INSTRUCTIONS for medical use of the medicinal product LINADEX (LINADEX)

Composition:

Active substance: lenalidomide;

1 hard capsule contains 5 mg, 10 mg, or 25 mg of lenalidomide;

Excipients:

Hard capsules of 5 mg or 25 mg: anhydrous lactose, microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hard gelatin capsules (composition: gelatin, titanium dioxide (E 171));

Hard capsules of 10 mg: anhydrous lact游戏副本

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

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

Specifically, lenalidomide inhibits proliferation and enhances apoptosis of certain hematological tumor cells (including plasma tumor cells in multiple myeloma (MM), tumor cells in follicular lymphoma (FL), and cells with chromosome 5 cytogenetic abnormalities), enhances T-cell and natural killer (NK) cell-mediated cellular immunity, and increases the number of NK cells, T cells, and NK T-cells. In myelodysplastic syndrome (MDS) with del(5q), lenalidomide has been shown to selectively suppress abnormal clonal growth by increasing apoptosis of del(5q) cells.

The combination of lenalidomide and rituximab enhances antibody-dependent cellular cytotoxicity (ADCC) and direct tumor apoptosis in follicular lymphoma cells.

The mechanism of action of lenalidomide also includes additional effects such as antiangiogenic and proerythropoietic properties. Lenalidomide inhibits angiogenesis by blocking endothelial cell migration, adhesion, and microvessel formation; enhances fetal hemoglobin production by CD34+ hematopoietic stem cells; and suppresses the production of proinflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Pharmacokinetics.

Lenalidomide has 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 and achieves maximum solubility in 0.1 M HCl buffer solution.

Absorption.

After oral administration under fasting conditions in healthy volunteers, lenalidomide is rapidly absorbed, with peak plasma concentration (C_max) reached within 0.5 to 2 hours after dosing. In both patients and healthy volunteers, C_max and area under the plasma concentration-time curve (AUC) increase proportionally with increasing dose. Repeated administration does not result in significant drug accumulation. In plasma, the relative exposure of S- and R-enantiomers of lenalidomide is approximately 56% and 44%, respectively.

Concomitant administration with a high-fat, high-calorie meal in healthy volunteers reduces the extent of drug absorption, resulting in approximately a 20% decrease in AUC and a 50% reduction in C_max in plasma. However, in the main pre-registration clinical trials in MM and MDS, where the efficacy and safety of lenalidomide were established, the drug was administered regardless of food intake. Therefore, lenalidomide may be administered independently of food.

Population pharmacokinetic analysis indicates that the extent of absorption after oral administration of lenalidomide is similar in patients with MM, MDS, and CLL.

Distribution.

In vitro, plasma protein binding of (14C)-lenalidomide is low in both MM patients and healthy volunteers, averaging 23% and 29%, respectively.

Lenalidomide is present in semen (< 0.01% of dose) after administration at 25 mg/day and is undetectable 3 days after discontinuation of the drug in healthy volunteers (see section "Special precautions").

Metabolism and elimination.

In vitro human metabolism studies indicate that cytochrome P450 isoenzymes are not involved in the metabolism of lenalidomide; therefore, pharmacokinetic interactions are unlikely when lenalidomide is co-administered with drugs that inhibit cytochrome P450 isoenzymes. In vitro studies show that lenalidomide does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1. Therefore, it is unlikely that lenalidomide causes any clinically significant drug interactions when administered concomitantly with substrates of these enzymes.

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

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

The majority of lenalidomide is excreted in urine. The renal contribution to total clearance in patients with normal renal function is 90%, with 4% of lenalidomide excreted in feces.

Lenalidomide undergoes minimal metabolism in the body, as 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. Thus, renal clearance exceeds the glomerular filtration rate, indicating that elimination involves a partially active process.

At doses of 5 to 25 mg/day, the elimination half-life in plasma is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients with MM, MDS, or CLL.

Elderly patients.

No specific clinical studies have been conducted to evaluate the pharmacokinetics of lenalidomide in elderly patients. Population pharmacokinetic analysis included individuals aged 39 to 85 years and indicates that age does not affect the clearance of lenalidomide (plasma exposure). However, since renal function may be reduced in elderly patients, caution should be exercised when selecting the dose. Renal function should be monitored.

Renal impairment.

The pharmacokinetics of lenalidomide were studied in individuals with renal impairment not caused by malignancy. Two methods were used to classify renal function in this study: 24-hour urinary creatinine clearance and creatinine clearance calculated by the Cockcroft-Gault formula. Results indicate that as renal function decreases (< 50 mL/min), the total clearance of lenalidomide decreases proportionally, resulting in increased AUC. AUC increased approximately 2.5-, 4-, and 5-fold in individuals with moderate, severe, and end-stage renal impairment, respectively, compared to the group combining individuals with normal renal function and mild renal impairment. The elimination half-life of lenalidomide increased from approximately 3.5 hours in individuals with creatinine clearance > 50 mL/min to more than 9 hours in those with creatinine clearance < 50 mL/min. However, renal impairment did not alter the oral absorption of lenalidomide. C_max was similar in healthy volunteers and patients with renal impairment. Approximately 30% of the drug in the body was removed during a 4-hour dialysis session. Recommended dose adjustments in patients with renal impairment are described in the section "Dosage and administration."

Hepatic impairment.

Population pharmacokinetic analysis included patients with mild hepatic impairment (N=16, total bilirubin > 1 to ≤ 1.5 × ULN [upper limit of normal] or AST > ULN) and indicates that mild hepatic impairment does not affect the clearance of lenalidomide (plasma exposure). No data are available for patients with moderate or severe hepatic impairment.

Other intrinsic factors.

Population pharmacokinetic analysis demonstrated that body weight (33–135 kg), sex, race, and type of hematological malignancy (MM, MDS, or CLL) have no clinically significant effect on the clearance of lenalidomide in adult patients.

Clinical Characteristics.

Indications.

Multiple Myeloma (MM)

Lenadex as monotherapy is indicated for maintenance treatment in adult patients with newly diagnosed MM who have undergone autologous stem cell transplantation (ASCT).

Lenadex in combination with dexamethasone, or bortezomib and dexamethasone, or melphalan and prednisolone is indicated for the treatment of adult patients with previously untreated MM who are ineligible for transplantation.

Lenadex in combination with dexamethasone is indicated for the treatment of adult patients with MM who have received at least one prior therapy.

Myelodysplastic Syndromes (MDS)

As monotherapy, Lenadex is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1 risk MDS associated with isolated del(5q) cytogenetic abnormality when other treatment options are inadequate or unacceptable.

Mantle Cell Lymphoma (MCL)

As monotherapy, Lenadex is indicated for the treatment of adult patients with relapsed or refractory MCL.

Follicular Lymphoma (FL)

Lenadex in combination with rituximab (anti-CD20 antibody) is indicated for the treatment of adult patients with previously treated FL (stages 1–3a).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients (see section "Composition");
• Pregnancy;
• Reproductive potential in women, except those who comply with all requirements of the "Pregnancy Prevention Programme" (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding").

Special Safety Precautions.

Capsules must not be opened or crushed. If lenalidomide powder comes into contact with the skin, the area must be washed immediately and thoroughly with soap and water. If lenalidomide comes into contact with mucous membranes, they should be thoroughly rinsed with water. Unused medication or waste must be returned for safe disposal according to local requirements.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister pack or capsules.

Pregnant women or women who suspect they may be pregnant must not handle the blister pack or capsule (see section "Special Warnings and Precautions for Use").

Interaction with Other Medicinal Products and Other Forms of Interaction.

Erythropoietic agents, as well as other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in patients with MM who are receiving lenalidomide in combination with dexamethasone (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions").

Oral Contraceptives

No studies of interaction with oral contraceptives have been conducted. Lenalidomide is not an enzyme inducer. In an in vitro study using human hepatocytes, lenalidomide at various tested concentrations did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4/5. Therefore, when lenalidomide is used alone, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected. However, dexamethasone is known to be a weak or moderate inducer of CYP3A4 and may also affect other enzymes and transporters. A reduction in the efficacy of oral contraceptives during treatment cannot be excluded. Effective measures to prevent pregnancy should be taken (see sections "Special Warnings and Precautions for Use" and "Use in Pregnancy or Breastfeeding").

Warfarin

Concomitant administration of multiple doses of lenalidomide 10 mg did not affect the pharmacokinetics of a single dose of R- and S-warfarin. Concomitant administration of a single 25 mg dose of warfarin did not affect the pharmacokinetics of lenalidomide. However, it is unknown whether an interaction exists during clinical use (concomitant administration with dexamethasone). Dexamethasone is a weak or moderate enzyme inducer, and its effect on warfarin is unknown. Close monitoring of warfarin concentration is recommended during treatment.

Digoxin

Concomitant administration with lenalidomide 10 mg once daily increased plasma exposure to digoxin (0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52–28.2%]. It is unknown whether a different effect occurs during clinical use (higher doses of lenalidomide and concomitant administration with dexamethasone). Therefore, monitoring of digoxin levels is recommended during lenalidomide treatment.

Statins

There is an increased risk of rhabdomyolysis when statins are used concomitantly with lenalidomide, which may be simply additive. Enhanced clinical and laboratory monitoring should be performed, especially during the first weeks of treatment.

Dexamethasone

Concomitant administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically significant effect on the pharmacokinetics of multiple doses of lenalidomide (25 mg once daily).

Interaction with P-glycoprotein (P-gp) Inhibitors

In vitro, lenalidomide is a substrate of P-gp, but not an inhibitor of P-gp. Concomitant administration of multiple doses of the potent P-gp inhibitor quinidine (600 mg twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of lenalidomide (25 mg). Concomitant administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.

Special precautions for use.

