INSTRUCTION for medical use of the medicinal product LINALIDOL (LENALIDOL)

Composition:

Active substance: lenalidomide;

One hard capsule contains 5 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132));

One hard capsule contains 7.5 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), red iron oxide (E 172), indigocarmine (E 132), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132));

One hard capsule contains 10 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), indigocarmine (E 132), yellow iron oxide (E 172), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132));

One hard capsule contains 15 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132));

One hard capsule contains 20 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), indigocarmine (E 132), yellow iron oxide (E 172), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132));

One hard capsule contains 25 mg of lenalidomide;

Excipients: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule (body/cap): gelatin, titanium dioxide (E 171), black ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, concentrated ammonia solution, black iron oxide (E 172), potassium hydroxide (E 525), purified water), green ink (shellac, anhydrous ethanol, isopropyl alcohol, butanol, propylene glycol, ammonium hydroxide, titanium dioxide (E 171), yellow iron oxide (E 172), indigocarmine (E 132)).

Pharmaceutical form. Hard capsules.

Main physico-chemical properties:

Hard capsules 5 mg: opaque hard gelatin capsules No. 5 consisting of a body and cap of opaque white color, with black printing «LENALIDOMIDE» (on the cap) and green printing «5 mg» (on the body); the capsules contain white or almost white powder;

Hard capsules 7.5 mg: opaque hard gelatin capsules No. 4 consisting of a lavender-colored cap and a white body, with black printing «LENALIDOMIDE» (on the cap) and green printing «7.5 mg» (on the body); the capsules contain white or almost white powder;

Hard capsules 10 mg: opaque hard gelatin capsules No. 3 consisting of a green cap and a white body, with black printing «LENALIDOMIDE» (on the cap) and green printing «10 mg» (on the body); the capsules contain white or almost white powder;

Hard capsules 15 mg: opaque hard gelatin capsules No. 2 consisting of an orange cap and a white body, with black printing «LENALIDOMIDE» (on the cap) and green printing «15 mg» (on the body); the capsules contain white or almost white powder;

Hard capsules 20 mg: opaque hard gelatin capsules No. 1 consisting of a green cap and a white body, with black printing «LENALIDOMIDE» (on the cap) and green printing «20 mg» (on the body); the capsules contain white or almost white powder;

Hard capsules 25 mg: opaque hard gelatin capsules No. 0 consisting of a cap and body of opaque white color, with black printing «LENALIDOMIDE» (on the cap) and green printing «25 mg» (on the body); the capsules contain white or almost white powder.

Pharmacotherapeutic group.

Other immunosuppressants. Lenalidomide. ATC code L04A X04.

Pharmacological Properties

Pharmacodynamics

The mechanism of action of lenalidomide includes antineoplastic, antiangiogenic, proerythropoietic, and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain malignant hematopoietic cells (including multiple myeloma (MM) cells and hematopoietic tumor cells with chromosome 5 cytogenetic abnormalities), enhances T-lymphocyte- and natural killer (NK) cell-mediated immunity, increases the number of NK and T-cells, suppresses angiogenesis by inhibiting endothelial cell migration and adhesion and microvessel formation, increases fetal hemoglobin production by CD34+ hematopoietic stem cells, and inhibits the production of pro-inflammatory cytokines (e.g., tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6)) by monocytes.

In myelodysplastic syndromes (MDS) with chromosome 5 cytogenetic abnormalities, lenalidomide has demonstrated selective suppression of the abnormal clone by increasing apoptosis of cells with chromosome 5 cytogenetic abnormalities.

Lenalidomide directly binds to cereblon, a component of the Cullin-RING E3 ubiquitin ligase complex, which includes DNA damage-binding protein 1 (DDB1), Cullin 4 (CUL4), and RING protein Roc1. In the presence of lenalidomide, cereblon binds to substrate proteins Aiolos and Ikaros, which are lymphoid transcription factors, leading to their ubiquitination and subsequent degradation, resulting in cytotoxic and immunomodulatory effects.

Pharmacokinetics

Lenalidomide contains an asymmetric carbon atom and therefore can exist in two optically active forms, S(-) and R(+). Lenalidomide is a racemic mixture of these isomers. Lenalidomide is generally well soluble in organic solvents, but achieves maximum solubility in 0.1 M HCl buffer solution.

Absorption

Lenalidomide is rapidly absorbed from the gastrointestinal tract after oral administration in fasting healthy volunteers. Maximum plasma concentration is reached between 0.5 and 2 hours after administration. In patients with multiple myeloma, as well as in healthy volunteers, maximum concentrations (Cmax) and area under the concentration-time curve (AUC) increase proportionally with increasing dose. Repeated dosing does not lead to accumulation of the drug. Relative plasma exposure of S- and R-enantiomers of lenalidomide is approximately 56% and 44%, respectively.

Concomitant administration of lenalidomide with a high-fat, high-calorie meal reduces drug absorption in healthy volunteers, resulting in approximately a 20% decrease in AUC and a 50% decrease in Cmax plasma concentration. However, in the main registration trials in patients with multiple myeloma, where efficacy and safety of lenalidomide were established, the drug was administered regardless of food intake. Therefore, lenalidomide can be taken with or without food.

Population pharmacokinetic analysis indicates that the extent of oral absorption of lenalidomide is similar among patients with MM, MDS, and MCL.

Distribution

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

Lenalidomide is detected in semen (< 0.01% of the administered dose) after a 25 mg/day dose, but is not detectable 3 days after discontinuation of the drug in healthy volunteers (see section "Special precautions for use").

Metabolism and Excretion

Results of in vitro metabolism studies indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lenalidomide in humans; therefore, pharmacokinetic drug interactions with inhibitors of cytochrome P450 isoenzymes are unlikely. In vitro studies demonstrate no inhibitory effect of lenalidomide on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1 isoenzymes. Thus, it is unlikely that lenalidomide will cause any clinically significant drug interactions when co-administered with substrates of these isoenzymes.

In vitro data indicate that lenalidomide is not a substrate of the human breast cancer resistance protein (BCRP), multidrug resistance-associated proteins MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion-transporting polypeptide 1B1 (OATP1B1), organic cation transporter (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, or organic cation/carnitine transporters (OCTN) OCTN1 and OCTN2.

In vitro studies show that lenalidomide does not inhibit the human bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2 transporters.

The majority of lenalidomide is excreted in urine. Renal excretion accounts for 90% of total clearance in patients with normal renal function; 4% of lenalidomide is excreted in feces.

Lenalidomide is minimally metabolized in the body; 82% of the administered dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide account for 4.59% and 1.83% of the excreted dose, respectively. Renal clearance of lenalidomide exceeds the glomerular filtration rate, indicating both passive and active elimination processes.

After administration at doses of 5 to 25 mg/day, the elimination half-life in plasma of healthy volunteers is approximately 3 hours, and 3–5 hours in patients with MM, MDS, and MCL.

Elderly Patients

No specific clinical studies have been conducted to evaluate the pharmacokinetics of lenalidomide in elderly patients. Population analysis, including pharmacokinetic data from patients aged 39 to 85 years, did not reveal any effect of age on lenalidomide clearance (plasma exposure). Due to the increased likelihood of impaired renal function in elderly patients, caution should be exercised when selecting the dose and careful monitoring of renal function should be performed during therapy.

