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Lenalidomide

Class: Immunomodulatory Agents
Chemical Name: 3-(4-Amino-1-3-dihydro-1-oxo-2H-isoindol-2yl)-2,6-piperidinedione
Molecular Formula: C13H13N3O3
CAS Number: 191732-72-6
Brands: Revlimid

Medically reviewed by Drugs.com on Jan 25, 2022. Written by ASHP.

Warning

    Teratogenic Effects
  • Potential risk of teratogenicity and fetotoxicity due to structural similarity to thalidomide, a known human teratogen that can cause severe, life-threatening birth defects if administered during pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Contraindicated in pregnant women.

  • In females of reproductive potential, pregnancy must be excluded prior to treatment initiation with 2 negative pregnancy tests, and pregnancy must be prevented by abstinence or simultaneous use of 2 forms of reliable contraception. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Available only through a restricted distribution program. (See REMS under Dosage and Administration.)

    Hematologic Toxicity
  • Risk of severe thrombocytopenia and neutropenia. (See Hematologic Effects under Cautions.)

  • Monitor CBCs periodically. Dosage interruption and/or reduction may be required.

    Thromboembolic Effects
  • Increased risk of venous thromboembolism (e.g., DVT, PE) or arterial thromboembolism (e.g., MI, stroke).

  • Monitor for signs and symptoms of thromboembolism.

  • Thromboprophylaxis is recommended. (See Thromboembolic Events under Cautions.)

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for lenalidomide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of lenalidomide and consists of the following: elements to assure safe use and implementation system. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Introduction

Biologic response modifier; thalidomide analog with immunomodulatory, antineoplastic, and antiangiogenic activity.

Uses for Lenalidomide

Multiple Myeloma

In combination with dexamethasone for the treatment of multiple myeloma. Progression-free survival substantially improved with lenalidomide and dexamethasone compared with combination therapy with melphalan, prednisone, and thalidomide in patients with newly diagnosed multiple myeloma who are ineligible for hematopoietic stem cell transplant (HSCT). Combination therapy with dexamethasone substantially more effective than dexamethasone monotherapy in achieving overall, complete, and partial response in patients who have received at least one prior therapy.

Maintenance therapy in patients who have undergone autologous HSCT. Progression-free survival improved with lenalidomide compared with placebo in patients who have undergone autologous HSCT.

Designated an orphan drug by FDA for use in multiple myeloma.

Myelodysplastic Syndrome (MDS)

Treatment of RBC transfusion-dependent anemia associated with low- or intermediate-1-risk MDS in patients with a cytogenetic deletion abnormality involving the long arm of chromosome 5 (deletion 5q abnormality), with or without additional cytogenetic abnormalities (designated an orphan drug by FDA for this use).

Use of lenalidomide for the treatment of transfusion-dependent low-risk or intermediate-1-risk MDS without the deletion 5q chromosomal abnormality is a reasonable choice (accepted, with possible conditions).

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma that has relapsed or progressed after 2 prior therapies (including bortezomib).

Lenalidomide prolonged progression-free survival in patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation compared with standard monotherapy.

Designated an orphan drug by FDA for use in mantle cell lymphoma.

Follicular Lymphoma and Marginal-zone Lymphoma

Treatment of previously treated follicular lymphoma or marginal-zone lymphoma (in combination with rituximab).

Combination therapy with rituximab improved tumor response and progression-free survival in patients with relapsed or refractory follicular lymphoma or marginal-zone lymphoma compared with rituximab alone.

Designated an orphan drug by FDA for use in follicular lymphoma or marginal-zone lymphoma.

Lenalidomide Dosage and Administration

General

Pretreatment Screening

  • Tests to exclude pregnancy must be performed within 10–14 days and again within 24 hours immediately prior to treatment initiation.

  • Baseline absolute neutrophil count (ANC) and platelet counts.

  • Thyroid function.

  • Assess risk factors for thromboembolism.

Patient Monitoring

  • Multiple myeloma: Complete blood cell counts (CBCs) weekly during the first 2 cycles, on days 1 and 15 of cycle 3, and then every 28 days thereafter.

  • Myelodysplastic syndrome: CBCs weekly during first 8 weeks of therapy, and at least monthly thereafter.

  • Mantle cell lymphoma: CBCs weekly during the first cycle, every 2 weeks during cycles 2–4, and then monthly thereafter.

