Revlimid. Instructions for use

Release form, composition and packaging

Capsules

hard gelatin, No. 2, cylindrical, opaque, with a body and cap of white or almost white color, with black markings “5 mg” (on the body) and “REV” (on the cap); the contents of the capsules are powder from almost white to pale yellow.

1 capsule contains:

active substance:

lenalidomide – 5 mg;

Excipients:

lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, titanium dioxide, gelatin, black ink (TekPrint SW-9008/SW-9009) - shellac, ethanol, isopropanol, butanol, propylene glycol, water, aqueous ammonia, potassium hydroxide, iron oxide dye black.

7 pcs. - blisters (3) - cardboard packs.

Capsules

hard gelatin, No. 0, cylindrical, opaque, with a pale yellow body and a blue-green cap, marked in black “10 mg” (on the body) and “REV” (on the cap); the contents of the capsules are powder from almost white to pale yellow.

1 capsule contains:

active substance:

lenalidomide – 10 mg;

Excipients:

lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, indigo carmine dye FD&c Blue 2, iron oxide yellow dye, titanium dioxide, gelatin, black ink (TekPrint SW-9008/SW-9009) - shellac, ethanol, isopropanol, butanol, propylene glycol, water, aqueous ammonia, potassium hydroxide, black iron oxide dye.

7 pcs. - blisters (3) - cardboard packs.

Capsules

hard gelatin, No. 0, cylindrical, opaque, with a white or almost white body and a blue cap, with black markings “15 mg” (on the body) and “REV” (on the cap); the contents of the capsules are powder from almost white to pale yellow.

1 capsule contains:

active substance:

lenalidomide – 15 mg;

Excipients:

lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, indigo carmine dye FD&c Blue 2, titanium dioxide, gelatin, black ink (TekPrint SW-9008/SW-9009) - shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia aqueous, potassium hydroxide, iron oxide black dye.

7 pcs. - blisters (3) - cardboard packs.

Capsules

hard gelatin, No. 0, cylindrical, opaque, with a body and cap of white or almost white color, with black markings “25 mg” (on the body) and “REV” (on the cap); the contents of the capsules are powder from almost white to pale yellow.

1 capsule contains:

active substance:

lenalidomide – 25 mg;

Excipients:

7 pcs. - blisters (3) - cardboard packs.

Contraindications

- pregnancy;

- lactation period (breastfeeding);

— preserved reproductive potential, except in cases where it is possible to comply with all the necessary conditions of the Pregnancy Prevention Program;

- inability or inability to comply with necessary contraceptive measures;

— children's age (insufficient clinical experience of use);

- hereditary lactose intolerance, lactase deficiency or impaired absorption of glucose-galactose, because Revlimid capsules contain lactose;

- hypersensitivity to the components of the drug.

Carefully _

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

Dosage

Revlimid is for oral administration only.

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

Recommended initial

The dose of Revlimid is 25 mg 1 time / day on days 1-21 of repeated 28-day cycles.

Dexamethasone at a dose of 40 mg is prescribed 1 time / day on days 1-4, 9-12 and 17-20 of each 28-day cycle during the first 4 cycles of therapy, and then 40 mg 1 time / day on days 1-4 each subsequent 28-day cycle.

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

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

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

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

The pharmacokinetics of lenalidomide in elderly patients (over 65 years of age) have not been studied. In clinical trials, lenalidomide was administered to patients with multiple myeloma under the age of 86 years. The percentage of patients over 65 years of age who received lenalidomide/dexamethasone or placebo/dexamethasone was comparable. There were no differences in the effectiveness and safety of lenalidomide depending on age, although greater sensitivity to the drug in patients in the older age group cannot be excluded. Since elderly patients are more likely to have impaired renal function, the dose of the drug should be selected very carefully, and monitoring of renal function is recommended during treatment.

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

Lenalidomide is excreted primarily by the kidneys. Therefore, the risk of toxic reactions may increase with impaired renal function. For patients with mild renal impairment, no dose adjustment of Revlimid is required. For patients with moderate renal impairment, 10 mg 1 time / day (the dose of the drug can be increased to 15 mg 1 time / day after 2 cycles of therapy if there is no response to therapy, but is well tolerated), with severe - 15 mg every other day ( the dose of the drug can be increased to 10 mg 1 time / day if the therapy is well tolerated). In case of end-stage renal failure, it is necessary to take 5 mg 1 time per day of dialysis, after a hemodialysis session.

After initiation of treatment with lenalidomide, subsequent dose modification in patients with impaired renal function should be based on individual tolerance to treatment as previously stated.

Revlimid

Treatment with Revlimid must be carried out under the supervision of a hematologist or chemotherapist.

Myocardial infarction

There have been reports of cases of myocardial infarction in patients taking lenalidomide, in particular in individuals with risk factors for cardiovascular disease. If there are risk factors, including, first of all, a history of thrombosis, it is necessary to monitor the condition of patients, as well as take actions aimed at possibly reducing the influence of risk factors (smoking, arterial hypertension, hyperlipidemia).

Venous and arterial thromboembolism

During combination therapy with Revlimid and dexamethasone, there is an increase in the incidence of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), as well as arterial thromboembolism (mainly myocardial infarction and stroke) in patients with multiple myeloma. Therefore, it is necessary to monitor patients with risk factors for thromboembolism, incl. and a history of thrombosis. Measures should be taken to possibly eliminate risk factors such as smoking, arterial hypertension, and hyperlipidemia. The greatest prognostic significance is a history of thromboembolic complications, concomitant therapy with erythropoietin, and hormone replacement therapy. Therefore, drugs with erythropoietic activity, as well as other drugs that may increase the risk of thrombosis (for example, hormone replacement therapy) should be administered with caution to patients with multiple myeloma taking lenalidomide with dexamethasone. A hemoglobin concentration greater than 12 g% suggests discontinuation of erythropoietin therapy. Physicians and patients should carefully evaluate clinical symptoms indicating possible thromboembolism. Patients should be warned to seek immediate medical attention if symptoms such as shortness of breath, chest pain, or swelling of the upper or lower extremity occur.

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

If the patient develops symptoms of thromboembolism, treatment with lenalidomide should be discontinued and standard anticoagulant therapy should be instituted. Once the patient's condition has stabilized on anticoagulant therapy and symptoms of thromboembolism have resolved, treatment with lenalidomide at the same dose can be reinitiated if the benefit/risk ratio is favorable. The patient should continue anticoagulant therapy throughout the further period of treatment with lenalidomide.

Neutropenia and thrombocytopenia

A high incidence of grade 3 and 4 thrombocytopenia is observed in patients with multiple myeloma when Revlimid and dexamethasone are simultaneously prescribed (9.9% and 1.4%, respectively, in patients treated with Revlimid/dexamethasone, and 2.3% and 0.0% in patients treated with placebo/ dexamethasone). Close monitoring by both physician and patient for symptoms of increased bleeding, including petechiae and hemoptysis, is recommended. If necessary, the dose of the drug can be reduced.

During the first 2 months of treatment with Revlimid, it is recommended to conduct a detailed blood test every week, including determining the number of leukocytes, blood count, platelet count, hemoglobin, and hematocrit. Thereafter, blood tests should be performed monthly.

