Lenalidomide

Uses

Lenalidomide is a thalidomide analogue used for the treatment of patients with:

• Multiple myeloma (MM), in combination with dexamethasone
• MM, as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT)
• 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

Limitations of Use: Lenalidomide is not used and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials

Lenalidomide is also used to associated treatment for these conditions: Chronic Lymphocytic Leukemia (CLL) - Refractory, Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Multiple Myeloma (MM), Myelodysplastic Syndrome, Refractory Diffuse Large B Cell Lymphoma, Light chain amyloidosis

How Lenalidomide works

Lenalidomide is a drug with multiple mechanisms of action. Lenalidomide exerts immunomodulating effects by altering cytokine production, regulating T cell co-stimulation, and enhancing the NK cell-mediated cytotoxicity. Lenalidomide directly inhibits the cullin ring E3 ubiquitin ligase complex: upon binding to cereblon, a substrate adaptor of the complex, lenalidomide modulates substrate specificity of the complex to recruit substrate proteins of the ligase, including Ikaros (IKZF1), Aiolos (IKZF3), and CK1α. These substrates are then tagged for ubiquitination and subsequent proteasomal degradation. IKZF1 and IKZF3 are B-cell transcription factors that are essential for B-cell differentiation and survival of malignant cells. IKZF3 also regulates the expression of interferon regulatory factor 4 (IRF4), which is a transcription factor that regulates the aberrant myeloma-specific gene. The immunomodulatory actions of lenalidomide can be partly explained by the degradation of IKZF3, since it is a repressor of the interleukin 2 gene (IL2): as lenalidomide decreases the level of IKZF3, the production of IL-2 increases, thereby increasing the proliferation of natural killer (NK), NKT cells, and CD4+ T cells. Lenalidomide inhibits the production of pro-inflammatory cytokines TNF-α, IL-1, IL-6, and IL-12, while elevating the production of anti-inflammatory cytokine IL-10. Lenalidomide acts as a T-cell co-stimulatory molecule that promotes CD3 T-cell proliferation and increases the production of IL-2 and IFN-γ in T lymphocytes, which enhances NK cell cytotoxicity and ADCC. It inhibits the expression and function of T-regulatory cells, which are often overabundant in some hematological malignancies.

Lenalidomide directly exerts antitumour effects by inhibiting the proliferation and inducing apoptosis of tumour cells. Lenalidomide triggers the activation of pro-apoptotic caspase-8, enhances tumour cell sensitivity to FAS-induced apoptosis, and downregulates NF-κB, an anti-apoptotic protein. Independent of its immunomodulatory effects, lenalidomide mediates anti-angiogenic effects by inhibiting angiogenic growth factors released by tumour cells, such as vascular endothelial growth factor (VEGF), basic fibroblastic-growth factor (BFGF), and hepatocyte-growth factor. In vitro, lenalidomide inhibits cell adhesion molecules such as ICAM-1, LFA-1, β2 and β3 integrins, as well as gap-junction function, thereby preventing metastasis of malignant cells.

Dosage

Lenalidomide dosage

Multiple myeloma combination therapy: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. Refer to section 14.1 for dexamethasone dosing

Multiple myeloma maintenance therapy following autologous hematopoietic stem cell transplantation: 10 mg once daily continuously on Days 1-28 of repeated 28-day cycles

Myelodysplastic syndromes: 10 mg once daily

Mantle cell lymphoma: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles

Renal impairment: Adjust starting dose based on the creatinine clearance value

Side Effects

Deep vein thrombosis, MI, pulmonary embolism; pruritus, skin hyperpigmentation, hyperhidrosis, dry skin, peripheral oedema, GI disturbances, resp distress, interstitial pneumonitis, cough, fatigue, vertigo, pyrexia, dyspnoea, pancreatitis, CVA, alopecia, electrolyte disturbances, infections (e.g. herpes and pneumonia). Eye disorders (e.g. cataracts, blurred vision, irritation and loss of vision). Musculoskeletal effects (e.g. arthralgia, myalgia, muscle cramps, myopathy and musculoskeletal pain).

Toxicity

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.

Precaution

Pregnancy test is required prior initiation of therapy and should commence contraceptive measures following negative result. Pregnancy test must be repeated at a regular interval during therapy. History of thrombosis; smokers; patients with HTN, hyperlipidaemia, high tumour burden. Renal impairment. Elderly.

Interaction

May increase risk of thrombosis with erythropoietic agents. May increase plasma concentration of digoxin, ketoconazole, itraconazole, ciclosporin, verapamil, quinidine, clarithromycin.

Food Interaction

• Take at the same time every day. Skip the missed dose if it has been more than 12 hours since your regular time.
• Take with or without food. High-fat meals decrease absorption, but not to a clinically significant extent.

Lenalidomide Drug Interaction

Unknown: arginine, arginine, levocarnitine, levocarnitine, cysteine, cysteine, lithium, lithium, acetaminophen, acetaminophen, bortezomib, bortezomib, cyanocobalamin, cyanocobalamin, pyridoxine, pyridoxine, cholecalciferol, cholecalciferol, zoledronic acid, zoledronic acid

Lenalidomide Disease Interaction

Moderate: renal impairment, thromboembolic events, anemia

Volume of Distribution

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

Elimination Route

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.

Half Life

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.

Clearance

The renal clearance of lenalidomide exceeds the glomerular filtration rate. In healthy male subjects, the oral clearance was 318 ± 41 mL/min.

Elimination Route

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.

Pregnancy & Breastfeeding use

Category X: Studies in animals or human beings have demonstrated foetal abnormalities or there is evidence of foetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Contraindication

Pregnancy: Lenalidomide 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

Severe Hypersensitivity Reactions: Lenalidomide is contraindicated in patients who have demonstrated severe hypersensitivity

Special Warning

Renal Impairment-

Myelodysplastic disease:

• Moderate: 5 mg once daily.
• Severe (not requiring dialysis): 5 mg every other day.
• End-stage renal disease: 5 mg 3 times/wk after dialysis.

Multiple myeloma:

• Moderate: 10 mg once daily may be increased to 15 mg once daily after 2 cycles if needed.
• Severe (not requiring dialysis): 15 mg every other day, may be increased to 10 mg once daily if needed.
• End-stage renal disease: 5 mg once daily after dialysis.

Storage Condition

Store at 20 to 25° C; excursions permitted to 15 to 30° C

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