LENADES

Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties.

The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure: 3-(4-amino-1-oxo 1,3-dihydro-2 H -isoindol-2-yl) piperidine-2,6-dione The empirical formula for lenalidomide is C 13 H 13 N 3 O 3, and the gram molecular weight is 259.3.

Lenalidomide is a cream to light yellow color powder.

It is soluble in organic solvent/water mixtures, and buffered aqueous solvents.

Lenalidomide is more soluble in organic solvents and low pH solutions.

Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.

Lenalidomide is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg capsules for oral administration.

Each capsule contains lenalidomide as the active ingredient and the following inactive ingredients: anhydrous lactose.

The capsule shell ingredients common to all strengths are gelatin and titanium dioxide.

Additionally, the 20 mg capsule contains FD&C Blue #1, FD&C Yellow #6, and iron oxide yellow.

Each capsule is printed with black ink, which includes black iron oxide, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution.

Lenalidomide is a thalidomide analogue indicated for the treatment of adult patients with: Multiple myeloma (MM), in combination with dexamethasone.

Transfusion-dependent anemia due to low.

• or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities.

Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Lenalidomide capsules are not indicated and are not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials. 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.

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties.

Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex.

In vitro, in the presence of drug, substrate proteins (including Aiolos, Ikaros, and CK1α) are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.

Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro.

Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM.

Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

In MM cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a thorough QT study.

At a dose two times the maximum recommended dose, lenalidomide did not prolong the QTc interval.

The largest upper bound of the two-sided 90% CI for the mean differences between lenalidomide and placebo was below 10 ms. 12.3 Pharmacokinetics Absorption Following single and multiple doses of lenalidomide capsules in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose.

The single and multiple dose pharmacokinetic disposition of lenalidomide is linear with AUC and C max values increasing proportionally with dose.

Multiple doses of lenalidomide at the recommended dosage does not result in drug accumulation.

Administration of a single 25 mg dose of lenalidomide capsules with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in C max.

In the trials where the efficacy and safety were established for lenalidomide capsules, the drug was administered without regard to food intake.

Lenalidomide capsules can be administered with or without food.

The oral absorption rate of lenalidomide in patients with MCL is similar to that observed in patients with MM or MDS.

In vitro [ 14 C]-lenalidomide binding to plasma proteins is approximately 30%.

Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of lenalidomide 25 mg daily.

The mean half-life of lenalidomide is 3 hours in healthy subjects and to 5 hours in patients with MM, MDS or MCL.

Lenalidomide undergoes limited metabolism.

Unchanged lenalidomide is the predominant circulating component in humans.

Two identified metabolites are 5-hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.

Elimination is primarily renal.

Following a single oral administration of [ 14 C]-lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively.

Approximately 82% of the radioactive dose was excreted as lenalidomide in the urine within 24 hours.

Hydroxy-lenalidomide and

N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively.

The renal clearance of lenalidomide exceeds the glomerular filtration rate.

Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), 9 subjects with moderate renal impairment (CLcr to 49 mL/min), 4 subjects with severe renal impairment (CLcr < 30 mL/min), and 6 patients with end stage renal disease (ESRD) requiring dialysis were administered a single 25 mg dose of lenalidomide capsules.

Three healthy subjects of similar age with normal renal function (CLcr > 80 mL/min) were also administered a single 25 mg dose of lenalidomide capsules.

As CLcr decreased, half-life increased and drug clearance decreased linearly.

Patients with moderate and severe impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects.

Patients on hemodialysis (n=6) had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects.

Approximately 30% of the drug in body was removed during a 4-hour hemodialysis session.

Adjust the starting dose of lenalidomide capsules in patients with renal impairment based on the CLcr value.

Mild hepatic impairment (defined as total bilirubin > 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did not influence the disposition of lenalidomide.

No pharmacokinetic data is available for patients with moderate to severe hepatic impairment.

Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM, MDS or MCL) did not have a clinically relevant effect on lenalidomide clearance in adult patients.

Co-administration of a single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg).

Co-administration of lenalidomide capsules (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the C max or AUC of lenalidomide.

Co-administration of the

P-gp inhibitor and substrate temsirolimus (25 mg), with lenalidomide capsules (25 mg) did not significantly alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of temsirolimus).

In vitro studies demonstrated that lenalidomide is a substrate of P-glycoprotein (P-gp).

Lenalidomide is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2.

Lenalidomide is not an inhibitor of

P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.

Lenalidomide does not inhibit or induce

CYP450 isoenzymes.

Also, lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A11/1, UGT1A11/28, and UGT1A128/28.

