LENALIDOMIDE BIOPHARM

Lenalidomide (previously referred to as CC-5013) is an immunomodulatory drug with potent antineoplastic, anti-angiogenic, and anti-inflammatory properties.

It is a 4-amino-glutamyl analogue of thalidomide and like thalidomide, lenalidomide exists as a racemic mixture of the active S(-) and R(+) forms.

However, lenalidomide is much safer and potent than thalidomide, with fewer adverse effects and toxicities. 2, 3 Thalidomide and its analogues, including lenalidomide, are referred to as immunomodulatory imide drugs (also known as cereblon modulators), which are a class of immunomodulatory drugs that contain an imide group.

Lenalidomide works through various mechanisms of actions that promote malignant cell death and enhance host immunity.

Available as oral capsules, lenalidomide is approved by the FDA and EU for the treatment of multiple myeloma, myelodysplastic syndromes, mantle cell lymphoma, follicular lymphoma, and marginal zone lymphoma in selected patients.

Due to severe teratogenicity, pregnancy must be excluded before the start of treatment and patients must enroll in the lenalidomide Risk Evaluation and Mitigation Strategy (REMS) program to ensure contraception adherence.

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

It is also indicated as maintenance therapy in multiple myeloma following autologous hematopoietic stem cell transplantation (auto-HSCT).

It is 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.

Lenalidomide is 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.

In combination with a rituximab product, lenalidomide is indicated for the treatment of adult patients with previously treated follicular lymphoma (FL) or previously treated marginal zone lymphoma (MZL).

In hematological malignancies, the immune system is deregulated in the form of altered cytokine networks in the tumour microenvironment, defective T cell regulation of host-tumour immune interactions, and diminished NK cell activity.

Lenalidomide is an immunomodulatory agent with antineoplastic, antiangiogenic, and anti-inflammatory properties.

Lenalidomide exerts direct cytotoxicity by increasing apoptosis and inhibiting the proliferation of hematopoietic malignant cells.

It delays tumour growth in nonclinical hematopoietic tumour models in vivo, including multiple myeloma.

Lenalidomide also works to limit the invasion or metastasis of tumour cells and inhibits angiogenesis.

Lenalidomide also mediates indirect antitumour effects via its immunomodulatory actions: it inhibits the production of pro-inflammatory cytokines, which are implicated in various hematologic malignancies.

Lenalidomide enhances the host immunity by stimulating T cell proliferation and enhancing the activity of natural killer (NK) cells. 1, 6, 7 Lenalidomide is about 100–1000 times more potent in stimulating T cell proliferation than thalidomide.

In vitro, it enhances antibody-dependent cell-mediated cytotoxicity (ADCC), which is even more pronounced when used in combination with rituximab.

Due to its anti-inflammatory properties, lenalidomide has been investigated in the context of inflammatory and autoimmune diseases, such as amyotrophic lateral sclerosis.

Protein cereblon Inhibitor

Tumor necrosis factor ligand superfamily member 11 Inhibitor.

Following oral administration, lenalidomide is rapidly absorbed with high bioavailability.

It has a

T max ranging from 0.5 to six hours.

Lenalidomide exhibits a linear pharmacokinetic profile, with its AUC and C max increasing proportionally with dose.

Multiple dosing does not result in drug accumulation.

In healthy male subjects, the C max was 413 ± 77 ng/ml and the AUC infinity was 1319 ± 162 h x ng/ml.

In healthy male subjects, the apparent volume of distribution was 75.8 ± 7.3 L.

Lenalidomide is not subject to extensive hepatic metabolism involving CYP enzymes and metabolism contributes to a very minor extent to the clearance of lenalidomide in humans.

Lenalidomide undergoes hydrolysis in human plasma to form 5-hydroxy-lenalidomide and N-acetyl-lenalidomide.

Unchanged lenalidomide is the predominant circulating drug form, with metabolites accounting for less than five percent of the parent drug levels in the circulation.

Hover over products below to view reaction partners Lenalidomide 5­-Hydroxy-lenalidomide N-acetyl-lenalidomide.

Lenalidomide is eliminated predominantly via urinary excretion in the unchanged form.

Following oral administration of 25 mg of radiolabeled lenalidomide in healthy subjects, about 90% of the dose (4.59% as metabolites) was eliminated in urine and 4% of the dose (1.83% as metabolites) was eliminated in feces within ten days post-dose.

Approximately 85% of the dose was excreted as lenalidomide in the urine within 24 hours.

In healthy subjects, the mean half-life of lenalidomide is three hours in the clinically relevant dose range (5–50 mg).

Half-life can range from three to five hours in patients with multiple myeloma, myelodysplastic syndromes, or mantle cell lymphoma.

The renal clearance of lenalidomide exceeds the glomerular filtration rate.

In healthy male subjects, the oral clearance was 318 ± 41 mL/min.

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The lowest lethal dose (LDLo) in rats is >2000 mg/kg following oral administration and >40 mg/kg following intravenous administration.

The oral

Lowest published toxic dose (TDLo) in humans is 9 mg/kg/4W (intermittent).

There is limited clinical experience in managing lenalidomide overdose.

In single-dose studies, healthy subjects have been exposed to doses up to 400 mg. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

Toxicities associated with lenalidomide, some leading to fatality, include embryo-fetal toxicity, neutropenia, thrombocytopenia, venous (deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke), serious adverse cardiovascular reactions, second primary malignancies, hepatotoxicity, severe cutaneous reactions, tumour lysis syndrome, tumour flare reaction, hypothyroidism, and hyperthyroidism.

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.