Patients with Renal Impairment

The pharmacokinetics of lenalidomide have been studied in patients with non-malignant renal impairment. In this study, two methods were used to classify renal function: measurement of creatinine clearance in 24-hour urine and calculation of creatinine clearance using the Cockcroft-Gault formula. The study showed that with reduced renal function (< 50 mL/min), total drug clearance decreases proportionally, leading to an increase in AUC. AUC values increased approximately 2.5-, 4-, and 5-fold in patients with moderate, severe, and end-stage renal disease, respectively, compared to the group combining patients with normal renal function and mild renal impairment. The elimination half-life of lenalidomide increased from approximately 3.5 hours in patients with creatinine clearance > 50 mL/min to over 9 hours in patients with impaired renal function and creatinine clearance < 50 mL/min. However, renal impairment does not affect the absorption of lenalidomide from the gastrointestinal tract. No differences in Cmax were observed between healthy volunteers and patients with multiple myeloma. Approximately 30% of the drug was eliminated during a 4-hour dialysis session. Dose adjustment is recommended for patients with renal impairment (see section "Dosage and administration").

Patients with Hepatic Impairment

Population pharmacokinetic analysis in patients with mild hepatic impairment (N=16, total bilirubin > 1 and ≤ 1.5 x ULN [upper limit of normal], or AST > ULN) showed no effect of mild hepatic impairment on lenalidomide clearance (plasma exposure). Data on the effect of lenalidomide in patients with moderate or severe hepatic impairment are not available.

Other Endogenous Factors

Population pharmacokinetic analysis revealed no clinically significant effect of body weight (33–135 kg), sex, race, or type of hematologic malignancy (MM, MDS, or MCL) on lenalidomide clearance in adult patients.

Clinical characteristics.

Indications.

Multiple myeloma

Maintenance treatment (monotherapy) in adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation.

Treatment (in combination with other medicinal products, see section "Dosage and administration") of adult patients with previously untreated multiple myeloma who are not eligible for transplantation.

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

Myelodysplastic syndromes

Treatment (monotherapy) of adult patients with transfusion-dependent anemia due to low- or intermediate-risk myelodysplastic syndromes associated with deletion 5q cytogenetic abnormality, when other therapeutic treatment options are inadequate or inappropriate.

Mantle cell lymphoma

Treatment (monotherapy) of adult patients with relapsed or refractory mantle cell lymphoma (see sections "Special warnings and precautions for use", "Pharmacodynamics").

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the composition of the medicinal product.

Pregnancy, reproductive age except when all necessary conditions of the pregnancy prevention program can be adhered to.

Special precautions for safety.

If the contents of Lenalidomide capsules come into contact with the skin, wash immediately with soap and water. If lenalidomide comes into contact with mucous membranes, rinse thoroughly with copious amounts of water.

Interaction with other medicinal products and other forms of interaction.

Erythropoietic agents or other measures that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in patients with multiple myeloma receiving lenalidomide in combination with dexamethasone (see sections "Special warnings and precautions for use" and "Undesirable effects").

Oral contraceptives

Interaction studies with oral contraceptives have not been conducted. Lenalidomide is not an enzyme inducer. In an in vitro study using human hepatocytes, lenalidomide at various concentrations did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4/5. Therefore, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is unlikely when lenalidomide is administered as monotherapy. However, dexamethasone is a weak to moderate inducer of CYP3A4 and likely also affects other enzymes and transporters. A decrease in the effectiveness of oral contraceptives during treatment cannot be excluded. Effective contraceptive measures must be followed to prevent pregnancy (see sections "Special warnings and precautions for use" and "Use during pregnancy or lactation").

Warfarin

Multiple doses of lenalidomide 10 mg do not affect the pharmacokinetics of a single dose of R- and S-warfarin. Administration of a single 25 mg dose of warfarin does not affect the pharmacokinetics of lenalidomide. However, it is unknown whether an interaction exists during clinical use (combination therapy with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer, and its effect on warfarin is unknown. Careful monitoring of warfarin levels is recommended during treatment.

Digoxin

Concomitant administration of lenalidomide 10 mg once daily with digoxin (0.5 mg single dose) results in a 14% increase in digoxin plasma exposure, with a 90% confidence interval (CI) of [0.52–28.2%]. It is unknown whether the effect will change under different therapeutic conditions (higher doses of lenalidomide and concomitant use of dexamethasone). Therefore, monitoring of digoxin levels is recommended during lenalidomide treatment.

Statins

There is an increased risk of rhabdomyolysis when lenalidomide is co-administered with statins, possibly due to cumulative effects of these agents. Enhanced clinical and laboratory monitoring is required, particularly during the first weeks of treatment.

Dexamethasone

Single or multiple doses of dexamethasone (40 mg once daily) do not have a clinically significant effect on the pharmacokinetics of multiple doses of lenalidomide (25 mg once daily).

Interaction with P-glycoprotein (P-gp) inhibitors

Lenalidomide is in vitro a substrate of P-gp, but not an inhibitor. Concomitant administration of multiple doses of the strong P-glycoprotein inhibitor quinidine (600 mg twice daily) or the moderate inhibitor/substrate of P-gp, temsirolimus (25 mg), did not have a clinically significant effect on the pharmacokinetics of lenalidomide (25 mg/day). Concomitant administration of lenalidomide does not affect the pharmacokinetics of temsirolimus.

Special precautions for use.

Pregnancy warnings

Lenalidomide is a structural analogue of thalidomide. It is known that thalidomide, which has a pronounced teratogenic effect, causes severe internal organ malformations in the fetus when taken by pregnant women, which may be life-threatening. Experimental studies of lenalidomide in monkeys showed results similar to those previously described for thalidomide (see section "Use during pregnancy or breastfeeding"). The risk of congenital defects in humans is very high when lenalidomide is taken during pregnancy.

Strict adherence to all requirements of the Pregnancy Prevention Program applies to all patients of reproductive potential unless the absence of reproductive potential has been reliably confirmed.

Criteria for infertility in women

A patient or a male patient's partner is considered infertile if at least one of the following criteria is met:

• age ≥ 50 years and duration of natural amenorrhea ≥ 1 year (amenorrhea due to oncological therapy or during breastfeeding does not exclude the presence of reproductive potential);
• premature ovarian failure confirmed by a specialist gynecologist;
• history of bilateral salpingo-oophorectomy or hysterectomy;
• XY genotype, Turner syndrome, uterine agenesis.

Recommendations

Lenalidomide is contraindicated in women with preserved reproductive potential unless at least one of the following conditions is met, according to which the woman must:

• understand the expected teratogenic risk to the unborn child;
• understand the necessity of continuous effective contraceptive methods starting 4 weeks before treatment initiation, throughout the entire treatment cycle, and for 4 weeks after treatment completion;
• comply with all advice regarding effective contraception, even in the presence of amenorrhea;
• be capable of adhering to effective contraceptive methods;
• be informed and understand the possible consequences of pregnancy and the need for immediate consultation if pregnancy is suspected;
• understand the necessity of immediate initiation of effective contraceptive measures after lenalidomide prescription and confirmation of a negative pregnancy test;
• be aware of and perform a pregnancy test every 4 weeks, except in cases of confirmed tubal sterilization;
• confirm understanding of all possible adverse consequences and preventive measures during lenalidomide treatment.

For men who have taken lenalidomide, pharmacokinetic data show that lenalidomide is present in semen at extremely low levels during treatment and is undetectable 3 days after discontinuation in healthy individuals. As a precautionary measure and considering population characteristics with prolonged elimination periods, such as patients with impaired renal function, all male patients taking lenalidomide must meet the following requirements:

• be aware of the expected teratogenic risk when engaging in sexual intercourse with a pregnant woman or a woman of reproductive potential;
• understand the necessity of using a condom when having sexual intercourse with a pregnant woman or a woman of reproductive potential who is not using effective contraception (even if the man has undergone vasectomy) during treatment and for 1 week after treatment interruption and/or discontinuation;
• understand that if his female partner becomes pregnant during his lenalidomide treatment or immediately after therapy cessation, he must immediately inform his physician, and that his female partner should seek consultation from a teratology specialist.

The prescribing physician for lenalidomide treatment in women with preserved reproductive potential must ensure that:

• the patient complies with the requirements of the Pregnancy Prevention Program and adequately understands the program conditions;
• the patient consents to comply with all the above-mentioned conditions.