If lenalidomide is used in combination with other medicinal products, the respective instructions for medical use should be consulted before initiating treatment.

Use in specific populations.

Pregnancy warning

Lenalidomide is a structural analogue of thalidomide. Thalidomide is a known active substance with teratogenic effects in humans and may cause severe, life-threatening congenital malformations. Lenalidomide has caused developmental defects in monkeys similar to those described for thalidomide (see section "Adverse reactions"). If lenalidomide is administered during pregnancy, a teratogenic effect in humans is expected.

The requirement to comply with the Pregnancy Prevention Programme applies to all female patients, except in cases where there is convincing evidence that the patient is unable to bear children.

Criteria for women unable to bear children

Female patients or female partners of male patients are considered capable of bearing children unless at least one of the following criteria is met:

• age ≥ 50 years and duration of natural amenorrhea ≥ 1 year (amenorrhea due to anticancer therapy or during breastfeeding does not exclude fertility);
• confirmed premature ovarian failure by a specialist gynaecologist;
• previous bilateral salpingo-oophorectomy or hysterectomy in medical history;
• XY genotype, Turner syndrome, uterine agenesis.

Counselling

The use of lenalidomide in women capable of bearing children is contraindicated, except when all the following conditions are met:

• the woman understands the expected teratogenic risk to the unborn child;
• the woman understands the necessity of continuous use of effective contraception for 4 weeks before starting treatment, during treatment, and for 4 weeks after treatment;
• a woman capable of bearing children, even in the case of amenorrhea, must adhere to all rules of effective contraception;
• the woman must be able to comply with all rules of effective contraception;
• the woman has been informed and understands the possible consequences of pregnancy and the need to seek immediate consultation if pregnancy is suspected;
• the woman understands the necessity of immediate administration of lenalidomide after receiving negative pregnancy test results;
• the woman understands the necessity of testing and agrees to undergo pregnancy testing every 4 weeks, except in cases of confirmed tubal sterilization;
• the woman acknowledges that she understands the risks and necessary precautions associated with the use of lenalidomide.

Use in men

Pharmacokinetic studies in male patients receiving lenalidomide indicate that lenalidomide is present in seminal fluid at very low concentrations during treatment and is not detectable 3 days after discontinuation in healthy volunteers. As a precaution, considering the possible reduced elimination rate of lenalidomide in specific patient groups (e.g., patients with impaired renal function), all male patients receiving lenalidomide must meet the following requirements:

• must understand the expected teratogenic risk associated with sexual intercourse with a pregnant woman or a woman capable of bearing children;
• must understand the necessity of using a condom during sexual intercourse with a pregnant woman or a woman capable of bearing children who is not using reliable contraception (even if the man has undergone vasectomy), during treatment and for 4 weeks after treatment interruption/completion;
• male patients receiving lenalidomide must not donate semen for 4 weeks after discontinuation of treatment;
• must understand that if his sexual partner becomes pregnant while he is taking lenalidomide or shortly after he stops taking it, he must immediately inform his doctor, and his partner should be referred to a physician specializing in teratology or with experience in teratology for risk assessment and consultation.

The prescribing physician for women capable of bearing children must:

• ensure that the patient complies with all conditions of the Pregnancy Prevention Programme, including confirmation that she adequately understands the situation;
• ensure that the patient acknowledges the conditions listed above.

Contraception

Women capable of bearing children must use at least one effective method of contraception for 4 weeks before starting treatment, during lenalidomide therapy, and for 4 weeks after treatment ends, even during treatment interruptions. The only exception is for patients who completely abstain from sexual activity throughout the entire specified period, documented monthly. If a woman has not selected an effective contraceptive method, she should be referred to a physician qualified to select an effective contraceptive method to initiate its use.

Suitable contraceptive methods include:

• implant;
• intrauterine levonorgestrel-releasing system (IUS);
• depot medroxyprogesterone acetate preparations;
• tubal sterilization;
• sexual intercourse with a partner who has undergone vasectomy; partner's vasectomy confirmed by two negative semen analyses;
• progestin-only ovulation-inhibiting tablets (e.g., desogestrel).

Combined oral contraceptives are not recommended for patients with MM treated with lenalidomide in combination therapy, and to a lesser extent for patients with MM, MDS, and MCL receiving lenalidomide as monotherapy, due to an increased risk of venous thromboembolism. If a patient is using combined oral contraceptives, she should switch to one of the effective methods listed above. The risk of venous thromboembolism persists for 4–6 weeks after discontinuation of combined oral contraceptives. The effectiveness of contraceptive steroids may be reduced when used concomitantly with dexamethasone (see section « Interaction with other medicinal products and other forms of interaction»).

Implants and levonorgestrel-releasing IUS are associated with an increased risk of infectious complications at the time of insertion and irregular vaginal bleeding. Patients, especially those with neutropenia, should be prescribed prophylactic antibiotics.

The use of copper-releasing IUS is generally not recommended due to a high risk of infectious complications at the time of implantation and increased menstrual blood loss, which may exacerbate the severity of neutropenia or thrombocytopenia in patients.

Pregnancy testing

According to local practice, pregnancy testing in women of reproductive age should be performed under medical supervision as specified below (the minimum sensitivity of the test should be 25 mIU/mL). This requirement applies even to women capable of bearing children who completely and continuously abstain from sexual intercourse. Ideally, pregnancy testing, prescription issuance, and drug dispensing should occur on the same day. Lenalidomide should be dispensed to women of reproductive age within 7 days after prescription.

Before starting treatment

Pregnancy testing is performed during the consultation when lenalidomide is prescribed, in the presence of a healthcare provider, or within 3 days prior to the physician visit, after the patient has used an effective contraceptive method for at least 4 weeks. Test results must confirm the absence of pregnancy before initiating lenalidomide treatment.

Continuing and ending treatment

Pregnancy testing should be repeated under medical supervision every 4 weeks, covering 4 weeks after treatment completion, except in cases of confirmed tubal sterilization. These pregnancy tests should be performed on the day of prescription or within 3 days prior to the visit to the prescribing physician.

Additional safety measures

Patients should be informed that this medicinal product must not be given to other people, and all unused capsules at the end of treatment must be returned to their pharmacist for safe disposal.

Patients must not donate blood, seminal fluid, or sperm during therapy or for 7 days after discontinuation of lenalidomide.

Educational materials, prescribing and dispensing restrictions

To help patients avoid the effects of lenalidomide on the fetus, the marketing authorization holder must provide healthcare professionals with educational materials containing all warnings regarding the expected teratogenic effects of lenalidomide, recommendations for contraception before starting treatment, and the necessity of pregnancy testing. The prescribing physician must inform patients (men and women) about the expected teratogenic risk and strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme and provide patients with appropriate patient education brochures, patient cards, and/or equivalent documents according to the implemented national patient card system. A national controlled distribution system has been introduced in cooperation with each national competent authority. The controlled distribution system includes the use of a patient card and/or equivalent document to control prescribing and/or dispensing, as well as collection of detailed prescribing data for careful monitoring of misuse within the national territory. Pregnancy testing, prescription issuance, and drug dispensing must occur on the same day. Lenalidomide should be dispensed to women of reproductive age within 7 days after prescription, following a negative pregnancy test result performed in the presence of a healthcare provider. Dispensing of the medicinal product to women with preserved fertility should not exceed 4 weeks of treatment; for all other patient categories, dispensing should not exceed 12 weeks.

Other special warnings and precautions for use

Myocardial infarction

Cases of myocardial infarction have been reported in patients receiving lenalidomide, particularly in individuals with cardiovascular risk factors, within the first 12 months of treatment in combination with dexamethasone. In patients with known risk factors, particularly a history of thrombosis, careful monitoring is required, and measures should be taken to reduce the impact of modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).

Arterial and venous thromboembolism

An increased risk of venous thromboembolism (primarily deep vein thrombosis and pulmonary embolism) has been observed in patients with MM treated with lenalidomide in combination with dexamethasone, less frequently observed with the combination of lenalidomide with melphalan and prednisone.

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

An increased risk of arterial thromboembolism (primarily myocardial infarction and stroke) has been observed in patients with MM treated with lenalidomide in combination with dexamethasone, less frequently observed with the combination of lenalidomide with melphalan and prednisone. The risk of arterial thromboembolism is lower in patients with MM treated with lenalidomide as monotherapy compared to patients with MM receiving lenalidomide in combination therapy.

Therefore, careful monitoring is required for patients with known risk factors for thromboembolism, including a history of thrombosis. Measures should be taken to reduce the impact of modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia). Concomitant therapy with erythropoietic agents or a history of thromboembolic complications may also increase thrombotic risk. Thus, erythropoietic agents and other drugs that may increase the risk of thrombosis (e.g., hormone replacement therapy) should be used cautiously in patients with multiple myeloma receiving lenalidomide with dexamethasone. Erythropoietic therapy should be discontinued if hemoglobin concentration exceeds 120 g/L.

Physicians and patients should carefully evaluate signs and symptoms of 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. Prophylactic antithrombotic agents are recommended, especially for patients with additional risk factors for thrombosis. The decision to prescribe prophylactic antithrombotic agents should be made after careful assessment of the patient's individual risk factors.

If thromboembolism occurs, lenalidomide treatment should be discontinued and standard anticoagulant therapy initiated. After the patient's condition stabilizes on anticoagulant therapy and all complications caused by the thromboembolic event are resolved, lenalidomide treatment may be restarted at the initial dose depending on the benefit/risk assessment. The patient should continue anticoagulant therapy throughout the subsequent period of lenalidomide treatment.

Pulmonary hypertension

Cases of pulmonary hypertension, some fatal, have been reported in patients receiving lenalidomide. Patients should be evaluated for signs and symptoms of cardiopulmonary disease before and during lenalidomide therapy.