  • Follicular lymphoma or marginal-zone lymphoma: CBCs weekly for the first 3 weeks of cycle 1, every 2 weeks during cycles 2–4, and then monthly thereafter.

  • Signs or symptoms of neutropenia or thrombocytopenia (e.g., bleeding, bruising, infection).

  • Pregnancy tests weekly during the first month of therapy, then every 2 or 4 weeks in women with irregular or regular menstrual cycles, respectively.

  • Development of second primary malignancies.

  • Liver function tests periodically.

  • Tumor lysis syndrome in patients with a high tumor burden.

  • Thyroid function.

  • Manifestations of tumor flare reaction.

Premedication and Prophylaxis

  • Manufacturer recommends thromboprophylaxis; select an appropriate prophylactic regimen based on assessment of patient risk factors.

    Thromboprophylaxis in Patients with Multiple Myeloma
  • International Myeloma Working Group (IMWG) recommends thromboprophylaxis with aspirin for multiple myeloma patients receiving thalidomide with 1 or no underlying individual and/or myeloma-related risk factors for venous thromboembolism.

  • IMWG recommends thromboprophylaxis with a low molecular weight heparin (LMWH) for those with 2 or more individual and/or myeloma-related risk factors.

  • IMWG recommends thromboprophylaxis with a LMWH should be considered in thalidomide-treated patients receiving high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors.

  • IMWG states that full-dose warfarin (international normalized ratio [INR] 2–3) is an alternative to LMWH; however, there is limited clinical experience with this approach.

  • American Society of Clinical Oncology (ASCO) recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving lenalidomide in conjunction with dexamethasone or antineoplastic agents, and states that those at lower risk for thromboembolism may receive either aspirin or a LMWH, while those at higher risk should receive a LMWH.

Dispensing and Administration Precautions

    Handling and Disposal
  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

  • Avoid contact of capsule contents with skin or mucous membranes. If such contact occurs, wash affected areas of skin thoroughly with soap and water and rinse affected mucosa thoroughly with water.

REMS

  • Because lenalidomide is an analog of thalidomide (a known human teratogen that can cause severe, life-threatening birth defects if administered during pregnancy), commercially available lenalidomide must be obtained through a restricted distribution program, the Lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program, designed to help ensure that fetal exposure to the drug does not occur.

  • Clinicians, pharmacists, and patients must be registered in the Lenalidomide REMS program before they can prescribe, dispense, and receive lenalidomide, and compliance with all terms outlined in the program is mandatory.

  • The Lenalidomide REMS program controls access to lenalidomide; educates program participants (clinicians, pharmacists, patients) about the risks associated with lenalidomide and the procedural requirements for safe use of the drug; and monitors compliance with the registration, education, and safety requirements of the program. Clinicians may contact 888-423-5436 or visit [Web] for additional information and to enroll in the program.

  • No more than a 28-day supply of lenalidomide should be dispensed at one time.

Administration

Oral Administration

Administer orally with water once daily without regard to food.

Swallow capsules whole; do not break, chew, or open capsules.

Dosage

Adults

Multiple Myeloma
Oral

In combination with dexamethasone: 25 mg once daily given on days 1–21 of each 28-day cycle in combination with dexamethasone. Continue or adjust dosage based on clinical response and laboratory parameters (e.g., blood cell counts). In clinical studies, lenalidomide was continued until disease progression or unacceptable toxicity in patients who were not candidates for autologous HSCT. In patients undergoing autologous HSCT, stem cell mobilization should occur within 4 cycles of lenalidomide-containing therapy. Clinicians should consult published protocols for dexamethasone dosing. If thrombocytopenia and/or neutropenia occur, reduce dosage or interrupt therapy based on degree of myelosuppression. (See Table 1.)

Maintenance therapy following autologous HSCT: 10 mg once daily on days 1–28 of a 28-day cycle; increase dosage to 15 mg once daily after 3 cycles if well tolerated. Continue or adjust initial dosage based on clinical response and laboratory parameters (e.g., blood cell counts). Initiate therapy when ANC ≥1000/mm3 or and/or platelet count ≥75,000/mm3. Continue therapy until disease progression or unacceptable toxicity occurs. If thrombocytopenia and/or neutropenia occur, reduce dosage or interrupt therapy based on degree of myelosuppression. (See Table 2.)

Dosage Modification for Hematologic Toxicity in Patients with Multiple Myeloma Receiving Lenalidomide in Combination with Dexamethasone
Oral

If hematologic adverse effects occur, temporarily interrupt therapy and reduce dosage as described in Table 1.