The following clinically significant adverse reactions are described in detail in other sections of the prescribing information: Embryo-Fetal Toxicity Hematologic Toxicity Venous and Arterial Thromboembolism Increased Mortality in Patients with CLL Second Primary Malignancies Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone Hepatotoxicity Severe Cutaneous Reactions Tumor Lysis Syndrome Tumor Flare Reactions Impaired Stem Cell Mobilization Thyroid.

Disorders Early Mortality in Patients with MCL Hypersensitivity MM: Most common adverse reactions (≥20%) include 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, and tremor.

Most common adverse reactions (>15%) include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis.

Non-Hodgkin’s Lymphoma (NHL: MCL): Most common adverse reactions (≥15%) included neutropenia, thrombocytopenia, anemia, leukopenia, diarrhea, constipation, nausea, fatigue, pyrexia, cough, upper respiratory tract infection, and rash.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

MM – Lenalidomide Capsules Combination Therapy: Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of lenalidomide with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks).

The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia.

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 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

Continuous arm, the most common adverse reactions leading to dose interruption of lenalidomide were infection events (28.8%); overall, the median time to the first dose interruption of lenalidomide was 7 weeks.

The most common adverse reactions leading to dose reduction of lenalidomide in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of lenalidomide was 16 weeks.

Continuous arm, the most common adverse reactions leading to discontinuation of lenalidomide were infection events (3.4%).

In both

Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts.

The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Table 4: All Adverse Reactions in ≥5% and Grade 3/4 Adverse Reactions in ≥1% of Patients with MM in the Rd Continuous or Rd18 Arms* Body System Adverse Reaction All Adverse Reactions a Grade 3/4 Adverse Reactions b Rd Continuous (N=532) Rd18 (N=540) MPT (N=541) Rd Continuous (N=532) Rd18 (N=540) MPT (N=541) General disorders and administration site conditions Fatigue % 173 177 154 39 46 31 Asthenia 150 123 124 41 33 32 Pyrexia c 114 102 76 13 7 7 Non-cardiac chest pain f 29 31 18 <1% < 1% < 1% Gastrointestinal disorders Diarrhea 242 208 89 21 18 8 Abdominal pain %f 109 78 60 7 9 < 1% Dyspepsia f 57 28 36 <1% < 1% 0 Musculoskeletal and connective tissue disorders Back pain c 170 145 116 37 34 28 Muscle spasms f 109 102 61 < 1% < 1% < 1% Arthralgia f 101 71 66 9 8 8 Bone pain f 87 77 62 16 15 14 Pain in extremity f 79 66 61 8 8 7 Musculoskeletal pain f 67 59 36 < 1% < 1% < 1% Musculoskeletal chest pain f 60 51 39 6 < 1% < 1% Muscular weakness f 43 35 29 < 1% 8 < 1% Neck pain f 40 19 10 < 1% < 1% < 1%.

Infections and infestations Bronchitis c 90 59 43 9 6 < 1% Nasopharyngitis f 80 54 33 0 0 0 Urinary tract infection f 76 63 41 8 8 < 1% Upper respiratory tract infection c% f 69 53 31 < 1% 8 < 1% Pneumonia c@ 93 87 56 60 57 41 Respiratory tract infection % 35 25 21 7 < 1% < 1% Influenza f 33 23 15 < 1% < 1% 0 Gastroenteritis f 32 17 13 0 < 1% < 1% Lower respiratory tract infection 29 14 16 10 < 1% < 1% Rhinitis f 29 24 14 0 0 0 Cellulitis c < 5% < 5% < 5% 8 < 1% < 1% Sepsis c@ 33 26 18 26 20 13 Nervous system disorders Headache f 75 52 56 < 1% < 1% < 1% Dysgeusia f 39 45 22 < 1% 0 < 1% Blood and lymphatic system disorders d Anemia 233 193 229 97 85 102 Neutropenia 186 178 328 148 143 243 Thrombocytopenia 104 100 135 44 43 60 Febrile neutropenia 7 17 15 6 16 14 Pancytopenia < 1% 6 7 < 1% < 1% < 1% Respiratory, thoracic and mediastinal disorders Cough f 121 94 68 < 1% < 1% < 1% Dyspnea c,e 117 89 113 30 22 18 Epistaxis f 32 31 17 < 1% < 1% 0 Oropharyngeal pain f 30 22 14 0 0 0 Dyspnea exertional e 27 29 < 5% 6 < 1% 0 Metabolism and nutrition disorders Decreased appetite 123 115 72 14 7 < 1% Hypokalemia % 91 62 38 35 20 11 Hyperglycemia 62 52 19 28 23 9 Hypocalcemia 57 56 31 23 19 8 Dehydration % 25 29 17 8 13 9 Gout e < 5% < 5% < 5% 8 0 0 Diabetes mellitus % e < 5% < 5% < 5% 8 < 1% < 1% Hypophosphatemia e < 5% < 5% < 5% 7 < 1% < 1% Hyponatremia % e < 5% < 5% < 5% 7 13 6 Skin and subcutaneous tissue disorders Rash 139 151 105 39 38 33 Pruritus f 47 49 24 < 1% < 1% < 1% Psychiatric disorders Insomnia 147 127 53 < 1% 6 0 Depression 58 46 30 10 < 1% < 1% Vascular disorders Deep vein thrombosis c % 55 39 22 30 20 15 Hypotension c % 51 35 36 11 8 6 Injury, Poisoning, and Procedural Complications Fall f 43 25 25 < 1% 6 6 Contusion f 33 24 15 < 1% < 1% 0 Eye disorders Cataract 73 31 < 1% 31 14 < 1% Cataract subcapsular e < 5% < 5% < 5% 7 0 0.