Neutropenia and thrombocytopenia

Neutropenia and thrombocytopenia are the main dose-limiting toxicities of lenalidomide. During the first 8 weeks of lenalidomide treatment, a complete blood count, including white blood cell differential, platelet count, hemoglobin, and hematocrit, should be performed at the beginning of treatment and weekly. Thereafter, blood tests should be performed monthly to detect possible cytopenias. In patients with MCL, monitoring should be performed every 2 weeks during cycles 3 and 4, and then at the beginning of each cycle. Dose reduction may be required (see section "Dosage and administration").

In cases of neutropenia, the physician should consider the use of growth factors. Patients should be informed about the need to promptly report fever to their physician.

Close monitoring by both physician and patient for symptoms of increased bleeding tendency, including petechiae and epistaxis, is recommended, especially in patients receiving concomitant medications that may cause bleeding (see section "Adverse reactions", Hemorrhagic disorders).

Lenalidomide should be used with caution in combination with other myelosuppressive agents.

• Newly diagnosed multiple myeloma (NDMM): patients who have undergone ASCT and are receiving lenalidomide maintenance therapy

In the CALGB 100104 study, adverse reactions included events reported after high-dose melphalan and ASCT (HDM/ASCT), as well as events during the maintenance therapy period. A second analysis identified events occurring after the start of maintenance therapy. In the IFM 2005-02 study, adverse reactions were recorded only during the maintenance therapy period.

Overall, grade IV neutropenia was observed at a higher frequency in the lenalidomide maintenance therapy groups compared to placebo groups in two studies evaluating lenalidomide maintenance therapy in NDMM patients who underwent ASCT (32.1% vs 26.7% [16.1% vs 1.8% after start 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 occurred in 2.2% of patients in the CALGB 100104 study and in 2.4% of patients in the IFM 2005-02 study, respectively. In both studies, grade IV febrile neutropenia was reported at similar frequencies in patients receiving maintenance doses of lenalidomide compared to placebo groups (0.4% vs 0.5% [0.4% vs 0.5% after start of maintenance therapy] in the CALGB 100104 study and 0.3% vs 0% in the IFM 2005-02 study, respectively). Patients are advised to immediately report any episodes of fever, and treatment interruption and/or dose reduction may be necessary (see "Dosage and administration").

Grade III or IV thrombocytopenia was observed at a higher frequency in patients receiving maintenance doses of lenalidomide compared to placebo groups in studies evaluating lenalidomide maintenance therapy in NDMM patients who underwent ASCT (37.5% vs 30.3% [17.9% vs 4.1% after start of maintenance therapy] in the CALGB 100104 study and 13.0% vs 2.9% in the IFM 2005-02 study, respectively).

Close monitoring by physician and patient for signs and symptoms of increased bleeding tendency, including petechiae and epistaxis, is recommended, especially in patients receiving concomitant medications that may cause bleeding (see section "Adverse reactions", Hemorrhagic disorders).

• NDMM: patients ineligible for transplantation and treated with lenalidomide in combination with bortezomib and dexamethasone

Grade IV neutropenia was observed at a lower frequency in the group of patients treated with lenalidomide in combination with bortezomib and dexamethasone (RVd) compared to the Rd comparison group (2.5% vs 5.9%) in the SWOG S0777 study. Grade IV febrile neutropenia was reported at similar frequencies in the RVd and Rd groups (0.0% vs 0.4%). Patients should be warned about the need to immediately report fever. Treatment interruption and/or dose reduction may be possible (see section "Dosage and administration").

Grade III or IV thrombocytopenia was observed at a higher frequency in the RVd group compared to the Rd comparison group (17.2% vs 9.4%).

• NDMM: patients ineligible for transplantation and treated with lenalidomide in combination with low-dose dexamethasone

Grade IV neutropenia was observed to a lesser extent in lenalidomide groups in combination with low-dose dexamethasone compared to the comparison group (8.5% in Rd [long-term treatment] and Rd18 [treatment for 18 4-week cycles] vs 15% in the melphalan/prednisone/thalidomide group, see section "Adverse reactions"). Episodes of grade IV febrile neutropenia were consistent with the comparison group (0.6% in Rd and Rd18 in patients receiving lenalidomide/dexamethasone vs 0.7% in the melphalan/prednisone/thalidomide group, see section "Adverse reactions").

Grade III or IV thrombocytopenia was observed to a lesser extent in the Rd and Rd18 groups compared to the comparison group (8.1% vs 11.1%).

• NDMM: patients ineligible for transplantation and treated with lenalidomide in combination with melphalan and prednisone

The combination of lenalidomide with melphalan and prednisone in clinical trials of NDMM patients is associated with a higher frequency of grade IV neutropenia (34.1% in the melphalan, prednisone, and lenalidomide group, followed by patients receiving lenalidomide [MPR+R] and melphalan, prednisone, and lenalidomide, followed by patients receiving placebo [MPR+p] compared to 7.8% in MPp+p patients, see section "Adverse reactions"). Grade IV febrile neutropenia episodes were infrequent (1.7% in MPR+R/MPR+p patients vs 0.0% in MPp+p patients) (see section "Adverse reactions"). The combination of lenalidomide with melphalan and prednisone in MM patients is associated with a higher frequency of grade III and IV thrombocytopenia (40.4% in MPR+R/MPR+p patients vs 13.7% in MPp+p patients) (see section "Adverse reactions").

• MM: patients who have received at least one line of therapy

The combination of lenalidomide with dexamethasone in MM patients who have previously received at least one course of therapy is associated with a higher frequency of grade IV neutropenia (5.1% in the lenalidomide/dexamethasone group vs 0.6% in the placebo/dexamethasone group); grade IV febrile neutropenia episodes were rare (0.6% in the lenalidomide/dexamethasone group vs 0.0% in the placebo/dexamethasone group; see section "Adverse reactions"). The combination of lenalidomide with dexamethasone in MM is associated with a higher frequency of grade III-IV thrombocytopenia (9.9% and 1.4% respectively in the lenalidomide/dexamethasone group vs 2.3% and 0.0% in the placebo/dexamethasone group; see section "Adverse reactions").

• MDS

Lenalidomide treatment of MDS is associated with a higher frequency of grade III-IV neutropenia and thrombocytopenia compared to patients receiving placebo (see section "Adverse reactions").

• MCL

Lenalidomide treatment of MCL is associated with a higher frequency of grade III-IV neutropenia and thrombocytopenia compared to patients in the control group (see section "Adverse reactions").

• FL

The combination of lenalidomide with rituximab in FL patients is associated with a higher frequency of grade III-IV neutropenia and thrombocytopenia compared to patients in the placebo/rituximab group. Grade III-IV febrile neutropenia was more frequently reported in the lenalidomide/rituximab combination group (see section "Adverse reactions").

Thyroid function

Cases of hypothyroidism and hyperthyroidism have been reported. Concomitant conditions affecting thyroid function should be evaluated before starting treatment. Monitoring of thyroid function at the beginning and during treatment is recommended.

Peripheral neuropathy

Lenalidomide is a structural analogue of thalidomide, which is known to cause severe peripheral neuropathy. No increase in the incidence of peripheral neuropathy has been observed with lenalidomide used in combination with dexamethasone or melphalan and prednisolone, or as monotherapy, or with long-term lenalidomide treatment for NDMM.

A higher frequency of peripheral neuropathy has been reported with the combination of lenalidomide administered intravenously with bortezomib and dexamethasone for the treatment of MM patients. The frequency was lower with subcutaneous administration of bortezomib. For additional information, see section "Adverse reactions" and the respective instructions for this medicinal product.

Tumour flare reaction and tumour lysis syndrome

Since lenalidomide has antitumour activity, complications such as tumour lysis syndrome (TLS) may occur. Cases of TLS and tumour flare reaction (TFR), including fatal cases, have been reported (see section "Adverse reactions"). Patients at risk of developing TLS and TFR are those with high tumour burden before starting treatment. Caution should be exercised when treating these patients with lenalidomide. Close monitoring is required, especially during the first cycle or dose escalation, and appropriate preventive measures should be taken if necessary.

• Mantle cell lymphoma

Careful monitoring and evaluation for TFR are recommended. Patients diagnosed with high Mantle Cell Lymphoma International Prognostic Index (MIPI) or generalized lymphadenopathy (at least one lesion ≥ 7 cm in maximum diameter) at baseline are at risk of developing TFR. Tumour flare reaction may mimic disease progression. Patients experiencing grade I and II TFR received therapy with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for symptom management. The decision to initiate TFR therapy should be made after careful clinical evaluation of the individual patient (see sections "Dosage and administration", "Adverse reactions"). In a single phase 2 MCL study, one case of tumour flare reaction had a fatal outcome.

• Follicular lymphoma

Careful monitoring and evaluation for TFR are recommended. Tumour flare reaction may mimic disease progression. Patients experiencing grade I and II TFR received therapy with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for symptom management. The decision to initiate TFR therapy should be made after careful clinical evaluation of the individual patient (see section "Dosage and administration", "Adverse reactions").

Careful monitoring and evaluation for the development of TLS are recommended. TLS prophylaxis should include adequate hydration of patients and additional biochemical panel testing beyond weekly testing during the first cycle or longer if clinically indicated (see section "Dosage and administration", "Adverse reactions").

Tumour burden

• Mantle cell lymphoma

Lenalidomide is not recommended for the treatment of MCL patients with high tumour burden if alternative treatment options are available.

Early mortality

An overall increase in mortality at the beginning of treatment (within 20 weeks) was observed in the study. Patients with high tumour burden at the start of treatment have an increased risk of early death; 16/81 (20%) early deaths were observed in the lenalidomide group and 2/28 (7%) early deaths in the control group. At 52 weeks, the corresponding figures were 32/81 (40%) and 6/28 (21%).