The toxicity manifestations of Revlimid that most often limit its use include neutropenia and thrombocytopenia. In this regard, the decision to co-prescribe Revlimid and other immunosuppressive drugs should be clinically justified.

Kidney failure

Given the predominant excretion of Revlimid by the kidneys, renal function and the dose of Revlimid should be carefully monitored in patients with renal failure.

Thyroid function

Regular monitoring of thyroid function is necessary due to the possibility of Revlimid to cause hypothyroidism.

Peripheral neuropathy

The possibility of a neurotoxic effect of Revlimid during long-term use cannot be ruled out, given the structural similarity of the molecules of Revlimid and thalidomide, which is known for its pronounced neurotoxic side effect.

Tumor lysis syndrome

Due to the pronounced antineoplastic activity of Revlimid, the development of tumor lysis syndrome is possible, especially in patients with a large tumor mass. These patients should be subject to appropriate monitoring and the use of generally accepted preventive measures.

Allergic reactions

There have been reports of cases of allergic/hypersensitivity reactions. Due to the fact that there are scientific publications about possible cross-reactions between lenalidomide and thalidomide, the condition of patients who have a history of allergic reactions during treatment with thalidomide should be monitored with particular care.

Severe skin reactions

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. If ecfoliative or bullous skin rashes appear, or the development of Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected, the use of lenalidomide should be stopped immediately, treatment with which should not be resumed even after the skin manifestations have disappeared. The need to interrupt or discontinue lenalidomide should be considered if other types of skin reactions occur, depending on their severity. Lenalidomide should not be prescribed to patients who have a history of severe skin reactions associated with thalidomide use.

Lactose intolerance

Revlimid capsules contain lactose. Patients with rare diseases - galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption syndrome are not recommended to use the drug.

Development of primary malignant tumors of other localization (POML)

In clinical studies, a higher incidence of primary malignant tumors of other localizations was noted in patients previously treated with lenalidomide and dexamethasone (3.98 per 100 patient-years) compared to the control group (1.38 per 100 patient-years). Noninvasive PDLs included basal cell carcinoma and squamous cell carcinoma of the skin. The majority of invasive PDLs were solid tumors.

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

Of the invasive PDLs in patients receiving combination treatment with Revlimid and melphalan, or immediately after high-dose melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia, MDS (myeloid dysplasia syndrome) and solid tumors have been reported. Cases of B-cell tumors (including Hodgkin's lymphoma) have been reported in clinical studies when Revlimid was used after stem cell transplantation.

The risk of developing PDL should be considered before prescribing Revlimid. Physicians should carefully evaluate patients using standard diagnostic methods both before deciding to prescribe Revlimid and during the entire period of treatment with Revlimid. Treatment should be carried out according to generally accepted recommendations.

Patients should not share Revlimid with others. Unused medication must be returned to the medical facility.

Patients are not allowed to donate blood or sperm during treatment with Revlimid and for one week after treatment.

Impact on the ability to drive vehicles and operate machinery

Some side effects of Revlimid, such as dizziness, weakness, drowsiness and blurred vision, may adversely affect the ability to drive a car and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. In this regard, special care should be taken when driving vehicles and operating machinery.

Overdose

There is currently no specific management plan for lenalidomide overdose in patients with multiple myeloma, although some patients received doses up to 150 mg in dose-ranging studies and up to 400 mg in single-dose studies. The dose-limiting toxicities in these studies were exclusively hematological.

In case of overdose, symptomatic maintenance therapy is recommended.

Side effects

Infectious and parasitic diseases:

pneumonia, upper respiratory tract infections, sepsis, bacterial, viral and fungal infections (including opportunistic), sinusitis.

Benign, malignant and unspecified neoplasms:

basal cell carcinoma, squamous cell skin cancer.

Blood and lymphatic system disorders:

thrombocytopenia, neutropenia, anemia, hemorrhagic disorders, leukopenia, pancytopenia, hemolysis, hypercoagulation, coagulopathy.

Immune system disorders:

hypersensitivity reactions.

Endocrine system disorders:

hypothyroidism

Metabolic disorders:

hypokalemia, loss of appetite, hypomagnesemia, hypocalcemia, hypophosphatemia, dehydration.

Mental disorders:

loss of libido, depression.

Nervous system disorders:

peripheral neuropathy (except motor neuropathy), dizziness, tremor, taste disturbance, headache, ataxia, imbalance, stroke, dizziness, syncope, intracranial hemorrhage, transient ischemic attack, cerebral ischemia.

Visual disorders:

blurred vision, decreased visual acuity, cataracts, blindness.

Hearing and labyrinth disorders:

deafness (including hearing loss), tinnitus.

Vascular disorders:

thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism), arterial hypotension, arterial hypertension, ecchymosis, ischemia, peripheral ischemia, intracranial venous sinus thrombosis.

Cardiac disorders:

atrial fibrillation, bradycardia, arrhythmia, QT segment prolongation, atrial flutter, ventricular extrasystole, myocardial infarction, congestive heart failure, tachycardia.

Respiratory system disorders:

shortness of breath, nasopharyngitis, pharyngitis, bronchitis, nosebleeds, respiratory distress syndrome.

Gastrointestinal disorders:

constipation, diarrhea, nausea, vomiting, gastrointestinal bleeding (including rectal, hemorrhoidal, gingival and peptic ulcer bleeding), abdominal pain, dry mouth, stomatitis, dysphagia, colitis, typhlitis.

Disorders of the liver and biliary tract:

deviation of liver function test values from the norm.

Disorders of the skin and subcutaneous tissues:

rash, urticaria, hyperhidrosis, dry skin, itching, skin hyperpigmentation, eczema, skin discoloration, photosensitivity reactions.

Disorders of the musculoskeletal system:

muscle cramps, bone pain, pain and discomfort from the musculoskeletal and connective tissue, swelling of the joints.

Renal and urinary tract disorders:

hematuria, urinary retention, urinary incontinence, acquired Fanconi syndrome, renal failure, tubular renal necrosis.

Disorders of the genital organs and breast:

erectile dysfunction.

General disorders and disorders at the injection site:

fatigue, edema (including peripheral edema), fever, influenza-like syndrome (including fever, myalgia, musculoskeletal pain, headache and chills), chest pain, lethargy.

Lenalidomide-TL

When using lenalidomide/dexamethasone, the most frequently observed symptoms were: neutropenia (39.4%), muscle weakness (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramps (20.1%), thrombocytopenia (18.4%), anemia (17). %), diarrhea (14.2%) and rash (10.2%). The most severe were venous thromboembolism (deep vein thrombosis, PE), neutropenia grade 4. Neutropenia and thrombocytopenia were significantly dose-dependent and can be controlled by reducing the dose of lenalidomide/dexamethasone.

Frequency: very often: (more than 1/10); often (more than 1/100, less than 1/10); uncommon (more than 1/1000, less than 1/100), rare (more than 1/10000, less than 1/1000) and very rare (less than 1/10000, including isolated cases).

From the hematopoietic organs: very often - neutropenia*, thrombocytopenia*, anemia*; often - febrile neutropenia, pancytopenia, leukopenia*, lymphopenia*; uncommon - granulocytopenia, hemolytic anemia, incl. autoimmune, hemolysis, monocytopenia, leukocytosis, lymphadenopathy.

