Lenalidomide

LENALIDOMIDE- lenalidomide capsule
Teva Pharmaceuticals, Inc.

WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS and ARTERIAL THROMBOEMBOLISM

Embryo-Fetal Toxicity

Do not use lenalidomide capsules 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 lenalidomide treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after lenalidomide capsules treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, lenalidomide capsules are only available through a restricted distribution program, the Lenalidomide REMS program (5.2).

Information about the Lenalidomide REMS program is available at www.lenalidomiderems.com or by calling the toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

Lenalidomide capsules can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

Venous and Arterial Thromboembolism

Lenalidomide capsules have 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 lenalidomide capsules 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 [see Warnings and Precautions (5.4)].

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

Lenalidomide capsules in combination with dexamethasone are indicated for the treatment of adult patients with multiple myeloma (MM).

1.2 Myelodysplastic Syndromes

Lenalidomide capsules are indicated for the treatment of adult patients with 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.

1.3 Mantle Cell Lymphoma

Lenalidomide capsules are indicated for the treatment of adult patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

1.6 Limitations of Use

Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for Multiple Myeloma

Lenalidomide Capsules Combination Therapy

The recommended starting dose of lenalidomide capsules is 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients greater than 75 years old, the starting dose of dexamethasone may be reduced [see Clinical Studies (14.1)]. Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a lenalidomide-containing therapy [see Warnings and Precautions (5.12)].

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide capsules.

Table 1: Dose Adjustments for Hematologic Toxicities for MM

Platelet counts

Thrombocytopenia in MM

When Platelets

Recommended Course

Days 1 to 21 of repeated 28-day cycle

Fall below 30,000/mcL

Interrupt lenalidomide capsules treatment, follow CBC weekly

Return to at least 30,000/mcL

Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop below 30,000/mcL

Interrupt lenalidomide capsules treatment

Return to at least 30,000/mcL

Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils

Recommended Course

Days 1 to 21 of repeated 28-day cycle

Fall below 1,000/mcL

Interrupt lenalidomide capsules treatment, follow CBC weekly

Return to at least 1,000/mcL and neutropenia is the only toxicity

Resume lenalidomide capsules at 25 mg daily or initial starting dose

Return to at least 1,000/mcL and if other toxicity

Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily

For each subsequent drop below 1,000/mcL

Interrupt lenalidomide capsules treatment

Return to at least 1,000/mcL

Resume lenalidomide capsules at next lower dose. Do not dose below 2.5 mg daily

2.2 Recommended Dosage for Myelodysplastic Syndromes

The recommended starting dose of lenalidomide capsules is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings. Continue treatment until disease progression or unacceptable toxicity.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Platelet counts

If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline is at least 100,000/mcL

When Platelets

Recommended Course

Fall below 50,000/mcL

Interrupt lenalidomide capsules treatment

Return to at least 50,000/mcL

Resume lenalidomide capsules at 5 mg daily

If baseline is below 100,000/mcL

When Platelets

Recommended Course

Fall to 50% of the baseline value

Interrupt lenalidomide capsules treatment

If baseline is at least 60,000/mcL and returns to at least 50,000/mcL

Resume lenalidomide capsules at 5 mg daily

If baseline is below 60,000/mcL and returns to at least 30,000/mcL

Resume lenalidomide capsules at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets

Recommended Course

Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions

Interrupt lenalidomide capsules treatment

Return to at least 30,000/mcL

(without hemostatic failure)

Resume lenalidomide capsules at 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

Recommended Course

Fall below 30,000/mcL or below 50,000/mcL with platelet transfusions

Interrupt lenalidomide capsules treatment

Return to at least 30,000/mcL

(without hemostatic failure)

Resume lenalidomide capsules 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

Recommended Course

Fall below 750/mcL

Interrupt lenalidomide capsules treatment

Return to at least 1,000/mcL

Resume lenalidomide capsules at 5 mg daily

If baseline ANC is below 1,000/mcL

When Neutrophils

Recommended Course

Fall below 500/mcL

Interrupt lenalidomide capsules treatment

Return to at least 500/mcL

Resume lenalidomide capsules at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Neutrophils

Recommended Course

Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5°C)

Interrupt lenalidomide capsules treatment

Return to at least 500/mcL

Resume lenalidomide capsules 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

Recommended Course

Fall below 500/mcL for at least 7 days or below 500/mcL associated with fever (at least 38.5ºC)

Interrupt lenalidomide capsules treatment

Return to at least 500/mcL

Resume lenalidomide capsules at 2.5 mg daily

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