Adverse events

In the MCL-002 study, during treatment cycle 1, 11/81 (14%) patients with high tumour burden discontinued treatment in the lenalidomide group compared to 1/28 (4%) in the control group. The main reason for discontinuation in patients with high tumour burden during treatment cycle 1 in the lenalidomide group was adverse events, 7/11 (64%).

Therefore, patients with high tumour burden should be closely monitored for adverse reactions, particularly tumour flare reactions (TFR). Information on dose adjustment in case of such reactions is provided in the section "Dosage and administration". High tumour burden is defined as at least one lesion ≥ 5 cm in diameter or three lesions ≥ 3 cm in diameter.

Allergic reactions and severe skin reactions

Cases of allergic reactions, including angioedema, anaphylactic reaction, and severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in patients receiving lenalidomide (see section "Adverse reactions"). Physicians should inform patients about the signs or symptoms of these reactions and they should immediately notify healthcare professionals if such symptoms develop. Lenalidomide should be discontinued if angioedema, anaphylactic reaction, exfoliative or bullous dermatitis occurs, or if SJS, TEN or DRESS is suspected; lenalidomide should not be reinitiated after resolution of these reactions. Temporary discontinuation or withdrawal of lenalidomide may also be considered for other types of skin reactions, depending on severity. Patients with a history of allergic reactions during thalidomide treatment should be closely monitored, as cross-reactions between lenalidomide and thalidomide have been reported in the literature. Lenalidomide should not be prescribed to patients with a history of severe skin reactions to thalidomide.

Lactose intolerance

Capsules contain lactose. This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Secondary malignancies of other sites (SMOS)

A higher incidence of SMOS was observed in clinical trials among myeloma 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 SMOS included basal cell or squamous cell skin cancer. Most invasive SMOS were solid tumours.

In clinical trials in NDMM patients not eligible for transplantation, a 4.9-fold increase in the incidence of haematological forms of SMOS (cases of acute myeloid leukaemia (AML), MDS) was observed in patients receiving lenalidomide in combination with melphalan and prednisolone until progression (1.75 per 100 patient-years), compared to melphalan in combination with prednisolone (0.36 per 100 patient-years). A 2.12-fold increase in the incidence of solid tumour SMOS was observed in patients receiving lenalidomide (9 cycles) in combination with melphalan and prednisolone (1.57 per 100 patient-years), compared to melphalan in combination with prednisolone (0.74 per 100 patient-years).

In patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months, the incidence of haematological SMOS (0.16 per 100 patient-years) was not increased compared to patients receiving thalidomide in combination with melphalan and prednisolone (0.79 per 100 patient-years). A 1.3-fold increase in the incidence of solid tumour SMOS was observed in patients receiving lenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per 100 patient-years), compared to patients receiving thalidomide in combination with melphalan and prednisolone (1.19 per 100 patient-years).

In NDMM patients receiving lenalidomide in combination with bortezomib and dexamethasone, the incidence of haematological SMOS was 0.00–0.16 per 100 patient-years, and the incidence of solid tumour SMOS was 0.21–1.04 per 100 patient-years.

The increased risk of SMOS associated with lenalidomide is comparable to NDMM after autologous stem cell transplantation. Since the risk is not fully understood, this should be considered when considering and using lenalidomide under these conditions.

The incidence of haematological malignancies, most commonly AML, MDS, and B-cell malignancies (including Hodgkin's lymphoma), was 1.31 per 100 patient-years in lenalidomide groups and 0.58 per 100 patient-years in placebo groups (1.02 per 100 patient-years for patients receiving lenalidomide after ASCT and 0.60 per 100 patient-years for patients not receiving lenalidomide after ASCT). The incidence of solid tumour SMOS was 1.36 per 100 patient-years in lenalidomide groups and 1.05 per 100 patient-years in placebo groups (1.26 per 100 patient-years for patients receiving lenalidomide after ASCT and 0.60 per 100 patient-years for patients not receiving lenalidomide after ASCT).

The risk of haematological SMOS should be considered before starting treatment with the medicinal product or in combination with melphalan, or immediately after high-dose melphalan and ASCT. Physicians should carefully evaluate patients before and during treatment using standard cancer screening to detect SMOS and initiate timely treatment.

Progression to acute myeloid leukaemia in low- and intermediate-1-risk MDS

• Karyotype

Progression to AML in transfusion-dependent individuals with del(5q) abnormality is associated with baseline variables, particularly complex cytogenetics. In a combined analysis of two clinical trials of lenalidomide in low- or intermediate-1-risk MDS, patients with complex cytogenetics had the highest estimated 2-year cumulative risk of progression to AML (38.6%). The estimated 2-year progression rate to AML in patients with isolated del(5q) abnormality was 13.8%, compared to 17.3% for patients with del(5q) and one additional cytogenetic abnormality.

As a result, the benefit/risk ratio of lenalidomide when MDS is associated with del(5q) and complex cytogenetics 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 leukaemia. In a post-hoc analysis of a clinical trial of lenalidomide in low- or intermediate-1-risk MDS (MDS-004), the estimated 2-year progression rate to AML was 27.5% in patients with positive IHC-p53 (1% cutoff for nuclear staining using immunohistochemical evaluation of p53 protein as a surrogate for TP53 mutation status) and 3.6% in patients with negative IHC-p53 (p=0.0038) (see section "Adverse reactions").

Progression to other malignancies in MCL

In MCL, potential risks include AML, B-cell malignancies, and non-melanoma skin cancer (NMSC).

Secondary malignancies of other sites (SMOS) in FL

In a study involving patients with relapsed/refractory indolent non-Hodgkin's lymphoma (iNHL), including FL patients, no increased risk of SMOS was observed in the lenalidomide/rituximab group compared to the placebo/rituximab group. In the lenalidomide/rituximab combination group, the incidence of haematological SMOS, AML, was 0.29 per 100 patient-years compared to 0.29 per 100 patient-years in patients receiving placebo/rituximab. The overall incidence of haematological and solid tumour SMOS (excluding NMSC) was 0.87 per 100 patient-years in the lenalidomide/rituximab group compared to 1.17 per 100 patient-years in patients receiving placebo/rituximab with a median follow-up period of 30.59 months (range 0.6–50.9 months).

Identified risk includes non-melanoma skin cancers, including squamous cell carcinoma or basal cell carcinoma.

Physicians should carefully examine patients for the possibility of developing SMOS. When considering lenalidomide therapy, both potential risks, the benefit of lenalidomide, and the risk of SMOS should be taken into account.

Hepatic impairment

Hepatic failure, including fatal cases, has been reported in patients receiving lenalidomide as part of combination therapy. Disorders such as acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe hepatotoxicity caused by the drug are unknown, although in some cases risk factors may include a history of viral liver disease, elevated baseline liver enzyme levels, and possibly antibiotic therapy.

Numerous reports of abnormal liver function test results have been recorded, which were usually asymptomatic and returned to normal after discontinuation of treatment. After parameters return to baseline levels, continuation of the drug at a lower dose may be considered.

Lenalidomide is eliminated by the kidneys. It is important to adjust the dose in patients with impaired renal function to avoid plasma levels that may increase the risk of haematological adverse reactions or hepatotoxicity. Recommended monitoring of liver function, particularly when there is a history of viral liver infection, or when lenalidomide is combined with medicinal products associated with liver function disorders.

Infections in the absence or presence of neutropenia

Patients with MM are prone to infections, particularly pneumonia. A higher frequency of infections has been observed with lenalidomide in combination with dexamethasone compared to MPT (melphalan, prednisolone and thalidomide) in NDMM patients not eligible for transplantation, and with lenalidomide maintenance therapy compared to placebo in NDMM patients who underwent ASCT. Infections ≥ grade III occurred in the context of neutropenia in less than one-third of patients. Careful monitoring is required for patients with known risk factors for infection. All patients should be advised to seek immediate medical attention at the first signs of infection (e.g., cough, high fever, etc.) to initiate timely treatment and reduce symptom severity.

Viral reactivation

Viral reactivation, including serious cases of herpes zoster reactivation or hepatitis B virus (HBV) reactivation, has been reported in patients receiving lenalidomide.

Some cases of viral reactivation had fatal outcomes.

Some cases of herpes zoster reactivation resulted in disseminated herpes zoster, herpes zoster meningitis, or herpes zoster with ophthalmological complications, requiring temporary withholding or permanent discontinuation of lenalidomide treatment and initiation of adequate antiviral therapy.

Rare cases of hepatitis B reactivation have been reported in patients receiving lenalidomide who were previously infected with hepatitis B virus (HBV). Some of these cases progressed to acute hepatic failure, resulting in discontinuation of lenalidomide and initiation of adequate antiviral therapy. HBV status should be determined before starting lenalidomide treatment. Consultation with a physician experienced in the treatment of hepatitis B is recommended for patients with positive HBV infection results. Caution should be exercised when using lenalidomide in patients previously infected with HBV, particularly anti-HBc positive but HBsAg negative patients. Close monitoring for signs and symptoms of active HBV infection during treatment is required.

Progressive multifocal leukoencephalopathy (PML)

Cases of PML, including fatal cases, have been reported with the use of lenalidomide. PML has been reported from several months to several years after starting lenalidomide treatment. PML has been observed more frequently in patients concomitantly receiving dexamethasone or previously receiving immunosuppressive chemotherapy. Physicians should perform regular monitoring of patients and consider PML in the differential diagnosis of patients presenting with new or worsening neurological, cognitive, or behavioural signs and symptoms. Patients should also be advised to inform their partner or caregivers about their treatment, as they may notice symptoms the patient is unaware of.

