Each subsequent drop below 30,000/mcL: Interrupt therapy.
• Each subsequent return to 30,000/mcl or more: Resume therapy at next lower dose; do not dose below 2.5 mg/day.

MAINTENANCE THERAPY FOLLOWING AUTO-HSCT:

• Following auto-HSCT, initiate maintenance therapy after adequate hematologic recovery (ANC at least 1000/mcL and/or platelet counts at least 75,000/mcL).
• The recommended starting dose is 10 mg once daily continuously (Days 1 through 28 of repeated 28-day cycles) until disease progression or unacceptable toxicity.
• After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES DURING MM TREATMENT:
Dose modification guidelines are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia, or another Grade 3 or 4 toxicity judged to be related to this drug:
DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES FOR MM:
NEUTROPENIA:
When neutrophils:

• Fall to less than 500/mcL: Interrupt therapy and follow CBC weekly.
• Return to 500/mcL or more: Resume therapy at next lower dose continuously for Days 1 to 28 of repeated 28-day cycle.
• If at 5 mg/day dose:
• Subsequent Drop Below 500/mcL: Interrupt treatment; do not dose below 5 mg/day for Days 1 to 21 of 28-day cycle.
• Subsequent Return to Greater than 500/mcL: Resume treatment at 5 mg/day for Days 1 to 21 of 28-day cycle; do not dose below 5 mg/day.

THROMBOCYTOPENIA:
When platelets:

• Fall to less than 30,000/mcL: Interrupt therapy and follow CBC weekly.
• Return to 30,000/mcL or more: Resume therapy at next lower dose continuously for Days 1 to 28 of repeated 28-day cycle.
• If at 5 mg/day dose subsequent drop below 30,000/mcL: Interrupt therapy; do not dose below 5 mg/day for Days 1 to 21 of 28-day cycle.
• If at 5 mg subsequent return to 30,000/mcL or more: Resume therapy at 5 mg/day for Days 1 to 21 of 28-day cycle; do not dose below 5 mg/day.

DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES DURING MYELODYSPLASTIC SYNDROMES (MDS) TREATMENT:
Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:
IF THROMBOCYTOPENIA DEVELOPS WITHIN 4 WEEKS OF STARTING THERAPY AT 10 MG DAILY IN MDS:
IF BASELINE IS AT LEAST 100,000/MCL:
WHEN PLATELETS:

• Fall below 50,000/mcL: Interrupt therapy.
• Return at least 50,000/mcL: Resume therapy at 5 mg daily.

IF BASELINE IS BELOW 100,000/MCL:
WHEN PLATELETS:

• Fall to 50% of the baseline value: Interrupt therapy.
• If baseline is at least 60,000/mcL and returns to at least 50,000/mcL: Resume therapy at 5 mg daily.
• If baseline is below 60,000/mcL and returns to at least 30,000/mcL: Resume therapy at 5 mg daily.

IF THROMBOCYTOPENIA DEVELOPS AFTER 4 WEEKS OF STARTING THERAPY AT 10 MG DAILY IN MDS:
WHEN PLATELETS:

• Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions: Interrupt therapy.
• Return to at least 30,000/mcL (without hemostatic failure): Resume therapy at 2.5 mg daily.

Patients who experience thrombocytopenia at 5 mg daily should have their DOSAGE ADJUSTED AS FOLLOWS:
IF THROMBOCYTOPENIA DEVELOPS DURING TREATMENT AT 5 MG DAILY IN MDS:
When platelets:

• Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions: Interrupt therapy.
• Return to at least 30,000/mcL (without hemostatic failure): Resume therapy at 2.5 mg daily.

PATIENTS WHO ARE DOSED INITIALLY AT 10 MG AND EXPERIENCE NEUTROPENIA SHOULD HAVE THEIR DOSAGE ADJUSTED AS FOLLOWS:
ABSOLUTE NEUTROPHIL COUNTS (ANC):
IF NEUTROPENIA DEVELOPS WITHIN 4 WEEKS OF STARTING TREATMENT AT 10 MG DAILY IN MDS:
If baseline ANC is at least 1,000/mcL:
When neutrophils:

• Fall below 500/mcL: Interrupt therapy.
• Return to at least 1000/mcL: Resume therapy at 5 mg daily.

If baseline ANC is below 1,000/mcL:
When neutrophils:

• Fall below 500/mcL: Interrupt therapy.
• Return to at least 500/mcL: Resume therapy at 5 mg daily.

IF NEUTROPENIA DEVELOPS AFTER 4 WEEKS OF STARTING TREATMENT AT 10 MG DAILY IN MDS:
When neutrophils:

• Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5C): Interrupt therapy.
• Return to at least 500/mcL: Resume therapy at 5 mg daily.

PATIENTS WHO EXPERIENCE NEUTROPENIA AT 5 MG DAILY SHOULD HAVE THEIR DOSAGE ADJUSTED AS FOLLOWS:
IF NEUTROPENIA DEVELOPS DURING TREATMENT AT 5 MG DAILY IN MDS:
When neutrophils:

• Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5C): Interrupt therapy.
• Return to at least 500/mcL: Resume therapy at 2.5 mg daily.

DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES DURING MCL TREATMENT MANTLE CELL LYMPHOMA (MCL):
GRADE 3 OR 4 NEUTROPENIA OR THROMBOCYTOPENIA OR OTHER GRADE 3 OR 4 TOXICITIES:
THROMBOCYTOPENIA DURING TREATMENT IN MCL:
When platelets:

• Fall below 50,000/mcL: Interrupt therapy and follow CBC weekly.
• Return to at least 50,000/mcL: Resume therapy at 5 mg less than the previous dose; do not dose below 5 mg daily.

