Lenangio
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product LENANGIO (LENANGIO)
Composition:
Active substance: lenalidomide;
1 hard capsule contains lenalidomide in the form of Povidone Premix, calculated as lenalidomide 5 mg, or 10 mg, or 15 mg, or 25 mg;
Excipients:
Hard capsules 5 mg: mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hard gelatin capsule size 4 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171));
Hard capsules 10 mg: mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hard gelatin capsule size 2 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), indigo carmine (E 132), iron oxide yellow (E 172));
Hard capsules 15 mg: mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hard gelatin capsule size 1 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), indigo carmine (E 132));
Hard capsules 25 mg: mannitol (E 421), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hard gelatin capsule size 0 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171)).
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
Hard capsules 5 mg: hard gelatin capsules of size "4", consisting of an opaque white cap with "RDY" printed in black ink, and an opaque white body with "5 mg" printed in black ink, filled with white to almost white powder;
Hard capsules 10 mg: hard gelatin capsules of size "2", consisting of a pale green cap with "RDY" printed in black ink, and a pale yellow body with "10 mg" printed in black ink, filled with white to almost white powder;
Hard capsules 15 mg: hard gelatin capsules of size "1", consisting of a blue cap with "RDY" printed in black ink, and a white body with "15 mg" printed in black ink, filled with white to almost white powder;
Hard capsules 25 mg: hard gelatin capsules of size "0", consisting of an opaque white cap with "RDY" printed in black ink, and an opaque white body with "25 mg" printed in black ink, filled with white to almost white powder.
Pharmacotherapeutic group.
Immunosuppressants. Other immunosuppressants. ATC code L04AX04.
Pharmacological Properties
Pharmacodynamics
Mechanism of Action
The mechanism of action of lenalidomide is based on its antineoplastic, antiangiogenic, proerythropoietic, and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain hematopoietic tumor cells, including plasma cells in multiple myeloma (MM) and cells with chromosome 5 cytogenetic abnormalities. Lenalidomide enhances T-cell and natural killer (NK) cell-mediated cellular immunity and increases the number of NK T-cells. Lenalidomide inhibits angiogenesis by blocking endothelial cell migration and adhesion and microvessel formation, enhances fetal hemoglobin production by CD34+ hematopoietic stem cells, and suppresses the secretion of proinflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)) by monocytes.
In myelodysplastic syndrome with del(5q), lenalidomide has been shown to selectively inhibit the abnormal clone by increasing apoptosis of del(5q) cells.
Lenalidomide binds directly to cereblon protein, a component of the Cullin E3 ubiquitin ligase enzyme complex, which includes DNA damage-binding protein 1 (DDB1), Cullin 4 (CUL4), and regulator of cullin 1 (Roc1). In the presence of lenalidomide, cereblon binds to substrate proteins Aiolos and Ikaros, which are lymphoid transcription factors, leading to their ubiquitination and subsequent degradation, resulting in cytotoxic and immunomodulatory effects.
Pharmacokinetics
Lenalidomide 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 0.1N HCl buffer solution.
Absorption
Lenalidomide is rapidly absorbed after oral administration under fasting conditions in healthy volunteers, with peak plasma concentration (Cmax) reached within 0.5 to 2 hours after dosing. In patients as well as in healthy volunteers, Cmax and area under the plasma concentration-time curve (AUC) increase proportionally with dose. Repeated administration does not result in significant accumulation of the drug. In plasma, the relative exposure of S- and R-enantiomers of lenalidomide is approximately 56% and 44%, respectively.
Concomitant intake with a high-fat, high-calorie meal reduces the extent of drug absorption, resulting in approximately a 20% decrease in AUC and a 50% reduction in Cmax in plasma. However, in the main pre-registration clinical trials in multiple myeloma and myelodysplastic syndrome, where the efficacy and safety of lenalidomide were established, the drug was administered without regard to food intake. Therefore, lenalidomide can be administered independently of food.
Population pharmacokinetic analysis indicates that the rate of absorption following oral administration of lenalidomide is similar in patients with multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma.
Distribution
In vitro, binding of (14C)-lenalidomide to plasma proteins in patients with multiple myeloma and in healthy volunteers is low, averaging 23% and 29%, respectively.
Lenalidomide is present in human semen (< 0.01% of dose) after administration at 25 mg per day and is not detectable 3 days after discontinuation of the drug (see section "Special Warnings and Precautions").
Metabolism and Elimination
Human metabolism study data based on in vitro findings demonstrate that cytochrome P450 isoenzymes are not involved in the metabolism of lenalidomide; therefore, pharmacokinetic interactions with drugs that inhibit cytochrome P450 isoenzymes are unlikely. In vitro studies show no inhibitory effect of lenalidomide on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A, or UGT1A1 isoenzymes. Thus, lenalidomide is unlikely to cause any clinically significant drug-drug interactions when coadministered with substrates of these enzymes.
According to in vitro study data, 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 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.
Most of lenalidomide is excreted in urine. Renal excretion accounts for 90% of total clearance in patients with normal renal function, and 4% of lenalidomide is excreted in feces.
Lenalidomide is minimally metabolized in the body; 82% of the dose is excreted unchanged in urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide account for 4.59% and 1.83% of total excretion, respectively. Renal clearance of lenalidomide exceeds the glomerular filtration rate, indicating active secretion.
At doses of 5 to 25 mg per day, the plasma elimination half-life is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndrome, or mantle cell lymphoma.
Elderly Patients
No specific clinical studies have been conducted to evaluate pharmacokinetics in elderly patients. Population pharmacokinetic analysis included patients aged 39 to 85 years. Results indicate that age does not affect lenalidomide clearance (plasma exposure). Due to the increased likelihood of impaired renal function in elderly patients, caution should be exercised in dose selection, and careful monitoring of renal function during therapy is recommended.
Patients with Renal Impairment
The pharmacokinetics of lenalidomide have been studied in patients with renal impairment due to non-malignant conditions. In this study, two methods were used to classify renal function: measurement of creatinine clearance (CrCl) in 24-hour urine and estimation of CrCl using the Cockcroft-Gault formula. Results show that with decreasing renal function (< 50 mL/min), total lenalidomide clearance decreases proportionally, leading to increased AUC.
AUC was increased approximately 2.5-, 4-, and 5-fold in patients with moderate, severe, and end-stage renal disease, respectively, compared to the group combining patients with normal renal function and those with mild renal impairment. The elimination half-life of lenalidomide increased from approximately 3.5 hours in patients with CrCl > 50 mL/min to more than 9 hours in patients with reduced renal function (CrCl < 50 mL/min). However, renal impairment does not alter the oral absorption of lenalidomide. Cmax was similar in healthy volunteers and patients with renal impairment. Approximately 30% of the drug is removed during a single 4-hour hemodialysis session. Recommended dose adjustments for patients with renal impairment are described in the section "Dosage and Administration."
Patients with Hepatic Impairment
Population pharmacokinetic analysis included patients with mild hepatic impairment (N=16, total bilirubin >1 to ≤1.5 x ULN (upper limit of normal) or AST > ULN). Results indicate that mild hepatic impairment does not affect lenalidomide clearance (plasma exposure). There are no available data on the use of the drug in patients with moderate to severe hepatic impairment.
Other Intrinsic Factors
Population pharmacokinetic analysis demonstrated that body weight (33–135 kg), sex, race, and type of hematologic malignancy (multiple myeloma, myelodysplastic syndrome, or mantle cell lymphoma) have no clinically significant effect on lenalidomide clearance in adult patients.
Clinical characteristics.
Indications.
Multiple myeloma
As monotherapy, the medicinal product Lenangio is indicated for maintenance treatment in adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation.
The medicinal product Lenangio in combination therapy is indicated for the treatment of adult patients with previously untreated multiple myeloma who are ineligible for transplantation.
Lenangio in combination with dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior line of therapy.
Myelodysplastic syndromes
As monotherapy, the medicinal product Lenangio is indicated for the treatment of adult patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with the cytogenetic abnormality of isolated deletion 5q, when other treatment options are insufficient or unacceptable.
Mantle cell lymphoma
As monotherapy, the medicinal product Lenangio is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma.
Follicular lymphoma
The medicinal product Lenangio in combination with rituximab (anti-CD20 antibody) is indicated for the treatment of adult patients with previously treated follicular lymphoma (stage 1–3a).
Contraindications.
- Hypersensitivity to the active substance or to any of the excipients of the medicinal product (see section "Composition");
- Pregnancy;
- Reproductive age in women, except for those who comply with all requirements of the "Pregnancy Prevention Programme" (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
Special precautions.
Pregnancy
Lenalidomide is a structural analogue of thalidomide. Thalidomide is a known human teratogen that may cause severe, life-threatening birth defects or fetal death.
Preclinical studies of lenalidomide in primates showed results similar to those described for thalidomide (see section "Use during pregnancy or breastfeeding"). Teratogenic effects are expected if lenalidomide is taken during pregnancy.
All female patients must comply with the requirements of the Pregnancy Prevention Programme, unless there is reliable evidence that the patient has no reproductive potential.
Criteria for women without reproductive potential
A female patient or a female partner of a male patient is considered to have no reproductive potential unless she meets at least one of the following criteria:
- Age ≥ 50 years and, accordingly, has amenorrhea ≥ 1 year*;
- Premature ovarian failure confirmed by a specialist gynecologist;
- Previous bilateral salpingo-oophorectomy or hysterectomy;
- Genotype XY, Turner syndrome, or uterine agenesis.