PML evaluation should be based on neurological examination, brain MRI, cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR), or brain biopsy with JCV testing. A negative JCV PCR does not exclude PML. Additional observation and evaluation may be justified if an alternative diagnosis cannot be established.

If PML is suspected, further use of the drug should be suspended until PML is excluded. If PML is confirmed, lenalidomide treatment should be discontinued and the drug should not be re-prescribed.

Patients with NDMM

A higher frequency of intolerance (grade III or IV adverse events, serious adverse events, treatment discontinuation) was observed in patients aged > 75 years, ISS stage III, ECOG PS ≥ 2 or CLcr < 60 mL/min when lenalidomide was used in combination. Careful evaluation of patients for their ability to tolerate lenalidomide in combination, considering age, ISS stage III, ECOG PS ≥ 2 or CLcr < 60 mL/min, is required (see sections "Dosage and administration" and "Adverse reactions").

Cataract

Cataract has been reported more frequently in patients receiving lenalidomide in combination with dexamethasone, particularly with long-term use. Regular monitoring of vision is recommended.

Use during pregnancy or breastfeeding.

Due to the teratogenic potential of lenalidomide, it is prescribed only if the Pregnancy Prevention Programme is followed (see section "Special precautions for use"), except in cases where there is reliable evidence that the woman cannot become pregnant.

Women of reproductive age/contraception in men and women

Women of reproductive age must use an effective contraceptive method. If pregnancy is diagnosed in a woman being treated with lenalidomide, lenalidomide must be discontinued, and the patient should be referred to a specialist physician in the field of teratology for evaluation and clinical recommendations. If pregnancy is diagnosed in a woman who is a sexual partner of a patient receiving lenalidomide treatment, the woman should also be referred to a specialist physician in the field of teratology for evaluation and clinical recommendations.

Lenalidomide is present in human seminal fluid at very low concentrations during treatment and is not detectable 3 days after discontinuation in healthy volunteers. As a precaution, considering the possible reduced elimination rate of lenalidomide in specific patient groups (e.g., patients with impaired renal function), all male patients receiving lenalidomide must use a condom throughout the entire treatment course, during treatment interruption, and for 1 week after treatment discontinuation if the sexual partner is a pregnant woman or a woman of reproductive age not using highly effective contraception.

Pregnancy

Lenalidomide is a structural analogue of thalidomide. Thalidomide is a known active substance with teratogenic effects in humans and causes severe, life-threatening congenital malformations. Lenalidomide has caused developmental defects in monkeys similar to those described for thalidomide. Therefore, a teratogenic effect of lenalidomide is expected, and lenalidomide is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding

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

Fertility

Fertility studies in rats with lenalidomide doses up to 500 mg/kg (approximately 200–500 times higher than the recommended human doses of 25 mg and 10 mg, respectively, based on body surface area) showed no negative effect on fertility and did not cause parental toxicity.

Male patients receiving lenalidomide must not donate sperm for 4 weeks after discontinuation of treatment (see section "Use in specific populations").

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

Lenalidomide has a minor or moderate effect on the ability to drive vehicles and operate machinery. Fatigue, dizziness, somnolence, vertigo, and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving vehicles or operating other machinery.

Method of administration and dosing.

Treatment should be administered under the supervision of a physician experienced in the use of anticancer therapy.

For all indications described below:

• Dose modifications should be based on clinical and laboratory findings (see section "Special Instructions").
• Dose adjustments during treatment and re-treatment should be considered according to Grade III or IV thrombocytopenia, neutropenia, or any other Grade III or IV toxicity related to lenalidomide.
• In cases of neutropenia, the physician should consider administering growth factors to 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 dose at the usual time on the following day.

Dosing

Newly diagnosed multiple myeloma (NDMM)

• Lenalidomide in combination with dexamethasone until disease progression in patients who are not eligible for transplantation

Treatment should not be initiated if ANC < 1.0 × 10⁹/L and/or platelet count < 50 × 10⁹/L.

Recommended dose

The recommended starting 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 therapy with lenalidomide and dexamethasone until disease progression or until intolerance occurs.

Dose reduction steps

a dose reduction for both medicinal products can be performed separately;

* the drug is administered in the appropriate dosage.

Thrombocytopenia

If dose-limiting toxicity (DLT) occurs after day 15 of the cycle, lenalidomide administration should be discontinued for at least until the end of the current 28-day cycle.

Absolute neutrophil count (ANC) – neutropenia

and 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.

In the case of hematologic toxicity, the lenalidomide dose may be re-escalated to the next higher level (up to the initial dose) after bone marrow function has improved (absence of hematologic toxicity for at least 2 consecutive cycles: ANC ≥ 1.5 × 10⁹/L with platelet count ≥ 100 × 10⁹/L at the start of a new cycle).

Lenalidomide in combination with bortezomib and dexamethasone, followed by lenalidomide and dexamethasone therapy until disease progression in patients ineligible for transplantation

Initial treatment: Lenalidomide in combination with bortezomib and dexamethasone

Treatment with lenalidomide in combination with bortezomib and dexamethasone must not be initiated if ANC < 1.0 × 10⁹/L and/or platelet count < 50 × 10⁹/L.

The recommended initial dose of lenalidomide is 25 mg orally once daily on days 1 to 14 of each 21-day treatment cycle in combination with bortezomib and dexamethasone. Bortezomib should be administered by subcutaneous injection (1.3 mg/m² body surface area) twice weekly on days 1, 4, 8, and 11 of each 21-day cycle. For additional information on dosing, schedules, and dose adjustments of concomitantly administered drugs, refer to the section “Pharmacological properties” and the package leaflets of these medicinal products. Up to eight 21-day treatment cycles (24 weeks of initial treatment) are recommended.

Continuation treatment: lenalidomide in combination with dexamethasone until disease progression

Continue lenalidomide 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles in combination with dexamethasone. Treatment should continue until disease progression or unacceptable toxicity.

Dose reduction steps

and dose reduction for all medicinal products can be performed separately.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

and 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.

• Lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance therapy in patients ineligible for transplantation

Lenalidomide treatment must not be initiated if ANC < 1.5 × 10⁹/L and/or platelet count < 75 × 10⁹/L.

Recommended dose

The recommended initial dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles for 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 who cannot complete combination therapy due to intolerance receive lenalidomide monotherapy as follows: 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles until disease progression.

Dose reduction steps

and if neutropenia is the only type of toxicity at any dose level, add G-CSF and maintain the
lenalidomide dose level.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

and 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.

• Maintenance therapy with lenalidomide in patients who have undergone autologous stem cell transplantation (ASCT)

Maintenance therapy with lenalidomide should be initiated after adequate hematologic recovery post-ASCT in patients without evidence of disease progression. Lenalidomide treatment must 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, continuously (days 1 to 28 of repeated 28-day cycles), administered until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy with lenalidomide, the dose may be increased to 15 mg orally once daily, provided it is well tolerated.

Dose reduction guidelines

and after 3 cycles of lenalidomide maintenance therapy, the dose may be increased to 15 mg orally once daily, provided it is well tolerated.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

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

MM in patients who have received at least one prior therapy

Treatment with lenalidomide must not be initiated if ANC < 1 × 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 starting 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 to 4, 9 to 12, and 17 to 20 of each 28-day cycle during the first 4 treatment cycles, and thereafter 40 mg orally once daily on days 1 to 4 of every 28 days.

The prescribing physician must carefully evaluate the appropriate dose of dexamethasone to administer, taking into consideration the patient's condition and the severity of the disease.

Dose reduction steps

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

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

MDS

Treatment with lenalidomide must not be initiated if ANC < 0.5 × 10⁹/L and/or platelets < 25 × 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 steps

• in countries where 2.5 mg capsules are available, the drug is administered at the corresponding dosage.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

Discontinuation of lenalidomide

If patients have not achieved at least a minor erythroid response within 4 months after starting therapy—defined as at least a 50% reduction in red blood cell transfusion requirements or, in non-transfusion-dependent patients, an increase in hemoglobin of 1 g/dL—lenalidomide should be discontinued.

MDS

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 steps

• in countries where 2.5 mg capsules are available, the drug is administered at the corresponding dosage.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

PI

Treatment with lenalidomide must not be initiated if ANC < 1 × 109/litre and/or platelets < 50 × 109/litre, unless these abnormalities are due to bone marrow infiltration by lymphoma.

Recommended dose

The recommended starting dose of lenalidomide is 20 mg orally once daily on days 1 to 21 of repeated 28-day cycles for a treatment duration of up to 12 cycles. The recommended starting dose of rituximab is 375 mg/m2 administered intravenously (i.v.) weekly during cycle 1 (days 1, 8, 15, and 22) and on day 1 of each 28-day cycle for cycles 2–5.

Dose reduction steps

For dose adjustment due to rituximab toxicity, refer to the appropriate instructions for this medicinal product.

Thrombocytopenia

Absolute neutrophil count (ANC) – neutropenia

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

CLL or FL

Tumor Lysis Syndrome (TLS)

All patients should receive prophylaxis for TLS (with allopurinol, rasburicase, or an equivalent agent according to established guidelines) and maintain adequate oral fluid intake during the first week of the first cycle or for a longer period if clinically indicated. To monitor for TLS, patients should undergo a biochemical panel weekly during the first cycle and as clinically indicated.

Lenalidomide treatment may be continued (maintenance dose) in patients with laboratory TLS or clinical TLS Grade I, or at the physician’s discretion, the lenalidomide dose may be reduced by one level and treatment continued. Intensive intravenous hydration and appropriate medical support should be provided according to local treatment standards until electrolyte imbalances are corrected. Rasburicase may be required to manage hyperuricemia. Hospitalization of the patient is at the physician’s discretion.