From the cardiovascular system: often - atrial fibrillation, palpitations, deep vein thrombosis*, decreased blood pressure*, increased blood pressure, orthostatic hypotension, blood to the skin of the face; uncommon - congestive heart failure, pulmonary edema, valvular insufficiency, atrial flutter, trigeminy, bradycardia, tachycardia, prolongation of the QT interval on the ECG, vascular collapse, thrombosis and/or thrombophlebitis of the superficial or deep veins of the extremities, petechiae, hematoma, postphlebitic syndrome, ischemia peripheral vessels.

From the senses: often - dizziness, blurred vision, cataracts, decreased visual acuity, increased lacrimation; uncommon - deafness, hearing loss, ringing in the ears, pain or itching in the ears, blindness, atherosclerosis of the retinal vessels, thrombosis of the retinal veins, keratitis, swelling of the eyelids, conjunctivitis, itching of the eyes, redness of the eyes, inflammation of the eyes, eye syndrome.

From the endocrine system: often - Cushing's syndrome; uncommon - adrenal insufficiency, hypothyroidism, hirsutism.

From the digestive system: very often - constipation, diarrhea, nausea; often - vomiting, dyspepsia, epigastric pain, gastritis, abdominal pain, stomatitis, dry mouth, flatulence; uncommon - gastrointestinal bleeding, esophagitis, gastroesophageal reflux, colitis, gastroduodenitis, lack of salivation, gastroenteritis, pain in the esophagus, dysphagia, aphthous stomatitis, tongue, numbness of the oral mucosa, pain in the tongue and other organs of the oral cavity, feeling discomfort in the epigastric region, bleeding gums, gingivitis, proctitis, hemorrhoids.

Infections and infestations: often - pneumonia*, infections of the upper and lower respiratory tract, herpetic infections, urinary tract infections, sinusitis, candidiasis and other fungal infections of the oral mucosa; uncommon - septic shock, meningitis, sepsis, incl. against the background of neutropenia, subacute endocarditis, bronchopneumonia, Pneumocystis pneumonia, atypical pneumonia, viral infection (herpes zoster) of the optic nerve, fungal infections of the feet, bursitis, otitis media, pustular rash, bacteremia (Enterobacter spp.), erysipelas, candidiasis of the genital organs, esophagus, prostatitis, inflammation of the subcutaneous tissue, bursitis, sinusitis, furunculosis, viral lesions of the anal area.

From the side of metabolism: very often - increase or decrease in body weight; often - anorexia, dehydration, fluid retention; uncommon - metabolic acidosis, diabetes mellitus or its progression, cachexia, gout, increased appetite.

From the musculoskeletal system: very often - muscle cramps*, muscle weakness; often - myopathy (including steroid), myalgia, arthralgia, pain in the extremities, back pain, bone pain, chest pain; uncommon - osteonecrosis, muscle atrophy, muscle spasms, amyotrophy, swelling of the joints, in the joints, night cramps, deformity of the big toe.

From the nervous system: often - stroke, loss of consciousness, peripheral neuropathy (including sensory), dizziness, taste perversion, loss of taste sensitivity, paresthesia, headache, tremor*, hypoesthesia*, drowsiness, memory loss; uncommon - intracranial bleeding, venous sinus thrombosis, thrombotic stroke, cerebral ischemia, transient cerebrovascular accident, leukoencephalopathy, vasovagal attacks, neurotoxicity, peripheral motor neuropathy, dysesthesia, aphonia, dysphonia, impaired concentration, ataxia, balance disorders, postural vertigo, involuntary muscle contractions, dyskinesia, hyperesthesia, motor dysfunction, myasthenic syndrome, paresthesia of the oral mucosa, psychomotor hyperactivity, loss of smell.

From the mental side: very often - insomnia; often - loss of orientation, hallucinations, depression, aggression, agitation, nervousness, irritability, emotional lability; uncommon - psychosis, delirium, changes in mental status, exacerbation of depression, sleep disorders, vivid dreams, depressed mood, affective lability, apathy, decreased libido, nightmares, personality changes, panic attacks, anxiety.

From the genitourinary system: often - renal failure, erectile dysfunction, gynecomastia, metrorrhagia, nipple pain; uncommon - acute renal failure, increased frequency of urination, renal tubular necrosis, cystitis, hematuria, urinary retention, dysuria, acquired Fanconi syndrome, urinary incontinence, polyuria, nocturia.

From the respiratory system: often - pulmonary embolism, shortness of breath* (including during physical exertion), cough, bronchitis, hoarseness, hiccups, pharyngitis, nasopharyngitis; infrequently - bronchopneumopathy, bronchial asthma, pleural pain, respiratory distress, nasal congestion, congestion of the paranasal sinuses and pain in them, increased discharge from the pharynx, laryngitis, rhinorrhea, sensation in the throat.

From the skin: very often - skin rash*; often - facial swelling, dry skin, skin itching*, erythema, folliculitis, skin hyperpigmentation, exanthema, excessive sweating, night sweats, alopecia; uncommon - erythema nodosum, rash (including erythematous and itchy), lip pigmentation, eczema, erythroderma, superficial skin fissures, hyperkeratosis, exacerbation of acne, bedsores, rosacea, seborrheic dermatitis, prurigo, burning skin, skin desquamation, petechiae, photosensitivity, skin depigmentation.

Laboratory indicators: often - hyperglycemia, hypokalemia, hypocalcemia; infrequently - hyperuricemia, hyperphosphatemia, hypoalbuminemia, hyponatremia, hypomagnesemia, hypophosphatemia, prolongation of prothrombin time, increased MHO, prolonged aPTT, decreased urea in the blood serum, increased activity of alkaline phosphatase, LDH, ALT, CRP, increased concentrations of urea and creatinine, increased or decreased activity TSH, positive reaction to CMV, acquired hypogammaglobulinemia, chromosomal abnormalities.

Other: very often - weakness*, asthenia*, peripheral edema; often - fever, chills, inflammation of the mucous membranes, drowsiness, malaise; uncommon - increased body temperature, chest pain, chest pain, unsteady gait, thirst, flu-like syndrome, decreased performance, delayed wound healing; development of basal cell carcinoma, glioblastoma multiforme.

For most side effects, no differences in incidence were found depending on the type of therapy: lenalidomide/dexamethasone or placebo/dexamethasone. Side effects marked (*) occurred significantly more often during therapy with lenalidomide/dexamethasone.

Drug interactions

Erythropoietic agents

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

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

Digoxin

The simultaneous administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (Cmax of digoxin was 114%, and AUC0-∞ 108%). Therefore, monitoring digoxin concentrations is recommended during treatment with lenalidomide.

Oral contraceptives

Dexamethasone, which is a mandatory component of the treatment regimen with Revlimid, may reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, it is necessary to use the means specified in the Pregnancy Prevention Program.

Warfarin

There was no mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin. Considering the use of dexamethasone in combination with lenalidomide, the influence of the latter on the effects of warfarin cannot be excluded. Thus, during combination therapy with lenalidomide and dexamethasone, careful monitoring of warfarin concentrations is recommended.