* Amenorrhea following cancer treatment or during lactation does not exclude the presence of reproductive potential.
Counselling
The use of lenalidomide in women with preserved reproductive potential is contraindicated except when all the following conditions are met:
Woman:
- Understands the potential teratogenic effect of the drug on the fetus;
- Understands the necessity of continuous use of effective contraception methods starting 4 weeks before treatment initiation, throughout the entire treatment course, and for 4 weeks after discontinuation of lenalidomide;
- With reproductive potential, even if amenorrheic, must comply with all recommendations regarding effective contraception;
- Must be able to adhere to effective contraceptive measures;
- Must be informed and understand the possible consequences of pregnancy and the need for immediate consultation if there is a risk of becoming pregnant;
- Understands the necessity to initiate lenalidomide treatment immediately after a negative pregnancy test;
- Understands and agrees to undergo pregnancy testing every 4 weeks, except in cases of confirmed tubal sterilization;
- Acknowledges that she understands the risks and the necessity of preventive measures associated with the use of lenalidomide.
Regarding men taking lenalidomide, pharmacokinetic data have shown that lenalidomide is present in semen at very low levels during treatment and is undetectable in healthy men within 3 days after treatment discontinuation.
As a precautionary measure, all male patients taking lenalidomide must meet the following requirements.
Man:
- Must understand the expected teratogenic risk associated with sexual intercourse with a pregnant woman or a woman of reproductive potential;
- Must always understand the necessity of using a condom during sexual intercourse with a pregnant woman or a woman of reproductive potential not using effective contraception methods during treatment and for 4 weeks after discontinuation (even if the man has undergone vasectomy); male patients taking lenalidomide must not donate semen for 4 weeks after discontinuation of the drug;
- Must understand that if his partner becomes pregnant while he is taking lenalidomide or immediately after stopping it, he must immediately inform his physician; it is also recommended to refer the female partner to a physician specializing in or experienced in teratology for risk assessment and recommendations.
The prescribing physician must ensure that women with reproductive potential:
- Comply with the requirements of the Pregnancy Prevention Programme, including confirmation that they properly understand the issue;
- Acknowledge the above-mentioned conditions.
Contraception
Women with preserved reproductive potential must use one effective method of contraception for 4 weeks before starting treatment, during the entire treatment course, and for 4 weeks after treatment discontinuation with lenalidomide, even in case of temporary interruption of therapy, except when the patient confirms absolute and continuous abstinence from the drug for one month. If effective contraception is not achieved, the patient should be referred to a qualified healthcare provider for counseling on effective contraception to initiate it.
Acceptable methods of contraception include:
- Implants;
- Intrauterine levonorgestrel-releasing system (IUD);
- Medicinal products containing medroxyprogesterone acetate;
- Tubal sterilization;
- Partner's vasectomy (vasectomy must be confirmed by two negative semen analyses);
- Progesterone-containing oral contraceptives that suppress ovulation (desogestrel).
The use of combined oral contraceptives is not recommended in patients with multiple myeloma receiving lenalidomide as part of combination therapy, and to a lesser extent in patients with multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma receiving lenalidomide as monotherapy, due to an increased risk of venous thromboembolism. If a patient is currently using combined oral contraceptives, she should switch to one of the methods listed above. The risk of venous thromboembolism persists for 4–6 weeks after discontinuation of combined oral contraceptives. The effectiveness of hormonal contraceptives may be reduced when used concomitantly with dexamethasone (see section "Interaction with other medicinal products and other types of interactions").
The use of implants and intrauterine levonorgestrel-releasing systems is associated with an increased risk of infection during insertion and irregular vaginal bleeding. Patients, especially those with neutropenia, should carefully consider prophylactic antibiotic use.
Copper-containing IUDs are generally not recommended due to the potential risk of infection during insertion and menstrual bleeding, which may worsen the condition of patients with neutropenia or thrombocytopenia.
Pregnancy testing
According to local practice, pregnancy testing in women with reproductive potential must be performed under medical supervision as specified below. The minimum sensitivity of the test should be 25 mIU/mL. This requirement applies also to women of reproductive age practicing absolute and continuous abstinence. Pregnancy testing, prescription issuance, and drug dispensing must occur on the same day. Lenalidomide dispensing to women of reproductive age must occur within 7 days after prescription issuance.
Before starting treatment
Pregnancy testing must be performed under medical supervision during the consultation when lenalidomide has already been prescribed, or within 3 days before visiting the prescribing physician, if the patient has used effective contraception methods for at least the last 4 weeks. When starting lenalidomide treatment, the pregnancy test must confirm that the woman is not pregnant.
Subsequent and end of treatment
Pregnancy testing should be repeated under medical supervision every 4 weeks, including 4 weeks after treatment completion, except in cases of confirmed tubal sterilization. The pregnancy test should be performed on the day of prescription or within 3 days before visiting the prescribing physician.
Interaction with other medicinal products and other types of interactions.
Erythropoiesis-stimulating agents or other agents that may increase the risk of thrombosis (e.g., hormone replacement therapy) should be used with caution in patients with multiple myeloma receiving lenalidomide and dexamethasone (see sections "Special precautions" and "Adverse reactions").
Oral contraceptives
No drug interaction studies with oral contraceptives have been conducted. Lenalidomide is not an enzyme inducer. In vitro studies on human hepatocytes showed that lenalidomide, at various tested concentrations, does not induce cytochromes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5. Therefore, when lenalidomide is used alone, induction leading to reduced efficacy of drugs, including hormonal contraceptives, is not expected. However, dexamethasone is known to be a weak or moderate inducer of CYP3A4 and likely affects other enzymes and transporters as well. A reduction in the effectiveness of oral contraception during treatment cannot be excluded. To effectively prevent pregnancy, methods specified in the Pregnancy Prevention Programme must be used (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
Warfarin
Multiple doses of lenalidomide 10 mg do not affect the pharmacokinetics of a single dose of R- and S-warfarin. A single dose of 25 mg warfarin does not affect the pharmacokinetics of lenalidomide. However, it is unknown whether there is an interaction in clinical use (concomitant therapy with dexamethasone). Dexamethasone is a weak or moderate enzyme inducer; its effect on warfarin is unknown. Close monitoring of warfarin concentration is recommended during treatment.
Digoxin
Concomitant administration of lenalidomide 10 mg daily with digoxin increases digoxin plasma levels (0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%–28.2%]. It is unknown whether the effect would differ during clinical use (higher doses of lenalidomide in combination with dexamethasone). Therefore, monitoring of digoxin concentration is recommended during lenalidomide treatment.
Statins
There is an increased risk of rhabdomyolysis when statins are used with lenalidomide. Therefore, close clinical and laboratory monitoring is recommended during the first weeks of treatment.
Dexamethasone
Concomitant administration of one or multiple doses of dexamethasone (40 mg once daily) has no clinically significant effect on the pharmacokinetics of multiple doses of lenalidomide (25 mg daily).
Interaction with P-glycoprotein (P-gp) inhibitors
Lenalidomide is a substrate of P-gp, but not its inhibitor, in vitro. Concomitant administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) does not show a clinically significant effect on the pharmacokinetics of lenalidomide (25 mg daily). Concomitant administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.
Special precautions.
Additional warnings
Patients must not give this medicinal product to others; unused capsules should be returned to the healthcare facility after completion of treatment for safe disposal.
Patients should not donate blood during treatment and for 1 week after discontinuation of lenalidomide.
Healthcare professionals and caregivers handling the blister pack or capsules must wear disposable gloves.
Pregnant women or women who suspect they may be pregnant must not touch the blister pack or capsules.
Educational materials, prescribing and dispensing restrictions
To help patients prevent fetal exposure to lenalidomide, the marketing authorization holder must provide healthcare professionals with educational materials containing information to reinforce the warning regarding the expected teratogenic effect of lenalidomide, recommendations for contraception prior to initiating therapy, and the necessity of pregnancy testing. The physician must inform both male and female patients about the teratogenic risk of lenalidomide and the strict measures to prevent pregnancy, as outlined in the Pregnancy Prevention Programme (see sections "Special safety measures" and "Use during pregnancy or breastfeeding"), and must provide the patient with an educational brochure and a patient card and/or equivalent document according to the implemented national patient card system. A national controlled distribution system has been established in cooperation with each national competent authority. The controlled distribution system includes the use of a patient card and/or equivalent document to monitor prescribing and/or dispensing, and collection of detailed prescription data to enable thorough national monitoring of off-label use of the medicinal product. Ideally, pregnancy testing, treatment initiation, and dispensing of the medicinal product should occur on the same day. Dispensing of lenalidomide to women of reproductive potential must occur within 7 days of treatment initiation and a negative pregnancy test result. Dispensing of the medicinal product to women of childbearing potential 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
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and during the first 12 months of treatment when used in combination with dexamethasone. Close monitoring is required for patients with known risk factors, including history of thrombosis, and preventive measures should be taken to minimize all modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipidemia).