Patients with clinical TLS Grades II to IV should discontinue lenalidomide, and a biochemical panel should be performed weekly or as clinically indicated. Intensive intravenous hydration and appropriate medical support should be provided according to local treatment standards until electrolyte imbalances are corrected. The use of rasburicase and hospitalization of the patient are at the physician’s discretion. After TLS resolves to Grade 0, lenalidomide treatment may be resumed at a reduced dose at the physician’s discretion (see section “Dosage and Administration”).

Tumor Flare Reaction (TFR)

Patients with Grade I or II Tumor Flare Reaction (TFR) may, at the physician’s discretion, continue lenalidomide without interruption or dose modification. At the physician’s discretion, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), short-acting corticosteroids, and/or narcotic analgesics may be initiated. Patients with Grade III or IV TFR should discontinue lenalidomide and initiate treatment with NSAIDs, corticosteroids, and/or narcotic analgesics until TFR resolves to ≤ Grade I, after which lenalidomide treatment may be resumed at the same dose level for the remainder of that cycle. Patients may receive symptomatic treatment according to recommendations for Grade I and II TFR (see section “Dosage and Administration”).

All Indications

For other Grade III or IV toxicities related to lenalidomide, treatment should be discontinued and restarted at the next lower dose level once toxicity resolves to ≤ Grade II, at the physician’s discretion.

For Grade II or III skin rashes, lenalidomide administration should be interrupted or discontinued. Lenalidomide must be discontinued in cases of angioedema, Grade IV rash, exfoliative or bullous rash, or if Stevens–Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (DRESS) is suspected, and should not be restarted after discontinuation due to these reactions.

Special Patient Populations

Children

The drug should not be used in children under 18 years of age due to safety concerns (see section “Pharmacological Properties. Pharmacodynamics”).

Elderly Patients

Available pharmacokinetic data are described in the section “Pharmacological Properties. Pharmacokinetics.” Lenalidomide has been used in clinical trials in patients with MM up to 91 years of age, in patients with MDS up to 95 years of age, and up to 88 years of age in CLL (see section “Pharmacological Properties. Pharmacokinetics”).

Since elderly patients are more likely to have reduced renal function, careful dose selection is required, and renal function monitoring is recommended.

MM: Patients ineligible for transplantation

Patients with MM aged 75 years and older should be carefully evaluated before initiating treatment (see section “Dosage and Administration”).

For patients aged 75 years and older receiving lenalidomide in combination with dexamethasone, the starting dose of dexamethasone is 20 mg once daily on days 1, 8, 15, and 22 of each 28-day treatment cycle.

Dose adjustment is not required for patients aged 75 years and older receiving lenalidomide in combination with melphalan and prednisolone.

In patients with MM aged 75 years and older treated with lenalidomide, the incidence of serious adverse reactions and adverse reactions leading to discontinuation was higher.

Combination therapy with lenalidomide was less well tolerated in patients with MM aged 75 years and older compared to younger patients. These patients discontinued treatment more frequently due to intolerance (Grade III or IV adverse events and serious adverse events) compared to patients under 75 years of age.

MM: Patients with at least one prior therapy

The proportion of MM patients aged 65 years and older did not differ significantly between the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall differences in safety and efficacy were observed between these and younger patients, although increased susceptibility in older patients cannot be excluded.

MDS

For patients with MDS receiving lenalidomide, there are no differences in safety and efficacy between patients aged 65 years and older and younger patients.

CLL

For patients with CLL receiving lenalidomide treatment, no differences in safety and efficacy were observed between patients aged 65 years and older compared to those under 65 years of age.

FL

In patients with FL receiving lenalidomide in combination with rituximab, the overall frequency of adverse reactions is similar in patients aged 65 years and older compared to those under 65 years of age. No overall differences in efficacy were observed between the two age groups.

Patients with Renal Impairment

Lenalidomide is primarily eliminated by the kidneys; patients with greater degrees of renal impairment may tolerate treatment poorly (see section “Dosage and Administration”). Dose selection should be cautious, and monitoring of renal function is recommended.

Dose adjustment is not required for patients with mild renal impairment and MM, MDS, CLL, or FL.

The following dose adjustments are recommended at the start and during therapy for patients with moderate or severe renal impairment or end-stage renal disease (ESRD).

There is no Phase III study experience in end-stage renal disease (creatinine clearance (CrCl) < 30 mL/min, requiring dialysis).

Multiple Myeloma

The dose of the drug may be increased to 15 mg once daily after 2 cycles if the patient does not respond to treatment and tolerates the therapy.

2 in countries where 7.5 mg capsules are available.

Myelodysplastic syndromes

* recommended measures for dose reduction of the medicinal product during treatment and upon resumption of therapy to manage grade III-IV neutropenia or thrombocytopenia or other grade III-IV toxicities related to lenalidomide.

1 if necessary to use 2.5 mg doses—administer the medicinal product at the appropriate dosage strength.

Mantle cell lymphoma

The dose of the drug may be increased to 15 mg once daily after 2 cycles if the patient does not respond to treatment and tolerates therapy.

2 in countries where 7.5 mg capsules are available.

Follicular lymphoma

The dose of 15 mg once daily may be increased after 2 cycles if the patient does not respond to treatment and tolerates therapy.

For patients receiving an initial dose of 10 mg, dose reduction may be required in case of grade III-IV neutropenia or thrombocytopenia, or other grade III or IV toxicities. It has been demonstrated that lenalidomide does not exert toxic effects at doses below 5 mg daily or 2.5 mg once daily.

Patients with severe renal impairment or end-stage renal disease were excluded from the studies.

Following initiation of lenalidomide treatment, further dose modifications in patients with renal impairment should be based on individual tolerability of treatment.

Patients with hepatic impairment

The use of lenalidomide has not been formally studied in patients with hepatic impairment, and there are no specific recommendations for dose selection.

Method of administration

Oral use. Capsules should be taken at the same time each day according to the prescribed schedule. Capsules must not be opened, broken, or chewed. They should be swallowed whole, preferably with water, with or without food.

It is recommended to press only one end of the capsule when removing it from the blister pack, thereby minimizing the risk of capsule deformation or breakage.

Children.

For safety reasons, lenalidomide should not be used in children and adolescents under 18 years of age.

Overdose.

There is no specific experience in managing overdose of lenalidomide in patients. However, in dose-ranging studies, some patients received doses up to 150 mg, and in single-dose effect studies, some patients received up to 400 mg of the drug. The dose-limiting toxicities observed in these studies were exclusively hematological. In case of overdose, symptomatic and supportive therapy is recommended.

Adverse Reactions

Summary of Safety Profile

MM: Patients who underwent ASCT and are receiving lenalidomide maintenance therapy

A conservative approach was applied in determining adverse reactions in CALGB 100104. The adverse reactions described in Table 1 include events occurring after ASCT as well as those during the maintenance treatment period. A subsequent analysis identifying events occurring after initiation of maintenance therapy indicates that the frequencies described in Table 1 may be higher than those actually observed during the maintenance treatment period. In IFM 2005-02, adverse reactions were limited to the maintenance treatment period only.

Serious adverse reactions occurred more frequently (≥ 5%) with lenalidomide maintenance therapy compared to placebo and included:

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

In the IFM 2005-02 study, adverse reactions occurring more frequently with lenalidomide maintenance therapy than with placebo were: neutropenia (60.8%), 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 occurring more frequently with 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%]), upper respiratory tract infections (26.8% [26.8%]), fatigue (22.8% [17.9%]), leukopenia (22.8% [18.8%]), and anemia (21% [13.8%]).

MM: Patients ineligible for transplantation and treated with lenalidomide in combination with bortezomib and dexamethasone

In the SWOG S0777 study, serious adverse reactions occurred more frequently (≥ 5%) with lenalidomide in combination with bortezomib and dexamethasone compared to lenalidomide with dexamethasone, and included:

• Hypotension (6.5%), pulmonary infection (5.7%), dehydration (5.0%).

Adverse reactions occurring more frequently with lenalidomide in combination with bortezomib and dexamethasone than with lenalidomide and dexamethasone were: fatigue (73.7%), peripheral neuropathy (71.8%), thrombocytopenia (57.6%), constipation (56.1%), hypocalcemia (50.0%).

MM: Patients ineligible for transplantation and treated with lenalidomide in combination with low-dose dexamethasone

Serious adverse reactions occurred more frequently (≥ 5%) with lenalidomide in combination with low-dose dexamethasone (Rd and Rd18) compared to melphalan, prednisone, and thalidomide (MPT), and included:

• Pneumonia (9.8%);
• Renal failure, including acute (6.3%).

Adverse reactions occurring more frequently with Rd and Rd18 therapy than with 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%).

MM: Patients ineligible for transplantation and treated with lenalidomide in combination with melphalan and prednisone

Serious adverse reactions occurred more frequently (≥ 5%) with lenalidomide in combination with melphalan and prednisone followed by lenalidomide maintenance (MPR+R), or with melphalan and prednisone followed by placebo (MPR+p), compared to melphalan, prednisone, and placebo followed by placebo (MPp+p), and included:

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

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

MM: Patients who received at least one prior line of therapy

In two phase III placebo-controlled studies, 353 patients with MM received lenalidomide/dexamethasone combination therapy, and 351 received placebo/dexamethasone. The most severe adverse reactions occurred more frequently with lenalidomide/dexamethasone than with placebo/dexamethasone:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism);
• Grade IV neutropenia.

Adverse reactions occurred more frequently with lenalidomide/dexamethasone than with placebo/dexamethasone: 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%).

MDS

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

Most adverse reactions were generally observed within the first 16 weeks of lenalidomide therapy. Serious adverse reactions included:

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

In patients in the phase III study receiving lenalidomide, adverse reactions occurred more frequently compared to the control group and were generally: 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%).

MCL

The overall safety profile of lenalidomide in patients with MCL is based on data from 254 patients in the randomized, controlled phase II study MCL-002.