Contraceptive rules

Women with preserved reproductive potential must use one of the highly effective contraceptive methods for 4 weeks before treatment initiation, during treatment, and for 4 weeks after lenalidomide treatment completion, including during temporary treatment interruptions. The only exception is for patients who completely abstain from sexual intercourse throughout the specified period, with monthly documentation of abstinence. If necessary, the patient should be referred to a specialist for selection of an effective contraceptive method.

Examples of appropriate contraceptive methods include:

• subcutaneous hormonal implants;
• intrauterine systems releasing levonorgestrel (IUS);
• depot formulations of medroxyprogesterone acetate (for long-term contraception);
• tubal ligation;
• partner vasectomy (confirmed by two negative semen analyses);
• progestin-containing pills that inhibit ovulation (e.g., desogestrel).

Due to the increased risk of thromboembolic complications in patients with MM receiving lenalidomide in combination therapy and to a lesser extent in patients with MM, MDS, and mantle cell lymphoma (MCL) receiving lenalidomide monotherapy, the use of combined oral contraceptives is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If a patient is currently using combined oral contraceptives, she should switch to one of the effective contraceptive methods listed above. The risk of thromboembolic complications persists for 4–6 weeks after discontinuation of combined oral contraception. The effectiveness of contraceptive steroids may be reduced when lenalidomide is combined with dexamethasone (see section "Interaction with other medicinal products and other forms of interaction").

Subcutaneous hormonal implants or intrauterine systems releasing levonorgestrel are associated with an increased risk of infectious complications during insertion and spontaneous vaginal bleeding. Therefore, prophylactic antibiotics should be prescribed, especially in patients with neutropenia.

Copper-releasing intrauterine devices are generally not recommended due to possible risks of infectious complications at the time of insertion or due to menstrual blood loss, which may pose a threat to patients with neutropenia or thrombocytopenia.

Pregnancy testing

Pregnancy tests with sensitivity of at least 25 mIU/mL must be performed according to the methodology described below, under physician supervision, by all women with preserved reproductive potential, including those who permanently abstain from sexual intercourse. Tests are performed on the day of treatment prescription. The first dose of lenalidomide in a woman with preserved reproductive potential must be administered no later than 7 days after treatment prescription.

Prior to treatment initiation

Pregnancy tests are performed on the day of treatment prescription under physician supervision or up to 3 days before the physician visit, even if the patient has used effective contraceptive methods during the 4 weeks preceding treatment initiation. Test results must confirm the absence of pregnancy at the time of lenalidomide treatment initiation.

Monitoring period and treatment completion

Physician-supervised pregnancy tests are performed every 4 weeks, including 4 weeks after completion of lenalidomide intake, except for patients with tubal ligation. Such pregnancy tests are performed on the day of scheduled treatment prescription or up to 3 days before the physician visit.

Additional contraindications

Patients must not give Lenalidol to other individuals. Unused medication must be returned to the medical facility after treatment completion.

Patients are not allowed to donate blood or semen throughout the entire lenalidomide treatment course and for 1 week after treatment completion.

Educational materials, prescribing and dispensing restrictions

To enhance safety and reduce the risk of teratogenic effects during the use of Lenalidol, the marketing authorization holder provides physicians with necessary educational materials for their patients, including all required information about possible teratogenic effects due to lenalidomide use, recommendations for effective contraception before, during, and after therapy, as well as information on the use of pregnancy tests.

Other special warnings and contraindications for use

Myocardial infarction

There have been reports of myocardial infarction in patients taking lenalidomide, particularly in individuals with cardiovascular risk factors and during the first 12 months of use in combination with dexamethasone. Patients with known risk factors (including history of thrombosis) should be closely monitored, and measures should be taken to reduce all treatable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Venous and arterial thromboembolism

In patients with MM, the combination of lenalidomide with dexamethasone is associated with an increased risk of venous thromboembolism (primarily deep vein thrombosis and pulmonary embolism). A lower incidence of venous and arterial thromboembolism has been observed when combined with melphalan and prednisone.

In patients with MM, MDS, and MCL, lenalidomide monotherapy has been associated with a lower risk of venous thromboembolism (primarily deep vein thrombosis and pulmonary embolism) compared to patients with MM treated with lenalidomide in combination therapy (see section "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

In patients with MM, the combination of lenalidomide with dexamethasone has been associated with an increased risk of arterial thromboembolism (primarily myocardial infarction and cerebrovascular events). A lower risk has been observed when combined with melphalan and prednisone. The risk of arterial thromboembolism is lower in patients with MM treated with lenalidomide (monotherapy) compared to those treated with lenalidomide in combination with other medicinal products.

Therefore, patients with thromboembolic risk factors, including a history of thrombosis, should be monitored. Measures should be taken to eliminate manageable risk factors such as smoking, arterial hypertension, and hyperlipidemia. The most prognostically significant factors include a history of thromboembolic complications, concomitant erythropoietin therapy, and hormone replacement therapy. Thus, erythropoietic agents and drugs that may increase the risk of thrombosis (e.g., hormone replacement therapy) should be prescribed with caution to MM patients receiving lenalidomide in combination with dexamethasone. Hemoglobin concentration above 120 g/L indicates the need to discontinue erythropoietin therapy.

Physicians and patients should carefully evaluate clinical symptoms indicating possible thromboembolism. Patients should be warned to seek immediate medical attention if symptoms such as dyspnea, chest pain, or swelling of the upper or lower extremities occur. Antithrombotic agents are recommended for the prevention of venous thromboembolism, especially in patients with additional risk factors. The decision to prescribe prophylactic antithrombotic therapy should be made after careful assessment of individual risk factors.

If thromboembolic complications occur, treatment should be discontinued and standard anticoagulant therapy initiated. If the patient's condition stabilizes during anticoagulant therapy and thromboembolic complications are managed, lenalidomide treatment may be resumed at the initial dose depending on the benefit/risk assessment. The patient should continue anticoagulant therapy throughout the lenalidomide treatment course.

Neutropenia and thrombocytopenia

Neutropenia and thrombocytopenia are the main dose-limiting effects of lenalidomide. Complete blood count, including leukocyte count with differential, platelet count, hemoglobin level, and hematocrit, should be performed weekly during the first 8 weeks of lenalidomide treatment and monthly thereafter to prevent cytopenias. In patients with MCL, the monitoring schedule should be as follows: every 2 weeks during cycles 3 and 4, and then at the beginning of each subsequent cycle. Dose reduction may be necessary (see section "Method of administration and doses").

In cases of neutropenia, administration of growth factor agents may be appropriate. Patients should be informed about the necessity of promptly reporting fever to their physician. Lenalidomide should be used cautiously with other myelosuppressive agents. Patients and physicians are recommended to monitor for signs and symptoms of bleeding, including petechial hemorrhages and epistaxis, especially in patients concurrently receiving medications that may cause bleeding (see section "Adverse reactions").

Thyroid disorders

Cases of hypothyroidism and hyperthyroidism have been reported. Concomitant disorders affecting thyroid function should be evaluated before treatment initiation. Assessment of thyroid function is recommended before treatment initiation and regular monitoring during Lenalidol use.

Peripheral neuropathy

The lenalidomide molecule is structurally similar to thalidomide, which is known to cause severe peripheral neuropathy. However, no increased frequency of peripheral neuropathy has been observed during long-term lenalidomide use in the treatment of newly diagnosed MM.

Transient increase in tumor manifestations and tumor lysis syndrome

Since lenalidomide has antineoplastic activity, tumor lysis syndrome may occur. Cases of tumor lysis syndrome and transient increase in tumor manifestations, including fatal cases, have been reported (see section "Adverse reactions"). Patients with high tumor burden before treatment initiation had a higher likelihood of tumor lysis syndrome and transient increase in manifestations. Caution should be exercised when initiating these patients on lenalidomide. These patients require close monitoring, especially during the first cycle or dose escalation, with appropriate preventive measures and consideration of specific application features.