Venous and arterial thromboembolism
In patients with multiple myeloma, combination therapy with lenalidomide and dexamethasone is associated with an increased risk of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (mainly myocardial infarction and cerebrovascular events), which is less pronounced with lenalidomide in combination with melphalan and prednisolone (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). In patients with myelodysplastic syndromes, mantle cell lymphoma, and multiple myeloma, monotherapy with lenalidomide has been associated with a risk of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), but to a lesser extent than in patients with multiple myeloma treated with lenalidomide as part of combination therapy. The risk of arterial thromboembolic complications in patients with multiple myeloma is lower with lenalidomide monotherapy than with combination therapy. Therefore, close monitoring is required for patients with known risk factors for thromboembolism, including a history of thrombosis. Preventive measures should be taken to minimize all modifiable risk factors (e.g., smoking, arterial hypertension, hyperlipid游戏副本
Method of Administration and Dosage
Treatment should be administered under the supervision of a physician experienced in the use of anticancer therapies.
For all indications listed below:
- the dose should be modified based on clinical and laboratory assessments (see sections "Special Precautions" and "Special Instructions for Use");
- for dose adjustment during treatment and re-treatment, thrombocytopenia grade III–IV, neutropenia, or any other toxicity of grade III or IV considered related to lenalidomide should be taken into account;
- in case of neutropenia, consideration should be given to the use of growth factors in patient management;
- if less than 12 hours has passed since a missed dose, the patient may take the dose; if more than 12 hours have passed since the missed dose, the patient should not take the missed dose and should take the next dose at the scheduled time on the following day.
Method of Administration
Oral administration. Lenalidomide capsules should be taken at the same time each day according to the prescribed schedule. Capsules must not be opened, crushed, or chewed. Capsules should be swallowed whole, preferably with water, independent of food intake. 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.
Dosage
Newly Diagnosed Multiple Myeloma
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 following ASCT in patients without evidence of disease progression. Lenalidomide treatment should not be initiated if the absolute neutrophil count (ANC) is <1.0 × 10⁹/L and/or platelet count is <75 × 10⁹/L.
Recommended Dose
The recommended initial dose of lenalidomide is 10 mg orally once daily, continuously (days 1 to 28 of repeated 28-day cycles), administered until disease progression or until unacceptable toxicity occurs. After 3 cycles of lenalidomide maintenance therapy, the dose may be increased to 15 mg orally once daily, provided tolerability is good.
Dose Reduction Recommendations
| Initial dose (10 mg) |
If dose was increased (15 mg)a |
|
| Dose level 1 |
5 mg |
10 mg |
| Dose level 2 |
5 mg (days 1–21 every 28 days) |
5 mg |
| Dose level 3 |
not applicable |
5 mg (days 1–21 every 28 days) |
| dosing not less than 5 mg (days 1–21 every 28 days) |
||
a After 3 treatment cycles with lenalidomide, the dose may be increased to 15 mg orally once daily, provided it is well tolerated.
Thrombocytopenia
| Platelets |
Recommended course |
| When decreased to < 30 x 109/l |
Discontinue lenalidomide treatment |
| When recovered to ≥ 30 x 109/l |
Resume lenalidomide at dose level 1, taken once daily |
| With each subsequent decrease below 30 x 109/l |
Discontinue lenalidomide treatment |
| When recovered to ≥ 30 x 109/l |
Resume lenalidomide at the next lower dose level, once daily |
Neutropenia
| Neutrophils |
Recommended course* |
| When decreased to < 0.5 x 109/l |
Discontinue lenalidomide treatment |
| When recovered to ≥ 0.5 x 109/l |
Resume lenalidomide at dose level 1, taken once daily |
| With each subsequent decrease below 0.5 x 109/l |
Discontinue lenalidomide treatment |
| When recovered to ≥ 0.5 x 109/l |
Resume lenalidomide at the next lower dose level, once daily |
* At the physician's discretion, if neutropenia is the only toxicity at any dose level, granulocyte colony-stimulating factor (G-CSF) should be added to treatment and the lenalidomide dose level maintained.
Lenangio in combination with dexamethasone until disease progression in patients not eligible for transplantation
Treatment with lenalidomide must not be initiated if ANC is less than 1.0 x 10⁹/L and/or platelet count is less than 50 x 10⁹/L.
Recommended dose
The recommended initial dose of Lenangio 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 Lenangio and dexamethasone until disease progression or until signs of intolerance occur. The dosing regimen is continued or modified based on clinical and laboratory findings. For patients aged 75 years and older, the initial dose of dexamethasone is 20 mg daily on days 1, 8, 15, and 22 of each 28-day cycle. The recommended dose of Lenangio in patients with moderate renal impairment is 10 mg once daily.
Dose modification recommendations during treatment or upon re-initiation
The dose modifications outlined below are recommended for managing grade III-IV thrombocytopenia, neutropenia, or other grade III-IV toxicities related to lenalidomide.
Dose reduction steps
| Lenalidomide* |
Dexamethasone* |
|
| Initial dose |
25 mg |
40 mg |
| Dose level 1 |
20 mg |
20 mg |
| Dose level 2 |
15 mg |
12 mg |
| Dose level 3 |
10 mg |
8 mg |
| Dose level 4 |
5 mg |
4 mg |
| Dose level 5 |
2.5 mg** |
not applicable |
* - Dose reduction for both drugs can be applied independently.
** - If a dose of 2.5 mg is required, use the drug in the appropriate dosage formulation.
Thrombocytopenia
| Platelet count |
Recommended course |
| Decreased to 25 x 109/litre |
Discontinue treatment until the end of the cycle* |
| Recovered to ≥ 50 x 109/litre |
Reduce dose level by one level when resuming treatment during the next cycle |
- If dose-limiting toxicity (DLT) occurs by day 15 of the cycle, drug administration should be discontinued for at least the remainder of the current 28-day cycle.
Neutropenia
| Neutrophil count |
Recommended course |
| Decreased for the first time to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 1 x 109/litre, when neutropenia is the only toxicity manifestation |
Resume lenalidomide at the initial dose once daily |
| Recovered to ≥ 0.5 x 109/litre, when dose-dependent hematologic toxicity other than neutropenia is observed |
Resume lenalidomide at the next lower dose level once daily |
| At each subsequent decrease to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre |
Resume lenalidomide at the next lower dose level once daily |
In case of neutropenia, consider administering growth factor agents to the patient.
If the dose of lenalidomide has been reduced due to hematologic DLT, lenalidomide administration may be resumed at the next higher dose level (up to the starting dose) at the discretion of the treating physician, provided that continued treatment with lenalidomide/dexamethasone has led to improvement in bone marrow function (absence of DLT during at least two consecutive cycles, and ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L at the start of a new cycle at the current dose level).
Lenalidomide in combination with melphalan and prednisolone followed by maintenance monotherapy in transplant-ineligible patients
Treatment with lenalidomide must not be initiated if ANC < 1.5 x 109/L and/or platelets < 75 x 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 up to 9 cycles, melphalan 0.18 mg/kg orally on days 1 to 4 of each 28-day cycle, and prednisolone 2 mg/kg orally on days 1 to 4 of each 28-day cycle. Patients who have completed 9 cycles of treatment or who are unable to complete combination therapy due to drug intolerance should continue treatment with lenalidomide monotherapy at a dose of 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles until disease progression. The dosing regimen is continued or modified based on clinical and laboratory findings.
Dose adjustment recommendations during treatment or upon re-initiation
The dose adjustments outlined below are recommended for managing grade III-IV thrombocytopenia, neutropenia, or other grade III-IV toxicities considered related to lenalidomide.
Dose reduction steps
| Lenalidomide* |
Melphalan |
Prednisolone |
|
| Initial dose |
10 mg** |
0.18 mg/kg |
2 mg/kg |
| Dose level 1 |
7.5 mg |
0.14 mg/kg |
1 mg/kg |
| Dose level 2 |
5 mg |
0.10 mg/kg |
0.5 mg/kg |
| Dose level 3 |
2.5 mg |
not applicable |
0.25 mg/kg |
* - If doses of 2.5 mg or 7.5 mg are required, use the drug at the corresponding dosage strength.
** - If neutropenia is the only manifestation of toxicity at any dose level, add G-CSF to the treatment regimen and maintain the lenalidomide dose level.
Thrombocytopenia
| Platelet count |
Recommended action |
| First decreased to < 25 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 25 x 109/litre |
Resume lenalidomide and melphalan at dose level 1 |
| With each subsequent decrease to < 30 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 30 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2 or 3) once daily |
Neutropenia
| Neutrophil count |
Recommended course |
| First decreased to < 0.5 x 109/litre* |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre, when neutropenia is the only manifestation of toxicity |
Resume lenalidomide at the initial dose once daily |
| Recovered to ≥ 0.5 x 109/litre, when dose-dependent hematologic toxicity other than neutropenia is observed |
Resume lenalidomide at dose level 1, once daily |
| At each subsequent decrease to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre |
Resume lenalidomide at the next lower dose level once daily |
* If the patient is not receiving G-CSF therapy, it should be initiated. On day 1 of the next cycle, continue G-CSF treatment if needed and maintain the melphalan dose if neutropenia was the only manifestation of DLT. Otherwise, reduce the dose level at the start of the next cycle.
In case of neutropenia, consider administering growth factor agents to the patient.
Multiple myeloma with at least one prior line of therapy
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, followed by 40 mg once daily on days 1 to 4 every 28 days. The dosing regimen should be continued or modified based on clinical and laboratory findings. The treating physician should carefully evaluate the appropriate dexamethasone dose considering the patient's condition and disease status.
Lenalidomide treatment must not be initiated if ANC < 1.0 x 10⁹/liter and/or platelets < 75 x 10⁹/liter, or, depending on bone marrow infiltration by plasma cells, platelets < 30 x 10⁹/liter.
