Revlimid^® (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

Other immunosuppressants

Pharmacological Action

Antineoplastic drug, immunomodulator. Revlimid^® is a representative of a new class of immunomodulators (IMiDs^SM), which has both immunomodulatory and antiangiogenic properties.

Lenalidomide inhibits the secretion of proinflammatory cytokines, including TNF-α, 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-γ, and also increases 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. In addition, lenalidomide inhibits the synthesis of the proangiogenic vascular endothelial growth factor by PC-3 prostate tumor cells.

The clinical efficacy and safety of Revlimid^® was confirmed by the results of two multicenter randomized phase III studies, in which patients with multiple myeloma received Revlimid^® in combination with dexamethasone or dexamethasone alone as second-line therapy. In all efficacy criteria, including the rate of complete and partial response, combination therapy with Revlimid^® and dexamethasone was superior to monotherapy with dexamethasone.

Pharmacokinetics

Absorption

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

After oral administration to healthy volunteers, lenalidomide is rapidly absorbed. C_max is reached within 0.5-2.0 hours after a single dose. 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. Food intake does not affect the extent of absorption. 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 a lower clearance to filtration ratio (CL/F) in patients with multiple myeloma compared to healthy volunteers.

Distribution

In vitro binding of (¹⁴C)-lenalidomide to plasma proteins in patients with multiple myeloma and healthy volunteers was 23% and 29%, respectively.

Lenalidomide is present in semen (< 0.01% of the dose) after taking it at a dose of 25 mg/day, but is not detected in semen 3 days after discontinuation of the drug.

There are no data on the passage of lenalidomide into breast milk.

Metabolism and Excretion

Lenalidomide is almost not metabolized in the body, since 82% of its dose is excreted unchanged in the urine. Thus, renal clearance exceeds the glomerular filtration rate, nevertheless, the elimination process is also active.

When taken in recommended doses (5-25 mg/day), the T_1/2 of the drug is approximately 3 hours in healthy volunteers and patients with multiple myeloma.

Pharmacokinetics in Special Clinical Cases

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

The pharmacokinetics of lenalidomide in patients with impaired liver function has not been studied.

Indications

• In combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

ICD codes

Dosage Regimen

Capsules

Revlimid^® is for oral use only.

Revlimid^® capsules should not be broken or chewed. It is recommended to take the drug every day at the same time before or after meals, with water.

The recommended starting dose of Revlimid^® 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 – 40 mg once daily on days 1-4 of each subsequent 28-day cycle.

Dose modification should be based on clinical and laboratory data. The physician should carefully select the dose of dexamethasone, taking into account the patient’s condition and the stage of the disease.

If less than 12 hours have passed since the missed dose of Revlimid^®, the patient may take this missed dose of the drug, and if more than 12 hours have passed, the missed dose should not be taken. The next dose of Revlimid^® should be taken the next day, at the usual time.

Treatment with lenalidomide should not be started if the absolute neutrophil count is <1.0×10⁹/L, and/or the platelet count is <75×10⁹/L or, depending on the degree of bone marrow infiltration by plasma cells, the platelet count is <30×10⁹/L.

Dose modification during treatment or its resumption

The following are options for dose modification in case of development of neutropenia, thrombocytopenia or other types of grade 3 and 4 toxicity, the relationship of which with the use of Revlimid^® cannot be excluded.

Stepwise dose reduction

Thrombocytopenia

Neutropenia

In case of neutropenia, the physician should consider prescribing a growth factor to the patient.

The safety and efficacy of lenalidomide in children and adolescents under 18 years of age has not been studied.

The pharmacokinetics of lenalidomide in elderly patients (over 65 years of age) has not been studied. In clinical studies, lenalidomide was administered to patients with multiple myeloma up to 86 years of age. The percentage of patients over 65 years of age receiving lenalidomide/dexamethasone or placebo/dexamethasone was comparable. No differences in the efficacy and safety of lenalidomide depending on age were noted, although greater sensitivity to the drug in older patients cannot be ruled out. Since elderly patients are more likely to have impaired renal function, the dose of the drug should be selected very carefully, and renal function should be monitored during treatment.

