Mielanix (Capsules) Instructions for Use

ATC Code

L04AX04 (Lenalidomide)

Active Substance

Lenalidomide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunomodulator with antiangiogenic properties

Pharmacotherapeutic Group

Immunosuppressants; other immunosuppressants

Pharmacological Action

Antineoplastic agent, immunomodulator, which possesses both immunomodulatory and antiangiogenic properties.

It inhibits the secretion of proinflammatory cytokines, including TNFα, interleukin-1β (IL-1β), IL-6, and IL-12, from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC).

Lenalidomide increases the production of the anti-inflammatory cytokine IL-10 from LPS-stimulated PBMC, resulting in inhibition of expression, but not enzymatic activity, of COX-2.

Lenalidomide induces T-cell proliferation and increases the synthesis of IL-2 and interferon gamma-1, and also enhances the cytotoxic activity of natural killer cells.

Lenalidomide inhibits the proliferation of cells of various hematopoietic tumor lines, mainly those with cytogenetic defects of chromosome 5.

In a model of erythroid progenitor cell differentiation, Lenalidomide induces fetal hemoglobin expression, as judged by the differentiation of CD34⁺ hematopoietic stem cells.

Lenalidomide inhibits angiogenesis by blocking microvessel and endothelial tubule formation, as well as endothelial cell migration in an in vitro angiogenesis model. Furthermore, Lenalidomide inhibits the synthesis of the proangiogenic vascular endothelial growth factor by PC-3 prostate tumor cells.

Pharmacokinetics

Lenalidomide is a racemic mixture of two optically active forms: S(-) and R(+) with a total optical rotation equal to zero.

After oral administration, Lenalidomide is rapidly absorbed. C_max is reached within 0.625-1.5 hours after a single dose. Food intake does not affect the extent of absorption. The pharmacokinetic distribution is linear. C_max and AUC increase proportionally with increasing dose. Repeated administration of the drug does not lead to its accumulation.

In patients with multiple myeloma, Lenalidomide is rapidly absorbed, with C_max reached within 0.5-4 hours after administration, both on day 1 and on day 28. C_max and AUC increase proportionally with both single and repeated administration of the drug. According to C_max and AUC data, lenalidomide exposure in patients with multiple myeloma is higher than in healthy volunteers, which is explained by the lower clearance to filtration ratio (CL/F) in patients with multiple myeloma compared to healthy volunteers, 300 and 200 ml/min, respectively.

In vitro binding of (¹⁴C)-lenalidomide to plasma proteins in patients with multiple myeloma and healthy volunteers was 22.7% and 29.2%, respectively.

Approximately 60% of lenalidomide is excreted by the kidneys unchanged. This exceeds the glomerular filtration rate and, therefore, the process is both passive and active. T_1/2 increases with increasing dose, from approximately 3 hours at a dose of 5 mg to approximately 9 hours at a dose of 400 mg. Steady state is reached on day 4.

C_max does not differ between patients with normal and impaired renal function. However, the elimination of lenalidomide slows down proportionally to the degree of renal impairment. A decrease in CrCl to less than 50 ml/min is accompanied by an increase in AUC by 56%. The T_1/2 of lenalidomide increases from approximately 3.5 hours (in patients with CrCl greater than 50 ml/min) to approximately 9 hours (in patients with CrCl less than 50 ml/min).

Indications

Treatment of multiple myeloma – in combination with dexamethasone in patients who have received at least one prior therapy.

ICD codes

Dosage Regimen

Capsules

Take orally.

The recommended initial dose is 25 mg once daily on days 1-21 of repeated 28-day cycles. Dexamethasone at a dose of 40 mg is administered once daily on days 1-4, 9-12, and 17-20 of each 28-day cycle during the first 4 cycles of therapy, and then at 40 mg once daily on days 1-4 of each subsequent 28-day cycle.

If toxic effects develop, the dosage regimen is adjusted according to a specific scheme.

In patients with impaired renal function, dosage regimen adjustment is required.