Recommended dose modifications during treatment or upon reinitiation
The dose modifications outlined below are recommended for managing grade III-IV neutropenia or thrombocytopenia, or other grade III-IV toxicities considered related to lenalidomide administration.
Dose reduction steps
| Initial dose |
25 mg |
| Dose level 1 |
15 mg |
| Dose level 2 |
10 mg |
| Dose level 3 |
5 mg |
Thrombocytopenia
| Platelet count |
Recommended course |
| First decreased to < 30 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 30 x 109/litre |
Resume lenalidomide at dose level 1 |
| With each subsequent decrease to < 30 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 30 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2 or 3) once daily. Do not take less than 5 mg once daily. |
Neutropenia
| Neutrophil count |
Recommended course |
| First decreased to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre, when neutropenia is the only manifestation of toxicity |
Resume lenalidomide at the initial dose of 1 time daily |
| Recovered to ≥ 0.5 x 109/litre, when dose-dependent haematotoxicity other than neutropenia is observed |
Resume lenalidomide at dose level 1, take 1 time daily |
| At each subsequent decrease to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1, 2 or 3), 1 time daily. Do not take less than 5 mg 1 time daily. |
In case of neutropenia, the use of growth factor agents should be considered for the patient.
Myelodysplastic syndromes
Treatment with lenalidomide must not be initiated if ANC < 0.5 x 109/L and/or platelets < 25 x 109/L.
Recommended dose
The recommended starting dose of lenalidomide is 10 mg orally once daily on days 1 to 21 of repeated 28-day cycles. The dosing regimen should continue or be modified based on clinical and laboratory findings.
Recommended dose adjustments during treatment or upon re-initiation
The dose adjustments outlined below are recommended to manage grade III-IV neutropenia or thrombocytopenia, or other grade III-IV toxicities considered related to lenalidomide.
Dose reduction steps*
| Initial dose |
10 mg once daily on days 1 to 21 of every 28-day cycle |
| Dose level 1 |
5.0 mg once daily on days 1 to 28 of every 28-day cycle |
| Dose level 2 |
2.5 mg once daily on days 1 to 28 of every 28-day cycle |
| Dose level 3 |
2.5 mg every other day on days 1 to 28 of every 28-day cycle |
* If necessary, use doses of 2.5 mg by administering the drug at the corresponding dosage strength.
For patients who initially received 10 mg and in whom thrombocytopenia or neutropenia was observed.
Thrombocytopenia
| Platelet count |
Recommended course of action |
| Decreased to < 25 x 109/liter |
Discontinue lenalidomide treatment |
| Recovered to ≥ 25 x 109/liter - < 50 x 109/liter at least twice over ≥ 7 days or platelet count recovered to ≥ 50 x 109/liter at any time |
Resume lenalidomide at the next lower dose level (dose level 1, 2 or 3) |
Neutropenia
| Neutrophil count |
Recommended course |
| Decreased below 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 0.5 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1, 2 or 3) |
Discontinuation of lenalidomide
Patients who have not demonstrated at least minor erythroid responses within 4 months after initiation of therapy, defined as at least a 50% reduction in red blood cell transfusion requirements or, if not transfused, an increase in hemoglobin of 1 g/dL, should discontinue treatment with lenalidomide.
Mantle cell lymphoma
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 dosing regimen should be continued or modified based on clinical and laboratory findings.
Dose modification recommendations during treatment or upon re-initiation
The dose modifications outlined below are recommended for managing neutropenia or thrombocytopenia or other grade III–IV toxicities considered related to lenalidomide.
Dose reduction steps*
| Initial dose |
25 mg once daily on days 1 to 21 of each 28-day cycle |
| Dose level 1 |
20 mg once daily on days 1 to 21 of each 28-day cycle |
| Dose level 2 |
15 mg once daily on days 1 to 21 of each 28-day cycle |
| Dose level 3 |
10 mg once daily on days 1 to 21 of each 28-day cycle |
| Dose level 4 |
5 mg once daily on days 1 to 21 of each 28-day cycle |
| Dose level 5 |
2.5 mg once daily on days 1 to 21 of each 28-day cycle 5 mg every other day on days 1 to 21 of each 28-day cycle |
- If necessary, use the 2.5 mg dose of the drug as appropriate.
Thrombocytopenia
| Platelet count |
Recommended course of action |
| Decreased below 50 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 60 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1) |
| With each subsequent decrease below 50 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 60 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2, 3, 4 or 5). Dose – no lower than dose level 5 |
Neutropenia
| Neutrophil count |
Recommended action |
| Decreased to < 1 x 109/litre for at least 7 days, or Decreased to < 1 x 109/litre with concomitant fever (body temperature ≥ 38.5 °C) or decreased to < 0.5 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 1 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1) |
| With each subsequent decrease to < 1 x 109/litre for at least 7 days, or decrease to < 1 x 109/litre with concomitant fever (body temperature ≥ 38.5 °C), or decrease to < 0.5 x 109/litre |
Discontinue lenalidomide treatment |
| Recovered to ≥ 1 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2, 3, 4 or 5). Dose should not be lower than dose level 5 |
Follicular lymphoma
Treatment with lenalidomide must not be initiated if ANC < 1 x 109/L and/or platelet count < 50 x 109/L, except in cases where these values are secondary to lymphoma infiltration of the bone marrow.
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 (IV) weekly during cycle 1 (on days 1, 8, 15, and 22) and during cycles 2–5 on day 1 of each 28-day cycle.
Dose reduction steps
| Initial dose |
20 mg once daily on days 1 to 21 of every 28-day cycle |
| Dose level 1 |
15 mg once daily on days 1 to 21 of every 28-day cycle |
| Dose level 2 |
10 mg once daily on days 1 to 21 of every 28-day cycle |
| Dose level 3 |
5 mg once daily on days 1 to 21 of every 28-day cycle |
For dose adjustment due to rituximab toxicity, refer to the appropriate medical instructions for the medicinal product.
Trombocytopenia
| Platelet count |
Recommended course of action |
| Decreased to < 50 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 50 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1) |
| With each subsequent decrease below 50 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 50 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2 or 3). |
Neutropenia
| Neutrophil count |
Recommended action |
| Decreased to < 1 x 109/litre for at least 7 days, or Decreased to < 1 x 109/litre with accompanying fever (body temperature ≥ 38.5 °C) or decreased to < 0.5 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 1 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 1) |
| With each subsequent decrease below 1 x 109/litre for at least 7 days, or decrease to < 1 x 109/litre with accompanying fever (body temperature ≥ 38.5 °C), or decrease to < 0.5 x 109/litre |
Discontinue lenalidomide treatment and perform complete blood counts at least every 7 days |
| Recovered to ≥ 1 x 109/litre |
Resume lenalidomide at the next lower dose level (dose level 2 or 3). Dose should not be lower than dose level 3 |
a. At the physician's discretion, if neutropenia is the only toxicity at any dose level, add G-CSF.
Mantle cell lymphoma (MCL) or follicular lymphoma
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 hydration (orally) during the first week of the first cycle or for a longer period if clinically indicated. To monitor for TLS, patients should undergo weekly blood biochemistry testing during the first cycle and as clinically indicated.
Lenalidomide treatment may be continued (at maintenance dose) in patients with laboratory TLS or clinical Grade I TLS, 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 resolved. Rasburicase may be required to manage hyperuricemia. Hospitalization is at the physician’s discretion.
In patients with clinical TLS Grade II to IV, lenalidomide should be discontinued, and weekly blood biochemistry tests should be performed or conducted as clinically indicated. Intensive intravenous hydration and appropriate medical support should be provided according to local treatment standards until electrolyte imbalances are resolved. The use of rasburicase and hospitalization are at the physician’s discretion. After TLS has resolved to Grade 0, lenalidomide treatment may be resumed at a reduced dose, as determined by the physician.
Tumor flare reaction
Patients with Grade I–II tumor flare reaction (TFR) may continue lenalidomide without interruption or dose modification, at the physician’s discretion. The physician may prescribe therapy with NSAIDs, short-acting corticosteroids, and/or narcotic analgesics.
In patients with Grade III–IV TFR, lenalidomide should be discontinued and treatment initiated with NSAIDs, short-acting 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–II TFR.
All indications
In cases of Grade III or IV toxicity considered related to lenalidomide, treatment should be discontinued. It may be resumed, at the physician’s discretion, only at the next lower dose level once toxicity has resolved to ≤ Grade II.
For Grade II–III skin rashes, lenalidomide administration should be interrupted or withheld. Lenalidomide treatment should be permanently discontinued in cases of angioedema, Grade IV rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or DRESS syndrome is suspected. Treatment should not be restarted after resolution of these reactions.
Special patient populations
Elderly patients
Lenalidomide has been used in clinical trials in patients with multiple myeloma up to 91 years of age, in patients with myelodysplastic syndrome up to 95 years of age, and in patients with mantle cell lymphoma up to 88 years of age. Since elderly patients are more likely to have reduced renal function, a cautious approach to dose selection is recommended, and monitoring of renal function should be considered.
Newly diagnosed multiple myeloma: transplant-ineligible patients
In patients aged 75 years and older with newly diagnosed multiple myeloma receiving lenalidomide, there was a higher incidence of new serious adverse reactions and adverse reactions leading to treatment discontinuation. A careful assessment of patients aged 75 years and older with newly diagnosed multiple myeloma is recommended prior to initiating treatment.