The pharmacokinetics of lenalidomide has not been studied in patients with impaired liver function, so it is not possible to provide recommendations regarding dose adjustment in this category of patients.

Lenalidomide is excreted mainly by the kidneys. In this regard, the risk of toxic reactions may increase with impaired renal function. When prescribing Revlimid^® to patients with impaired renal function, it is recommended to follow the recommendations below.

For patients with mild renal impairment, no change in the dose of Revlimid^® is required. The table shows the initial doses of the drug recommended depending on the degree of renal impairment (for patients with moderate and severe renal impairment, as well as end-stage renal failure).

Initial dose of lenalidomide depending on the degree of renal impairment

* The drug dose may be increased to 15 mg once daily after 2 cycles of therapy in the absence of response to therapy, but with good tolerability.

** The drug dose may be increased to 10 mg once daily with good tolerability of therapy.

After initiation of lenalidomide treatment, subsequent dose modification in patients with renal impairment should be based on individual treatment tolerance as indicated earlier.

Adverse Reactions

In patients receiving Revlimid^®/dexamethasone, the most common adverse reactions were: 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%).

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

The greatest dependence of the development of neutropenia and thrombocytopenia on the drug dose was shown, which allows them to be successfully controlled by reducing the dose of Revlimid^®/dexamethasone.

Definition of frequency of the following adverse reactions: very common: (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10 000, <1/1000), very rare (<1/10 000, including isolated cases), frequency not known (cannot be estimated from the available data).

Adverse reactions noted in clinical studies in patients with multiple myeloma receiving Lenalidomide

Summary data on adverse reactions identified during the post-registration monitoring period in patients taking Lenalidomide

* Detailed information is presented at the end of this section.

¹ The following is a description of the noted adverse reactions:

Teratogenicity

Lenalidomide is a structural analogue of thalidomide, a substance with active teratogenic effects that causes severe life-threatening developmental abnormalities. Lenalidomide induced the appearance of congenital anomalies in monkeys similar to those described for thalidomide. If lenalidomide is taken during pregnancy, a teratogenic effect can be predicted, therefore lenalidomide is contraindicated in pregnancy.

Neutropenia and Thrombocytopenia

The use of the lenalidomide and dexamethasone combination in patients with multiple myeloma was associated with an increased incidence of Grade 4 neutropenia (in 5.1% of patients taking Lenalidomide with dexamethasone compared to 0.6% in patients taking the dexamethasone and placebo combination). Febrile neutropenia Grade 4 in patients taking the lenalidomide and dexamethasone combination was infrequent – 0.6% (in patients taking the dexamethasone and placebo combination – 0.0%).

The use of the lenalidomide and dexamethasone combination in multiple myeloma was associated with an increased probability of developing Grade 3 and Grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in patients taking Lenalidomide with dexamethasone, relative to 2.3% and 0.0% in patients taking the dexamethasone and placebo combination).

Venous Thromboembolism

The use of the lenalidomide and dexamethasone combination in patients with multiple myeloma was associated with an increased risk of deep vein thrombosis and pulmonary embolism. Concurrent administration of erythropoietic agents or a history of deep vein thrombosis may also increase the risk of thrombotic complications in this patient group.

Myocardial Infarction

Cases of myocardial infarction have been reported in patients taking Lenalidomide, especially in the presence of known risk factors.

Hemorrhagic Complications

Hemorrhagic complications are presented according to system organ classes: blood and lymphatic system disorders; nervous system disorders (intracranial hemorrhage); respiratory system disorders (epistaxis); gastrointestinal disorders (rectal, hemorrhoidal, gingival bleeding); renal and urinary disorders (hematuria); vascular disorders (ecchymoses); injuries, poisonings and procedural complications (contusions).

Allergic Reactions

There are reports of allergic reactions/hypersensitivity reactions. Possible cross-reactivity between lenalidomide and thalidomide has been described.