Investigations Weight decreased 72 78 48 11 < 1% < 1% Cardiac disorders Atrial fibrillation c 37 25 25 13 9 6 Myocardial infarction (including acute) c,e < 5% < 5% < 5% 10 < 1% < 1% Renal and Urinary disorders Renal failure (including acute) c@,f 49 54 37 28 33 29 Neoplasms benign, malignant and unspecified (Including cysts and polyps) Squamous cell carcinoma c e < 5% < 5% < 5% 8 < 1% 0 Basal cell carcinoma c e,f < 5% < 5% < 5% < 1% < 1% 0 Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse events in at least 5% of subjects in the Rd Continuous or Rd18 Arms and at least a 2% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse events in at least 1% of subjects in the Rd Continuous or Rd18 Arms and at least a 1% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable. f Footnote “b” not applicable. @.

• adverse reactions in which at least one resulted in a fatal outcome. %.

• adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases). * Adverse reactions included in combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalized, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis After At Least One Prior Therapy for MM: Data were evaluated from 703 patients in two studies who received at least one dose of lenalidomide/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the lenalidomide/dexamet.

There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL.

In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs.

In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

Pregnancy ( Boxed Warning, 4.1, 5.1, 8.1 ).

Demonstrated severe hypersensitivity to lenalidomide. 4.1 Pregnancy Lenalidomide capsules can cause fetal harm when administered to a pregnant female.

Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis.

This effect was seen at all doses tested.

Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide 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 a fetus. 4.2 Severe Hypersensitivity Reactions Lenalidomide capsules are contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide.

combination therapy: 25 mg once daily orally on Days to 21 of repeated 28-day cycles. .

MDS: 10 mg once daily.

MCL: 25 mg once daily orally on Days to 21 of repeated 28-day cycles.

Renal impairment

Adjust starting dose based on the creatinine clearance value.

For concomitant therapy doses, see Full Prescribing Information. 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 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.

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.

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 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 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 2.3 Recommended Dosage for Mantle Cell Lymphoma The recommended starting dose of lenalidomide capsules is 25 mg/day orally on Days to 21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to lenalidomide capsules.

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall below 50,000/mcL Interrupt lenalidomide capsules treatment and follow CBC weekly Return to at least 50,000/mcL Resume lenalidomide capsules at 5 mg less than the previous dose.

Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall below 1,000/mcL for at least 7 days OR Falls below 1,000/mcL with an associated temperature at least 38.5°C OR Falls below 500/mcL Interrupt lenalidomide capsules treatment and follow CBC weekly Return to at least 1,000/mcL Resume lenalidomide capsules at 5 mg less than the previous dose.

Do not dose below 5 mg daily 2.5 Dosage Modifications for Non-Hematologic Adverse Reactions For non-hematologic Grade 3/4 toxicities judged to be related to lenalidomide capsules, hold treatment and restart at the physician's discretion at next lower dose level when toxicity has resolved to Grade 2 or below.

Permanently discontinue lenalidomide capsules for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions. 2.6 Recommended Dosage for Patients with Renal Impairment The recommendations for dosing patients with renal impairment are shown in the following table.

Table 3: Dose Adjustments for Patients with Renal Impairment Renal Function (Cockcroft-Gault) Dose in Lenalidomide Capsules Combination Therapy for MM and MCL Dose in Lenalidomide Capsules for MDS CLcr to 60 mL/min 10 mg once daily 5 mg once daily CLcr below 30 mL/min (not requiring dialysis) 15 mg every other day 2.5 mg once daily CLcr below 30 mL/min (requiring dialysis) 5 mg once daily.