For patients aged 75 years and older receiving lenalidomide in combination with dexamethasone, the starting dose of dexamethasone is 20 mg 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. However, patients aged 75 years and older receiving lenalidomide have an increased risk of serious adverse reactions that may lead to treatment discontinuation.
In clinical studies of newly diagnosed myeloma in transplant-ineligible patients, the combination therapy with lenalidomide was less well tolerated in patients aged 75 years and older compared to younger patients. Discontinuation of the drug occurred at a higher rate due to intolerance (Grade III–IV adverse reactions and serious adverse reactions) in elderly patients compared to younger patients (under 75 years of age).
Multiple myeloma with at least one prior therapy
The proportion of patients with multiple myeloma aged 65 years and older did not differ significantly between groups receiving lenalidomide plus dexamethasone or placebo plus dexamethasone. No differences in safety and efficacy profiles were observed between these and younger patients, although increased susceptibility in elderly individuals cannot be ruled out.
Myelodysplastic syndromes
For patients with myelodysplastic syndromes receiving lenalidomide, there were no differences in safety and efficacy between patients aged 65 years and older and younger patients.
Since elderly patients are more likely to have reduced renal function, careful dose selection is required. Monitoring of renal function in these patients is also recommended.
Mantle cell lymphoma
For patients with mantle cell lymphoma receiving lenalidomide, no differences in safety and efficacy were observed between patients aged 65 years and older and younger patients.
Since elderly patients are more likely to have reduced renal function, careful dose selection is required, and monitoring of renal function is recommended in these patients.
Follicular lymphoma
In patients with follicular lymphoma receiving lenalidomide in combination with rituximab, the overall frequency of adverse reactions was similar in patients aged 65 years and older compared to younger patients. No overall differences in efficacy were observed between the two age groups.
Patients with renal impairment
Lenalidomide is primarily eliminated via the kidneys; patients with more severe renal impairment may tolerate treatment less well. Caution is advised in dose selection, and monitoring of renal function is recommended.
Dose adjustment is not required for patients with mild renal impairment and multiple myeloma, myelodysplastic syndrome, mantle cell lymphoma, or follicular lymphoma. The following dose adjustments are recommended at the start of treatment and during therapy for patients with moderate or severe renal impairment or for patients with end-stage renal disease (ESRD).
There are no data from Phase III clinical trials in patients with ESRD (creatinine clearance < 30 mL/min requiring dialysis).
Multiple myeloma
| Renal function (CrCl) |
Dose adjustment (from day 1 to day 21 of a 28-day cycle) |
| Moderate renal impairment (30 ≤ CrCl < 50 mL/min) |
10 mg once daily1 |
| Severe renal impairment (CrCl < 30 mL/min, dialysis not required) |
7.5 mg once daily2 15 mg every other day |
| ESRD (CrCl < 30 mL/min, dialysis required) |
5 mg once daily. On dialysis days, the drug should be administered after dialysis. |
1 - The dose 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 case of necessity to use 7.5 mg doses – administer the medicinal product at the corresponding dosage strength.
Myelodysplastic syndromes^
| Renal function (CLCR) |
Dose adjustments |
|
| Moderate renal impairment (30 ≤ CLCR < 50 mL/min) |
Initial dose |
5 mg once daily. (from day 1 to day 21 of a 28-day cycle) |
| Dosing level 1* |
2.5 mg once daily. (from day 1 to day 28 of a 28-day cycle) |
|
| Dosing level 2* |
2.5 mg every two days (from day 1 to day 28 of a 28-day cycle) |
|
| Severe renal impairment (CLCR < 30 mL/min, not on dialysis) |
Initial dose |
2.5 mg once daily. (from day 1 to day 21 of a 28-day cycle) |
| Dosing level 1* |
2.5 mg every other day (from day 1 to day 28 of a 28-day cycle) |
|
| Dosing level 2* |
2.5 mg twice weekly (from day 1 to day 28 of a 28-day cycle) |
|
| ESRD (CLCR < 30 mL/min, on dialysis) On dialysis days, the drug should be administered after dialysis. |
Initial dose |
2.5 mg once daily. (from day 1 to day 21 of a 28-day cycle) |
| Dosing level 1* |
2.5 mg every other day (from day 1 to day 28 of a 28-day cycle) |
|
| Dosing level 2* |
2.5 mg twice weekly (from day 1 to day 28 of a 28-day cycle) |
|
* - 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.
^ - If doses of 2.5 mg are required, administer the medicinal product at the corresponding dosage strength.
Mantle cell lymphoma
| Renal function (CrCl) |
Dose adjustment (from day 1 to day 21 of a 28-day cycle) |
| Moderate renal impairment (30 ≤ CrCl < 50 mL/min) |
10 mg once daily1 |
| Severe renal impairment (CrCl < 30 mL/min, dialysis not required) |
7.5 mg once daily2 15 mg every other day |
| End-stage renal disease (ESRD) (CrCl < 30 mL/min, dialysis required) |
5 mg once daily. On dialysis days, administration of the medicinal product should be scheduled after dialysis. |
1 - The dose 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 case it is necessary to use 7.5 mg doses – administer the medicinal product at the corresponding dosage strength.
Follicular lymphoma
| Renal function (CrCl) |
Dose adjustment (from day 1 to day 21 of a 28-day cycle) |
| Moderate renal impairment (30 ≤ CrCl < 50 mL/min) |
10 mg once daily1,2 |
| Severe renal impairment (CrCl < 30 mL/min, not on dialysis) |
5 mg once daily |
| ESRD (CrCl < 30 mL/min, on dialysis) |
5 mg once daily. On dialysis days, the drug should be administered after dialysis. |
1 - If the patient tolerated the therapy for 2 cycles, the dose may be increased to 15 mg once daily.
2 - For patients starting at a dose of 10 mg, in case of dose reduction due to grade III or IV neutropenia or thrombocytopenia, or other grade III or IV toxic effects. If a toxic effect related to lenalidomide develops, doses below 5 mg every other day or 2.5 mg once daily should not be administered.
After initiation of lenalidomide treatment, subsequent dose adjustments in patients with renal impairment should be based on individual patient tolerability as described above.
Patients with hepatic impairment
The use of lenalidomide has not been formally studied in patients with hepatic dysfunction, and there are no specific recommendations for dose selection.
Children
For safety reasons, lenalidomide should not be used in children and adolescents under 18 years of age.
Overdose
There are no specific data regarding lenalidomide overdose, although in dose-finding studies some patients received up to 150 mg, and in single-dose studies some patients received doses up to 400 mg. The dose-limiting toxicity in these studies was primarily hematological. In case of overdose, supportive therapy is recommended.
Adverse Reactions
Summary of Safety Profile
Newly diagnosed multiple myeloma: patients who underwent autologous stem cell transplantation and received lenalidomide maintenance therapy
Serious adverse reactions observed more frequently (≥5%) with lenalidomide maintenance therapy compared to placebo were:
- Pneumonia, pulmonary infection, upper respiratory tract infection, neutropenia, bronchitis, diarrhea, nasopharyngitis, muscle spasms, leukopenia, asthenia, cough, thrombocytopenia, rash, gastroenteritis and influenza-like illness, fatigue, leukopenia, anemia.
Newly diagnosed multiple myeloma in patients receiving lenalidomide in combination with low-dose dexamethasone
Severe adverse reactions observed more frequently (≥5%) with lenalidomide in combination with low-dose dexamethasone compared to melphalan, prednisone, and thalidomide (MPT) were pneumonia and renal failure. Adverse reactions observed more frequently: diarrhea, fatigue, back pain, asthenia, insomnia, rash, decreased appetite, cough, pyrexia, and muscle spasms.
Newly diagnosed multiple myeloma in transplant-ineligible patients receiving lenalidomide in combination with melphalan and prednisone
Severe adverse reactions observed more frequently (≥5%) with melphalan, prednisone, and lenalidomide (MPR), either followed by lenalidomide maintenance or MPR followed by placebo, compared to melphalan, prednisone, and placebo followed by placebo, were: febrile neutropenia, anemia.
- Adverse reactions observed more frequently: neutropenia, anemia, thrombocytopenia, leukopenia, constipation, diarrhea, rash, pyrexia, peripheral edema, cough, decreased appetite, and asthenia.
Multiple myeloma in patients with at least one prior therapy
- The most severe adverse reactions observed more frequently with the combination of lenalidomide and dexamethasone compared to placebo and dexamethasone were: venous thromboembolism (deep vein thrombosis, pulmonary embolism), grade IV neutropenia.
- Unfavorable adverse reactions occurred more frequently with the combination of lenalidomide and dexamethasone compared to placebo and dexamethasone: fatigue, neutropenia, constipation, diarrhea, muscle spasms, anemia, thrombocytopenia, and rash.
Myelodysplastic Syndromes
- The majority of adverse reactions were generally observed within the first 16 weeks of lenalidomide therapy. Serious adverse reactions included venous thromboembolism (deep vein thrombosis, pulmonary embolism); grade III–IV neutropenia, febrile neutropenia, and grade III–IV thrombocytopenia.
In patients receiving lenalidomide treatment, adverse reactions occurred more frequently compared to the control group: neutropenia, thrombocytopenia, diarrhea, constipation, nausea, pruritus, rash, fatigue, and muscle spasms.
Mantle Cell Lymphoma
Serious adverse reactions observed in the lenalidomide group compared to the control group were: neutropenia, pulmonary embolism, diarrhea.