Severe Skin Reactions

There are reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Lenalidomide should not be prescribed to patients who have experienced severe forms of rash while taking thalidomide in the past.

Primary Malignant Tumors of Other Sites

*New malignant neoplasms observed in clinical studies in patients with myeloma after using the lenalidomide and dexamethasone combination compared to control were mainly basal cell or squamous cell skin cancer.

Contraindications

• Pregnancy;
• Lactation (breastfeeding);
• Preserved reproductive potential, except in cases where it is possible to comply with all necessary conditions of the Pregnancy Prevention Programme;
• Inability or failure to comply with necessary contraceptive measures;
• Pediatric age (insufficient clinical experience of use);
• Hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption, because Revlimid^® capsules contain lactose;
• Hypersensitivity to the drug components.

The drug should be used with caution in elderly patients, in patients with renal failure, and in patients with multiple myeloma taking Lenalidomide together with dexamethasone, because drugs with erythropoietic activity, as well as hormone replacement therapy, may increase the risk of thrombosis.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Lenalidomide is a structural analogue of thalidomide, which has a pronounced teratogenic effect. It is known that taking thalidomide by pregnant women causes severe and life-threatening malformations of the internal organs of the fetus. Experimental studies in monkeys showed results similar to those previously described for thalidomide. The risk of congenital defects is very high if Revlimid^® is taken during pregnancy.

Women of reproductive potential should use effective methods of contraception during treatment with Revlimid^®. The use of lenalidomide must be discontinued if pregnancy is diagnosed in a woman, and the patient should be referred for consultation to a physician experienced in monitoring pregnant women for assessment and clinical advice. If a pregnancy is diagnosed in a woman who is the sexual partner of a patient being treated with lenalidomide, the woman should also be referred to a physician specializing in teratology for assessment of the situation and clinical advice.

It is not known whether Lenalidomide passes into breast milk. Therefore, breastfeeding should be discontinued during treatment with lenalidomide.

Strict adherence to all requirements of the Pregnancy Prevention Programme must apply to both women and men.

For women not of childbearing potential

A female patient or a woman who is the sexual partner of a male patient is not considered capable of childbearing if at least one of the following factors is present

• Age ≥ 50 years and duration of natural amenorrhea ≥ 1 year*;
• Premature ovarian failure confirmed by a gynecologist;
• History of bilateral salpingo-oophorectomy or hysterectomy;
• XY genotype, Turner syndrome, anatomical defect of the uterus.

*- amenorrhea due to anticancer therapy does not exclude the presence of reproductive potential.

The use of lenalidomide in women of childbearing potential is contraindicated unless one of the following statements is true

A woman of childbearing potential must

• Be aware of the teratogenic effect of Revlimid^® on the fetus;
• Understand the need for continuous use of effective contraceptive methods for 4 weeks before starting treatment, during treatment, and for 4 weeks after treatment with Revlimid^®;
• Comply with all rules of effective contraception even in case of amenorrhea;
• Be capable of complying with all rules of effective contraception;
• Know and understand the possible consequences of pregnancy, as well as the need to promptly seek consultation if pregnancy is suspected;
• Understand the need to take Revlimid^® immediately after receiving negative pregnancy test results;
• Be aware of the need for testing and perform a pregnancy test every 4 weeks;
• Confirm that she understands the risk of all possible adverse consequences and the need for their prevention during treatment with Revlimid^®.

Use in men

Data from pharmacokinetic studies of lenalidomide in male volunteers indicate that Lenalidomide may be present in the seminal fluid of patients during treatment in extremely low concentrations and is not detected 3 days after discontinuation in healthy volunteers. As a precaution, considering the possible reduction in the elimination rate of lenalidomide in special patient groups (in patients with impaired renal function), the following statements must be true for all male patients taking Revlimid^®

A man taking Revlimid^® must

• Understand the possible risk of the teratogenic effect of Revlimid^® during sexual contact with a pregnant woman or a woman of childbearing potential;
• Understand the need to use condoms during sexual contact with pregnant women or women of childbearing potential not using reliable methods of contraception during treatment, during treatment interruptions, and for 1 week after completion of treatment.