Description of the drug LENALIDOMIDE

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

Close monitoring by both physician and patient for symptoms of increased bleeding, including petechiae and hemoptysis, is recommended.

During the first 2 months of treatment with lenalidomide, it is recommended to conduct a detailed blood test every week, including determining the number of leukocytes, blood count, platelet count, hemoglobin, and hematocrit. Thereafter, blood tests should be performed monthly.

The toxicities of lenalidomide that most often limit its use include neutropenia and thrombocytopenia. In this regard, the decision to use lenalidomide and other immunosuppressive drugs together should be clinically justified.

Given the predominant excretion of lenalidomide by the kidneys, renal function and the dose of lenalidomide should be carefully monitored in patients with renal impairment.

Regular monitoring of thyroid function is necessary due to the possibility of developing hypothyroidism under the influence of lenalidomide.

The possibility of a neurotoxic effect of lenalidomide during long-term use cannot be excluded, given the structural similarity of the molecules of lenalidomide and thalidomide, which is known for its pronounced neurotoxic side effects.

Due to the pronounced antineoplastic activity of lenalidomide, the development of tumor lysis syndrome is possible, especially in patients with a large tumor mass. The condition of such patients should be monitored and appropriate prophylaxis carried out.

Patients are not allowed to donate blood or sperm during treatment with lenalidomide and for one week after treatment.

Impact on the ability to drive vehicles and operate machinery

Some side effects of lenalidomide, such as dizziness, weakness, drowsiness and blurred vision, may impair the ability to drive and perform potentially hazardous activities that require increased concentration and psychomotor speed. In this regard, special care should be taken when driving vehicles and operating machinery.

special instructions

Treatment with Revlimid must be carried out under the supervision of a hematologist or chemotherapist.

Myocardial infarction

Venous and arterial thromboembolism

Neutropenia and thrombocytopenia

Kidney failure

Given the predominant excretion of Revlimid by the kidneys, renal function and the dose of Revlimid should be carefully monitored in patients with renal failure.

Thyroid function

Regular monitoring of thyroid function is necessary due to the possibility of Revlimid to cause hypothyroidism.

Peripheral neuropathy

Tumor lysis syndrome

Allergic reactions

Severe skin reactions

Lactose intolerance

Revlimid capsules contain lactose. Patients with rare diseases - galactose intolerance, lapp lactase deficiency or glucose-galactose malabsorption syndrome are not recommended to use the drug.

Development of primary malignant tumors of other localization (POML)

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

Patients should not share Revlimid with others. Unused medication must be returned to the medical facility.

Patients are not allowed to donate blood or sperm during treatment with Revlimid and for one week after treatment.

Impact on the ability to drive vehicles and operate machinery

Some side effects of Revlimid, such as dizziness, weakness, drowsiness and blurred vision, may adversely affect

Revlimid, 5 mg, capsules, 21 pcs.

Treatment with Revlimid must be carried out under the supervision of a hematologist or chemotherapist.

Lenalidomide is a structural analogue of thalidomide, which has a pronounced teratogenic effect. It is known that taking thalidomide by pregnant women causes severe and life-threatening damage to the internal organs of the fetus. Experimental studies in monkeys showed results similar to those previously described for thalidomide. The risk of developing birth defects is very high if Revlimid is used during pregnancy (see "Contraindications"). Women of reproductive age should use effective methods of contraception during treatment with Revlimid. Lenalidomide should be discontinued if a woman is diagnosed with pregnancy, and the patient should be referred for consultation with a physician experienced in monitoring pregnant women for assessment and clinical recommendations.

When a woman who is the intimate partner of a patient receiving lenalidomide treatment is diagnosed with pregnancy, the woman is also referred to a teratology specialist for assessment and clinical recommendations.

Lactation period

It is unknown whether lenalidomide passes into breast milk. In this regard, breastfeeding should be discontinued during treatment with lenalidomide.

Strict compliance with all requirements of the Pregnancy Prevention Program must apply to both women and men.

For women of non-childbearing age

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

— age >50 years and duration of natural amenorrhea >1 year;*

— early ovarian failure, confirmed by a gynecologist;

- history of bilateral salpingo-oophorectomy or hysterectomy;

- genotype XY, Turner syndrome, anatomical defect of the uterus.

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

The use of lenalidomide in women of childbearing potential is contraindicated unless the patient meets one of the following requirements:

- awareness of the possible teratogenic effect of Revlimid on an unborn child;

- understanding of the need for continuous use of effective methods of contraception for 4 weeks before treatment, during treatment and 4 weeks after treatment with Revlimid;

- even in the case of amenorrhea, compliance with all the rules of effective contraception;

- ability to comply with all rules of effective contraception;

- knowledge and understanding of the possible consequences of pregnancy, as well as the need to urgently seek advice if pregnancy is suspected;

- understanding the need to immediately take Revlimid after receiving negative pregnancy test results;

- awareness of the need for a test and performing a pregnancy test every 4 weeks;

- the patient must confirm that she understands the risk of possible undesirable consequences and the need to prevent them during treatment with Revlimid.

Use in men

Data from studying the pharmacokinetics of lenalidomide in male volunteers indicate that lenalidomide may be contained in extremely low concentrations in the seminal fluid of patients during treatment, and is not detected 3 days after cessation of use in healthy volunteers (see “Pharmacokinetics”).

As a precaution, given the possible decrease in the elimination rate of lenalidomide in special groups of patients (with impaired renal function), all men taking Revlimid should comply with the following requirements:

- understanding the possible risk of teratogenic effects of the drug Revlimid during sexual contact with a pregnant woman or a woman of childbearing age;

- understanding the need to use condoms during sexual contact with pregnant women or women of childbearing age who do not use reliable methods of contraception during the treatment period, during a break in treatment and for 1 week after completion of treatment.

A doctor prescribing treatment with Revlimid for women of childbearing age

, must be sure:

— that the patient satisfies all the conditions of the Pregnancy Prevention Program, including confirmation that she adequately understands the situation;

— in obtaining the informed consent of the patient regarding her mandatory compliance with all the conditions of the above Program.

Contraception rules

Women of childbearing potential should use a highly effective method of contraception for 4 weeks before starting treatment, during treatment with Revlimid, and for 4 weeks after treatment, even during treatment interruptions. The only exceptions are patients who abstain from heterosexual relationships throughout the entire specified period, which is documented monthly. If the patient does not have an effective method of contraception, she should be referred to a gynecologist to select an effective method of contraception. The patient should immediately begin using an effective method of contraception.

Highly effective methods of contraception include: subcutaneous hormonal implants; intrauterine systems that release levonorgestrel; depot preparations of medroxyprogesterone acetate; tubal ligation; partner's vasectomy (confirmed by two negative semen tests); progesterone-containing tablets that inhibit ovulation (for example, desogestrel).

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

Neutropenic patients using subcutaneous hormonal implants or levonorgestrel-releasing intrauterine systems for contraception should receive prophylactic antibiotics due to the increased risk of infectious complications at the time of insertion of these therapeutic systems.