Adverse reactions occurring more frequently in the lenalidomide group compared to the control group: neutropenia, anemia, diarrhea, fatigue, constipation, pyrexia, rash (including allergic dermatitis). Patients with high tumor burden at baseline are at increased risk of early mortality.
Follicular Lymphoma
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, pulmonary embolism, pneumonia.
The most common adverse reactions in the lenalidomide/rituximab group compared to the placebo/rituximab group (with a frequency difference of at least 2%) were: neutropenia, diarrhea, leukopenia, constipation, cough, and fatigue.
List of adverse reactions presented in tabular form
Adverse reactions observed in patients receiving lenalidomide treatment are listed below in Table 1 and classified by frequency and by system organ class. The frequency of the adverse reactions listed below was determined according to the following grading: 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).
Table 1 is derived from data collected during multiple myeloma monotherapy clinical trials.
Table 1
Adverse reactions observed in patients with multiple myeloma treated with lenalidomide as monotherapy
| System organ class/Preferred term |
All adverse reactions/Frequency |
Grade III-IV adverse reactions/Frequency |
| Infections and infestations |
Very common Pneumonia1,4, upper respiratory tract infections, neutropenic infections, bronchitis1, influenza1, gastroenteritis1, sinusitis, nasopharyngitis, rhinitis. Common Infections1, urinary tract infections1,2, lower respiratory tract infections, pulmonary infections |
Very common Pneumonia1,4, neutropenic infections, Common Sepsis1,5, bacteremia, pulmonary infections1, bacterial lower respiratory tract infections, bronchitis1, influenza1, gastroenteritis1, herpes zoster1, infections1 |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Common Myelodysplastic syndromes1,2 |
|
| Blood and lymphatic system disorders |
Very common Neutropenia3,1, febrile neutropenia3,1, thrombocytopenia3,1, anemia, leukopenia1, lymphopenia |
Very common Neutropenia3,1, febrile neutropenia3,1, thrombocytopenia3,1, anemia, leukopenia1, lymphopenia Common Pancytopenia1 |
| Metabolism and nutrition disorders |
Very common Hypokalemia |
Common: Hypokalemia, dehydration |
| Nervous system disorders |
Very common Paresthesia Common Peripheral neuropathy6 |
Common Headache |
| Vascular disorders |
Common Pulmonary embolism1,2 |
Common Deep vein thrombosis 3,1,7 |
| Respiratory, thoracic and mediastinal disorders |
Very common Cough Common Dyspnea1, rhinorrhea |
Common Dyspnea1 |
| Gastrointestinal disorders |
Very common Diarrhea, constipation, abdominal pain, nausea Common Vomiting, upper abdominal pain |
Common Diarrhea, vomiting, nausea |
| Hepatobiliary disorders |
Very common Abnormal liver function tests |
Common Abnormal liver function tests |
| Skin and subcutaneous tissue disorders |
Very common Rash, dry skin |
Common Rash, pruritus |
| Musculoskeletal and connective tissue disorders |
Very common Muscle spasms Common Myalgia, muscle pain, bone pain |
|
| General disorders and administration site conditions |
Very common Fatigue, asthenia, chills |
Common Fatigue, asthenia |
1 - Adverse reactions reported as serious in clinical trials in patients with MM who underwent ASCT.
2 - Applies only to serious adverse reactions.
3 - See description of individual adverse reactions.
4 - The combined term "Pneumonia" includes the following conditions: bronchopneumonia, lobar pneumonia, Pneumocystis jiroveci pneumonia, pneumonia, Klebsiella pneumonia, Legionella pneumonia, mycoplasmal pneumonia, pneumococcal pneumonia, streptococcal pneumonia, viral pneumonia, lung disorders, pneumonitis.
5 - The combined term "Sepsis" includes the following conditions: bacterial sepsis, pneumococcal sepsis, septic shock, staphylococcal sepsis.
6 - The term "Peripheral neuropathy" includes the following conditions: peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy.
7 - "Deep vein thrombosis" is a combined term that includes the following conditions: deep vein thrombosis, thrombosis, venous thrombosis.
Adverse reactions observed in patients with multiple myeloma who received lenalidomide as part of combination therapy
The table 2 below is derived from data collected during trials involving patients with multiple myeloma receiving combination therapy. The data were not adjusted for treatment duration in the lenalidomide group up to disease progression compared to the control group in the main multiple myeloma studies.
Table 2
Adverse reactions observed in patients with multiple myeloma treated with lenalidomide in combination with dexamethasone or melphalan with prednisolone
| System organ class / Preferred term |
All adverse reactions / Frequency |
Grade III-IV adverse reactions / Frequency |
| Infections and infestations |
Very common Pneumonia, upper respiratory tract infection, bacterial, viral and fungal infections (including opportunistic infections), nasopharyngitis, pharyngitis, bronchitis Common Sepsis, sinusitis |
Common Pneumonia, bacterial, viral and fungal infections (including opportunistic infections), sepsis, bronchitis |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Uncommon Basal cell carcinoma, squamous cell carcinoma of the skin^* |
Common Acute myeloid leukemia, myelodysplastic syndrome, squamous cell carcinoma of the skin** Uncommon Acute T-cell leukemia, basal cell carcinoma, tumor lysis syndrome |
| Blood and lymphatic system disorders |
Very common Neutropenia^, thrombocytopenia^, anemia, hemorrhagic disorders^, leukopenia Common Febrile neutropenia, pancytopenia Uncommon Hemolysis, autoimmune hemolytic anemia, hemolytic anemia |
Very common Neutropenia^, thrombocytopenia^, anemia, leukopenia Common Febrile neutropenia^, pancytopenia, hemolytic anemia Uncommon Hypercoagulation, coagulopathy |
| Immune system disorders |
Uncommon Hypersensitivity reactions^ |
|
| Endocrine disorders |
Common Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common Hypokalemia, hyperglycemia, hypocalcemia, decreased appetite, weight loss Common Hypomagnesemia, hyperuricemia, dehydration |
Common Hypokalemia, hyperglycemia, hypocalcemia, diabetes mellitus, hypophosphatemia, hyponatremia, hyperuricemia, gout, loss of appetite, weight loss |
| Psychiatric disorders |
Very common Depression, insomnia Uncommon Loss of libido |
Common Depression, insomnia |
| Nervous system disorders |
Very common Peripheral neuropathies (excluding motor neuropathy), dizziness, tremor, dysgeusia, headache Common Ataxia, disturbance of equilibrium |
Common Cerebrovascular accident, dizziness, loss of consciousness Uncommon Intracranial hemorrhage^, transient ischemic attack, cerebral ischemia |
| Eye disorders |
Very common Cataract, blurred vision Common Decreased visual acuity |
Common Cataract Uncommon Blindness |
| Ear and labyrinth disorders |
Common Deafness (including hearing impairment), tinnitus |
|
| Cardiac disorders |
Common Atrial fibrillation, bradycardia Uncommon Arrhythmia, QT interval prolongation, atrial flutter, ventricular extrasystoles |
Common Myocardial infarction (including acute)^, atrial fibrillation, congestive heart failure, tachycardia, heart failure, myocardial ischemia |
| Vascular disorders |
Very common Vein thromboembolism, predominantly deep vein thrombosis and pulmonary artery embolism^ Common Arterial hypotension, arterial hypertension, ecchymosis^ |
Very common Vein thromboembolism, predominantly deep vein thrombosis and pulmonary artery embolism^ Common Vasculitis Uncommon Ischemia, peripheral ischemia, thrombosis of intracranial venous sinuses |
| Respiratory, thoracic and mediastinal disorders |
Very common Dyspnea, epistaxis^ |
Common Respiratory failure, dyspnea |
| Gastrointestinal disorders |
Very common Diarrhea, constipation, abdominal pain, nausea, vomiting, dyspepsia Common Gastrointestinal hemorrhage (including rectal bleeding, hemorrhoidal bleeding, bleeding from gastric peptic ulcer, gingival bleeding)^, dry mouth, stomatitis, dysphagia Uncommon Colitis, cecitis |
Common Diarrhea, constipation, abdominal pain, nausea, vomiting |
| Hepatobiliary disorders |
Common Abnormal liver function tests Uncommon Hepatic failure^ |
Common Cholestasis, abnormal liver function tests Uncommon Hepatic failure^ |
| Skin and subcutaneous tissue disorders |
Very common Rash, pruritus Common Urticaria, hyperhidrosis, dry skin, skin hyperpigmentation, eczema, erythema Uncommon Skin discoloration, photosensitivity reaction |
Common Rash |
| Musculoskeletal and connective tissue disorders |
Very common Muscle spasms, bone pain, musculoskeletal and connective tissue pain and discomfort, joint pain Common Muscle weakness, joint swelling, muscle pain |
Common Muscle weakness, bone pain Uncommon Joint swelling |
| Renal and urinary disorders |
Very common Renal failure (including acute) Common Hematuria^, urinary retention, urinary incontinence Uncommon Acquired Fanconi syndrome |
Uncommon Tubular renal necrosis |
| Reproductive system and breast disorders |
Common Erectile dysfunction |
|
| General disorders and administration site conditions |
Very common Fatigue, edema (including peripheral edema), hyperthermia, asthenia, influenza-like syndrome (including chills, cough, myalgia, bone pain, headache, shivering, muscle rigidity) Common Chest pain, lethargy |
Common Fatigue, chills, asthenia |
| Investigations |
Common Increased concentration of C-reactive protein |
|
| Injury, poisoning and procedural complications |
Common Falls, contusions^ |
^ - See description of individual adverse reactions.