The physician prescribing Revlimid^® to women of childbearing potential must

• Be sure that the patient meets all the conditions of the Pregnancy Prevention Programme, including confirmation that she adequately understands the situation;
• Obtain the patient’s informed consent to mandatory compliance with all conditions of the aforementioned Programme.

Contraception rules

Women of childbearing potential must use one highly effective method of contraception for 4 weeks before starting treatment, during therapy with Revlimid^®, and for 4 weeks after the end of treatment, even in case of treatment interruptions. The only exception is patients who abstain from heterosexual relationships throughout the specified period, which is documented monthly. If an effective method of contraception has not been selected for the patient, she must be referred to a gynecologist to select a method of effective contraception. The patient must immediately begin using an effective method of contraception.

Highly effective methods of contraception include:

• Subcutaneous hormonal implants;
• Levonorgestrel-releasing intrauterine systems;
• Depot preparations of medroxyprogesterone acetate;
• Tubal ligation;
• Partner vasectomy (confirmed by two negative semen analyses);
• Progesterone-containing oral contraceptives inhibiting ovulation (e.g., desogestrel).

The use of combined oral contraceptives is not indicated for patients with multiple myeloma due to the increased risk of thromboembolic complications during treatment with Revlimid^® and dexamethasone. For effective contraception, these patients are recommended to use one of the methods listed above. The increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives. The effectiveness of hormonal contraceptives may be reduced with the simultaneous administration of dexamethasone.

Patients with neutropenia using subcutaneous hormonal implants or levonorgestrel-releasing intrauterine systems as a contraceptive method should be prophylactically prescribed antibiotics due to the increased risk of infectious complications at the time of insertion of these therapeutic systems.

The use of copper-releasing intrauterine systems is generally not recommended due to the high risk of infectious complications at the time of insertion and increased blood loss during menstruation, which may exacerbate the severity of neutropenia or thrombocytopenia in the patient.

Pregnancy tests (sensitivity of at least 25 mIU/ml) must be performed in the presence of a physician for all women of childbearing potential, including those who completely exclude and long-term abstain from heterosexual relationships. After patients have used an effective method of contraception for 4 or more weeks, tests are performed on the day of treatment prescription or 3 days before the visit to the attending physician, and then every 4 weeks, including after the end of Revlimid^® intake. The test results must confirm the absence of pregnancy in the patient during treatment with Revlimid^®.

Male patients must use condoms throughout the course of treatment with Revlimid^® and for 1 week after interruption or discontinuation of treatment if the sexual partner is a pregnant woman or a woman of childbearing potential not using highly effective methods of contraception.

Educational materials

To increase the safety of therapy with Revlimid^® and reduce the risk of teratogenic effects, educational materials are provided to assist patients, which include all necessary information about the drug, as well as the Pregnancy Prevention Programme. The marketing authorisation holder provides physicians with the necessary materials for their patients. The physician conveys detailed information about the teratogenic risk of Revlimid^® and pregnancy prevention measures to women of childbearing potential and sexually active men.

Use in Hepatic Impairment

The pharmacokinetics of lenalidomide have not been studied in patients with impaired hepatic function, so it is not possible to provide recommendations regarding dose adjustment in this category of patients.

Use in Renal Impairment

Lenalidomide is eliminated primarily by the kidneys. Therefore, the risk of toxic reactions may be increased in impaired renal function. When prescribing Revlimid^® to patients with impaired renal function, it is recommended to follow the recommendations below.

Initial dose of lenalidomide depending on the degree of renal impairment

* The drug dose may be increased to 15 mg once daily after 2 therapy cycles in the absence of a response to therapy, but with good tolerability.

Given the predominant renal elimination of Revlimid^®, patients with renal failure must carefully monitor renal function and the dose of Revlimid^®.

Pediatric Use

Contraindication: pediatric age (insufficient clinical experience of use).

