Lenalidomide - instructions for use, dose, side effects, contraindications

Lenalidomide inhibits the secretion of pro-inflammatory cytokines, including tumor necrosis factor, interleukin-1β, IL-6 and IL-12, from liposaccharide-stimulated peripheral blood mononuclear cells. Lenalidomide increases the production of anti-inflammatory cytokine IL-10 and liposaccharide-stimulated peripheral blood mononuclear cells, thereby inhibiting the expression, but not the enzymatic activity of cyclooxygenase-2. Lenalidomide induces the proliferation of T cells and increases the synthesis of IL-2 and interferon-1, as well as increases the cytotoxic activity of the own killer cells. Lenalidomide inhibits the proliferation of cells of various lines of hematopoietic tumors, mainly those that have cytogenetic defects of the chromosome 5. Lenalidomide inhibits angiogenesis, blocking the formation of microvessels and endothelial canals, as well as the migration of endothelial cells on the model of angiogenesis in vitro. Besides, lenalidomide inhibits the synthesis of the proangiogenic vascular endothelial growth factor by means of the 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 quickly absorbed; the maximum concentration is achieved after 0.6-1.5 hours after a single dose. Eating does not affect the degree of absorption. The pharmacokinetic distribution is linear. The maximum concentration (C_max) and the area under the curve "concentration-time" (AUC) increase in proportion to the increase in dose. Repeated drug administration does not lead to its cumulation. In patients with multiple myeloma lenalidomide quickly absorbed, with the maximum concentration achieved after 0.5-4.0 hours after admission, both on the first day and on day 28. FROM_maxand AUC increase in proportion with both single and repeated administration of the drug. According to C_maxand AUC The exposure of lenalidomide in patients with multiple myeloma is higher than in healthy volunteers, which is explained by the lower ratio of clearance to filtration in patients with multiple myeloma compared to healthy volunteers (300 and 200 ml / min, respectively). In vitro binding (¹⁴C) -lenalidomide with plasma proteins of 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 rate of glomerular filtration and, therefore, the process is both passive and active. The half-life of the drug increases with increasing dose, from about 3 hours at a dose of 5 mg to about 9 hours at doses of 400 mg. The equilibrium state is reached on the 4th day. The pharmacokinetics of lenalidomide in patients with impaired liver function has not been studied. In patients with impaired renal function, the absorption of lenalidomide does not change.

Indications:

Treatment (in combination with dexamethasone) in patients with multiple myeloma who received at least one line of therapy.

ICD-10

II.C81-C96.C90.0 Multiple myeloma

Contraindications:

Pregnancy; lactation period (breastfeeding); childbearing age; lack of ability to comply with necessary contraceptive measures; childhood; increased sensitivity to lenalidomide.

Carefully:

Elderly patients with renal insufficiency; patients with multiple myeloma, taking lenalidomide along with dexamethasone, since drugs with erythropoietic activity, as well as hormone replacement therapy, can increase the risk of thrombosis.

Pregnancy and lactation:

Contraindicated in pregnancy and lactation (breastfeeding).

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

Strict adherence to contraception applies to women and men.

FDA recommendation category X.

Dosing and Administration:

Is taken internally.

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

With the development of toxic effects, the dosage regimen is corrected according to a special scheme.

Patients with impaired renal function require a correction of the dosing regimen.

Side effects:

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

On the part of the hematopoiesis system: very often - neutropenia, thrombocytopenia, anemia; often - leukopenia, lymphopenia.

From the cardiovascular system: often deep vein thrombosis, lowering blood pressure.

Infections and infestations: often - pneumonia.

From the musculoskeletal system: very often - muscle cramps.

From the nervous system: often - a tremor, a hypesthesia.

From the respiratory system: often - shortness of breath (including physical exertion).

From the skin and subcutaneous fat: very often - skin rash; often itchy skin.

Common reactions: very often - weakness, asthenia.

Most often when applying the combination lenalidomide + dexamethasone: 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%).

Overdose:

A special plan of action for an overdose of lenalidomide in patients with multiple myeloma has not been developed, despite the fact that in studies to determine the dose range, some patients received doses up to 150 mg, and in studies of single dose exposure up to 400 mg of the drug. Toxic manifestations, which limited the dose in these studies, were exclusively hematological.

Treatment: in case of an overdose, symptomatic maintenance therapy is recommended.

Interaction:

Erythropoietic agents, as well as other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in patients with multiple myeloma taking lenalidomide in combination with dexamethasone.

Mutual influence on the metabolism of lenalidomide and other drugs is unlikely due to the fact that lenalidomide It is not metabolized by the cytochrome P450 system.

Digoxin

Simultaneous administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin. Against the background of treatment with lenalidomide, it is recommended to monitor the concentration of digoxin.

Oral contraceptives

Dexamethasone, which is an obligatory component of the treatment regimen with lenalidomide, can reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, use the drugs indicated in the Pregnancy Protection Program.

Warfarin

There was no mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin. Taking into account the use of dexamethasone in combination with lenalidomide, one can not exclude the influence of the latter on the effects of warfarin.Thus, against a background of combined therapy with lenalidomide and dexamethasone, careful monitoring of the concentration of warfarin is recommended.

Special instructions:

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

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

It is recommended that careful monitoring by both the doctor and the patient of symptoms of increased bleeding, including petechiae and hemoptysis.

During the first 2 months of lenalidomide treatment, it is recommended that a detailed blood test be performed every week, including determining the number of leukocytes, blood counts, platelets, hemoglobin, hematocrit. Subsequently, blood tests should be performed monthly.

To the manifestations of toxicity of lenalidomide, which most often limit its use, include neutropenia and thrombocytopenia.In this regard, the decision to jointly use lenalidomide and other immunosuppressive drugs should be clinically justified.

Given the primary allocation of lenalidomide by the kidneys, patients with renal insufficiency should carefully monitor the status of kidney function and the dose of lenalidomide.

Regular monitoring of thyroid function is necessary in connection with the possibility of developing hypothyroidism under the influence of lenalidomide.

We can not exclude the possibility of neurotoxic effects of lenalidomide with prolonged his admission, given the structural similarity of molecules of lenalidomide and thalidomide, which is known for its severe neurotoxic side effects.

In connection with the pronounced antineoplastic activity of lenalidomide, the development of tumor lysis syndrome is possible, especially in patients with a large tumor mass. It is necessary to monitor the condition of such patients and to conduct appropriate prophylaxis.

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

Impact on the ability to drive vehicles and manage mechanisms

Some of the side effects of lenalidomide, such as dizziness, weakness, drowsiness and blurred vision can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions. In this connection, care should be taken when driving vehicles and working with machinery.

Instructions

Lenalidomide (Lenalidomidum)