Table 1. Dosage Modification for Hematologic Adverse Effects in Patients with Multiple Myeloma Receiving Lenalidomide in Combination with Dexamethasone1

Adverse Reaction and Severity

Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 25 mg daily on days 1–21 of each 28-day cycle)

Thrombocytopenia

Platelet count <30,000/mm3

First occurrence: Withhold therapy and monitor CBCs weekly; when platelet count ≥30,000/mm3, then resume next lower dosage (do not administer dosages lower than 2.5 mg daily)

Platelet count <30,000/mm3

Subsequent occurrences: Withhold therapy until platelet count ≥30,000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily)

Neutropenia

Absolute neutrophil count (ANC) <1000/mm3

First occurrence (neutropenia is only toxicity): Withhold therapy and monitor CBCs weekly; when ANC ≥1000/mm3, then resume at 25 mg daily or initial starting dosage

Platelet count <30,000/mm3

First occurrence (in presence of other toxicity): Withhold therapy and monitor CBCs weekly; when ANC ≥1000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily)

Platelet count <30,000/mm3

Subsequent occurrence: Withhold therapy until ANC ≥1000/mm3, then resume at next lower dosage (do not administer dosages lower than 2.5 mg daily)

Dosage Modification for Hematologic Toxicity in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy
Oral

If hematologic adverse effects occur, temporarily interrupt therapy and reduce dosage as described in Table 2.

Table 2. Dosage Modification for Hematologic Adverse Effects in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy1

Adverse Reaction and Severity

Lenalidomide Dosage Modification (Lenalidomide Dosage = 10 or 15 mg daily on days 1–28 of each 28-day cycle)

Thrombocytopenia

Platelet count <30,000/mm3

First occurrence: Withhold therapy and monitor CBCs weekly; when platelet count ≥30,000/mm3, resume at next lower dosage and administer continuously (for 28 days of each 28-day cycle)

Platelet count <30,000/mm3

For subsequent occurrences in patients receiving a reduced dosage of 5 mg daily: Withhold therapy; when platelet count ≥30,000/mm3, resume therapy at 5 mg daily on days 1–21 of each 28-day cycle (do not administer dosages lower than 5 mg daily)

Neutropenia

ANC <500/mm3

First occurrence: Withhold therapy and monitor CBCs weekly; when ANC ≥500/mm3, resume at next lower dosage and administer continuously (for 28 days of each 28-day cycle)

ANC <500/mm3

For subsequent occurrences in patients receiving a reduced dosage of 5 mg daily: Withhold therapy; when ANC ≥500/mm3, resume therapy at 5 mg daily on days 1–21 of each 28-day cycle (do not administer dosages lower than 5 mg daily)

Myelodysplastic Syndrome
Oral

10 mg once daily. Continue or adjust dosage based on clinical response and laboratory parameters (e.g., blood cell counts). Continue therapy until disease progression or unacceptable toxicity occurs.

If thrombocytopenia and/or neutropenia occur, reduce dosage or interrupt therapy based on degree of myelosuppression. (See Tables 3 and 4.)

MDS without Deletion 5q Abnormality†
Oral

Dosage of 10 mg once daily has been used.

Dosage Modification for Toxicity in Patients with MDS
Oral
Table 3. Dosage Modification for Thrombocytopenia in Patients with MDS1

Severity

Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 10 mg daily)

Platelet count <50,000/mm3 occurs within 4 weeks of therapy

Baseline platelet count ≥100,000/mm3

Withhold therapy until platelet count ≥50,000/mm3, then resume at 5 mg daily

Platelet count decreases to 50% of baseline value within 4 weeks of therapy

Baseline platelet count ≥60,000/mm3 to <100,000/mm3

Withhold therapy until platelet count ≥50,000/mm3, then resume at 5 mg daily

Platelet count decreases to 50% of baseline value within 4 weeks of therapy

Baseline platelet count <60,000/mm3

Withhold therapy until platelet count ≥30,000/mm3, then resume at 5 mg daily

Thrombocytopenia occurring after 4 weeks of therapy

Platelet count <30,000/mm3 or <50,000/mm3 and requiring platelet transfusions

Withhold therapy until platelet count ≥30,000/mm3 (without hemostatic failure), then resume at 5 mg daily