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

Pregnancy tests

(sensitivity - at least 25 mIU/ml) should be performed in the presence of a doctor for all women of childbearing age, including those who completely exclude and abstain from heterosexual relationships for a long time. After patients have been using an effective method of contraception for 4 weeks or more, tests are performed on the day of treatment or 3 days before the visit to the attending physician, and then every 4 weeks, incl. and after finishing taking Revlimid. The test results should confirm that the patient is not pregnant during treatment with Revlimid.

Male patients should use condoms throughout the course of treatment with Revlimid, and for 1 week after a break or cessation of treatment if the sexual partner is a pregnant woman or a woman of childbearing age who is not using highly effective methods of contraception.

Additional Precautions

Patients should not share Revlimid with others. Unused medication must be returned to the medical facility.

Patients are not allowed to donate blood or sperm as a donor during the entire course of treatment with Revlimid and for 1 week after its completion.

Educational materials

To increase the safety of Revlimid therapy and reduce the risk of teratogenic effects, educational materials are provided to help patients, which include all the necessary information about the drug, as well as the Pregnancy Prevention Program. The holder of the registration certificate provides doctors with the materials necessary for their patients. The doctor provides detailed information about the teratogenic risk of Revlimid and measures to prevent pregnancy to patients of childbearing age and sexually active men.

Other special instructions and precautions

Cardiovascular diseases

Myocardial infarction.

There have been reports of cases of myocardial infarction in patients taking lenalidomide, particularly in those with risk factors for cardiovascular disease. If there are risk factors, including primarily a history of thrombosis, it is necessary to monitor the patient’s condition, as well as take actions aimed at possibly reducing the influence of risk factors (smoking, arterial hypertension, hyperlipidemia) (see also “Side effects”).

Venous and arterial thromboembolism.

During combination therapy with Revlimid and dexamethasone, there is an increased incidence of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), as well as arterial thromboembolism (mainly myocardial infarction and stroke) in patients with multiple myeloma - see “Interaction” and “Side effects” "). Therefore, it is necessary to monitor patients with risk factors for thromboembolism, incl. and a history of thrombosis. Measures should be taken to possibly eliminate risk factors such as smoking, arterial hypertension, and hyperlipidemia. The greatest prognostic significance is a history of thromboembolic complications, concomitant therapy with erythropoietin, and hormone replacement therapy. Thus, drugs with erythropoietic activity, as well as other drugs that may increase the risk of thrombosis (for example, hormone replacement therapy) should be prescribed with caution to patients with multiple myeloma taking lenalidomide with dexamethasone. A hemoglobin concentration greater than 12 g% suggests discontinuation of erythropoietin therapy. Physicians and patients should carefully evaluate clinical symptoms indicating possible thromboembolism. Patients should be warned to seek immediate medical attention if symptoms such as shortness of breath, chest pain, or swelling of the upper or lower extremity occur. For the prevention of venous thromboembolism, especially in patients with additional risk factors, it is recommended to use low molecular weight heparins or warfarin. The decision to prescribe antithrombotic therapy should be made after a careful assessment of individual risk factors. If the patient develops symptoms of thromboembolism, treatment with lenalidomide should be discontinued and standard anticoagulant therapy should be instituted. Once the patient's condition has stabilized on anticoagulant therapy and symptoms of thromboembolism have resolved, treatment with lenalidomide at the same dose can be reinitiated if the benefit/risk ratio is favorable. The patient should continue anticoagulant therapy throughout the further period of treatment with lenalidomide.

Neutropenia and thrombocytopenia

The risk of developing grade 4 neutropenia in patients with multiple myeloma when Revlimid and dexamethasone are co-administered is very high (5.1% in the group of patients receiving Revlimid/dexamethasone, and 0.6% in the group of patients receiving placebo/dexamethasone). Episodes of febrile neutropenia are reported infrequently (0.6% in the group of patients receiving Revlimid/dexamethasone, and 0% in the group of patients receiving placebo/dexamethasone). Patients should be informed of the need to promptly report fever (above 38 °C) to their doctor. If necessary, the dose of the drug can be reduced (see “Method of administration and dosage”). In cases of severe neutropenia, it is advisable to prescribe growth factor drugs. A high incidence of thrombocytopenia of the 3rd and 4th severity is observed in patients with multiple myeloma when Revlimid and dexamethasone are prescribed simultaneously (9.9 and 1.4%, respectively, in patients treated with Revlimid/dexamethasone and 2.3 and 0% - during treatment with placebo/dexamethasone). Close monitoring by both physician and patient for symptoms of increased bleeding, including petechiae and hemoptysis, is recommended, especially in cases where concomitant medications may increase bleeding tendency (see Venous and Arterial Thromboembolism

and Side effects,
hemorrhagic complications
). If necessary, the dose of the drug can be reduced (see “Method of administration and dosage”). During the first 2 months of treatment with Revlimid, it is recommended to conduct a detailed blood test every week, including determining the number of leukocytes, blood count, platelet count, hemoglobin, and hematocrit. Thereafter, blood tests should be performed monthly. The toxicity manifestations of Revlimid that most often limit its use include neutropenia and thrombocytopenia. In this regard, the decision to co-prescribe Revlimid and other immunosuppressive drugs should be clinically justified.

Kidney failure

Given the predominant excretion of Revlimid by the kidneys, in patients with renal failure it is necessary to carefully monitor the state of renal function and the dose of Revlimid (see "Dosage and Administration").

Thyroid function

Regular monitoring of thyroid function is necessary due to the possibility of Revlimid to cause hypothyroidism.

Peripheral neuropathy

Tumor lysis syndrome

Allergic reactions

There have been reports of cases of allergic/hypersensitivity reactions (see "Side effects"). Due to the fact that there are scientific publications about possible cross-reactions between lenalidomide and thalidomide, the condition of patients who have a history of allergic reactions during treatment with thalidomide should be monitored with particular care.

Severe skin reactions

Cases of SJS and TEN have been reported. If exfoliative or bullous rashes appear on the skin or the development of SJS or TEN is suspected, the use of lenalidomide should be stopped immediately, treatment with which should not be resumed even after the skin manifestations have disappeared. The need to interrupt or discontinue lenalidomide should be considered if other types of skin reactions occur, depending on their severity. Lenalidomide should not be prescribed to patients who have a history of severe skin reactions associated with thalidomide use.

Lactose intolerance

Revlimid capsules contain lactose. Patients with rare diseases - galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption syndrome - are not recommended to use the drug (see “Contraindications”).

Development of malignant primary tumors of other localization (POTL)

In clinical studies, a higher incidence of malignant PDL was noted in patients previously treated with lenalidomide and dexamethasone (3.98 per 100 patient-years) compared with the control group (1.38 per 100 patient-years). Noninvasive PDLs included basal cell carcinoma and squamous cell carcinoma of the skin. The majority of invasive PDLs were solid tumors.

In clinical studies in patients with newly diagnosed multiple myeloma receiving Revlimid, there was a 4-fold increase (7%) in the incidence of PDL compared with the control group (1.8%).

Cases of acute myeloid leukemia, myeloid dysplasia syndrome, and solid tumors have been reported among invasive PDL in patients receiving combination treatment with Revlimid and melphalan or immediately after high-dose melphalan and autologous stem cell transplantation. Cases of B-cell tumors (including Hodgkin's lymphoma) have been reported in clinical studies when Revlimid was used after stem cell transplantation.