Tumor burden

Lenalidomide is not recommended for the treatment of MCL patients with high tumor burden if alternative treatment options are available. In study MCL-002, an overall increase in early mortality (within 20 weeks) was observed. Patients with high tumor burden should be closely monitored for adverse effects (see section "Adverse reactions"), including signs of transient increase in tumor manifestations.

High tumor burden was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm in diameter.

Transient increase in tumor manifestations

Close monitoring and assessment of transient increase in tumor manifestations are recommended in patients with MCL. The risk of transient increase in tumor manifestations may threaten patients with established high international prognostic index MCL or massive lymphadenopathy (at least 1 tumor ≥ 7 cm in longest diameter). This symptom may also mimic disease exacerbation. Patients in trials MCL-002 and MCL-001 who experienced transient increase in tumor manifestations of grade I and II were treated with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or narcotic analgesics. Therapeutic measures should be decided after detailed clinical evaluation of each individual patient (see section "Method of administration and doses").

Allergic reactions

There have been reports of allergic reactions/hypersensitivity reactions in patients taking lenalidomide (see section "Adverse reactions"). Patients with a history of allergic reactions during thalidomide treatment should be closely monitored, as cross-allergic reactions between lenalidomide and thalidomide are possible, as indicated in the literature.

Severe skin reactions

Severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), have been reported during lenalidomide use. Immediate medical attention is required if these symptoms occur.

Lenalidomide treatment should be discontinued in cases of skin desquamation and bullous eruptions or if Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms are suspected. The decision to interrupt or discontinue lenalidomide use should be based on identification of the type of skin reaction depending on its severity. Lenalidomide is contraindicated in patients who have had severe rashes caused by thalidomide.

Lactose intolerance

Lenalidol contains lactose. Lenalidol is contraindicated in patients with rare hereditary problems of lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Secondary primary malignancies of other localization (SPNOL)

In clinical trials, a higher incidence of SPNOL was observed among 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 SPNOL included basal cell carcinoma or squamous cell carcinoma of the skin. Most invasive SPNOL were solid tumors.

In clinical trials among patients with newly diagnosed MM receiving lenalidomide, a 4-fold increase in SPNOL (7.0%) was observed compared to the control group (1.8%). Among invasive SPNOL in patients receiving combined therapy with lenalidomide and melphalan, or immediately after high-dose melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia, MDS, and development of solid tumors were observed. Cases of B-cell malignancies (including Hodgkin's lymphoma) were reported in clinical trials when lenalidomide was used after autologous stem cell transplantation.

The risk of SPNOL development should be considered before prescribing lenalidomide. Physicians should carefully examine patients using standard diagnostic methods to detect malignancies both before deciding on Lenalidol prescription and throughout the treatment period. Treatment should be conducted according to generally accepted guidelines.

Progression to acute myeloid leukemia in low or intermediate-1-risk MDS Karyotype

Baseline chromosomal abnormalities, including complex cytogenetics, are associated with progression to acute myeloid leukemia in transfusion-dependent patients with del(5q) abnormality. In a combined analysis of two clinical trials of lenalidomide in low or intermediate-1-risk MDS, subjects with complex cytogenetics had the highest established cumulative 2-year risk of progression to acute myeloid leukemia (38.6%). The established 2-year progression rate to acute myeloid leukemia in patients with isolated del(5q) abnormality is 13.8%, compared to 17.3% for patients with del(5q) abnormality and one additional cytogenetic abnormality. Consequently, the benefit/risk ratio of lenalidomide use when MDS is accompanied by del(5q) abnormality and one additional cytogenetic abnormality is unknown.

TP53 status

TP53 mutation is present in 20–25% of lower-risk MDS patients with del(5q) and is associated with a higher risk of progression to acute myeloid leukemia.

Progression to other malignancies in MCL

Potential risks exist for MCL, acute myeloid leukemia, B-cell malignancies, and non-melanoma skin cancer.

Hepatic impairment

Reports of hepatic failure, including fatal cases, have been received among patients receiving combination therapy with lenalidomide. Cases of acute hepatic failure, toxic, cytolytic or cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have also been reported. Mechanisms of severe drug-induced hepatotoxicity remain unknown, although in some cases risk factors may include concomitant viral liver diseases, elevated liver enzymes, and possibly antibiotic treatment.

Abnormal liver tests, often asymptomatic and reversible after drug discontinuation, have been frequently reported. After liver test parameters return to baseline values, treatment may be continued with a reduced dose. Lenalidomide is excreted by the kidneys. Dose adjustment should be considered in patients with renal impairment to avoid plasma levels capable of increasing the risk of hematological adverse effects or hepatotoxicity. Monitoring of liver function is recommended in patients with past or existing viral liver diseases and when combining lenalidomide with drugs known to cause hepatotoxicity.

Infections in the absence or presence of neutropenia

Patients with MM are prone to developing infections, including pneumonia. The most frequent occurrence of infections is observed with the combination of lenalidomide and dexamethasone, followed by MPT in newly diagnosed MM patients not eligible for transplantation. Grade ≥ III infections were observed with concomitant neutropenia in less than 1/3 of patients. Patients with known risk factors for infection should be closely monitored by specialists. Medical attention should be sought immediately at the first signs of infection (e.g., cough, fever), allowing early correction to prevent serious conditions.

Cases of viral reactivation have been reported in patients receiving lenalidomide, including severe cases of herpes zoster or hepatitis B virus reactivation. Some cases of viral reactivation had fatal outcomes.

Some cases of herpes zoster reactivation progressed to disseminated herpes zoster, herpes zoster meningitis, or herpes zoster ophthalmicus, requiring temporary or permanent discontinuation of lenalidomide treatment and appropriate antiviral therapy.

Hepatitis B virus reactivation has been rarely reported in patients receiving lenalidomide who were previously infected with hepatitis B virus. Some of these cases progressed to acute hepatic failure, leading to discontinuation of lenalidomide treatment and initiation of appropriate antiviral therapy. Hepatitis B virus status should be determined before initiating lenalidomide treatment. Patients with positive hepatitis B virus test results are recommended to consult a physician competent in hepatitis B treatment. Contraindications should be considered when using lenalidomide in patients previously infected with hepatitis B virus, including patients positive for hepatitis B core antibody but negative for hepatitis B surface antigen. These patients should be closely monitored for signs and symptoms of active hepatitis B virus during therapy.

Patients with newly diagnosed MM

A higher level of intolerance (grade III or IV adverse reactions, serious adverse reactions, treatment discontinuation) has been observed in patients aged > 75 years, ISS stage III, ECOG PS ≥ 2, CLcr < 60 mL/min when lenalidomide was prescribed in combination with other drugs. Careful assessment of the patient's ability to tolerate lenalidomide in combinations should be performed considering age, ISS stage III, ECOG PS ≥ 2, or CLcr < 60 mL/min (see sections "Method of administration and doses" and "Adverse reactions").

Cataract

Cataract has been reported more frequently in patients receiving lenalidomide in combination with dexamethasone, especially during long-term therapy. Regular vision monitoring is recommended.

Use during pregnancy or breastfeeding.

Due to the teratogenic potential of lenalidomide, it should be prescribed within the Pregnancy Prevention Program (see section "Special precautions for use") unless there is reliable evidence that the patient lacks reproductive potential.

Women with preserved reproductive potential/contraception for men and women

Women with preserved reproductive potential should use effective contraceptive methods. If pregnancy occurs during lenalidomide treatment, treatment should be immediately discontinued, and the patient should be referred to a gynecologist or teratology specialist for examination and further recommendations. If pregnancy occurs in the female sexual partner of a patient receiving lenalidomide treatment, she should also be advised to consult a gynecologist or teratology specialist for examination and recommendations.