Thrombocytopenia recurs on a reduced dosage of 5 mg daily

Platelet count <30,000/mm3 or <50,000/mm3 and requiring platelet transfusions

Withhold therapy until platelet count ≥30,000/mm3 (without hemostatic failure), then resume at 2.5 mg daily

Table 4. Dosage Modification for Neutropenia in Patients with MDS1

Severity

Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 10 mg daily)

ANC <750/mm3 occurs within 4 weeks of therapy

Baseline ANC ≥1,000/mm3

Withhold therapy until ANC ≥1000/mm3, then resume at 5 mg daily

ANC <500/mm3 within 4 weeks of therapy

Baseline ANC is <1,000/mm3

Withhold therapy until ANC ≥500/mm3, then resume at 5 mg daily

Neutropenia occurring after 4 weeks of therapy

ANC <500/mm3 for ≥7 days or <500/mm3 with fever (≥38.5°C)

Withhold therapy until ANC ≥500/mm3, then resume at 5 mg daily

Neutropenia recurs on a reduced dosage of 5 mg daily

ANC <500/mm3 for ≥7 days or <500/mm3 with fever (≥38.5°C) on a reduced dosage of 5 mg daily

Withhold therapy until ANC ≥500/mm3, then resume at 2.5 mg daily

Mantle Cell Lymphoma
Oral

25 mg once daily on days 1–21 of a 28-day cycle. Continue therapy until disease progression or unacceptable toxicity occurs.

Continue or adjust dosage based on clinical response and laboratory parameters (e.g., blood cell counts).

Dosage Modification for Hematologic Toxicity in Patients with Mantle Cell Lymphoma
Oral

If hematologic adverse effects occur, temporarily interrupt therapy and reduce dosage as described in Table 5.

Table 5. Dosage Modification for Hematologic Adverse Effects in Patients with Mantle Cell Lymphoma1

Adverse Reaction and Severity

Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 25 mg daily)

Thrombocytopenia

Platelet count <50,000/mm3

Withhold therapy and monitor CBC weekly; when platelet count ≥50,000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily)

Neutropenia

ANC <1000/mm3 for ≥7 days, or <1000/mm3 with fever (≥38.5°C), or <500/mm3

Withhold therapy and monitor CBC weekly; when ANC ≥1000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily)

Follicular Lymphoma or Marginal-zone Lymphoma
Oral

20 mg once daily on days 1–21 of a 28-day cycle in combination with rituximab.

Dosage Modification for Hematologic Toxicity in Patients with Follicular Lymphoma or Marginal-zone Lymphoma
Oral

If hematologic adverse effects occur, temporarily interrupt therapy and reduce dosage, as described in Table 6.

Table 6. Dosage Modification for Hematologic Adverse Effects in Patients with Follicular Lymphoma or Marginal-zone Lymphoma

Adverse Reaction and Severity

Lenalidomide Dosage Modification (Lenalidomide Starting Dosage = 20 mg daily)

Thrombocytopenia

Platelet count <50,000/mm3

Withhold therapy and monitor CBC weekly; when platelet count ≥50,000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily; if initial dosage was 10 mg daily, do not administer dosages lower than 2.5 mg daily)

Neutropenia

ANC <1000/mm3 for ≥7 days, or <1000/mm3 with fever (≥38.5°C), or <500/mm3

Withhold therapy and monitor CBC weekly; when ANC ≥1000/mm3, resume at dosage reduced by 5 mg (do not administer dosages lower than 5 mg daily; if initial dosage was 10 mg daily, do not administer dosages lower than 2.5 mg daily)

Dosage Modification for Nonhematologic Adverse Reactions

If angioedema, anaphylaxis, grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction occurs, permanently discontinue lenalidomide. (See Hypersensitivity Reactions and also Cutaneous Reactions under Cautions.)

If grade 3 or 4 nonhematologic toxicities occur, withhold lenalidomide; when toxicity resolves or improves to grade 2 or less, resume lenalidomide at the next lower dosage level.

Special Populations

Hepatic Impairment

No specific dosage adjustment recommended.

Renal Impairment

Initial dosage reduction may be necessary in patients with renal impairment (see Table 7).