* - Squamous cell carcinoma of the skin was reported in clinical trials of patients previously treated for myeloma with lenalidomide in combination with dexamethasone, compared to the control group.
** - Squamous cell carcinoma of the skin was reported in a clinical trial of patients with newly diagnosed multiple myeloma who received lenalidomide with dexamethasone, compared to the control group.
Adverse reactions observed during monotherapy for myelodysplastic syndrome and mantle cell lymphoma
Adverse reactions observed in patients treated for myelodysplastic syndrome and mantle cell lymphoma are listed below in Table 3 and classified by frequency and system organ class. Within each frequency category, adverse reactions are listed in order of decreasing severity. Frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).
Table 3
Adverse reactions observed in patients with myelodysplastic syndrome who received treatment with lenalidomide
| System organ class/Preferred term |
All adverse reactions/Frequency |
Grade III-IV adverse reactions/Frequency |
| Infections and infestations |
Very common Bacterial, viral and fungal infections (including opportunistic infections) |
Very common Pneumonia◊ Common Bacterial, viral and fungal infections (including opportunistic infections)◊, bronchitis |
| Blood and lymphatic system disorders |
Very common Thrombocytopenia^, neutropenia^, leukopenia |
Very common Thrombocytopenia^◊, neutropenia^◊, leukopenia Common Febrile neutropenia^◊ |
| Endocrine disorders |
Very common Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common Decreased appetite Common Iron overload, weight loss |
Common Hypoglycemia◊, decreased appetite |
| Psychiatric disorders |
Common Mood alteration◊~ |
|
| Nervous system disorders |
Very common Dizziness, headache Common Paraesthesia |
|
| Cardiac disorders |
Common Acute myocardial infarction^◊, atrial fibrillation◊, heart failure◊ |
|
| Vascular disorders |
Common Arterial hypertension, haematomas |
Common Venous thromboembolism, predominantly deep vein thrombosis and pulmonary embolism^◊ |
| Respiratory, thoracic and mediastinal disorders |
Common Bronchitis Very common Nasal haemorrhage^ |
|
| Gastrointestinal disorders |
Very common Diarrhoea, abdominal pain (including epigastric pain), nausea, vomiting, constipation Common Dry mouth, dyspepsia |
Common Diarrhoea◊, nausea, toothache |
| Hepatobiliary disorders |
Common Abnormal liver function tests |
Common Abnormal liver function tests |
| Skin and subcutaneous tissue disorders |
Very common Rash, dry skin, pruritus |
Common Rash, pruritus |
| Musculoskeletal and connective tissue disorders |
Very common Myalgia, musculoskeletal pain (including back pain, limb pain), arthralgia, muscle spasms |
Common Back pain◊ |
| Renal and urinary disorders |
Common Renal failure◊ |
|
| General disorders and administration site conditions |
Very common Fatigue, peripheral oedema, influenza-like illness (including hyperthermia, cough, pharyngitis, myalgia, bone and musculoskeletal pain, headache) |
Common Hyperthermia |
| Injury, poisoning and procedural complications |
Common Fall |
^ - See description of individual adverse reactions.
◊ - Adverse reactions reported as severe during clinical trials in the treatment of myelodysplastic syndrome.
Table 4
Adverse reactions observed in patients with mantle cell lymphoma receiving lenalidomide treatment
| System organ class / Preferred term |
All adverse reactions / Frequency |
Grade III-IV adverse reactions / Frequency |
| Infections and infestations |
Very common Bacterial, viral and fungal infections (including opportunistic infections), nasopharyngitis, pneumonia Common Sinusitis |
Common Bacterial, viral and fungal infections (including opportunistic infections)◊, pneumonia◊ |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Common "Tumour flare" reaction |
Common "Tumour flare" reaction, squamous cell carcinoma of the skin^◊, basal cell carcinoma◊ |
| Blood and lymphatic system disorders |
Very common Thrombocytopenia^, neutropenia^, leukopenia, anemia Common Febrile neutropenia |
Very common Thrombocytopenia^, neutropenia^◊, anemia◊ Common Febrile neutropenia^◊, leukopenia◊ |
| Metabolism and nutrition disorders |
Very common Decreased appetite, weight loss, hypokalemia Common Dehydration |
Common Dehydration◊, hyponatremia, hypocalcemia |
| Psychiatric disorders |
Common Insomnia |
|
| Nervous system disorders |
Common Dysgeusia, headache, peripheral neuropathy |
Common Peripheral sensory neuropathy, lethargy |
| Ear and labyrinth disorders |
Common Dizziness |
|
| Cardiac disorders |
Common Acute myocardial infarction (including acute)^◊, heart failure |
|
| Vascular disorders |
Common Arterial hypotension |
Common Deep vein thrombosis◊, pulmonary embolism^◊, arterial hypotension◊ |
| Respiratory, thoracic and mediastinal disorders |
Very common Dyspnea |
Common Dyspnea◊ |
| Gastrointestinal disorders |
Very common Diarrhea, nausea◊, vomiting◊, constipation Common Abdominal pain |
Common Diarrhea◊, abdominal pain◊, constipation |
| Skin and subcutaneous tissue disorders |
Very common Rash (including allergic dermatitis), pruritus Common Nocturnal sweating, dry skin |
Common Rash |
| Musculoskeletal and connective tissue disorders |
Very common Muscle spasms, back pain Common Arthralgia, limb pain, muscle weakness |
Common Back pain, muscle weakness◊, arthralgia, limb pain |
| Renal and urinary disorders |
Common Renal failure◊ |
|
| General disorders and administration site conditions |
Very common Fatigue, asthenia, peripheral edema, flu-like syndrome (including hyperthermia, cough) Common Chills |
Common Hyperthermia◊, asthenia◊, fatigue |
^ - See description of individual adverse reactions.
◊ - Adverse reactions reported as severe during clinical trials of mantle cell lymphoma treatment.
Summary table of adverse reactions recorded during the use of lenalidomide in combination therapy for follicular lymphoma
The data in Table 5 were obtained during the use of combination therapy with lenalidomide and rituximab for the treatment of follicular lymphoma.
Table 5
Adverse reactions recorded in clinical trials among patients with follicular lymphoma who received lenalidomide in combination with rituximab
| System organ class/Preferred term |
All adverse reactions/frequency |
Grade III-IV adverse reactions/frequency |
| Infections and infestations |
Very common Upper respiratory tract infections Common Pneumonia◊, influenza, bronchitis, sinusitis, urinary tract infection |
Common Pneumonia◊, sepsis◊, pulmonary infection, bronchitis, gastroenteritis, sinusitis, urinary tract infections, cellulitis◊ |
| Benign, malignant and unspecified neoplasms (incl. cysts and polyps) |
Very common Tumour flare^ Common Squamous cell carcinoma of the skin◊,^,+ |
Common Basal cell carcinoma^,◊ |
| Blood and lymphatic system disorders |
Very common Neutropenia^,◊, anemia◊, thrombocytopenia^, leukopenia**, lymphopenia*** |
Very common Neutropenia^,◊ Common Anemia◊, thrombocytopenia^, febrile neutropenia◊, pancytopenia, leukopenia**, lymphopenia*** |
| Metabolism and nutrition disorders |
Very common Decreased appetite, hypokalemia Common Hypophosphatemia, dehydration |
Common Dehydration, hypercalcemia◊, hypokalemia, hypophosphatemia, hyperuricemia |
| Psychiatric disorders |
Common Depression, insomnia |
|
| Nervous system disorders |
Very common Headache, dizziness Common Peripheral sensory neuropathy, dysgeusia |
Common Syncope |
| Cardiac disorders |
Uncommon Arrhythmia◊ |
|
| Vascular disorders |
Common Arterial hypotension |
Common Pulmonary embolism^,◊, arterial hypotension |
| Respiratory, thoracic and mediastinal disorders |
Very common Dyspnea◊, cough Common Oropharyngeal pain, dysphonia |
Common Dyspnea◊ |
| Gastrointestinal disorders |
Very common Abdominal pain◊, diarrhea, constipation, nausea, vomiting, dyspepsia Common Upper abdominal pain, stomatitis, dry mouth |
Common Abdominal pain◊, diarrhea, constipation, stomatitis |
| Skin and subcutaneous tissue disorders |
Very common Rash*, pruritus Common Dry skin, night sweats, erythema |
Common Rash*, pruritus |
| Musculoskeletal and connective tissue disorders |
Very common Muscle spasms, back pain, arthralgia Common Limb pain, muscle weakness, musculoskeletal pain, myalgia, neck pain |
Common Muscle weakness, neck pain |
| Renal and urinary disorders |
Common Acute kidney injury◊ |
|
| General disorders and administration site conditions |
Very common Fever, fatigue, asthenia, peripheral edema Common Malaise, chills |
Common Fatigue, asthenia |
| Investigations |
Very common Increased alanine aminotransferase levels Common Weight decreased, increased blood bilirubin levels |
^ - See description of individual adverse reactions.
◊ - Adverse reactions recorded as serious during clinical trials in patients with follicular lymphoma.
-
- Refers only to serious adverse drug reactions.
* - 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.
Adverse reactions observed in post-marketing experience
In addition to the adverse reactions listed above identified during clinical trials, Table 6 is derived from data collected in post-marketing studies.