Impact on the ability to drive a car and operate machinery.

Pregnancy and lactation

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

in monkeys showed results similar to those previously described for thalidomide. The risk of developing birth defects is very high if Revlimid is taken during pregnancy.

Women of reproductive age should use effective methods of contraception during treatment with Revlimid. Lenalidomide should be discontinued if a woman is diagnosed with pregnancy, and the patient should be referred for consultation with a physician experienced in monitoring pregnant women for assessment and clinical recommendations. When a woman who is the intimate partner of a patient receiving lenalidomide treatment is diagnosed with pregnancy, the woman is also referred to a teratology specialist for assessment and clinical recommendations.

It is unknown whether lenalidomide passes into breast milk. In this regard, breastfeeding should be discontinued during treatment with lenalidomide.

Strict compliance with all requirements of the Pregnancy Prevention Program must apply to both women and men.

For women of non-childbearing age

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

— age ≥ 50 years and duration of natural amenorrhea ≥ 1 year*;

— early ovarian failure, confirmed by a gynecologist;

- history of bilateral salpingo-oophorectomy or hysterectomy;

- genotype XY, Turner syndrome, anatomical defect of the uterus.

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

The use of lenalidomide in women of childbearing age is contraindicated if one of the following statements is not true:

A woman of childbearing age should:

— know about the teratogenic effect of Revlimid on the fetus;

- understand the need for continuous use of effective methods of contraception for 4 weeks before treatment, during treatment and 4 weeks after treatment with Revlimid;

- even in case of amenorrhea, follow all the rules of effective contraception;

- be able to comply with all the rules of effective contraception;

- know and understand the possible consequences of pregnancy, as well as the need to quickly seek advice if you suspect a pregnancy;

- understand the need to immediately take Revlimid after receiving negative pregnancy test results;

- be aware of the need for a test and perform a pregnancy test every 4 weeks;

- confirm that you understand the risk of all possible undesirable consequences and the need to prevent them during treatment with Revlimid.

Application in men:

Data from a study of the pharmacokinetics of lenalidomide in male volunteers indicate that lenalidomide may be contained in the seminal fluid of patients during the treatment period in extremely low concentrations and is not detected 3 days after cessation of use in healthy volunteers. As a precaution, given the possible decrease in the elimination rate of lenalidomide in special groups of patients (patients with impaired renal function), the following statements should be true in all male patients taking Revlimid:

A man taking Revlimid should:

- understand the possible risk of Revlimid’s teratogenic effect during sexual contact with a pregnant woman or a woman of childbearing age;

- understand the need to use condoms during sexual contact with pregnant women or women of childbearing age who do not use reliable methods of contraception during treatment, during a break in treatment and for 1 week after completion of treatment.

A physician prescribing Revlimid treatment to women of childbearing age should:

- be confident that the patient satisfies all the conditions of the Pregnancy Prevention Program, including confirmation that she adequately understands the situation;

— obtain the informed consent of the patient regarding her mandatory compliance with all the conditions of the above Program.

Contraception rules

Women of childbearing potential should use a highly effective method of contraception for 4 weeks before starting treatment, during treatment with Revlimid, and for 4 weeks after finishing treatment, even during treatment breaks. The only exceptions are patients who abstain from heterosexual relationships throughout the entire specified period, which is documented monthly. If the patient does not have an effective method of contraception, she should be referred to a gynecologist to select an effective method of contraception. The patient should immediately begin using an effective method of contraception.

Highly effective methods of contraception include:

— subcutaneous hormonal implants;

- intrauterine systems that release levonorgestrel;

- depot preparations medroxyprogesterone acetate;

- tubal ligation;

- vasectomy of the partner (confirmed by two negative tests of seminal fluid);

- progesterone-containing tablets that inhibit ovulation (for example, desogestrel).

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

Pregnancy tests (sensitivity of at least 25 mIU/ml) should be performed in the presence of a doctor for all women of childbearing age, including those who completely exclude and abstain from heterosexual relationships for a long time. After patients have been using an effective method of contraception for 4 weeks or more, tests are performed on the day of treatment or 3 days before the visit with their doctor, and then every 4 weeks, incl. and after finishing taking Revlimid. The test results should confirm that the patient is not pregnant during treatment with Revlimid.

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

Lenalidomide

Treatment with lenalidomide should be initiated and administered under the supervision of an experienced hematologist or chemotherapy physician.

Pregnancy prevention program

Strict compliance with all requirements of the Pregnancy Prevention Program must apply to both women and men.

For women with unpreserved childbearing potential:

A female patient or a female sexual partner of a male patient is NOT considered fertile if at least one of the following factors is present:

— age ≥50 years and duration of natural amenorrhea ≥1 year*

– early ovarian failure, confirmed by a gynecologist

- history of bilateral salpingo-oophorectomy or hysterectomy

— genotype XY, Turner syndrome, anatomical defect of the uterus

*- amenorrhea due to anticancer therapy or during breastfeeding does not exclude the presence of childbearing potential.

The use of lenalidomide in women of childbearing potential is contraindicated unless the following conditions are met: woman

- should be aware of the possible teratogenic effect of lenalidomide on the fetus

- must understand the need for continuous use of effective methods of contraception for 4 weeks before starting treatment, during treatment and 4 weeks after the end of treatment

- even in case of amenorrhea, the recommendation to use effective contraception should be followed

- be able to comply with all the rules of effective contraception

- must know and understand the possible consequences of pregnancy, as well as the need to urgently seek advice if pregnancy is suspected

- must understand the need to urgently begin treatment with lenalidomide immediately after receiving a negative pregnancy test result

- must be aware of the need for the test and perform a pregnancy test every 4 weeks, with the exception of patients who have undergone sterilization by tubal ligation

- must confirm that she understands the risk of possible undesirable consequences and the need to prevent them during treatment with lenalidomide.

Application in men:

Data from studying the pharmacokinetics of lenalidomide in male volunteers indicate that during treatment, lenalidomide can be contained in extremely low concentrations in the seminal fluid of patients and is not detected 3 days after discontinuation of the drug in healthy volunteers (see “Pharmacological action, Pharmacokinetics”) . As a precaution, given the possible decrease in the elimination rate of lenalidomide in special patient populations (patients with impaired renal function), the following conditions should be met for all men taking lenalidomide: man

- must understand the possible risk of teratogenicity of lenalidomide during sexual contact with a pregnant woman or a woman of preserved childbearing potential

- must understand the need to use condoms (even after a vasectomy) during sexual contact with pregnant women or women with preserved childbearing potential who do not use reliable methods of contraception, during treatment, and for 1 week after stopping treatment and/or completing treatment

- should understand that if his partner becomes pregnant during his treatment with lenalidomide or shortly after stopping treatment with lenalidomide, he should immediately inform his doctor and his partner is advised to seek examination and advice from a teratologist.

Physicians prescribing treatment with lenalidomide to women of preserved childbearing potential should

— make sure that the patient meets all the conditions of the Pregnancy Prevention Program,

including confirmation that she adequately understands the situation

— obtain the patient’s consent to her mandatory compliance with all the conditions of the above Program.