Subsequent dosage adjustments should be based on patient tolerance

Administer lenalidomide after dialysis

Table 7. Recommended Initial Dosage of Lenalidomide in Patients with Renal Impairment1

Clcr (mL/minute)

Multiple Myeloma (Combination Therapy with Dexamethasone)

Mantle Cell Lymphoma

Follicular Lymphoma and Marginal-zone Lymphoma (Combination Therapy with Rituximab)

Multiple Myeloma (Maintenance Therapy) and MDS

30–60

10 mg once daily

If reduced dosage is tolerated, consider increasing dosage to 15 mg once daily after 2 cycles

10 mg once daily

10 mg once daily

If reduced dosage is tolerated, consider increasing dosage to 15 mg once daily after 2 cycles

5 mg once daily

<30 (not requiring dialysis)

15 mg every other day

15 mg every other day

5 mg once daily

2.5 mg once daily

<30 (requiring dialysis)

5 mg once daily

5 mg once daily

5 mg once daily

2.5 mg once daily

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function; reduced dosages may be required. (See Renal Impairment under Dosage and Administration.)

Cautions for Lenalidomide

Contraindications

  • Pregnancy. (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Known hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN]) to lenalidomide or any ingredient in the formulation.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; contraindicated in pregnant women. Teratogenic effects of lenalidomide not fully established, but considered a potential teratogen due to structural similarity to thalidomide, a known human teratogen associated with severe birth defects and fetal death. (See REMS under Dosage and Administration.)

Pregnancy must be prevented (even in females with a history of infertility) by simultaneous use of 2 forms of effective contraception for ≥4 weeks before, throughout, and for ≥4 weeks after therapy, including during dosage interruptions. Must include at least 1 highly effective contraceptive method (e.g., intrauterine device [IUD], hormonal contraceptive, tubal ligation, vasectomized partner); other method may be an effective barrier method (e.g., latex or synthetic condom, diaphragm, cervical cap). Mandatory contraception not required for females who have undergone hysterectomy or bilateral oophorectomy, who are postmenopausal and have had no menses for ≥24 consecutive months, or who practice continuous abstinence from heterosexual contact.

Lenalidomide distributes into semen; sexually mature males (including those who have undergone successful vasectomy) must use a latex or synthetic condom each time they have sexual contact with a woman of reproductive potential during and for up to 28 days after therapy. Men must not donate semen during and for 28 days after therapy.

Patients must not donate blood during and for ≥1 month after therapy because of potential for presence of the drug in blood, and possibility of transfusion into a pregnant woman.

Obtain 2 negative pregnancy test reports prior to initiating therapy in women of reproductive potential; tests to exclude pregnancy must be performed within 10–14 days and again within 24 hours immediately prior to treatment initiation. Repeat pregnancy tests weekly during the first month of therapy, then every 2 or 4 weeks in women with irregular or regular menstrual cycles, respectively.

Provide pregnancy testing and counseling if a patient misses her period or has abnormalities in menstrual bleeding. Discontinue drug during evaluation.

If pregnancy occurs, immediately discontinue treatment and apprise the patient of potential fetal hazard. Refer patient to obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to FDA MedWatch Program at 800-FDA-1088 and to manufacturer at 888-423-5436.

Hematologic Effects

Risk of severe (grade 3 or 4) neutropenia and/or thrombocytopenia.

Grade 3 or 4 neutropenia or thrombocytopenia reported in up to 59 or 38%, respectively, of patients treated with the combination of lenalidomide and dexamethasone for multiple myeloma.

Grade 3 or 4 hematologic toxicities reported in about 80% of patients with MDS. Generally occurs during initial weeks (approximately 6 weeks for neutropenia and 4 weeks for thrombocytopenia) of treatment and reverses with dosage reduction or discontinuance.

Grade 3 or 4 neutropenia or thrombocytopenia reported in 43 or 28%, respectively, of patients with mantle cell lymphoma.

In patients with follicular lymphoma or marginal-zone lymphoma, grade 3 or 4 neutropenia reported in 50 or 33%, respectively, of patients treated with lenalidomide and rituximab; grade 3 or 4 thrombocytopenia reported in 2 or 8% of lenalidomide-treated patients, respectively.

Carefully monitor hematologic status during therapy. Obtain baseline CBCs.

In patients with multiple myeloma, monitor CBCs weekly for the first 2 cycles, followed by CBCs on days 1 and 15 of cycle 3, and then every 4 weeks thereafter. (See Dosage Modification for Hematologic Toxicity in Patients with Multiple Myeloma Receiving Lenalidomide in Combination with Dexamethasone and also Dosage Modification for Hematologic Toxicity in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance Therapy under Dosage and Administration.)