On dialysis days, administer the dose following dialysis. 2.5 mg once daily.

On dialysis days, administer the dose following dialysis.

Lenalidomide Capsules Combination Therapy for MM

For CLcr of to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of lenalidomide without dose-limiting toxicity.

Lenalidomide Capsules Therapy for MCL and MDS: Base subsequent lenalidomide capsules dose increase or decrease on individual patient treatment tolerance. 2.7 Administration Advise patients to take lenalidomide capsules orally at about the same time each day, either with or without food.

Advise patients to swallow lenalidomide capsules whole with water and not to open, break, or chew them.

Lenalidomide capsules are available as follows: 2.5 mg – Each size 4 capsule with white cap and body printed with “NAT” on cap and “2.5mg” on body in black ink contains 2.5 mg of lenalidomide. 2.5 mg bottles of 28 (NDC 0480-1241-28) 5 mg – Each size 2 capsule with white cap and body printed with “NAT” on cap and “5mg” on body in black ink contains 5 mg of lenalidomide. 5 mg bottles of 28 (NDC 0480‐1242‐28) 10 mg – Each size 2 capsule with white cap and body printed with “NAT” on cap and “10mg” on body in black ink contains 10 mg of lenalidomide. 10 mg bottles of 28 (NDC 0480‐1243‐28) 15 mg – Each size 2 capsule with white cap and body printed with “NAT” on cap and “15mg” on body in black ink contains 15 mg of lenalidomide. 15 mg bottles of 21 (NDC 0480‐1244‐21) 20 mg – Each size 2 capsule with green cap and blue body printed with “NAT” on cap and “20 mg” on body in black ink contains 20 mg of lenalidomide. 20 mg bottles of 21 (NDC 0480-1245-21) 25 mg – Each size 2 capsule with white cap and body printed with “NAT” on cap and “25mg” on body in black ink contains 25 mg of lenalidomide. 25 mg bottles of 21 (NDC 0480‐1246‐21) 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) . 16.3 Handling and Disposal Care should be exercised in the handling of lenalidomide capsules.

Lenalidomide capsules should not be opened or broken.

If powder from lenalidomide capsules contacts the skin, wash the skin immediately and thoroughly with soap and water.

If lenalidomide contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered.

Several guidelines on the subject have been published.

Dispense no more than a 28-day supply.

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lenalidomide capsules during pregnancy as well as female partners of male patients who are exposed to lenalidomide capsules.

This registry is also used to understand the root cause for the pregnancy.

Based on the mechanism of action and findings from animal studies, lenalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy.

Lenalidomide is a thalidomide analogue.

Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Lenalidomide caused thalidomide-type limb defects in monkey offspring.

Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats.

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 a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug.

Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk in the

U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data Animal data

In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis.

Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre.

• and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation.

The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area).

The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring.

As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide.

Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20% to 40% of the maternal C max.

Following a single oral dose to pregnant rats, lenalidomide was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues.

These data indicated that lenalidomide crossed the placenta.

Safety and effectiveness have not been established in pediatric patients.

Overall, of the 1613 patients in the NDMM study who received study treatment, 94% (1521/1613) were 65 years of age or older, while 35% (561/1613) were over 75 years of age.

The percentage of patients over age was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%).

Overall, across all treatment arms, the frequency in most of the adverse reaction categories (eg, all adverse reactions, grade 3/4 adverse reactions, serious adverse reactions) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects.

Grade 3 or 4 adverse reactions in the General.

Disorders and Administration Site Conditions body system were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms.

Grade 3 or 4 adverse reactions in the.

Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue.

Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms.

For other body systems (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 adverse reactions in older vs younger subjects across all treatment arms Serious adverse reactions were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms.

MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies and 2, 45% were age 65 or over while 12% of patients were age and over.

The percentage of patients age 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups.

Of the 353 patients who received lenalidomide/dexamethasone, 46% were age and over.

In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of lenalidomide capsules.

No differences in efficacy were observed between patients over 65 years of age and younger patients.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age and over, while 33% were age and over.

Although the overall frequency of adverse reactions (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (54% vs. 33%).

A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse reactions than the proportion of younger patients (27% vs.16%).

Of the 134 patients with MCL enrolled in the MCL trial, 63% were age and over, while 22% of patients were age and over.

The overall frequency of adverse reactions was similar in patients over 65 years of age and in younger patients (98% vs. 100%).

The overall incidence of grade and 4 adverse reactions was also similar in these 2 patient groups (79% vs. 78%, respectively).

The frequency of serious adverse reactions was higher in patients over 65 years of age than in younger patients (55% vs. 41%).

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection.

Monitor renal function.