Table 6
Adverse reactions observed during the post-marketing period in patients receiving lenalidomide treatment
| System organ class / Preferred term |
All adverse reactions/frequency |
Grade III-IV adverse reactions/frequency |
| Infections and infestations |
Frequency unknown Viral infections, including herpes zoster and reactivation of hepatitis B virus |
Frequency unknown Viral infections, including herpes zoster and reactivation of hepatitis B virus |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare Tumor lysis syndrome |
|
| Blood and lymphatic system disorders |
Frequency unknown Acquired hemophilia |
|
| Immune system disorders |
Rare Anaphylactic reaction^ Frequency unknown Rejection of transplanted solid organs |
Rare Anaphylactic reaction^ |
| Endocrine disorders |
Common Hyperthyroidism |
|
| Respiratory, thoracic and mediastinal disorders |
Uncommon Pulmonary hypertension |
Rare Pulmonary hypertension Frequency unknown Interstitial pneumonitis |
| Gastrointestinal disorders |
Frequency unknown Pancreatitis, gastrointestinal perforation (including diverticular, perforation of small and large intestine)^ |
|
| Hepatobiliary disorders |
Frequency unknown Acute liver failure^, toxic hepatitis^, cytolytic hepatitis^, cholestatic hepatitis^, mixed cytolytic/cholestatic hepatitis^ |
Frequency unknown Acute liver failure^, toxic hepatitis^ |
| Skin and subcutaneous tissue disorders |
Uncommon Angioedema (Quincke's edema) Rare Stevens-Johnson syndrome^, toxic epidermal necrolysis^ Frequency unknown Leukocytoclastic vasculitis, drug reaction with eosinophilia and systemic symptoms (DRESS)^ |
^ - See description of individual adverse reactions.
Description of individual adverse reactions
Teratogenicity
Lenalidomide is a structural analogue of thalidomide. Thalidomide is a known human teratogen that can cause severe, life-threatening birth defects or fetal death.
Experimental studies of lenalidomide in monkeys showed results similar to those described for thalidomide. If lenalidomide is taken during pregnancy, its teratogenic effect is expected.
Neutropenia and thrombocytopenia
Patients with newly diagnosed multiple myeloma who underwent ASCT and received lenalidomide treatment
Maintenance therapy with lenalidomide after ASCT is associated with a higher incidence of grade IV neutropenia compared to placebo. In some cases, urgent management of neutropenia required discontinuation of lenalidomide treatment. The incidence of grade IV neutropenia in the lenalidomide maintenance therapy groups was comparable to placebo in both studies. Maintenance therapy with lenalidomide after ASCT is associated with a higher incidence of grade III or IV thrombocytopenia compared to placebo.
- Newly diagnosed multiple myeloma in patients receiving lenalidomide in combination with low-dose dexamethasone
The combination of lenalidomide with low-dose dexamethasone in patients with newly diagnosed multiple myeloma was associated with a reduced incidence of grade III-IV neutropenia. Grade IV febrile neutropenia was observed less frequently.
- Newly diagnosed multiple myeloma in patients taking lenalidomide in combination with melphalan and prednisolone
The combination of lenalidomide with melphalan and prednisolone in patients with newly diagnosed multiple myeloma was associated with an increased incidence of grade III-IV neutropenia. Episodes of grade IV febrile neutropenia were observed more frequently.
- Multiple myeloma with at least one prior line of therapy
The use of the combination of lenalidomide with dexamethasone in patients with multiple myeloma is associated with an increased incidence of grade III-IV neutropenia. Episodes of grade IV febrile neutropenia were observed less frequently.
- Myelodysplastic syndromes
In patients with myelodysplastic syndrome, the use of lenalidomide is associated with a higher incidence of grade III-IV neutropenia. Episodes of grade III-IV febrile neutropenia were observed in 2.2% of patients receiving lenalidomide compared to 0.0% in the placebo group.
- Mantle cell lymphoma
In patients with mantle cell lymphoma, the use of lenalidomide is associated with a higher incidence of grade III-IV neutropenia (43.7% of patients receiving lenalidomide compared to 33.7% in the control group).
- Patients with follicular lymphoma
The use of the combination of lenalidomide with rituximab in follicular lymphoma is associated with a higher incidence of grade III or IV neutropenia (50.7% among patients receiving lenalidomide/rituximab compared to 12.2% among patients receiving placebo/rituximab). All cases of grade III or IV neutropenia were reversible upon discontinuation or dose reduction and/or use of supportive therapy with growth factors. Additionally, febrile neutropenia was infrequent (2.7% among patients receiving lenalidomide/rituximab compared to 0.7% among patients receiving placebo/rituximab).
The use of lenalidomide in combination with rituximab is also associated with a higher incidence of grade III or IV thrombocytopenia (1.4% among patients receiving lenalidomide/rituximab compared to 0% among patients receiving placebo/rituximab).
Venous thromboembolism
An increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) is associated with the use of lenalidomide with dexamethasone in patients with multiple myeloma, and to a lesser extent in patients receiving lenalidomide in combination with melphalan and prednisolone or in patients with multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma receiving lenalidomide as monotherapy. Concomitant use of erythropoiesis-stimulating agents or a history of DVT may also increase the risk of thrombosis in these patients.
Myocardial infarction
Myocardial infarction has been reported in patients receiving lenalidomide treatment, particularly in those with existing risk factors.
Bleeding disorders
Bleeding disorders have been reported in several organ system classes: blood and lymphatic system disorders, nervous system disorders (intracranial hemorrhage); respiratory, thoracic and mediastinal disorders (epistaxis); gastrointestinal disorders (gingival bleeding, hemorrhoidal bleeding, rectal bleeding); renal and urinary disorders (hematuria); injury, poisoning and procedural complications (contusions); and vascular disorders (ecchymoses).
Allergic reactions
Cases of allergic reactions/hypersensitivity reactions have been reported. Cross-reactivity between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Lenalidomide should not be prescribed to patients with a history of severe rashes associated with thalidomide treatment.
Secondary malignancies
In clinical trials involving patients previously treated for myeloma with lenalidomide and dexamethasone, secondary malignancies in the control group were predominantly basal cell or squamous cell skin cancers.
Acute myeloid leukemia
- Multiple myeloma
Cases of acute myeloid leukemia (AML) were observed in clinical trials in patients with newly diagnosed multiple myeloma who received lenalidomide in combination with melphalan, or immediately after high-dose melphalan and ASCT (autologous stem cell transplantation). This increase was not observed in clinical trials of patients with newly diagnosed multiple myeloma receiving lenalidomide in combination with low-dose dexamethasone, compared to thalidomide in combination with melphalan and prednisolone.
- Myelodysplastic syndromes
Baseline factors, including complex cytogenetic abnormalities and TP53 mutations, are associated with progression to AML in transfusion-dependent patients with the Del(5q) genetic abnormality. The estimated two-year cumulative risk of AML progression is 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.
Hepatic disorders
In the post-marketing period, adverse reactions (frequency unknown) have been reported: acute liver failure and cholestasis (both potentially fatal), toxic hepatitis, cytolitic hepatitis, mixed cytolitic/cholestatic hepatitis.
Rhabdomyolysis
Rhabdomyolysis has been observed rarely, in some cases when lenalidomide was used concomitantly with statins.
Thyroid function disorders
Cases of hypothyroidism and hyperthyroidism have been reported.
Tumor flare reaction and tumor lysis syndrome
In a clinical trial of mantle cell lymphoma (MCL), a "tumor flare" reaction occurred in 13/134 (approximately 10%) of patients receiving lenalidomide treatment compared to 0% in the control group. Most cases occurred during the first cycle, were considered treatment-related, and were of grade I or II severity. All events occurred in cycle 1, and one patient experienced a recurrence of the "tumor flare" reaction in cycle 11. In the AUGMENT trial in patients with follicular lymphoma (FL) or marginal zone lymphoma, "tumor flare" reaction was reported in 19/176 (10.8%) patients in the lenalidomide/rituximab group; one patient in this group experienced a grade III tumor flare reaction. In the MAGNIFY trial, 9/222 (4.1%) patients experienced a "tumor flare" reaction; all reports were of grade I or II severity, one of which was serious. In a separate phase 2 MCL trial, one case of tumor flare reaction resulted in a fatal outcome. Patients with a high prognostic index for mantle cell lymphoma or generalized lymphadenopathy (at least one lesion ≥7 cm in the longest diameter) at the start of therapy may be at risk of tumor flare reaction. Cases of tumor lysis syndrome (TLS) have also been reported. Most cases occurred in the first cycle, were of grade I or II severity, and were considered treatment-related.
Gastrointestinal disorders
Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to gastrointestinal bleeding and septic complications and may be associated with fatal outcomes.
Reporting of suspected adverse reactions
Reporting of adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua
Shelf life.
2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging.
28 capsules in a container (for 5 mg and 10 mg dosage) or 21 capsules in a container (for 15 mg and 25 mg dosage) made of high-density polyethylene (HDPE) with a child-resistant cap. Inside the container, a desiccant sachet with a warning label is included. One container per cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Dr. Reddy’s Laboratories Ltd, FTO-7
Manufacturer’s location and address of business operations.
Plot No. R1-R9, Phase - III, VSE3, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India
To report an adverse reaction or lack of efficacy when using the medicinal product, please call (24/7):
+380 44 207 51 97 or +380 50 414 39 39; or send an email to: [email protected]