During lenalidomide intake, it is detected in semen at very low concentrations and is undetectable 3 days after discontinuation in healthy volunteers (see section "Pharmacokinetics"). As a precautionary measure and considering the prolonged elimination time in renal impairment, male patients should use condoms throughout the entire lenalidomide treatment course, during treatment interruptions, and for 1 week after treatment discontinuation if their sexual partner is a pregnant woman or a woman with preserved reproductive potential not using highly effective contraceptive methods.

Pregnancy

Lenalidomide is structurally related to thalidomide. Thalidomide is a known teratogenic substance in humans, causing severe life-threatening congenital malformations.

Abnormalities caused by lenalidomide administration in monkey studies were similar to previously described results for thalidomide. Since the risk of congenital defects is very high, lenalidomide is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

It is unknown whether lenalidomide is excreted in breast milk. Therefore, breastfeeding should be discontinued during lenalidomide treatment.

Fertility

Fertility studies in rats showed that lenalidomide at doses up to 500 mg/kg (approximately 200–500 times higher than the therapeutic doses for humans, 25 mg and 10 mg, on a body surface area basis) did not cause fertility impairment or toxic effects on parental organisms.

Ability to affect reaction speed when driving vehicles or operating machinery.

Some adverse effects of lenalidomide, such as dizziness, weakness, somnolence, and blurred vision, may negatively affect the ability to drive vehicles or operate machinery. Therefore, special caution should be exercised when driving vehicles or operating machinery.

Method of Administration and Dosage

Treatment with Lenalidol must be conducted under the supervision of a qualified oncologist with relevant experience.

For all indications listed below:

− Dose modifications should be based on clinical and laboratory findings obtained (see section "Special Warnings and Precautions for Use").

− Dose adjustments during treatment and re-treatment are recommended according to grade 3 or 4 thrombocytopenia, neutropenia, or any other lenalidomide-related toxicity of grade 3 or 4.

− In cases of neutropenia, the use of a growth factor should be considered for the patient.

− If less than 12 hours have passed since a missed dose, the patient may take the missed dose. If more than 12 hours have passed since the missed dose, the patient should not take the missed dose but should take the next scheduled dose at the usual time on the following day.

Dosage

Newly Diagnosed Multiple Myeloma (NDMM)

Treatment with lenalidomide in patients who have undergone autologous stem cell transplantation (ASCT)

Lenalidomide should be initiated after adequate hematologic recovery following ASCT in patients without evidence of progressive disease. Therapy should not be initiated if the absolute neutrophil count (ANC) is < 1.0 × 10⁹/L and/or platelet count is < 75 × 10⁹/L.

Recommended Dose

The recommended starting dose of lenalidomide is 10 mg orally once daily (on days 1 to 28 of repeated 28-day cycles), administered until disease progression or unacceptable toxicity. After 3 cycles of lenalidomide treatment, the dose may be increased to 15 mg orally once daily if the drug is well tolerated by the patient.

Dose Reduction

and after 3 cycles of lenalidomide treatment, the dosage may be increased to more than 15 mg orally once daily if the drug is well tolerated

Thrombocytopenia

Neutropenia

а At the physician's discretion, if neutropenia is the only toxicity at any dose level, add granulocyte-colony stimulating factor (G-CSF) and maintain the lenalidomide dose level.

MM in patients ineligible for transplantation who have received lenalidomide in combination with low-dose dexamethasone

Do not initiate treatment with Lenalidol if ANC < 1.0 x 10⁹/L and/or platelet count < 50 x 10⁹/L.

Recommended dosage

The recommended initial dose of lenalidomide is 25 mg orally once daily (on days 1 to 21 of repeated 28-day cycles).

The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15, and 22 of repeated 28-day cycles. Patients may continue treatment with lenalidomide and dexamethasone until disease progression or until drug intolerance occurs.

Dose reduction

and dose reduction for both medicinal products may be adjusted independently.

* lenalidomide preparations are administered at the appropriate dosage.

Thrombocytopenia

If dose-limiting toxicity (DLT) is observed on > 15th day of the cycle, lenalidomide treatment will be interrupted for at least the remainder of the current 28-day cycle.

Neutropenia

In the case of hematologic toxicity, lenalidomide therapy may be resumed at the next higher dose level (compared to the starting dose) upon improvement of bone marrow function (absence of hematologic toxicity for at least 2 consecutive cycles: ANC ≥ 1.5 × 10⁹/L with platelets ≥ 100 × 10⁹/L at the start of a new cycle).

MM in patients ineligible for transplantation who have received treatment with lenalidomide in combination with melphalan and prednisone

Do not initiate treatment with Lenalidol if ANC < 1.5 × 10⁹/L and/or platelet count < 75 × 10⁹/L.

Recommended dose

The recommended starting dose of lenalidomide is 10 mg orally once daily (on days 1 to 21 of repeated 28-day cycles up to 9 cycles), melphalan 0.18 mg/kg orally on days 1 to 4 of repeated 28-day cycles, prednisone 2 mg/kg orally on days 1 to 4 of repeated 28-day cycles. Patients who complete 9 cycles or are unable to complete combination therapy due to drug intolerance will receive lenalidomide monotherapy as follows: 10 mg once daily on days 1 to 21 of repeated 28-day cycles, continued until disease progression.

Dose reduction

and if neutropenia is the only toxicity at any dose level, granulocyte colony-stimulating factor (G-CSF) should be added and lenalidomide dose level maintained.

* administer lenalidomide at the appropriate dose level.

Thrombocytopenia

If the subject has not received G-CSF therapy, initiate G-CSF therapy. On day 1 of the next cycle, continue G-CSF and maintain the lenalidomide dose level if neutropenia is the only dose-limiting toxicity. Otherwise, reduce the dose by one level at the start of the next cycle.

Multiple myeloma in patients who have received at least one prior therapy

Do not initiate treatment with Lenalidol if ANC < 1.0 × 10⁹/L and/or platelet count < 75 × 10⁹/L, or, depending on bone marrow infiltration by plasma cells, platelet count < 30 × 10⁹/L.

Recommended dose

The recommended initial dose of lenalidomide is 25 mg orally once daily on days 1–2 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1–4, 9–12, and 17–20 of each 28-day cycle for the first 4 treatment cycles, followed by 40 mg once daily on days 1–4 every 28 days thereafter.

Physicians prescribing this medicinal product must carefully evaluate the appropriate dose of dexamethasone to use, taking into account the patient's condition and disease status.

Dose escalation

Thrombocytopenia

Neutropenia

Myelodysplastic syndromes

Treatment with lenalidomide should not be initiated if ANC < 0.5 x 10⁹/L and/or platelet count < 25 x 10⁹/L.

Recommended dose

The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles.

Dose reduction

* lenalidomide is administered at the appropriate dosage.

Thrombocytopenia

Neutropenia

Discontinuation of lenalidomide

If patients have not achieved at least a minor erythroid response within 4 months after initiation of therapy, demonstrated by at least a 50% reduction in red blood cell transfusion requirement or, in the absence of transfusions, an increase in hemoglobin of 1 g/dL, lenalidomide should be discontinued.

Mantle cell lymphoma (MCL)

Recommended dose

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles.

Dose reduction

1 in countries where 2.5 mg capsules are available

* lenalidomide is administered at the appropriate dosage.

Thrombocytopenia

Neutropenia

Transient increase in tumor symptoms reaction

Treatment with lenalidomide may be continued in patients with Grade I-II transient increase in tumor symptoms reaction without discontinuation of treatment or dose modification at the physician's discretion. In patients with Grade III-IV transient increase in tumor symptoms reaction, treatment with lenalidomide must be discontinued until the reaction resolves to ≤ Grade I, and patients may resume treatment for symptom management according to the recommendations for managing Grade I and II transient increase in tumor symptoms reactions (see section "Special precautions").