Additionally, adverse reactions from the supportive study MCL-001 were included in Table 3.

In study MCL-002, the most common serious adverse reactions occurring more frequently (by at least 2 percentage points) in the lenalidomide group compared to the control group were:

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

In study MCL-002, the most common adverse reactions occurring more frequently in the lenalidomide group compared to the control group 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 study MCL-002, there was an overall increased incidence of early mortality (within 20 weeks). Patients with high tumor burden at baseline had an increased risk of early death: 16/81 (20%) early deaths in the lenalidomide group and 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, therapy was discontinued in 11/81 (14%) patients with high tumor burden in the lenalidomide group compared to 1/28 (4%) in the control group. In the lenalidomide group, the primary reason for discontinuation during the first cycle in patients with high tumor burden was adverse reactions, occurring in 7/11 (64%). High tumor burden was defined as at least one tumor lesion ≥ 5 cm in diameter or three lesions ≥ 3 cm in diameter.

FL

The overall safety profile of lenalidomide in combination with rituximab in previously treated follicular lymphoma patients is based on data from 294 patients in the randomized, controlled phase 3 study NHL-007. Additionally, adverse drug reactions from the supportive study NHL-008 were included in Table 5.

In study NHL-007, the most common serious adverse reactions (with a difference of at least 1 percentage point) in the lenalidomide/rituximab group compared to the placebo/rituximab group were:

• Febrile neutropenia (2.7%);
• Pulmonary embolism (2.7%);
• Pneumonia (2.7%).

In study NHL-007, adverse reactions occurring more frequently in the lenalidomide/rituximab group compared to the placebo/rituximab group (with a frequency difference of at least 2%) were: neutropenia (58.2%), diarrhea (30.8%), leukopenia (28.8%), constipation (21.9%), cough (21.9%), and fatigue (21.9%).

Tabulated List of Adverse Reactions

Adverse reactions observed in patients treated with lenalidomide are listed by system organ class and frequency. Within each frequency category, adverse reactions are presented in descending order of severity. Frequencies are 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); frequency 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 MM

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

Adverse reactions reported during clinical trials in MM patients receiving lenalidomide maintenance therapy

Table 1

1 - Adverse reactions reported as serious in clinical trials in patients with MM who received TAC.

2 - Apply only to serious adverse reactions.

3 - See description of individual adverse reactions in the section "Adverse Reactions".

4 - "Pneumonia" – a combined adverse reaction term encompassing the following: bronchopneumonia; lobar pneumonia; Pneumocystis pneumonia; pneumonia; pneumonia due to Klebsiella pneumoniae; Legionella pneumonia; mycoplasma pneumonia; pneumococcal pneumonia; streptococcal pneumonia; viral pneumonia; lung disorder; pneumonitis.

5 - "Sepsis" – a combined adverse reaction term encompassing the following: bacterial sepsis, pneumococcal sepsis, septic shock, staphylococcal sepsis.

6 - "Peripheral neuropathy" – a combined adverse reaction term encompassing the following: peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy.

7 - "Deep vein thrombosis" – a combined adverse reaction term encompassing the following: deep vein thrombosis, thrombosis, venous thrombosis.

Summary table of adverse reactions during combination therapy for MM

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 treatment duration in the lenalidomide group compared to the control group in the main clinical trials of multiple myeloma.

Adverse reactions observed in patients with MM who received lenalidomide in combination with bortezomib and dexamethasone, dexamethasone, or melphalan and prednisone

Table 2

◊ - Adverse reactions considered "serious" during clinical studies in MM patients receiving lenalidomide in combination with bortezomib and dexamethasone.

1 - Adverse reactions reported as serious in clinical trials in WM patients receiving lenalidomide in combination with dexamethasone or with melphalan and prednisolone.

2 - See description of individual adverse reactions in the section "Adverse Reactions."

3 - Squamous cell carcinoma of the skin was reported in clinical studies in previously treated myeloma patients comparing lenalidomide/dexamethasone with the control group.

4 - Squamous cell carcinoma of the skin was reported in clinical studies in patients with newly diagnosed myeloma comparing lenalidomide/dexamethasone with the control group.

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 MDS and MCL.

Adverse reactions observed during clinical studies in MDS patients receiving lenalidomide treatment #

Table 3

1 - Adverse reactions considered as "serious" during clinical trials in patients with MDS.

2 - See description of individual adverse reactions in section "Adverse Reactions".

3 - Mood changes were recorded as common adverse reactions during MDS treatment in Phase III clinical trials; however, they were not considered adverse reactions of severity grade III-IV.

Algorithm applied for inclusion into SmPC: All adverse reactions recorded according to the Phase III study protocol algorithm are included in the EU SmPC. For these adverse reactions, an additional check of the frequency was performed based on data from the Phase II study protocol algorithm; if the frequency of adverse reactions in the Phase II study was higher than in the Phase III study, the event was included into the EU SmPC using the frequency observed in the Phase II study.

Algorithm applied in MDS:

• MDS, Phase III study (double-blind in the safety population, difference between lenalidomide 5/10 mg and placebo groups in the initial dosing regimen, observed in at least 2 patients):

  o All treatment-emergent adverse reactions occurring in ≥ 5% of patients receiving lenalidomide and with at least a 2% difference in proportion between lenalidomide and placebo.

  o All treatment-emergent adverse reactions of Grade III or IV severity occurring in 1% of patients receiving lenalidomide and with at least a 1% difference in proportion between lenalidomide and placebo.

  o All treatment-emergent serious adverse reactions occurring in 1% of patients receiving lenalidomide and with at least a 1% difference in proportion between lenalidomide and placebo.

• MDS, Phase II study:

  o All treatment-emergent adverse reactions occurring in ≥ 5% of patients receiving lenalidomide.

  o All treatment-emergent adverse reactions of Grade III or IV severity occurring in 1% of patients receiving lenalidomide.

  o All treatment-emergent serious adverse reactions occurring in 1% of patients receiving lenalidomide.

Adverse reactions observed in patients with CLL who received lenalidomide treatment

Table 4

1 - Adverse reactions considered as "serious" during clinical trials in patients with MCL. The algorithm used to include adverse reactions observed in patients with MCL:

• MCL, controlled phase II study

  o All adverse reactions occurring during treatment in ≥ 5% of patients receiving lenalidomide and at least a 2% difference in frequency between the lenalidomide group and the control group.

  o All grade III or IV adverse reactions occurring during treatment in ≥ 1% of patients receiving lenalidomide and at least a 1% difference in incidence rate between the lenalidomide group and the control group.

  o All serious adverse reactions occurring during treatment in ≥ 1% of patients receiving lenalidomide and at least a 1% difference in incidence rate between the lenalidomide group and the control group.

• MCL, single-arm phase II study

  o All adverse reactions occurring during treatment in ≥ 5% of patients receiving lenalidomide.

  o All grade III or IV adverse reactions occurring during treatment in 2 or more patients.

  o All serious adverse reactions occurring during treatment in 2 or more patients.

2 - See description of individual adverse reactions in the section "Adverse Reactions".

Summary table of adverse reactions during combination therapy with R² (lenalidomide + rituximab) in follicular lymphoma

The data in the following table were obtained from the main studies (NHL-007 and NHL-008) evaluating combination therapy with lenalidomide and rituximab for the treatment of follicular lymphoma.

Adverse reactions observed in patients with FL treated with lenalidomide in combination with rituximab

Table 5

1 - Adverse reactions considered as "serious" during clinical trials in patients with FL.

2 - See description of individual adverse reactions in the section "Adverse Reactions".

Algorithm used for inclusion of adverse reactions in patients with FL:

Controlled – Phase III trial:

o Adverse reactions in study NHL-007: all adverse reactions occurring during treatment in ≥ 5.0% of subjects in the lenalidomide/rituximab group and at least 2.0% higher frequency in the lenalidomide group compared to the control group – (safety evaluation population).

o Grade III or IV adverse reactions in study NHL-007: all Grade III or IV adverse reactions occurring during treatment in at least 1.0% of patients in the lenalidomide/rituximab group and at least 1.0% higher frequency in the lenalidomide group compared to the control group – (safety evaluation population).

o Serious adverse reactions in study NHL-007: all serious adverse reactions occurring during treatment in at least 1.0% of patients in the lenalidomide/rituximab group and at least 1.0% higher frequency in the lenalidomide group compared to the control group – (safety evaluation population).

Single-arm trial – Phase III study in patients with FL:

o Adverse reactions in study NHL-008: all adverse reactions occurring during treatment in ≥ 5.0% of subjects.

o Grade III or IV adverse reactions in study NHL-008: all Grade III or IV adverse reactions occurring during treatment in 1.0% of subjects.

o Serious adverse reactions in study NHL-008: all serious adverse reactions occurring during treatment in 1.0% of subjects.

3 - Applies only to serious adverse reactions to the drug.

* - Rash includes preferred terms such as rash and maculopapular rash.

** - Leukopenia includes preferred terms such as leukopenia and decreased white blood cell count.

*** - Lymphopenia includes preferred terms such as lymphopenia and decreased lymphocyte count.

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 experience.

Adverse reactions reported from post-marketing data in patients treated with lenalidomide

Table 6

1 - See description of individual adverse reactions in the section "Adverse Reactions".

Description of individual adverse reactions

Teratogenicity

Lenalidomide is a structural analogue of thalidomide. Thalidomide is a known human teratogen which can cause severe, life-threatening birth defects. Experimental studies in monkeys have shown results similar to those described for thalidomide (see section "Use during pregnancy or breastfeeding"). There is a high risk of fetal birth defects if lenalidomide is used during pregnancy.