Contraception rules:

Women of childbearing potential should use a highly effective method of contraception for 4 weeks before starting treatment, during treatment, and for 4 weeks after ending treatment with lenalidomide, even during breaks in treatment. The exception is patients who abstain from heterosexual relationships throughout the entire specified period, which is documented monthly. If the patient does not have an effective method of contraception, she should be referred to a gynecologist to select an effective method of contraception. The patient should immediately begin using an effective method of contraception.

Highly effective methods of contraception include:

— Subcutaneous hormonal implants;

- Intrauterine systems that release levonorgestrel;

— Depot preparations medroxyprogesterone acetate;

— Tubal ligation;

— Vasectomy of the partner (confirmed by two negative tests of seminal fluid);

- Progesterone-containing tablets that inhibit ovulation (for example, desogestrel). The use of combined oral contraceptives is not indicated for patients with MM due to the increased risk of thromboembolic complications during combination therapy with lenalidomide. For effective contraception, these patients are recommended to use one of the methods listed above. The increased risk of thromboembolism continues for 4-6 weeks after stopping combined contraceptives.

The effectiveness of hormonal contraceptives may be reduced when dexamethasone is co-administered. Neutropenic patients using subcutaneous hormonal implants or levonorgestrel-releasing intrauterine systems for contraception should receive prophylactic antibiotics due to the increased risk of infectious complications at the time of insertion of these therapeutic systems.

Pregnancy test

(sensitivity of at least 25 mIU/ml) should be performed in the presence of a physician for all women with preserved childbearing potential, including those who completely and continuously abstain from heterosexual relations. After patients have been using an effective method of contraception for 4 weeks or more, tests are performed on the day of treatment or 3 days before the appointment with the health care provider, and then every 4 weeks, including for 4 weeks after completion of treatment. with the exception of those patients in whom sterilization by tubal ligation has been confirmed. The test results should confirm that the patient is not pregnant at the time of initiation of therapy.

Male patient

must use condoms throughout the course of treatment, during a break in treatment and for 1 week after stopping treatment if his sexual partner is a pregnant woman or a woman of preserved childbearing potential who does not use highly effective methods of contraception (even if the man has had a vasectomy).

Additional Precautions

Patients should not share lenalidomide with others. The unused drug must be returned to the medical facility at the end of treatment.

Patients are not allowed to donate blood or sperm during treatment with lenalidomide and for 1 week after treatment.

Educational materials, restrictions on prescribing and dispensing the drug

To help patients prevent fetal exposure to lenalidomide, the marketing authorization holder will provide educational materials to healthcare personnel to justify warnings regarding the teratogenicity of lenalidomide, recommend contraception before initiating therapy, and explain the need for pregnancy tests. The physician should inform male and female patients about the risk of teratogenic effects of lenalidomide and strict measures to prevent pregnancy in accordance with the Pregnancy Prevention Program. The physician must provide the patient with an educational brochure and patient record, as well as other equivalent instructions in accordance with the state patient record system. A controlled distribution system involves the use of patient records and/or an equivalent tool to monitor the prescription and/or dispensing of a drug and to collect detailed indication-specific data to closely monitor use for indications not approved in the Russian Federation. Ideally, the pregnancy test, treatment prescription, and drug dispensing should occur on the same day. The distribution of lenalidomide to women with preserved reproductive potential should occur no later than 7 days after the prescription of therapy and receipt of a negative result of a pregnancy test performed under the supervision of a physician. In women of reproductive age, lenalidomide can be dispensed/prescribed for a maximum period of up to 4 weeks, while in other patients it can be given for a maximum period of 12 weeks.

Cardiovascular diseases

Myocardial infarction

There have been reports of cases of myocardial infarction in patients taking lenalidomide, particularly in those with cardiovascular risk factors and during the first 12 months of combined use with dexamethasone. If there are risk factors, including, first of all, a history of thrombosis, it is necessary to monitor the patient’s condition, as well as take actions aimed at possibly reducing the influence of risk factors (smoking, arterial hypertension, hyperlipidemia).

Venous and arterial thromboembolism

During combination therapy with lenalidomide and dexamethasone, there is an increase in the incidence of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), as well as arterial thromboembolism (mainly myocardial infarction and stroke) in patients with multiple myeloma. Venous thromboembolism was less frequently observed when taking lenalidomide in combination with melphalan and prednisolone for newly diagnosed MM and when monotherapy for myelodysplastic syndrome (see “Interaction with other drugs” and “Side effects”). Therefore, it is necessary to monitor patients who have risk factors for thromboembolism, including a history of thrombosis. Measures should be taken to possibly eliminate risk factors such as smoking, arterial hypertension, and hyperlipidemia. The greatest prognostic significance is a history of thromboembolic complications, concomitant therapy with erythropoietin, and hormone replacement therapy. Therefore, drugs with erythropoietic activity, as well as other drugs that may increase the risk of thrombosis (eg, hormone replacement therapy) should be administered with caution to patients with MM taking lenalidomide with dexamethasone. A hemoglobin concentration above 120 g/L suggests discontinuation of erythropoietin therapy.

Physicians and patients should carefully evaluate clinical symptoms indicating possible thromboembolism. Patients should be warned to seek immediate medical attention if symptoms such as shortness of breath, chest pain, or swelling of the upper or lower extremity occur.

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

Neutropenia and thrombocytopenia

Severe dose-limiting toxicities of lenalidomide are neutropenia and thrombocytopenia. A complete blood count, including determination of white blood cell count, blood count, platelet count, hemoglobin, and hematocrit, should be performed prior to initiation of therapy, every week during the first 8 weeks of lenalidomide therapy, and then monthly to monitor cytopenias. If neutropenia develops, it may be necessary to reduce the dose of the drug (see “Dosage and Administration”). In case of development of neutropenia, it is advisable to prescribe growth factor drugs. Patients should be informed of the need to promptly report any increases in temperature to their physician. Caution should be used when lenalidomide is administered with other myelosuppressive drugs.

Newly diagnosed MM in patients receiving lenalidomide in combination with low-dose dexamethasone

Grade 4 neutropenia was observed less often in patients receiving lenalidomide in combination with low-dose dexamethasone than in the control group (8.5% in continuous treatment or treatment for 18 four-week cycles, lenalidomide/dexamethasone group, compared with 15% in the group taking melphalan/prednisolone/thalidomide (MPT), see section “Side effects”). Episodes of grade 4 febrile neutropenia occurred with the same frequency in the lenalidomide/dexamethasone group and in the comparison group (0.6 %

in patients receiving lenalidomide/dexamethasone compared to 0.7% in the group receiving MPT, see section "Side effects"). Patients should be advised to promptly report febrile episodes; dose reduction may be required (see Dosage and Administration).

Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the lenalidomide/dexamethasone group than in the control group (8.1% versus 11.1%, respectively). Patients and physicians are advised to monitor for signs and symptoms of bleeding, including petechiae and epistaxis, especially when concomitant medications may increase bleeding tendency (see Adverse Reactions, Bleeding Complications).