Geriatric Use

The pharmacokinetics of lenalidomide in elderly patients have not been studied. In clinical studies, Lenalidomide was prescribed to patients up to 95 years of age. No differences in the efficacy and safety of lenalidomide depending on age were noted, although greater sensitivity to the drug in older patients cannot be excluded. Since elderly patients are more likely to have impaired renal function, the drug dose must be selected very carefully, and it is recommended to monitor renal function during treatment

Special Precautions

Treatment with Revlimid^® should be carried out under the supervision of a hematologist or oncologist.

Myocardial infarction

There are reports of cases of myocardial infarction in patients taking Lenalidomide, in particular, in individuals with risk factors for cardiovascular diseases. In the presence of risk factors, including, first of all, a history of thrombosis, it is necessary to monitor the condition of patients and also take actions aimed at possibly reducing the influence of risk factors (smoking, arterial hypertension, hyperlipidemia).

Venous and arterial thromboembolism

During combination therapy with Revlimid^® and dexamethasone, an increased frequency of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), as well as arterial thromboembolism (mainly myocardial infarction and stroke) is observed in patients with multiple myeloma. Consequently, it is necessary to monitor patients who have risk factors for thromboembolism, including a history of thrombosis. Measures should be taken to possibly eliminate such risk factors as smoking, arterial hypertension, hyperlipidemia. The greatest prognostic significance is a history of thromboembolic complications, concomitant therapy with erythropoietin, and hormone replacement therapy. Thus, drugs with erythropoietic activity, as well as other drugs that may increase the risk of thrombosis (for example, hormone replacement therapy) should be prescribed with caution to patients with multiple myeloma taking Lenalidomide together with dexamethasone. A hemoglobin concentration above 12 g% suggests discontinuation of erythropoietin therapy. Physicians and patients should carefully evaluate clinical symptoms indicative of possible thromboembolism. Patients should be warned about the need to immediately consult a physician if symptoms such as shortness of breath, chest pain, swelling of the upper or lower limb appear.

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.

If a patient develops symptoms of thromboembolism, it is necessary to discontinue treatment with lenalidomide and prescribe standard anticoagulant therapy. After the patient’s condition has stabilized on anticoagulant therapy and the symptoms of thromboembolism have been eliminated, treatment with lenalidomide can be restarted at the same dose, provided the benefit/risk assessment is favorable. The patient should continue anticoagulant therapy throughout the further period of treatment with lenalidomide.

Neutropenia and thrombocytopenia

The risk of developing Grade 4 neutropenia in patients with multiple myeloma with the simultaneous administration of Revlimid^® and dexamethasone is very high (5.1% in the group of patients receiving Revlimid^®/dexamethasone, and 0.6% in the group of patients receiving placebo/dexamethasone). Episodes of febrile neutropenia are infrequently reported (0.6% in the group of patients receiving Revlimid^®/dexamethasone, and 0.0% in the group of patients receiving placebo/dexamethasone). Patients should be informed of the need to promptly inform the attending physician about fever (above 38°C (100.4°F)). If necessary, the drug dose may be reduced. In case of severe neutropenia, the administration of growth factors is advisable.

A high frequency of Grade 3 and Grade 4 thrombocytopenia is observed in patients with multiple myeloma with the simultaneous administration of Revlimid^® and dexamethasone (9.9% and 1.4%, respectively, in patients during treatment with Revlimid^®/dexamethasone, and 2.3% and 0.0% – during treatment with placebo/dexamethasone). Careful monitoring by both the physician and the patient for symptoms of increased bleeding, including petechiae and hemoptysis, is recommended. If necessary, the drug dose may be reduced.

During the first 2 months of treatment with Revlimid^®, it is recommended to perform a complete blood count weekly, including determination of leukocyte count, differential count, platelet count, hemoglobin, and hematocrit. Subsequently, blood tests should be performed monthly.

The manifestations of Revlimid^® toxicity that most often limit its use are neutropenia and thrombocytopenia. In this regard, the decision to co-administer Revlimid^® and other immunosuppressive drugs must be clinically justified.

Renal failure

Given the predominant renal elimination of Revlimid^®, patients with renal failure must carefully monitor renal function and the dose of Revlimid^®.