All indications

For other Grade III-IV toxicities related to lenalidomide, treatment should be discontinued and may be resumed only at a lower dose level once toxicity has resolved to ≤ Grade II at the physician’s discretion.

Treatment interruption or discontinuation of lenalidomide should be considered in case of Grade II-III skin rash. Lenalidomide treatment must be discontinued in case of angioneurotic edema, Grade IV rash, skin desquamation, or bullous rash, or if Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS) is suspected, and lenalidomide must not be restarted upon subsequent re-exposure.

Special patient groups

Children

Lenalidomide must not be administered to children and adolescents under 18 years of age due to safety concerns.

Elderly patients

Pharmacokinetic data of lenalidomide in elderly patients are presented in the section "Pharmacokinetics". In clinical trials, lenalidomide was administered to patients up to 86 years of age (see section "Pharmacodynamics"). The proportion of patients aged 65 years and older was not significantly different between treatment groups receiving lenalidomide/dexamethasone or placebo/dexamethasone. Overall, no major differences in efficacy and safety of lenalidomide were observed between younger and elderly patients, although increased sensitivity in older patients cannot be excluded. Since elderly patients have a higher likelihood of impaired renal function, dose selection should be cautious, and monitoring of renal function is recommended during treatment.

Patients with renal impairment

Lenalidomide is predominantly eliminated via the kidneys; therefore, dose selection should be cautious, and monitoring of renal function is recommended.

Dose adjustment is not required for patients with mild renal impairment. The table below provides recommended starting doses of the drug for patients with moderate or severe renal impairment, as well as for patients with end-stage renal disease.

There is no experience from Phase III trials in patients with end-stage renal disease (ESRD) (CLcr < 30 mL/min requiring dialysis).

Multiple myeloma

1 The dose of the drug may be increased to 15 mg once daily after 2 cycles of therapy in case of lack of response to treatment and if the medicinal product is well tolerated.

2 In countries where 7.5 mg capsules are available.

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

Myelodysplastic syndromes

Recommended dose reduction steps during treatment and retreatment for grade III-IV neutropenia or thrombocytopenia or other grade III-IV toxicities considered related to lenalidomide, as specified above.

* lenalidomide products are administered at the appropriate dosage.

Mantle cell lymphoma

1 The dose of the medicinal product may be increased to 15 mg once daily after 2 treatment cycles in case of absence of response to therapy and provided that the medicinal product is well tolerated.

2 In countries where 7.5 mg capsules are available.

Following initiation of lenalidomide treatment, subsequent dose modifications in patients with renal impairment should be based on the individual patient's response to treatment, as described above.

Patients with hepatic impairment

As no specific studies of lenalidomide in patients with impaired liver function have been conducted, there are no specific dosage recommendations for this patient population.

Method of administration

For oral use.

Lenalidol capsules should be taken once daily at the same time each day. The capsules must not be opened, broken, or chewed; they should be swallowed whole with water, regardless of food intake. It is recommended to press only on one end of the capsule to remove it from the blister, thereby reducing the risk of capsule deformation or breakage.

Ability to affect reaction speed when driving or operating machinery.

Some adverse effects of lenalidomide, such as dizziness, weakness, somnolence, and blurred vision, may negatively affect the ability to drive a vehicle or perform potentially hazardous activities. Therefore, caution should be exercised when driving or operating machinery.

Children.

The safety and efficacy of Lenalidol in children under 18 years of age have not been established. There are no data on the use of the medicinal product in this patient group.

Overdose.

There is currently no specific management plan for lenalidomide overdose, despite the fact that in dose-ranging studies some patients received doses up to 150 mg, and in single-dose effect studies—up to 400 mg of the drug. Dose-limiting toxicity in these studies was exclusively hematological. In case of overdose, supportive therapy is recommended.

Adverse Reactions

Summary of Safety Profile

Newly Diagnosed MM in Patients Who Underwent Autologous Stem Cell Transplantation with Lenalidomide Maintenance Therapy

A conservative approach was used in the CALGB 100104 study to determine adverse reactions. The adverse reactions listed in Table 1 describe events recorded after high-dose melphalan (HDM)/autologous stem cell transplantation (ASCT) in patients, as well as adverse reactions during maintenance therapy. A second analysis identifying events occurring after initiation of maintenance therapy showed that the incidence rates listed in Table 1 may be higher than actually observed during the maintenance therapy period. In the IFM 2005-02 study, adverse reactions occurred only during the maintenance therapy phase.

Serious adverse effects observed more frequently (≥ 5%) during lenalidomide maintenance therapy compared to placebo were:

• Pneumonia (10.6%; preferred term) in the IFM 2005-02 study;
• Pulmonary infection (9.4% [9.4% after initiation of maintenance therapy]) in the CALGB 100104 study.

In the IFM 2005-02 study, adverse reactions observed more frequently with lenalidomide maintenance therapy than with placebo were: neutropenia (60.5%), bronchitis (47.4%), diarrhea (38.9%), nasopharyngitis (34.8%), muscle spasms (33.4%), leukopenia (31.7%), asthenia (29.7%), cough (27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%), and pyrexia (20.5%).

In the CALGB 100104 study, adverse reactions observed more frequently during lenalidomide maintenance therapy than with placebo were: neutropenia (79.0% [71.9% after initiation of maintenance therapy]), thrombocytopenia (72.3% [61.6%]), diarrhea (54.5% [46.4%]), rash (31.7% [25.0%]), upper respiratory tract infections (26.8% [26.8%]), fatigue (22.8% [17.9%]), leukopenia (22.8% [18.8%]), and anemia (21.0% [13.8%]).

Newly Diagnosed MM in Transplant-Ineligible Patients Receiving Lenalidomide in Combination with Low-Dose Dexamethasone

Serious adverse effects observed more frequently (≥ 5%) during lenalidomide therapy in combination with low-dose dexamethasone (Rd and Rd18) compared to melphalan, prednisone, and thalidomide (MPT) were:

• Pneumonia (9.8%);
• Renal dysfunction (including acute forms) (6.3%).

Adverse reactions observed more frequently during Rd and Rd18 therapy than during MPT were: diarrhea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%).

Newly Diagnosed MM in Transplant-Ineligible Patients Receiving Lenalidomide in Combination with Melphalan and Prednisone

Serious adverse effects observed more frequently (≥ 5%) during therapy with melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR + R) or melphalan, prednisone, and lenalidomide followed by placebo (MPR+p), compared to melphalan, prednisone, and placebo followed by placebo (MPp+p), were:

• Febrile neutropenia (6.0%);
• Anemia (5.3%).

Adverse reactions observed more frequently during MPR+R or MPR+p therapy than during MPp+p were: neutropenia (83.3%), anemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhea (33.3%), rash (28.9%), fatigue (27.0%), peripheral edema (25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).

MM in Patients Who Have Received at Least One Prior Therapy

In two placebo-controlled Phase III studies, 353 patients with MM received the combination of lenalidomide/dexamethasone, and 351 patients received placebo/dexamethasone.

The most serious adverse reactions observed with the lenalidomide/dexamethasone combination compared to placebo/dexamethasone were:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section "Special Warnings and Precautions for Use");
• Grade 4 neutropenia (see section "Special Warnings and Precautions for Use").

Adverse reactions observed more frequently with the lenalidomide/dexamethasone combination compared to placebo/dexamethasone in clinical trials of multiple myeloma (MM-009 and MM-010) were: fatigue (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhea (38.5%), muscle spasms (33.4%), anemia (31.4%), thrombocytopenia (21.5%), and rash (21.2%).

Myelodysplastic Syndromes

The overall safety profile of lenalidomide is based on data from one Phase II and one Phase III study involving 286 patients with myelodysplastic syndromes. In the Phase II study, all 148 patients received lenalidomide treatment. In the Phase III study, 69 patients received 5 mg lenalidomide, another 69 patients received 10 mg, and 67 patients received placebo during the double-blind phase of the study.