In patients with MDS, perform weekly CBCs during first 8 weeks of therapy, and at least monthly thereafter. (See Dosage Modification for Toxicity in Patients with MDS under Dosage and Administration.)

In patients with mantle cell lymphoma, perform weekly CBCs during the first cycle, every 2 weeks during cycles 2–4, and then monthly thereafter. (See Dosage Modification for Hematologic Toxicity in Patients with Mantle Cell Lymphoma under Dosage and Administration.)

In patients with follicular lymphoma or marginal-zone lymphoma, perform weekly CBCs for the first 3 weeks of cycle 1, every 2 weeks during cycles 2–4, and then monthly thereafter. (See Dosage Modification for Hematologic Toxicity in Patients with Follicular Lymphoma or Marginal-zone Lymphoma under Dosage and Administration.)

Thromboembolic Events

Increased risk of venous and arterial thromboembolism (e.g., DVT, PE, MI, stroke).

Thromboprophylaxis is recommended. Carefully assess risk factors for thromboembolism. Selection of an appropriate thromboprophylaxis regimen (e.g., aspirin, anticoagulant) should be based on careful assessment of the patient’s risk factors for thromboembolism.

International Myeloma Working Group (IMWG) recommends aspirin for lenalidomide-treated multiple myeloma patients with ≤1 individual and/or myeloma-related risk factor and a low molecular weight heparin (LMWH) for those with ≥2 such risk factors. IMWG also recommends that thromboprophylaxis with an LMWH be considered in patients receiving lenalidomide with high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors. IMWG states full-dose warfarin (INR 2–3) is an alternative to LMWHs, but clinical experience is limited.

ASCO recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving lenalidomide with dexamethasone or antineoplastic agents. Those at lower risk for thromboembolism may receive aspirin or an LMWH; those at higher risk should receive an LMWH.

Other Warnings and Precautions

Treatment-related Mortality

Increased mortality reported in patients receiving lenalidomide compared with chlorambucil in patients with chronic lymphocytic leukemia (CLL). Patients with CLL should not receive lenalidomide outside of a clinical trial.

Increased mortality reported in patients with multiple myeloma receiving pembrolizumab in combination with a thalidomide analog and dexamethasone. Patients with multiple myeloma should not receive an anti-programmed death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) in combination with a thalidomide analog and dexamethasone outside of a clinical trial.

Early deaths reported in patients with mantle cell lymphoma in a clinical trial; high tumor burden, baseline MCL International Prognostic Index (MIPI) score, and high WBC count at baseline were factors associated with early death.

Development of Second Primary Malignancy

Second primary malignancies, including acute myeloid leukemia (AML), MDS or solid tumors, reported in patients receiving lenalidomide in clinical trials.

Monitor for development of second primary malignancies; consider the risk of second primary malignancies along with the potential benefit of lenalidomide.

Hepatotoxicity

Hepatic failure, sometimes fatal, reported in patients receiving lenalidomide in combination with dexamethasone.

Pre-existing liver disease of viral etiology, elevated baseline liver enzymes, and those receiving concomitant medications may be at increased risk.

Monitor LFTs periodically; withhold therapy and consider dosage reduction for increased LFTs. (See Dosage Modification for Nonhematologic Adverse Reactions under Dosage and Administration.)

Cutaneous Reactions

Severe, and potentially fatal, cases of cutaneous reactions (SJS, TEN, and drug reaction with eosinophilia and systemic symptoms [DRESS]) reported.

If grade 2 or 3 skin rash occurs, consider withholding or discontinuing lenalidomide. If grade 4 rash, exfoliative or bullous rash, or other severe cutaneous reactions (SJS, TEN, or DRESS) occur, permanently discontinue drug. (See Advice to Patients.)

Tumor Lysis Syndrome

Tumor lysis syndrome may occur.

Risk is increased in patients with a high tumor burden. Monitor such patients and institute appropriate precautions.

Tumor Flare Reaction

Tumor flare reaction (i.e., lymph node swelling, low grade fever, pain, rash), which may mimic disease progression, has been reported. Lenalidomide should not be used in patients with CLL outside of clinical trials. Patients with mantle cell lymphoma, follicular lymphoma, or marginal-zone lymphoma should be monitored and evaluated for tumor flare reaction.

If grade 1 or 2 tumor flare reaction occurs, continue lenalidomide without dosage adjustment or interruption of therapy. For grade 3 or 4 tumor flare reaction, withhold lenalidomide until resolution to grade 1 or less. Symptomatic treatment for tumor flare reaction may include corticosteroids, non-steroidal anti-inflammatory drugs, and/or opiate analgesics.