NEUTROPENIA DURING TREATMENT IN MCL:
When neutrophils:

• Fall below 1000/mcL for at least 7 days OR falls below 1000/mcL with an associated temperature at least 38.5C OR falls below 500/mcL: Interrupt therapy and follow CBC weekly.
• Return to at least 1000/mcL: Resume therapy at 5 mg less than the previous dose; do not dose below 5 mg daily.

DOSE ADJUSTMENTS FOR HEMATOLOGIC TOXICITIES DURING FOLLICULAR LYMPHOMA (FL) OR MARGINAL ZONE LYMPHOMA (MZL):
DOSE MODIFICATION GUIDELINES, SUMMARIZED BELOW, ARE RECOMMENDED FOR GRADE 3 OR 4 NEUTROPENIA OR THROMBOCYTOPENIA OR ANOTHER GRADE 3 OR 4 TOXICITY:
When platelets:

• Fall below 50,000/mcL: Interrupt therapy and follow CBC weekly.
• Return to at least 50,000/mcL: If patient starting dose was 20 mg daily, resume at 5 mg less than the previous dose; do not dose below 5 mg daily. If patient starting dose was 10 mg daily, resume at 5 mg less than previous dose; do not dose below 2.5 mg daily.

NEUTROPENIA DURING TREATMENT IN FL OR MZL:
WHEN NEUTROPHILS:

• Fall below 1000/mcL for at least 7 days OR falls below 1000/mcL with an associated temperature at least 38.5C OR falls below 500 /mcL: Interrupt therapy and follow CBC weekly.
• Return to at least 1000/mcL: If patient starting dose was 20 mg daily, resume at 5 mg less than the previous dose; do not dose below 5 mg daily. If patient starting dose was 10 mg daily, resume at 5 mg less than previous dose; do not dose below 2.5 mg daily.

DOSE MODIFICATIONS FOR NONHEMATOLOGIC ADVERSE REACTIONS:

• For nonhematologic Grade 3 or 4 toxicities: Withhold therapy and restart at the physician's discretion at next lower dose level when toxicity has resolved to Grade 2 or below.
• Permanently discontinue therapy for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for lenalidomide. It includes elements to assure safe use and an implementation system. For additional information: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:
EMBRYOFETAL TOXICITY:

• This drug is a thalidomide analog and is contraindicated in pregnancy.
• It caused limb abnormalities in a developmental monkey study.
• Thalidomide is a known human teratogen that causes severe life-threatening human birth defects.
• If this drug is used during pregnancy, it may cause birth defects or embryofetal death.

Recommendations:

• In females of reproductive potential, obtain 2 negative pregnancy tests before starting therapy.
• Instruct females of reproductive potential to use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after taking this drug.
• To avoid embryofetal exposure, this drug 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):

• This drug can cause significant neutropenia and thrombocytopenia.
• Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction.
• 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.

Recommendations:

• 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.

VENOUS and ARTERIAL THROMBOEMBOLISM:

• This drug 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 multiple myeloma who were treated with this drug and dexamethasone therapy.

Recommendations:

• Monitor for and advise patients about signs of thromboembolism.
• Advise patients to seek immediate medical care if they develop symptoms (e.g., shortness of breath, chest pain, 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:

• Hypersensitivity to the active component or any of the ingredients
• Pregnancy

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

See RENAL IMPAIRMENT

Other Comments

Administration Advice:

• Administer this drug at about the same time on the scheduled days, preferably with water and either with or without food.
• Instruct patients to swallow capsules whole; capsules should not be opened, broken, or chewed.
• Consult the manufacturer product information for instructions on administering this drug to patients with swallowing difficulties.
• Advise patients that in the event of a missed dose, the dose can be taken if less than 12 hours have elapsed since missing the dose; if more than 12 hours have elapsed, that dose should be skipped and the next dose should be taken at the normal time on the following day.
• If the powder from drug capsules makes contact with skin or mucous membranes, direct patients to wash affected skin immediately and thoroughly with soap and water and to flush affected membranes with water.

Storage Requirements:

• Store below 25 degrees Celsius.
• Keep drug in the original package.

Monitoring:
CARDIOVASCULAR: Signs/symptoms of thromboembolism
EMBRYOFETAL TOXICITY: Pregnancy (in females of reproductive potential)
ENDOCRINE: ENDOCRINE: Thyroid function
HEMATOLOGICAL: Signs/symptoms of neutropenia and thrombocytopenia:

• MM: CBC (weekly for the first 2 cycles, on Days 1 and 15 of cycle 3, and every 28 days thereafter)
• MDS: CBC (weekly for the first 8 weeks and at least monthly thereafter)
• MCL: CBC (weekly for the first 28-day cycle, every 2 weeks during Cycles 2 to 4, and monthly thereafter)

HEPATIC: Liver enzymes
OCULAR: Visual ability
ONCOLOGIC: Second primary malignancies

Patient Advice:

• Avoid potentially dangerous activities such as driving and operating machinery until you know how this drug affects you.
• Consult your healthcare provider on recommended methods of birth control to use while taking this drug.
• When removing a drug capsule from a blister pack, press only on one end of the capsule to reduce the risk of breaking the capsule.