Thyroid function

Regular monitoring of thyroid function is necessary due to the possibility of Revlimid^® causing hypothyroidism.

Peripheral neuropathy

The possibility of neurotoxic effects of Revlimid^® with long-term use cannot be excluded, given the structural similarity of the Revlimid^® and thalidomide molecules, the latter being known for its pronounced neurotoxic side effect.

Tumor lysis syndrome

Due to the pronounced antineoplastic activity of Revlimid^®, tumor lysis syndrome may develop, especially in patients with a large tumor mass. These patients should be provided with appropriate monitoring and the application of commonly accepted preventive measures.

Allergic reactions

There are reports of cases of allergic reactions/hypersensitivity reactions. Since there are scientific publications on possible cross-reactions between lenalidomide and thalidomide, the condition of patients with a history of allergic reactions during treatment with thalidomide should be monitored with particular care.

Severe Skin Reactions

There have been reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. If exfoliative or bullous skin rashes appear, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, lenalidomide should be discontinued immediately and not restarted even after the skin manifestations have resolved. The need to interrupt or discontinue lenalidomide should be considered in case of other types of skin reactions depending on their severity. Lenalidomide should not be prescribed to patients with a history of severe skin reactions associated with thalidomide use.

Lactose Intolerance

Revlimid^® capsules contain lactose. Patients with rare conditions – galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome – are not recommended to use the drug.

Development of Secondary Primary Malignancies (SPM)

Clinical studies have noted a higher incidence of secondary primary malignancies in patients previously treated with lenalidomide and dexamethasone (3.98 per 100 patient-years) compared to the control group (1.38 per 100 patient-years). Non-invasive SPMs included basal cell carcinoma and squamous cell carcinoma of the skin. The majority of invasive SPMs were solid tumors.

In clinical studies of patients with newly diagnosed multiple myeloma receiving Revlimid^®, a 4-fold increase (7%) in SPM cases was observed compared to the control group (1.8%).

Among invasive SPMs in patients receiving combination therapy with Revlimid^® and melphalan, or immediately after high-dose melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia, MDS (myelodysplastic syndrome), and solid tumors have been noted. Cases of B-cell malignancies (including Hodgkin’s lymphoma) were observed in clinical studies when Revlimid^® was used after stem cell transplantation.

The risk of developing SPM should be considered before prescribing Revlimid^®. Physicians should carefully examine patients using standard diagnostic methods both before deciding to prescribe Revlimid^® and throughout the entire treatment period with Revlimid^®. Treatment should be carried out in accordance with generally accepted recommendations.

Patients should not pass Revlimid^® on to other persons. Unused medication must be returned to the healthcare facility.

Patients are not permitted to donate blood or sperm as a donor throughout the treatment with Revlimid^® and for one week after its completion.

Effect on Ability to Drive and Use Machines

Some side effects of Revlimid^®, 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 operating machinery.

Overdose

There is currently no specific action plan for lenalidomide overdose in patients with multiple myeloma, although in dose-range studies some patients received doses up to 150 mg, and in single-dose exposure studies – up to 400 mg of the drug. The toxic manifestations that limited the dose level in these studies were exclusively hematological.

In case of overdose, symptomatic supportive therapy is recommended.

Drug Interactions

Erythropoietic Agents, as well as other agents that may increase the risk of thrombosis, such as hormone replacement therapy drugs, 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 because Lenalidomide is not metabolized by the cytochrome P450 system.

Digoxin

Concomitant administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (C_max of digoxin was 114%, and AUC_0-∞ was 108%). Thus, it is recommended to monitor digoxin concentration during treatment with lenalidomide.

Oral Contraceptives

Dexamethasone, which is a mandatory component of the treatment regimen with Revlimid^®, may reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, the means specified in the Pregnancy Prevention Program must be used.

Warfarin

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. Thus, during combined therapy with lenalidomide and dexamethasone, careful monitoring of warfarin concentration is recommended.

Storage Conditions

The drug should be stored out of the reach of children, in a dry place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.