Neutropenia and thrombocytopenia

• MM: patients who underwent ASCT and are receiving lenalidomide maintenance therapy

The use of lenalidomide maintenance therapy after ASCT is associated with a higher incidence of Grade IV neutropenia compared to placebo (32.1 % vs 26.7 % [16.1 % vs 1.8 % after initiation of maintenance therapy] in CALGB 100104 and 16.4 % vs 0.7 % in IFM 2005-02, respectively). Adverse reactions of neutropenia leading to discontinuation of lenalidomide were reported in 2.2 % of patients in CALGB 100104 and in 2.4 % of patients in IFM 2005-02, respectively. Febrile neutropenia Grade IV was reported with similar frequency in the lenalidomide maintenance groups compared to placebo groups in both studies (0.4 % vs 0.5 % [0.4 % vs 0.5 % after initiation of maintenance therapy] in CALGB 100104 and 0.3 % vs 0 % in IFM 2005-02, respectively). The use of lenalidomide maintenance therapy after ASCT is associated with a higher incidence of Grade III or 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).

• MM: transplant-ineligible patients receiving lenalidomide in combination with bortezomib and dexamethasone

In the SWOG S0777 study, Grade IV neutropenia was observed less frequently in the RVd group than in the Rd control group (2.7 % vs 5.9 %). Febrile neutropenia Grade IV was reported with similar frequency in the RVd group compared to the Rd group (0.0 % vs 0.4 %). Grade III or IV thrombocytopenia was observed more frequently in the RVd group than in the Rd control group (17.2 % vs 9.4 %).

• MM: transplant-ineligible patients receiving lenalidomide in combination with low-dose dexamethasone

The use of lenalidomide in combination with low-dose dexamethasone in patients with MM was associated with reduced incidence of Grade IV neutropenia (8.5 % in Rd and Rd18 compared to 15 % in MPT). Febrile neutropenia Grade IV was infrequent (0.6 % in Rd and Rd18 compared to 0.7 % in MPT).

The use of lenalidomide in combination with low-dose dexamethasone in patients with MM is associated with a lower incidence of Grade III and IV thrombocytopenia (8.1 % in Rd and Rd18) compared to MPT (11 %).

• MM: transplant-ineligible patients receiving lenalidomide in combination with melphalan and prednisone

The use of lenalidomide in combination with melphalan and prednisone in patients with MM is associated with an increased incidence of Grade IV neutropenia compared to the control group (34.1 % in MPR+R/MPR+p) compared to MPp+p (7.8 %). A higher incidence of febrile neutropenia Grade IV was observed (1.7 % in MPR+R/MPR+p compared to 0.0 % in MPp+p).

The use of lenalidomide in combination with melphalan and prednisone in patients with MM is associated with a higher incidence of Grade III and IV thrombocytopenia (40.4 % in MPR+R/MPR+p) compared to MPp+p (13.7 %).

• MM: patients with at least one prior line of therapy

The use of lenalidomide in combination with dexamethasone in patients with MM is associated with an increased incidence of Grade IV neutropenia (5.1 % in patients treated with lenalidomide/dexamethasone compared to 0.6 % in patients receiving placebo/dexamethasone).

The use of lenalidomide in combination with dexamethasone in patients with MM is associated with a higher incidence of Grade III and IV thrombocytopenia (9.9 % and 1.4 %, respectively, in patients treated with lenalidomide/dexamethasone compared to 2.3 % and 0.0 % in patients receiving placebo/dexamethasone).

• Patients with MDS

In patients with MDS, lenalidomide treatment is associated with a higher incidence of Grade III or IV neutropenia (74.6 % in patients treated with lenalidomide compared to 14.9 % in patients receiving placebo in the Phase III study).

Episodes of febrile neutropenia Grade III or IV occurred in 2.2 % of patients receiving lenalidomide treatment compared to 0.0 % in the placebo group. Lenalidomide use is associated with a higher incidence of Grade III or IV thrombocytopenia (37 % in patients treated with lenalidomide compared to 1.5 % in patients receiving placebo in the Phase III study).

• Patients with MCL

In patients with MCL, lenalidomide treatment is associated with a higher incidence of Grade III or IV neutropenia (43.7 % in patients treated with lenalidomide compared to 33.7 % in the control group of the Phase II study). Episodes of febrile neutropenia Grade III or IV occurred in 6.0 % of patients receiving lenalidomide treatment compared to 2.4 % in the control group.

• Patients with FL

The use of lenalidomide in combination with rituximab in patients with FL is associated with a higher incidence of Grade III or IV neutropenia (50.7 % in patients receiving lenalidomide/rituximab compared to 12.2 % in patients receiving placebo/rituximab). All cases of Grade III or IV neutropenia were reversible upon discontinuation or dose reduction and/or use of supportive growth factor therapy. Additionally, febrile neutropenia occurred infrequently (2.7 % in the lenalidomide/rituximab treatment group compared to 0.7 % in the placebo/rituximab group).

The use of lenalidomide in combination with rituximab is also associated with a higher incidence of Grade III or IV thrombocytopenia (1.4 % in the lenalidomide/rituximab treatment group compared to 0 % in the placebo/rituximab group).

Vein thromboembolism

An increased risk of deep vein thrombosis (DVT) 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 lenalidomide in combination with melphalan and prednisolone or in patients with MM, MDS, and MCL receiving lenalidomide monotherapy (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of erythropoiesis-stimulating agents or a history of DVT may also increase the risk of thrombotic events in these patients.

Myocardial infarction

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with existing risk factors.

Bleeding disorders

Bleeding disorders have been reported in several system organ classes: blood and lymphatic system disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal bleeding, rectal bleeding); renal and urinary disorders (haematuria); injury, poisoning and procedural complications (contusion); vascular disorders (ecchymosis).

Allergic reactions and serious skin reactions

Cases of allergic reactions, including angioedema, anaphylactic reaction, and severe skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in patients receiving lenalidomide. There are reports in the scientific literature of possible cross-reactivity between lenalidomide and thalidomide. Lenalidomide must not be prescribed to patients with a history of severe skin reactions to thalidomide (see section "Special warnings and precautions for use").

Secondary primary malignancies

In clinical trials in patients with myeloma previously treated with lenalidomide/dexamethasone compared to the control group, basal cell carcinoma or squamous cell carcinoma of the skin were predominantly observed.

Acute myeloid leukaemia (AML)

• MM

Cases of AML were observed during clinical trials in patients with HMM receiving lenalidomide in combination with melphalan, or immediately after high-dose melphalan (HDM) and ASCT (see section "Special warnings and precautions for use"). This increase was not observed in clinical trials in patients with MM receiving lenalidomide in combination with low-dose dexamethasone compared to thalidomide in combination with melphalan and prednisone.

• MDS

Baseline variables, including a complex cytogenetic profile and TP53 mutations, are associated with progression to AML in transfusion-dependent patients with del(5q) genetic abnormality. The estimated two-year cumulative risk of progression to AML was 13.8 % in patients with del(5q) abnormality compared to 17.3 % in patients with del(5q) abnormality and one additional cytogenetic abnormality, and 38.6 % in patients with a complex karyotype.

In a retrospective analysis of a clinical trial of lenalidomide in MDS, the estimated two-year progression rate to AML was 27.5 % in patients with positive IHC-p53 and 3.6 % in patients with negative IHC-p53. Among patients with positive IHC-p53, a lower progression rate to AML was observed in those who achieved transfusion independence response (11.1 %) compared to those who did not achieve response (34.8 %).

Liver disorders

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

Rhabdomyolysis

Cases of rhabdomyolysis have been rarely observed, some of which occurred during concomitant use of lenalidomide with statins.

Thyroid disorders

Cases of hypothyroidism and hyperthyroidism have been reported (see section "Special warnings and precautions for use").

Tumour flare reaction (TFR) and tumour lysis syndrome (TLS)

In the MCL-002 clinical trial, approximately 10 % of patients receiving lenalidomide treatment experienced TFR compared to 0 % in the control group. Most cases occurred during the first cycle, all were considered treatment-related, and the majority were Grade I or II in severity. Patients with a high MIPI (Mantle Cell Lymphoma International Prognostic Index) score or large tumour burden (at least one tumour ≥ 7 cm in longest diameter) at baseline may be at risk of TFR. In the MCL-002 study, TLS was reported in one patient in each of the two treatment groups. In the additional MCL-001 study, approximately 10 % of subjects experienced TFR; all reports were Grade I or II in severity and all were considered treatment-related. Most cases occurred in the first cycle. There were no reports of TLS in the MCL-001 study (see section "Special warnings and precautions for use").

In the NHL-007 study, TFR was reported in 13.0 % of patients in the lenalidomide/rituximab group compared to 0.7 % in the placebo/rituximab group. The majority of TFR reports (18 out of 19) in the lenalidomide/rituximab group occurred during the first two cycles of treatment. In the lenalidomide/rituximab group, one patient with FL experienced Grade III TFR, whereas no such reaction was reported in the placebo/rituximab group. In the NHL-008 study, TFR was observed in 4.0 % of patients with FL (3 reports of Grade I and 4 reports of Grade II severity); one report was considered serious. In the NHL-007 study, TLS was observed in two patients with FL (1.4 %) in the lenalidomide/rituximab group and in none of the patients with FL in the placebo/rituximab group; none of the patients had Grade III or IV reactions. TLS was observed in one patient with FL (0.6 %) in the NHL-008 study. This event was identified as a serious adverse reaction of Grade III. In the NHL-007 study, no patient discontinued therapy with lenalidomide/rituximab due to TFR or TLS.

Gastrointestinal tract disorders

Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcomes.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the appropriate reporting system.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of the reach of children.

Packaging.

10 capsules in a blister; 1 or 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of its operations.

Unit-V, Block-VB, TSIIC Formulation SEZ, Sy. No. 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.