Adverse Reactions

Most frequently with the use of the Lenalidomide/dexamethasone combination: neutropenia (39.4%), muscle weakness (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramps (20.1%), thrombocytopenia (18.4%), anemia (17%), diarrhea (14.2%), rash (10.2%).

Most severe adverse reactions: venous thromboembolism (deep vein thrombosis, pulmonary embolism), grade 4 neutropenia.

From the hematopoietic system: very common – neutropenia, thrombocytopenia, anemia; common – leukopenia, lymphopenia.

From the cardiovascular system: common – deep vein thrombosis, decreased blood pressure.

Infections and infestations: common – pneumonia.

From the musculoskeletal system: very common – muscle cramps.

From the nervous system: common – tremor, hypesthesia.

From the respiratory system: common – dyspnea (including exertional dyspnea).

From the skin and subcutaneous tissue: very common – skin rash; common – skin itching.

General reactions: very common – weakness, asthenia.

Contraindications

Pregnancy; lactation (breastfeeding); childbearing potential; inability to comply with necessary contraceptive measures; childhood; hypersensitivity to lenalidomide.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Lenalidomide is a structural analogue of thalidomide, which has a pronounced teratogenic effect. It is known that the use of thalidomide by pregnant women causes severe and life-threatening malformations of the internal organs of the fetus (with a frequency of up to 30%). Experimental studies in monkeys showed results similar to those previously described for thalidomide. The risk of congenital defects is very high if Lenalidomide is used during pregnancy.

Strict adherence to contraception applies to both women and men.

Special Precautions

For the prevention of venous thromboembolism, especially in patients with additional risk factors, the use of low molecular weight heparins or warfarin is recommended. The decision to prescribe antithrombotic therapy should be made after a thorough assessment of individual risk factors.

The risk of developing grade 4 neutropenia in patients with multiple myeloma with the simultaneous use of lenalidomide and dexamethasone is very high.

Careful monitoring by both the physician and the patient for symptoms of increased bleeding, including petechiae and hemoptysis, is recommended.

During the first 2 months of treatment with lenalidomide, a complete blood count, including white blood cell count, differential, platelet count, hemoglobin, and hematocrit, should be performed weekly. Subsequently, blood tests should be performed monthly.

The manifestations of lenalidomide toxicity that most often limit its use are neutropenia and thrombocytopenia. In this regard, the decision on the combined use of lenalidomide and other immunosuppressive drugs must be clinically justified.

Given the predominant excretion of lenalidomide by the kidneys, in patients with renal insufficiency, renal function and the dose of lenalidomide should be carefully monitored.

Regular monitoring of thyroid function is necessary due to the possibility of hypothyroidism developing under the influence of lenalidomide.

The possibility of neurotoxic effects of lenalidomide with long-term use cannot be excluded, given the structural similarity of the molecules of lenalidomide and thalidomide, which is known for its pronounced neurotoxic side effect.

Due to the pronounced antineoplastic activity of lenalidomide, tumor lysis syndrome may develop, especially in patients with a high tumor burden. Such patients should be monitored and appropriate prophylaxis should be carried out.

Patients are not allowed to donate blood or sperm as a donor throughout the treatment with lenalidomide and for one week after its completion.

Effect on the ability to drive vehicles and operate machinery

Some side effects of lenalidomide, such as dizziness, weakness, drowsiness, and blurred vision, may adversely affect the ability to drive a car and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. In this regard, special caution should be exercised when driving vehicles and working with machinery.

Drug Interactions

Mutual influence on the metabolism of lenalidomide and other drugs is unlikely because Lenalidomide is not metabolized by the cytochrome P450 system.

Concomitant administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (C_max of digoxin was 114%, AUC – 108%). Thus, during treatment with lenalidomide, it is recommended to monitor the concentration of digoxin.

Dexamethasone, which is a mandatory component of the therapeutic regimen with lenalidomide, may reduce the effectiveness of oral contraceptives.

No mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin was noted. Given the use of dexamethasone in combination with lenalidomide, the influence of the latter on the effects of warfarin cannot be excluded. Therefore, during combined therapy with lenalidomide and dexamethasone, careful monitoring of the warfarin concentration is recommended.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.