The most frequent adverse reactions occurred during the first 16 weeks of lenalidomide therapy. Serious adverse reactions included:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section "Special Warnings and Precautions for Use");
• Grade III–IV neutropenia, febrile neutropenia, and Grade III–IV thrombocytopenia (see section "Special Warnings and Precautions for Use").

The most common adverse reactions observed in the lenalidomide group compared to the control group in the Phase III study were: neutropenia (76.8%), thrombocytopenia (46.4%), diarrhea (34.8%), constipation (19.6%), nausea (19.6%), pruritus (25.4%), rash (18.1%), fatigue (18.1%), and muscle spasms (16.7%).

Mantle Cell Lymphoma

The overall safety profile of lenalidomide is based on results from a randomized, controlled Phase II study (MCL-002) in 254 patients with mantle cell lymphoma.

Information on adverse reactions occurring during the MCL-001 study is provided in Table 3.

Serious adverse effects observed most frequently in the lenalidomide group compared to the control group during the MCL-002 study (with a difference of at least 2 percentage points) were:

• Neutropenia (3.6%);
• Pulmonary embolism (3.6%);
• Diarrhea (3.6%).

Adverse reactions most frequently observed in the lenalidomide group compared to the control group in the MCL-002 study were: neutropenia (50.9%), anemia (28.7%), diarrhea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and rash (including allergic dermatitis) (16.2%).

In the MCL-002 study, an overall increase in early mortality (within 20 weeks) was observed. Patients with high baseline tumor burden had an increased risk of early mortality (16/81 (20%) in the lenalidomide group vs. 2/28 (7%) in the control group). At 52 weeks, the corresponding rates were 32/81 (39.5%) and 6/28 (21%).

During the first treatment cycle, 11/81 (14%) patients with high tumor burden were withdrawn from the lenalidomide treatment group compared to 1/28 (4%) in the control group. The main reason for discontinuation of lenalidomide in patients with high tumor burden during the first treatment cycle was adverse effects, in 7/11 (64%).

High tumor burden was defined as at least one lesion ≥ 5 cm in diameter or three lesions ≥ 3 cm.

Tabulated List of Adverse Reactions

Adverse reactions observed in patients during treatment with lenalidomide are listed below by system organ class and frequency of occurrence. Within each group, adverse reactions are listed in decreasing order of severity. Frequency of adverse reactions is categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data).

Adverse reactions were assigned to the appropriate categories in the table below based on the most frequent adverse reaction observed in any of the main clinical studies.

Summary Table of Adverse Reactions in Monotherapy for MCL

The data in the following table were obtained from studies in newly diagnosed multiple myeloma in patients who underwent ASCT followed by lenalidomide maintenance therapy. The data were not adjusted for the longer treatment duration in the lenalidomide groups, which continued until disease progression, compared to the placebo group in the main clinical studies of multiple myeloma.

Adverse reactions observed during clinical studies in patients with MM receiving lenalidomide maintenance therapy

Table 1.

1 Adverse reactions considered as "serious" during clinical trials in patients with newly diagnosed multiple myeloma who underwent ASCT.

2 "Pneumonia" includes the following adverse effects: bronchopneumonia, lobar pneumonia, Pneumocystis pneumonia, pneumonia, Klebsiella pneumoniae pneumonia, Legionella pneumonia, mycoplasma pneumonia, pneumococcal pneumonia, streptococcal pneumonia, viral pneumonia, lung disorder, pneumonitis.

3 "Sepsis" includes the following adverse effects: bacterial sepsis, pneumococcal sepsis, septic shock, staphylococcal sepsis.

4 Apply only to serious adverse reactions.

5 See detailed description in the section "Adverse Reactions".

6 "Peripheral neuropathy" includes the following adverse effects: peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy.

7 "Deep vein thrombosis" includes the following adverse effects: deep vein thrombosis, thrombosis, venous thrombosis.

Summary table of adverse reactions during combination therapy for multiple myeloma

The data in the following table were obtained during the use of combination therapy for the treatment of multiple myeloma. The data were not adjusted for the longer duration of treatment in the lenalidomide group compared to the control group in the main clinical trials of multiple myeloma.

Adverse reactions observed during clinical trials in patients with MM receiving combination therapy with lenalidomide/dexamethasone or melphalan/prednisone

Table 2.

1 Adverse reactions considered "serious" during clinical trials in patients with multiple myeloma who received lenalidomide in combination with dexamethasone or with melphalan and prednisone.

2 See detailed description in the section "Adverse Reactions".

3 Cases of cutaneous squamous cell carcinoma were reported during clinical trials in patients with multiple myeloma who received lenalidomide in combination with dexamethasone compared to control.

4 Cases of cutaneous squamous cell carcinoma were reported during clinical trials in patients previously treated for myeloma who received lenalidomide in combination with dexamethasone compared to control.

5 Applies only to serious adverse reactions.

Summary table of adverse reactions during monotherapy

The data in the following table were obtained during the use of lenalidomide monotherapy for the treatment of myelodysplastic syndromes and mantle cell lymphoma.

Adverse reactions observed during clinical trials in MDS patients who received lenalidomide

Table 3.

1 Adverse reactions considered as "serious" during clinical trials in patients with myelodysplastic syndromes.

2 See detailed description in the section "Adverse Reactions".

3 Mood alterations were recorded as common adverse reactions during treatment of myelodysplastic syndromes in phase III clinical trials; however, they were not considered as severe adverse reactions of grade III–IV.

Adverse reactions observed during clinical trials in patients with MDS receiving lenalidomide

Table 4.

1 Adverse reactions considered "serious" during clinical trials in patients with mantle cell lymphoma.

2 See detailed description in section "Adverse Reactions".

Summary table of adverse reactions from post-marketing experience

In addition to the above-mentioned adverse reactions identified during the main clinical trials, the following table includes data collected from post-marketing studies.

Adverse reactions reported from post-marketing data in patients receiving lenalidomide

Table 5.

1 See detailed description in the section "Adverse Reactions".

Description of Selected Adverse Reactions

Teratogenicity

Lenalidomide is a structural analogue of thalidomide, a substance with pronounced teratogenic effects leading to severe congenital fetal malformations that are life-threatening. Experimental studies in monkeys showed results similar to those described for thalidomide (see section "Use in Pregnancy or Breastfeeding"). If lenalidomide is used during pregnancy, there is a high risk of fetal congenital malformations.

Neutropenia and Thrombocytopenia

Newly diagnosed MM in patients who underwent autologous stem cell transplantation and received lenalidomide as maintenance therapy

Use of lenalidomide after ASCT was associated with an increased incidence of grade IV neutropenia compared to placebo (32.1% vs. 26.7% [16.1% vs. 1.8% after initiation of maintenance therapy] in the CALGB 100104 study and 16.4% vs. 0.7% in the IFM 2005-02 study, respectively). Neutropenia leading to discontinuation of lenalidomide was reported in 2.2% of patients in the CALGB 100104 study and 2.4% in the IFM 2005-02 study, respectively. Rates of grade IV febrile neutropenia were similar during lenalidomide maintenance therapy compared to placebo (0.4% vs. 0.5% [0.4% vs. 0.5% after initiation of maintenance therapy] in the CALGB 100104 study and 0.3% vs. 0% in the IFM 2005-02 study, respectively).

Use of lenalidomide after ASCT was associated with a higher likelihood of developing grade III-IV thrombocytopenia compared to placebo (37.5% vs. 30.3% [17.9% vs. 4.1% after initiation of maintenance therapy] in CALGB 100104 and 13.0% vs. 2.9% in IFM 2005-02, respectively).