Impaired Stem Cell Mobilization

The number of CD 34+ cells collected may decrease in patients who have received ≥4 cycles of lenalidomide.

Promptly refer patients who are candidates for autologous HSCT to a transplant center to optimize the timing of the stem cell collection. In patients who have received >4 cycles of lenalidomide-containing therapy or those who previously failed to achieve adequate CD34+ peripheral blood progenitor cells (PBPCs) collection following mobilization with G-CSF alone, hematopoietic stem cell mobilization combination regimens (e.g., G-CSF and cyclophosphamide; G-CSF and CXCR4 chemokine-receptor antagonist) may be used.

Thyroid Disorders

Hyperthyroidism and hypothyroidism reported; monitor thyroid function before initiating lenalidomide and during therapy.

Hypersensitivity

Angioedema, anaphylaxis, and anaphylactic reactions reported. Permanently discontinue lenalidomide if angioedema or anaphylaxis occurs.

Specific Populations

Pregnancy

Contraindicated for use during pregnancy. (See REMS under Dosage and Administration and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Females or Males of Reproductive Potential

Exclude pregnancy prior to treatment initiation and throughout therapy. Avoid pregnancy for ≥4 weeks prior to and during therapy, during dosage interruptions, and for 4 weeks after completion of therapy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Distributed into semen at 2 and 24 hours following administration of lenalidomide 25 mg daily.

Lactation

Not known whether lenalidomide is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No substantial differences in efficacy relative to younger adults; however, increased incidence of serious adverse effects reported in patients >65 years of age compared with younger patients. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics not altered in mild hepatic impairment; not studied in moderate to severe hepatic impairment. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Substantially eliminated by kidneys; possible increased toxicity in patients with renal impairment.

Monitor renal function; adjust dosage based on degree of renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Multiple myeloma (≥20%): Diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, tremor.

MDS (>15%): Thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, epistaxis.

Mantle cell lymphoma, follicular lymphoma, or marginal-zone lymphoma (≥15%): Neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, rash.

Interactions for Lenalidomide

Does not inhibit or induce CYP isoenzymes.

Does not inhibit P-glycoprotein (P-gp), bile salt export pump (BSEP), breast cancer resistance protein (BCRP), multidrug resistance-associated protein (MRP) 2, organic anion transporter (OAT) 1 or 3, organic anion transport protein (OATP) 1B1 or 1B3, or organic cation transporter (OCT) 2.

Substrate, but not an inhibitor, of P-gp.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drug interactions unlikely.

Drugs Affecting Efflux Transport Systems

P-gp inhibitors: No clinically significant alterations in lenalidomide exposure.

Drugs Associated with an Increased Risk of Thrombosis

Concomitant use with erythropoietic agents, estrogen-containing drugs, or other agents that increase the risk of thrombosis may increase risk of thrombosis.

Use with caution in patients receiving lenalidomide; only use if the potential benefits of concomitant therapy outweigh the risks.

Specific Drugs

Drug

Interaction

Comments

Digoxin

Increased systemic exposure of digoxin

Monitor plasma digoxin concentrations

Warfarin

No pharmacokinetic interaction observed with single dose of warfarin

Closely monitor PT and INR

Lenalidomide Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration.

In patients with multiple myeloma or MDS, peak plasma concentrations attained within 0.5–6 hours following oral administration.

AUC increases in a dose-proportional manner.

Food

Following administration of a single 25-mg dose of lenalidomide with a high-fat meal, extent of absorption was reduced and peak plasma concentration or AUC decreased by 50 or 20%, respectively.

Distribution

Extent

Not known whether distributed into human milk.

Crosses placenta in humans; embryocidal effects observed in rabbits.

Distributed into semen. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Plasma Protein Binding

Approximately 30%.

Elimination

Metabolism

Minimally metabolized; 5-hydroxy-lenalidomide and N-acetyl-lenalidomide metabolites each account for <5% of lenalidomide plasma concentration.

Elimination Route

Primarily excreted in urine (82%) within 24 hours.

Partially (about 30%) removed by hemodialysis.

Half-life

Approximately 3 hours in healthy subjects and 3–5 hours in patients with multiple myeloma, MDS, or mantle cell lymphoma.

No evidence of drug accumulation with multiple dosing.

Special Populations

In patients with renal impairment (Clcr <50 mL/minute), clearance reduced, systemic exposure increased, and half-life prolonged.

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).

Actions

  • A thalidomide analog with immunomodulatory, antineoplastic, and antiangiogenic activity.

  • Induces direct cytotoxic and immunomodulatory effects following ubiquitination and degradation of substrate proteins (e.g., Aiolos, Ikaros, CK1α).

  • Induces apoptosis and inhibits proliferation of hematopoietic tumor cells.

  • Increases count and activation of T cells and natural killer (NK) cells resulting in direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via inhibition of production of proinflammatory cytokines (e.g., tumor necrosis factor [TNF; TNF-α], interleukin-6 [IL-6]), increased secretion of IL-2 and interferon gamma, and increased NK cells.

  • Concomitant use of lenalidomide and dexamethasone results in synergistic inhibition of cell proliferation and induction of apoptosis in multiple myeloma cells.

  • In vitro, combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells and increases ADCC in marginal-zone lymphoma cells compared with rituximab alone.

Advice to Patients

  • Importance of educating patients regarding the Lenalidomide Risk Evaluation and Mitigation Strategy (REMS) restricted distribution program for obtaining lenalidomide. (See REMS under Dosage and Administration.)

  • Importance of informing patients of Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to lenalidomide during pregnancy.

  • Importance of advising patients to swallow capsules intact and not to break, chew, or open capsules.

  • Importance of advising patients that a missed dose may be taken up to 12 hours after the scheduled administration time; if more than 12 hours have elapsed, the missed dose should be omitted, and the regular dosing schedule resumed the following day. Importance of not taking 2 doses at the same time to make up for a missed dose.

  • Risk of fetal harm. Necessity of advising women of reproductive potential to use effective methods of contraception beginning at least 4 weeks prior to initiation of therapy, throughout therapy, during dosage interruptions, and for at least 4 weeks after discontinuance of therapy (see Fetal/Neonatal Morbidity and Mortality under Cautions); importance of obtaining pregnancy tests at appropriate intervals during therapy and of immediately discontinuing therapy and contacting their clinician if pregnancy is suspected. Necessity of advising men (including those who have successfully undergone vasectomy) to use a latex or synthetic condom during sexual encounters with women of reproductive potential; these contraceptive measures are required during and for at least 4 weeks after discontinuance of lenalidomide therapy.

  • Importance of advising women to avoid breast-feeding while receiving lenalidomide therapy.

  • Importance of advising men to avoid donating semen while receiving lenalidomide and for 4 weeks after discontinuing the drug.

  • Necessity of monitoring CBCs for neutropenia and thrombocytopenia during lenalidomide therapy.

  • Risk of venous and arterial thromboembolic events; importance of advising patients to seek medical care if they develop symptoms of shortness of breath, chest pain, or swelling of the arms or legs. (See Thromboembolic Events under Cautions.)

  • Possible increased mortality and risk of serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure in patients with CLL.

  • Risk of developing a second primary malignancy.

  • Risk of hepatotoxicity, including hepatic failure and death; importance of advising patients to report signs and symptoms of hepatotoxicity to their clinician for evaluation.

  • Risk of severe skin reactions; importance of advising patients to seek medical care for signs and symptoms of SJS, TEN, or DRESS. Lenalidomide therapy should be avoided in patients with a history of grade 4 rash associated with thalidomide. (See Cutaneous Reactions under Cautions.)

  • Risk of tumor lysis syndrome. Importance of informing clinician if signs and symptoms of tumor lysis syndrome occur.

  • Risk of tumor flare reaction. Importance of informing clinician of signs and symptoms of tumor flare reaction.

  • Importance of informing patients with mantle cell lymphoma of the risk of early death.

  • Risk of severe hypersensitivity reactions; importance of advising patients to seek medical care for signs and symptoms of hypersensitivity reactions.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Because lenalidomide is an analog of thalidomide (a known human teratogen that can cause severe, life-threatening birth defects if administered during pregnancy), distribution of lenalidomide is restricted. See REMS and also see REMS under Dosage and Administration.

Lenalidomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

2.5 mg

Revlimid

Celgene

5 mg

Revlimid

Celgene

10 mg

Revlimid

Celgene

15 mg

Revlimid

Celgene

20 mg

Revlimid

Celgene

25 mg

Revlimid

Celgene

AHFS DI Essentials™. © Copyright 2022, Selected Revisions January 25, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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