Newly diagnosed MM in patients receiving lenalidomide in combination with melphalan and prednisone

The use of lenalidomide with melphalan and prednisone in clinical trials in patients with newly diagnosed MM was associated with a higher incidence of grade 4 neutropenia. Episodes of grade 4 febrile neutropenia were rare. The use of lenalidomide with melphalan and prednisolone in patients with MM was associated with a higher incidence of grade 3 and 4 thrombocytopenia. Patients and physicians are advised to monitor for signs and symptoms of bleeding, including petechiae and epistaxis, especially when concomitant medications may increase bleeding tendency (see Adverse Reactions: Bleeding Complications).

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

The risk of developing grade 4 neutropenia in patients with MM when lenalide and dexamethasone are co-administered is very high (5.1% in the group of patients receiving lenalidomide/dexamethasone, relative to 0.6% in the group of patients receiving placebo/dexamethasone). Episodes of grade 4 febrile neutropenia are reported infrequently (0.6% in the group of patients receiving lenalidomide/dexamethasone, relative to 0.0% in the group of patients receiving placebo/dexamethasone). Patients should be advised to promptly report febrile episodes; dose reduction may be required (see Dosage and Administration). If neutropenia develops, the appropriateness of prescribing a growth factor to the patient should be considered. A high incidence of thrombocytopenia of grade 3 and 4 is observed in patients with MM with simultaneous administration of lenalidomide and dexamethasone (9.9% and 1.4%, respectively, during treatment with lenalidomide/dexamethasone, relative to 2.3% and 0.0% - against the background of treatment with placebo/dexamethasone). Close monitoring on the part of both the physician and the patient for symptoms of increased bleeding, including petechiae and nosebleeds, is recommended, especially in cases where concomitantly used drugs can increase the tendency to bleeding (see "Venous and arterial thromboembolism" and "Side effects, hemorrhagic complications ").

Infection with or without neutropenia

Patients with MM are susceptible to developing infections, including pneumonia. A higher rate of infection was observed when lenalidomide was given in combination with dexamethasone rather than with MAT. Infections > 3 severity developed in conditions of neutropenia in less than one third of patients. Patients with known risk factors for infection should be closely monitored. All patients are advised to seek immediate medical attention at the first sign of infection (e.g. cough, fever, etc.), allowing early treatment to reduce severity.

Kidney failure

Given the predominant excretion of lenalidomide by the kidneys, renal function and the dose of lenalidomide should be carefully monitored in patients with renal failure (see "Dosage and Administration").

Thyroid diseases

There are reports of cases of hypothyroidism and hyperthyroidism. Before starting treatment, concomitant diseases that may affect thyroid function should be assessed. It is recommended to assess thyroid function before starting treatment and regularly monitor it while using lenalidomide.

Peripheral neuropathy

Lenalidomide is structurally similar to thalidomide, which is known to cause severe peripheral neuropathy. However, there was no increased incidence of peripheral neuropathy with long-term use of lenalidomide in the treatment of newly diagnosed MM.

Tumor lysis syndrome

Due to the pronounced antineoplastic activity of lenalidomide, the development of tumor lysis syndrome is possible, especially in patients with a large tumor mass. These patients should be closely monitored and appropriate preventive measures taken.

Allergic reactions

There have been reports of cases of allergic/hypersensitivity reactions in patients taking lenalidomide (see "Side effects"). Due to the fact that there are scientific publications about possible cross-reactions between lenalidomide and thalidomide, the condition of patients who have a history of allergic reactions during treatment with thalidomide should be monitored with particular care.

Severe skin reactions

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

Development of primary malignant tumors of other localization (POML)

In clinical studies, a higher incidence of primary malignant tumors of other sites was noted in patients previously treated with lenalidomide and dexamethasone (3.98 per 100 patient-years) compared with the control group (1.38 per 100 patient-years). Noninvasive PDLs included basal cell carcinoma and squamous cell carcinoma of the skin. The majority of invasive PDLs were solid tumors.

In clinical trials in patients with newly diagnosed MM not eligible for HSCT who received lenalidomide in combination with melphalan and prednisolone until progression (1.75 per 100 person-years), there was a 4-fold increase in the incidence of hematologic AML (acute myeloid leukemia, myelodysplastic syndrome) .9 times compared to melphalan in combination with prednisolone (0.36 per 100 person-years).

A 2.12-fold increase in the incidence of solid PDL was observed in patients receiving lenalidomide (9 cycles) in combination with melphalan and prednisolone (1.57 per 100 person-years) compared with melphalan in combination with prednisolone (0.74 per 100 person-years). -years).

In patients receiving lenalidomide in combination with dexamethasone before progression or for 18 months, the incidence of hematologic POML was not increased (0.16 per 100 person-years) compared with MAT (0.79 per 100 person-years).

A 1.3-fold increase in the incidence of solid PDL was reported in patients receiving lenalidomide in combination with dexamethasone before progression or within 18 months (1.58 per 100 person-years) compared with MAT (1.19 per 100 person-years) ).

In clinical trials in patients with newly diagnosed MM who were eligible for HSCT, an increased incidence of hematologic AML was observed in those patients who received lenalidomide immediately after high-dose melphalan and autologous HSCT compared with patients who received placebo (1.27 - 1.56 compared to 0.46 - 0.53 per 100 person-years, respectively). Cases of B-cell malignancies (including Hodgkin lymphoma) observed in clinical trials occurred in patients receiving lenalidomide during the post-HSCT period.

The risk of developing hematological PDL should be considered before prescribing lenalidomide, both in combination with melphalan and after high-dose melphalan and HSCT. Clinicians should carefully evaluate patients using standard diagnostic methods to identify PDL both before starting therapy and throughout the treatment period. Treatment should be carried out according to generally accepted recommendations.

Liver disorders

Liver failure, including fatal cases, has been reported in patients receiving lenalidomide as part of combination therapy: acute liver failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis and mixed cytolytic/cholestatic hepatitis. The mechanisms of severe drug-induced hepatotoxicity remain unknown, although in some cases, previous viral liver disease, baseline elevated liver enzymes, and possibly antibiotic treatment may be risk factors.

Liver functional abnormalities were frequently reported, but were usually asymptomatic and reversible after discontinuation of therapy. After restoration of indicators to the initial level, therapy can be resumed at a lower dose. Lenalidomide is excreted by the kidneys. It is important to adjust the dose of the drug in patients with renal impairment to avoid achieving plasma concentrations that may increase the risk of developing hematological adverse reactions or hepatotoxicity. It is recommended to monitor liver function, especially in the presence or history of concomitant viral liver disease, or when using lenalidomide in combination with drugs that cause liver dysfunction.

Patients with newly diagnosed MM

Patients aged over 75 years, with International Staging System (ISS) stage III, ECOG score ≤ 2 or CK < 60 ml/min, had a higher rate of intolerance (grade 3 or 4 ADRs, serious ADRs, discontinuation of treatment) when taking lenalidomide in combination. Before prescribing lenalidomide in combination with other drugs, the tolerability of this therapy in elderly patients should be carefully assessed, taking into account age, ISS stage III, ECOG ≤ 2 or CC < 60 ml/min (see section "Dosage and Administration" and "Side Effects" ).

Cataract

A higher incidence of cataracts was observed in patients receiving lenalidomide in combination with dexamethasone, especially with long-term therapy. Regular vision monitoring is recommended.

Unused capsules

Patients should be warned never to share their medication with other patients and to return unused capsules to their prescriber at the end of the course of therapy.