Newly diagnosed MM in transplant-ineligible patients treated with lenalidomide in combination with low-dose dexamethasone

Combination of lenalidomide with low-dose dexamethasone for treatment of patients with newly diagnosed multiple myeloma was associated with a lower frequency of grade IV neutropenia (8.5% in Rd and Rd18 vs. 15% in MPT). Grade IV febrile neutropenia was rarely observed (0.6% in Rd and Rd18 vs. 0.7% in MPT).

Combination of lenalidomide with low-dose dexamethasone for treatment of patients with newly diagnosed multiple myeloma was associated with a lower frequency of grade 3/4 thrombocytopenia (8.1% in Rd and Rd18 vs. 11% in MPT).

Newly diagnosed MM in transplant-ineligible patients treated with lenalidomide in combination with melphalan and prednisone

Lenalidomide in combination with melphalan and prednisone for treatment of patients with newly diagnosed multiple myeloma was associated with a higher frequency of grade IV neutropenia (34.1% in MPR+R/MPR+p vs. 7.8% in MPp+p). A higher incidence of grade IV febrile neutropenia was observed (1.7% in MPR+R/MPR+p vs. 0.0% in MPp+p).

Combination of lenalidomide with melphalan and prednisone for treatment of patients with newly diagnosed multiple myeloma was associated with a higher frequency of grade III-IV thrombocytopenia (40.4% in MPR+R/MPR+p vs. 13.7% in MPp+p).

MM in patients who received at least one prior line of therapy

Use of the lenalidomide/dexamethasone combination in patients with multiple myeloma was associated with an increased frequency of grade IV neutropenia (5.1% in patients receiving lenalidomide/dexamethasone vs. 0.6% in patients receiving dexamethasone/placebo). Grade IV febrile neutropenia in patients receiving the lenalidomide/dexamethasone combination was infrequent – 0.6% (0.0% in patients receiving dexamethasone/placebo).

Use of the lenalidomide/dexamethasone combination in multiple myeloma was associated with an increased likelihood of developing grade III-IV thrombocytopenia (9.9% and 1.4% in patients receiving lenalidomide/dexamethasone vs. 2.3% and 0.0% in patients receiving dexamethasone/placebo, respectively).

Patients with MDS

In patients with MDS treated with lenalidomide, a higher frequency of grade III-IV neutropenia was observed (74.6% in patients receiving lenalidomide vs. 14.9% in placebo group in phase III studies). Grade III-IV febrile neutropenia was observed in 2.2% of patients receiving lenalidomide vs. 0.0% in the placebo group. Lenalidomide use is associated with an increased risk of grade III-IV thrombocytopenia (37% in patients receiving lenalidomide vs. 1.5% in patients receiving placebo in phase III studies).

Patients with MCL

In patients with MCL treated with lenalidomide, a higher frequency of grade III-IV neutropenia was observed (43.7% in patients vs. 33.7% in the control group in phase II studies). Grade III-IV febrile neutropenia was observed in 6.0% of patients receiving lenalidomide vs. 2.4% in the control group.

Venous Thromboembolism

An increased risk of deep vein thrombosis and pulmonary embolism is associated with the use of lenalidomide in combination with dexamethasone in patients with MM, and to a lesser extent in patients receiving melphalan/prednisone combination. Use of lenalidomide as monotherapy in MM, MDS, and MCL may also be associated with an increased risk of these events. Concomitant use of lenalidomide with erythropoietic agents or a history of deep vein thrombosis may further increase the risk of thrombotic complications in these patients (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Myocardial Infarction

Cases of myocardial infarction have been observed in patients receiving lenalidomide, particularly in those with known risk factors.

Bleeding Disorders

Bleeding disorders are listed by system organ class: blood and lymphatic system disorders; nervous system disorders (intracranial hemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival, hemorrhoidal, rectal bleeding); renal and urinary disorders (hematuria); injury, poisoning and procedural complications (contusion); and vascular disorders (ecchymoses).

Allergic Reactions

Cases of allergic reactions/hypersensitivity reactions have been reported. Cases of cross-allergic reactions between lenalidomide and thalidomide have been described in the literature.

Serious Skin Reactions

Serious skin adverse reactions have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS syndrome. Lenalidomide should not be administered to patients with a history of severe rash during thalidomide treatment (see section "Special Precautions").

Secondary Malignancies at Other Sites

New malignancies observed during clinical trials in patients with myeloma after use of lenalidomide with dexamethasone compared to control were primarily basal cell or squamous cell skin cancers.

Acute Myeloid Leukemia

Cases of acute myeloid leukemia were observed during clinical trials in patients with newly diagnosed multiple myeloma who received lenalidomide in combination with melphalan or immediately after HDM/ASCT (see section "Special Precautions"). Acute myeloid leukemia was not observed during clinical trials in patients with newly diagnosed multiple myeloma receiving lenalidomide in combination with low-dose dexamethasone compared to thalidomide in combination with melphalan and prednisone.

Baseline factors, including complex cytogenetics and TP53 mutation, are associated with progression to acute myeloid leukemia in transfusion-dependent patients with del(5q) abnormality (see section "Special Precautions"). The estimated 2-year cumulative risk of progression to acute myeloid leukemia was 13.8% for patients with del(5q) abnormality, 17.3% for patients with del(5q) and one additional cytogenetic abnormality, and 38.6% for patients with complex karyotype.

In a post-hoc analysis of a clinical trial of lenalidomide in myelodysplastic syndromes, the 2-year cumulative risk of progression to acute myeloid leukemia was 27.5% for patients with positive IHC-p53 and 3.6% for patients with negative IHC-p53 (p = 0.0038). Among patients with positive IHC-p53, a lower rate of acute myeloid leukemia progression was observed in 11.1% of those achieving transfusion independence compared to 34.8% of patients without clinical response.

Hepatic Disorders

During the post-marketing period, the following hepatic disorders (frequency unknown) have been reported: acute liver failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, and mixed cytolytic/cholestatic hepatitis.

Rhabdomyolysis

Rare cases of rhabdomyolysis have been observed, some occurring during concomitant use of lenalidomide with statins.

Thyroid Disorders

Cases of hypothyroidism and hyperthyroidism have been reported (see section "Special Precautions").

Transient Tumor Flare Reactions and Tumor Lysis Syndrome

In study MCL-002, transient tumor flare reactions were observed in approximately 10% of patients receiving lenalidomide compared to 0% in the control group. Most reactions occurred within cycle 1, were considered treatment-related, and were of grade III-IV severity. Patients with a high MIPPI score at diagnosis or generalized lymphadenopathy (at least one lesion ≥7 cm in diameter at baseline) may be at risk of transient tumor flare reactions. In study MCL-002, transient tumor flare reactions were reported in one patient in each of the two treatment groups. In the additional study MCL-001, transient tumor flare reactions were observed in approximately 10% of patients; these were considered treatment-related and were of grade I-II severity. Most reactions occurred within cycle 1. No reports of transient tumor flare reactions were received in the main study MCL-001 (see section "Special Precautions").

Gastrointestinal Disorders

Gastrointestinal perforation, which may lead to septic complications and fatal outcomes, has been reported during lenalidomide treatment.

Shelf Life. 3 years.

Storage Conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

7 capsules per blister, 3 blisters per cardboard box.

Prescription Category. Prescription only.

Manufacturer.

RELIANCE LIFE SCIENCES PRIVATE LIMITED (PLANT 6)

RELIANCE LIFE SCIENCES PRIVATE LIMITED (PLANT 6)

Manufacturer's Address and Place of Business.

DHIRUBHAI AMBANI LIFE SCIENCES CENTRE (DALS), THANE, BELAPUR ROAD, RABALE, NAVI MUMBAI, IN-400701, INDIA

DHIRUBHAI AMBANI LIFE SCIENCES CENTRE (DALS), THANE, BELAPUR ROAD, RABALE, NAVI MUMBAI, IN-400701, INDIA

Marketing Authorization Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom