Index of drugs

Combination therapy with Dexamethasone in adult patients with multiple myeloma who have had at least one treatment regimen. In addition, capsules of 5 mg and 10 mg - the treatment of patients with anemia dependent on transfusions in the course of myelodysplastic syndromes with low or indirect-1 risk, associated with cytogenetic abnormalities in the form of an isolated 5q deletion, if other treatments are insufficient or inappropriate.

1 capsule contains 5 mg, 10 mg, 15 mg or 25 mg of lenalidomide; capsules contain lactose.

The mechanism of action of lenalidomide includes anticancer, anti-angiogenesis, pro-erythropoietic and immunomodulatory effects. Lenalidomide inhibits the proliferation of certain hematopoietic cancer cells (including myeloma cells and those with deletions within chromosome 5), increases cellular T cell and natural killer cell-mediated immunity, increases NKT cell number, inhibits angiogenesis by inhibiting endothelial cell migration and adhesion microvessel formation, increases fetal hemoglobin production by hematopoietic CD34 + stem cells and inhibits the production of proinflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Lenalidomide is a racemic mixture. After oral administration, it absorbs quickly, the maximum blood concentration reaches 0.5-2 hours after administration. The relative concentrations of the enantiomers S (-) and R (+) lenalidomide in plasma are approximately 56% and 44% respectively. The degree of binding to plasma proteins is 23% on average. The majority of lenalidomide is excreted in the urine - 90%, 4% excreted in the faeces. The drug is metabolized to a small extent - 82% of the dose is excreted unchanged in the urine. T_0,5 is about 3 hours (for doses from 5 to 25 mg / day). In patients with impaired renal function, AUC increases and T_0,5 Lenalidomide is prolonged.

Hypersensitivity to the active substance or to any of the excipients. Pregnancy. Women of child-bearing age if all the conditions of the pregnancy prevention program are not met.

All patients must meet the conditions of the pregnancy prevention program unless there is credible evidence that the patient can not get pregnant. Patient or partner of the patient is considered to be able to become pregnant if it does not meet at least one of the following criteria: age ≥50 years and a natural lack of menstruation for ≥1 year (lack of menstruation after anticancer treatment or during lactation does not exclude the possibility of occurrence in pregnancy); premature ovarian failure confirmed by a gynecologist; previous bilateral resection of ovaries with fallopian tubes or hysterectomy, genotype XY, Turner syndrome, uterine agenesis. Lenalidomide is contraindicated in women of childbearing potential if all of the following conditions are not met: the patient understands the expected risk of teratogenicity for an unborn child; The patient understands the need for effective contraception for 4 weeks continuously prior to treatment, for the duration of the treatment and for 4 weeks after stopping lenalidomide treatment (even if the medicine is stopped, unless the patient commits to absolute and continuous sexual abstinence confirmed every month); even if a woman's reproductive age experiences a lack of menstruation, she must follow all recommendations for effective contraception; the patient is able to use and follow effective methods of contraception; the patient was informed and understood the potential consequences of pregnancy and the need for immediate consultation in the event of a suspicion of pregnancy; the patient understands the need to start treatment immediately after the release of lenalidomide preceded by a negative pregnancy test result; the patient understands the need and agrees to perform pregnancy tests every 4 weeks, except in cases of confirmed sterilization by tubal ligation; the patient confirms that she understands the risks and necessary precautions associated with the use of lenalidomide.In the case of a woman taking lenalidomide, appropriate contraceptive methods may include the following examples: implant; intrauterine levonorgestrel releasing hormone system; medroxyprogesterone acetate in the form of depot; sterilization by tubal ligation; sexual intercourse only with a man after vasectomy (vasectomy must be confirmed by two negative sperm tests); ovulation-inhibiting pills containing only Progesterone (ie, desogestrel). Due to the increased risk of venous thromboembolism, the use of binary oral contraceptives is not recommended. If a patient is currently using a two-pack oral contraceptive, she should switch to one of the effective methods listed above. The risk of venous thromboembolism persists for 4-6 weeks after the end of the use of two-component oral contraceptives. The concomitant use of dexamethasone may reduce the effectiveness of steroid contraceptives. Levonorgestrel releasing implants and intrauterine systems are associated with an increased risk of infection at the time of implantation and irregular vaginal bleeding, therefore prophylactic administration of antibiotics should be considered, particularly in patients with neutropenia. In general, intrauterine copper releasing inserts are not recommended due to the potential risk of infection during introduction and loss of menstrual blood, which may worsen the condition of neutropenic patients or thrombocytopenia. Before starting treatment, a pregnancy test must be carried out under the supervision of a physician during a visit during which lenalidomide was saved or 3 days before a visit to the doctor who saved the medicine, if the patient used effective contraception for at least 4 weeks. This requirement also applies to women of childbearing age, who practice ruthless and continuous sexual abstinence. Pregnancy tests must have a minimum sensitivity of 25 mIU / ml. The test must confirm that the patient is not pregnant during the initiation of lenalidomide treatment. Ideally, a pregnancy test, writing out a prescription and dispensing should take place on the same day. Lenalidomide should be given to women of childbearing age within 7 days of being prescribed. Pregnancy testing under the supervision of a physician must be repeated every 4 weeks during treatment, and 4 weeks after treatment, except in cases of confirmed sterilization by tubal ligation. These tests should be performed on the day of the visit during which the medicine is prescribed or 3 days before the visit to the doctor registering the medicine. As a precautionary measure, men taking lenalidomide must understand the risk of teratogenicity of the drug and the need to use condoms (even if the man has undergone vasectomy in the past) during treatment and up to one week after the last dose and / or termination of lenalidomide treatment in case of sexual intercourse with a pregnant woman or a woman of childbearing potential not using effective contraceptives, and if the partner becomes pregnant when a man takes lenalidomide or shortly after discontinuing treatment, they must understand the need to inform their attending physician; it is recommended that the partner is referred to a doctor who specializes or has experience in the field of teratology, to conduct research and to obtain advice. During treatment with lenalidomide and for 1 week after treatment, the patient can not donate blood. Co-administration of lenalidomide and dexamethasone in patients with multiple myeloma is associated with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and thromboembolic artery disease (mainly myocardial infarction and cerebrovascular events). In patients with myelodysplastic syndromes, lenalidomide monotherapy was also associated with the risk of venous thromboembolism (mainly deep venous thrombosis and pulmonary embolism), but to a lesser extent than in patients with multiple myeloma. Patients with known risk factors for thromboembolism (including previous episodes of thrombosis) should be closely monitored. Action should be taken to minimize all possible risk factors (eg smoking, hypertension and hyperlipidemia).Factors affecting erythropoiesis or other drugs that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution. At hemoglobin concentration> 12 g / dl, treatment with factors affecting erythropoiesis should be stopped. It is recommended that patients and physicians pay special attention to the signs and symptoms of thromboembolism. The prophylactic use of anticoagulants is recommended, especially in patients with additional risk factors for thrombosis. If you have any episodes of thromboembolism, stop treatment and start standard anticoagulant therapy. After stabilizing the patient in anticoagulant therapy and after controlling any symptoms of thromboembolism, according to risk assessment and potential benefits, lenalidomide may be re-initiated at the initial dose. Particularly cautiously used in patients with risk factors for myocardial infarction, measures should be taken to minimize all risk factors for which it is possible (eg smoking, hypertension and hyperlipidemia). To control the cytopenia before starting treatment with lenalidomide, weekly for the first 8 weeks of treatment and then once a month, blood counts should be performed, including the number of white blood cells with smear, platelet counts, hemoglobin and hematocrit. Patients should be advised to report febrile episodes promptly; it may be necessary to reduce the dose of the drug. If neutropenia occurs, growth factors should be considered. Caution should be exercised when lenalidomide is co-administered with other myelosuppressive agents. It is recommended that patients and physicians pay particular attention to signs and symptoms of bleeding, including petechiae and nosebleeds; it may be necessary to reduce the dose. There may be complications in the form of tumor lysis syndrome. The risk of tumor lysis syndrome refers to patients with a larger tumor size prior to treatment; these patients should be closely monitored and appropriate precautions should be taken. Particular attention should be paid to the possibility of a second primary tumor. Before starting treatment and during treatment, the patient should be carefully examined using standard oncological screening methods, whether they have a second primary tumor and implement treatment as indicated. In patients treated with both lenalidomide and Dexamethasone, cases of hepatic failure (including fatal cases) have been reported. Ingested viral hepatitis, elevated liver enzymes and antibiotic therapy can be risk factors. Liver function should be monitored, particularly in patients with a history of viral hepatic infection or when lenalidomide is used concomitantly with hepatic impairment. Abnormal liver function tests have been commonly reported. Hepatic dysfunctions confirmed by the results of the tests were basically asymptomatic and resolved after discontinuation of treatment. After the parameters return to their initial values, a lower dose may be considered. In elderly patients and / or patients with impaired activities, the dose should be carefully selected and renal function monitored. During the treatment, thyroid function should be monitored due to the risk of hypothyroidism. A potential neurotoxic effect of lenalidomide associated with long-term use can not be excluded. The use of lenalidomide should be discontinued if exfoliative or bladder rashes occur, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected; you should not resume treatment after these reactions have subsided. In the case of other forms of skin reactions, depending on the severity, discontinuation or termination of treatment should be considered. Close follow-up should be given to patients who have experienced allergic reactions during thalidomide therapy due to the risk of a cross-reactivity between lenalidomide and thalidomide. Patients who have experienced severe rash in the past due to thalidomide therapy should not receive lenalidomide. The safety and efficacy of the preparation has not yet been established in children from 0 to 17 years of age - no data are available.Due to the lactose content, the preparation should not be used in patients with rare hereditary galactose intolerance, lactase deficiency (Lapp type) or malabsorption of glucose-galactose.

Lenalidomide has a structure similar to that of thalidomide, which is teratogenic in humans and causes severe, life-threatening congenital malformations. Lenalidomide caused congenital malformations similar to those described after thalidomide in monkeys. Lenalidomide is contraindicated during pregnancy. Women of childbearing potential must use an effective method of contraception. If a woman becomes pregnant during lenalidomide treatment, treatment must be discontinued and the patient should be referred to a specialist experienced in evaluating the teratogenic effect of the treatment to carry out the assessment and to obtain appropriate advice. Lenalidomide is present in human semen at extremely low concentrations during treatment and is undetectable in human semen 3 days after the end of drug administration to a healthy male. As a precautionary measure, and taking into account specific populations with prolonged excretion times, as in the case of renal failure, all male patients using lenalidomide must use condoms throughout treatment, during an interruption of treatment and for 1 week after treatment (even if the male in the past he underwent a vasectomy procedure) if the partner is pregnant or is of childbearing age and does not use contraception. If the partner of a lenalidomide-treated man becomes pregnant, it is recommended that he or she be referred to a doctor who specializes in or has experience in teratology. It is not known whether lenalidomide is excreted in human milk. Breast-feeding should be discontinued during treatment with lenalidomide.

Adverse reactions observed in patients with multiple myeloma and patients with myelodysplastic syndromes. Very common: pneumonia, upper respiratory tract infection, bacterial, viral and fungal infections (including opportunistic infections), thrombocytopenia, neutropenia, anemia, haemorrhagic disorders, leukopenia, hypokalemia, decreased appetite, peripheral neuropathies (excluding motor neuropathy), dizziness , tremor, dysgeusia, headache, blurred vision, episodes of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism), dyspnea, nasopharyngitis, pharyngitis, bronchitis, epistaxis, constipation, diarrhea, abdominal pain, nausea, vomiting, rash, dry skin, pruritus, muscle cramps, bone pain, pain and discomfort associated with musculoskeletal and connective tissue, joint pain, muscle pain, fatigue, edema (including peripheral edema), fever, symptoms Flu-like (including fever, cough, muscle pain, pain in my skeletal, headache, tremor). Common: sepsis, sinusitis, pancytopenia, neutropenic fever, hypothyroidism, hypomagnesaemia, hypocalcaemia, dehydration, iron overload, hypophosphatemia, hyperglycaemia, reduced appetite, depression, mood changes, ataxia, balance disorders, cerebrovascular events, fainting, reduced severity vision, cataracts, deafness (including hearing loss), tinnitus, atrial fibrillation, bradycardia, myocardial infarction, atrial fibrillation, congestive heart failure, tachycardia, heart failure, hypotension, hypertension, ecchymosis, hematoma, acute respiratory distress, bronchitis, bleeding from the gastrointestinal tract (including: rectal bleeding, bleeding from bleeding nodules, bleeding from stomach ulcers, gum bleeding), dry mouth, stomatitis, dysphagia, indigestion, toothache, abnormal liver function tests, soreness, excessive perspiration, excessive skin pigmentation, eczema, swelling of the joints, muscle weakness, back pain, hematuria, urinary retention, urinary incontinence, renal failure, erectile dysfunction, chest pain, lethargy, falls, contusion. Uncommon: basal cell carcinoma, squamous cell carcinoma, haemolysis, autoimmune haemolytic anemia, hemolytic anemia, hypercoagulability, coagulopathy, hypersensitivity reaction, libido loss, intracranial hemorrhage, transient ischemic attack, ischemic stroke, blindness, arrhythmias, QT interval prolongation, atrial flutter , additional ventricular contractions, ischemia, peripheral ischemia, intracranialthrombophlebitis, colitis, inflammation of the caecum, liver failure, skin discoloration, hypersensitivity to light, swelling of the joints, acquired Fanconi syndrome, renal tubular necrosis. Rarely: tumor decay syndrome, Stevens-Johnson syndrome, toxic epidermal epidermal necrolysis. Not known: interstitial alveolitis, pancreatitis, acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic / cholestatic hepatitis. In clinical trials of previously treated patients with myeloma receiving lenalidomide and dexamethasone, an increase in the incidence of secondary primary tumors was observed. Non-invasive second primary cancers include basal cell or squamous skin cancers. Most invasive second primary tumors were solid tumors. Among the invasive second primary tumors, patients who received lenalidomide in combination with melphalan or immediately after administration of high doses of melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and solid tumors were observed. In patients with myelodysplastic syndromes, baseline variables, including complex cytogenetic changes and mutations within the TP53 gene, are associated with progression to acute myeloid leukemia in patients dependent on transfusions with 5q deletion. The estimated cumulative risk of 2-year progression to acute myeloid leukemia in patients with isolated 5q deletion was 13.8%, compared to 17.3% in patients with 5q deletion and one more cytogenetic abnormality. In lenalidomide studies in myelodysplastic syndromes with low or intermediate-1 risk, a 2-year progression to acute myeloid leukemia equal to 27.5% was obtained in IHC-p53 positive patients (1% cut off level with respect to strong nuclear staining cellular, using immunochemical determination of the p53 protein as a marker of mutation within the TP53 gene) and 3.6% in the negative patients in the IHC-p53 test. In the group of positive patients in the IHC-p53 test, progression to acute myeloid leukemia was less frequent in patients who achieved independence from transfusions than in non-responders.

Orally. Treatment should be supervised by a physician experienced in the use of anti-cancer therapies.Multiple myeloma. The starting dose of lenalidomide is 25 mg once a day on days 1 - 21. in repeated 28-day cycles. The dose of dexamethasone is 40 mg once a day on days 1 to 4, 9 to 12. and 17-20. each 28-day cycle for the first 4 cycles of treatment, followed by 40 mg once a day on days 1-4. every 28 days. Dosing is continued or modified based on the results of laboratory tests. The dose of dexamethasone to be used should be assessed taking into account the patient's condition and the severity of the disease. Lenvenomide therapy must not be initiated if the absolute neutrophil count (ANC) is <1.0 x 10⁹/ l and (or) the platelet count is <75 x 10⁹/ l or <30 x 10⁹/ l, depending on the infiltration of the bone marrow by plasma cells.The recommended dose adjustment during treatment and when resuming treatment. Dose adjustments are recommended for neutropenia or grade 3 or 4 thrombocytopenia or other grade 3 or 4 toxic effects considered to be related to lenalidomide treatment. The dosage of lenalidomide can be modified by 3 levels, according to the scheme: starting dose of 25 mg; dose level -1 = 15 mg; dose level -2 = 10 mg; dose level -3 = 5 mg.thrombocytopenia. If the platelet count first decreases <30 x 10⁹/ l lenalidomide should be discontinued when the platelet count returns to ≥30 x 10⁹/ l you can resume lenalidomide at a dose of -1; if the platelet count drops again <30 x 10⁹/ l discontinuation of lenalidomide should the platelet count return to ≥30 x 10⁹/ l you can restart treatment with lenalidomide at the Next lower dose (dose level -2 or -3) once a day. Do not use doses below 5 mg daily.neutropenia. If the neutrophil count (ANC) first decreases <0.5 x 10⁹/ l lenalidomide should be discontinued if the ANC count returns to ≥0.5 x 10⁹/ l and neutropenia is the only observed toxic effect, lenalidomide may be restarted at the initial dose once a day; if the ANC returns to the value ≥ 0.5 x 10⁹/ l and there are dose-dependent haematological toxicities other than neutropenia, lenalidomide may be resumed at a dose level of -1 daily; if the ANC decreases again <0.5 x 10⁹/ l lenalidomide should be discontinued when ANC returns to ≥ 0.5 x 10⁹/ l you can restart treatment with lenalidomide at the next lower dose (dose level -1, -2 or -3) once a day. Do not use doses below 5 mg daily. If neutropenia occurs, the physician should consider the use of growth factors in therapeutic management.Myelodysplastic syndromes. Lenvenomide treatment must not be initiated if the absolute neutrophil count (ANC) is <0.5 x 10⁹/ l and (or) the platelet count is <25 x 10⁹/ L. The starting dose of lenalidomide is 10 mg once a day on days 1 - 21. in repeated 28-day cycles. Dosing is continued or modified based on clinical observations and laboratory results.The recommended dose adjustment during treatment and when resuming treatment. Dose adjustments are recommended for neutropenia or grade 3 or 4 thrombocytopenia or other grade 3 or 4 toxic effects considered to be related to lenalidomide treatment. The dosage of lenalidomide can be modified by 3 levels, according to the schedule: starting dose of 10 mg once a day on days 1 - 21. in repeated 28-day cycles; dose level -1 = 5.0 mg once a day on days 1 - 28. in repeated 28-day cycles; dose level -2 = 2.5 mg once a day on days 1 - 28. in repeated 28-day cycles; dose level -3 = 2.5 mg every other day on days 1 - 28. every 28 days.thrombocytopenia. If the platelet count decreases <25 x 10⁹/ l lenalidomide should be discontinued when the platelet count returns to ≥25 x 10⁹/ l - <50 x 10⁹/ l at least 2 times within ≥7 days or if the number of plaques at any moment increases again to ≥50 x 10⁹/ l you can resume lenalidomide treatment at the next lower dose (dose level -1, -2 or -3).neutropenia. If the neutrophil count (ANC) decreases <0.5 x 10⁹/ l lenalidomide should be discontinued if the ANC count returns to ≥0.5 x 10⁹/ l you can resume lenalidomide treatment at the next lower dose (dose level -1, -2 or -3). In the event of other grade 3 or grade 4 toxicities that have been associated with the use of lenalidomide, treatment should be discontinued and restarted after resolution of toxicity up to ≤2, as determined by the physician. If second or third grade skin rash occurs, discontinuation or discontinuation of lenalidomide should be considered. The use of lenalidomide should be discontinued if there is a vasomotor edema, grade 4 rash, skin rash associated with blistering rash or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected. If treatment has been interrupted because of these symptoms, do not resume treatment after they have resolved. The use of lenalidomide should be discontinued in patients who have not experienced at least a minimum response from erythroid cells within 4 months of starting treatment, manifested by at least a 50% decrease in the need for transfusions or in the absence of transfusions, increased by 1g / dL in hemoglobin concentration.Special groups of patients. Elderly patients should be cautious when choosing a dose and monitor their renal function.Patients with impaired renal function. Caution should be exercised when choosing a dose and it is advisable to monitor renal function. No dose adjustment is required in patients with mild renal impairment and multiple myeloma or myelodysplastic syndromes. In patients with moderate or severe renal impairment or end stage renal failure, the following dose adjustment is recommended at the beginning of treatment.Multiple myeloma. 30 ≤ creatinine clearance (CCr) <50 ml / min - 10 mg once daily on days 1 - 21. in repeated 28-day cycles (the dose can be increased after 2 cycles to 15 mg once a day in the absence of response to treatment and with good tolerance of treatment by the patient); CCr <30 ml / min, without dialysis - 7.5 mg once a day on days 1 - 21.in repeated 28-day cycles (in countries where the product is available in capsules with 7.5 mg power) or 15 mg every other day (the dose can be increased to 10 mg once a day if the patient tolerates the treatment well); CCr <30 ml / min, need dialysis - 5 mg once a day on days 1 - 21. in repeated 28-day cycles (on dialysis days the dose should be administered after dialysis).Myelodysplastic syndromes: 30 ≤ CCr <50 ml / min - starting dose: 5 mg once a day on days 1 - 21. in repeated 28-day cycles, a dose of -1: 2.5 mg once a day on days 1 - 28. in repeated 28-day cycles, a dose of -2: 2.5 mg every other day on days 1 - 28. in repeated 28-day cycles; CCr <30 ml / min, without dialysis - initial dose: 2.5 mg once a day on days 1 - 21. in repeated 28-day cycles, a dose of -1: 2.5 mg every other day on days 1 - 28. in repeated 28-day cycles, a dose of -2: 2.5 mg 2 times a week on days 1 - 28. in repeated 28-day cycles; CCr <30 ml / min, need dialysis - initial dose: 2.5 mg once a day on days 1 - 21. in repeated 28-day cycles, a dose of -1: 2.5 mg every other day on days 1 - 28. in repeated 28-day cycles, a dose of -2: 2.5 mg 2 times a week on days 1 - 28. in repeated 28-day cycles (on dialysis days the dose should be administered after dialysis).Patients with impaired liver function. Lenalidomide has not been officially studied in patients with impaired hepatic function and there are no specific dosing recommendations.
The capsules should be swallowed whole with water, regardless of the meal. Do not open, break or chew the capsules. It should be taken at approximately the same time each day. If less than 12 hours have passed since the prescribed hour of taking the missed dose, the patient may take an overdue dose; if it has been more than 12 hours, the patient should no longer take an overdue dose and take the next dose at the scheduled time the next day.