Lenalidomide-native - instructions for use, dose, side effects, contraindications

Name component	2.5 mg	5 mg	7.5 mg	10 mg	15 mg	20 mg	25 mg
Contents of the capsule:
Active substance
Lenalidomide	2,5	5,0	7,5	10,0	15,0	20,0	25,0
Excipients
Lactose Monohydrate	73,5	147,0	144,5	294,0	289,0	244,5	200,0
Microcrystalline cellulose	20,0	40,0	40,0	80,0	80,0	120,5	159,0
Croscarmellose sodium	3,0	6,0	6,0	12,0	12,0	12,0	12,0
Magnesium stearate	1,0	2,0	2,0	4,0	4,0	3,0	4,0
Weight of capsule contents	100,0	200,0	200,0	400,0	400,0	400,0	400,0
Capsule, composition in %
Capsule number	4	2	2	0	0	0	0
Housing
Gelatin	Before 100	Up to 100	Up to 100	Up to 100	Up to 100	Up to 100	Up to 100
Titanium dioxide	2,0000	2,0000	0,5000	0,5000	2,0000	2,0000	2,0000
Dye iron oxide yellow	-	-	0,4500	0,4500	-	-	-
Iron Oxide Red Dye Oxide	-	-	0,2000	0,2000	-	-	-
Dye azorubin (E 122)	-	-	0,1400	0,1400	-	-	-
Coloring indigotine	-	-	-	-	0,0905	-	-
Cover
Gelatin	Up to 100	Up to 100	Up to 100	Up to 100	Up to 100	Up to 100	Up to 100
Titanium dioxide	0,5000	2,0000	0,5000	0,5000	2,0000	0,5000	1,0000
Dye iron oxide yellow	0,4500	-	0,4500	0,4500	-	0,4500	-
Iron Oxide Red Dye Oxide	0,2000		0,2000	0,2000		0,2000
Dye azorubin (E 122)	0,1400	-	0,1400	0,1400	-	0,1400	-
Coloring indigotine	-	-	-	-	0,0905	-	0,1333

Description:

Dosage 2.5 mg: hard gelatin capsules number 4, body white, lid red.

Dosage 5 mg: hard gelatin capsules №2, white body, white lid.

Dosage 7.5 mg: hard gelatin capsules №2, the case of red color, the lid of red color.

Dosage of 10 mg: hard gelatin capsules №0, body of red color, lid of red color.

Dosage of 15 mg: hard gelatin capsules №0, the case of blue color, the lid of blue color.

Dosage of 20 mg: hard gelatin capsules №0, white body, lid of red color.

Dosage of 25 mg: hard gelatin capsules №0, body of white color, lid of blue color.

The contents of the capsules are white or white with a yellowish tinge powder.

Pharmacotherapeutic group:Immunomodulating agent

ATX: & nbsp

L.04.A.X.04 Lenalidomide

L.04.A.X Other immunosuppressants

Pharmacodynamics:

Lenalidomide is the leading compound of a new class of immunomodulators that possesses both immunomodulating and anti-angiogenic properties. Lenalidomide inhibits the secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-1β), IL-6 and IL-12, from liposaccharides (LPS) -stimulated peripheral mononuclear blood cells (PMCC).

Lenalidomide increases the production of anti-inflammatory cytokine IL-10 from LPS-stimulated PMCK, resulting in inhibition of expression, but not enzymatic activity of cyclooxygenase-2 (COX-2). Lenalidomide induces the proliferation of T cells and increases the synthesis of IL-2 and interferon-1γ, and also increases the cytotoxic activity of the own killer cells.

Lenalidomide inhibits the proliferation of cells of various lines of hematopoietic tumors, mainly those that have cytogenetic defects of the chromosome 5.

On the model of differentiation of erythroid progenitor cells lenalidomide induces the expression of fetal hemoglobin, which can be judged by differentiation Cd34⁺ stem hemopoietic cells.

Lenalidomide inhibits angiogenesis, blocking the formation of microvessels and endothelial canals, as well as the migration of endothelial cells on the model of angiogenesis in vitro. Besides, lenalidomide inhibits the synthesis of the proangiogenic vascular endothelial growth factor by means of the PC-3 prostate tumor cells.

Pharmacokinetics:

Lenalidomide is a racemic mixture of two optically active forms: S(-) and R(-) with a total optical rotation equal to zero.

Suction

After ingestion by healthy volunteers lenalidomide quickly absorbed; with the maximum concentration achieved after 0.5-2 hours after a single dose.

The pharmacokinetic distribution is linear. Maximum concentration (FROM_m_Oh) and the area under the "concentration-time" curve (AUC) increase in proportion to the increase in dose. Repeated techniques of lenalidomide do not lead to its cumulation. Lenalidomide can be taken regardless of food intake. FROM_m_Oh and AUC increase in proportion with both a single and repeated admission of lenalidomide. According to FROM_m_Oh and AUC The exposure of lenalidomide to patients with multiple myeloma is higher than that of healthy volunteers, which is explained by a lower clearance to filtration ratio (CL/F) in patients with multiple myeloma compared with healthy volunteers.

Distribution

In vitro binding (¹⁴C) -lenalidomide with plasma proteins of patients with multiple myeloma and healthy volunteers is 23% and 29%, respectively. Lenalidomide is present in the semen (<0.01% of the dose) after taking it at a dose of 25 mg per day, but is not detected in the seminal fluid 3 days after discontinuation.

Metabolism

Results of metabolic studies in vitro indicate that the isoenzymes of the cytochrome P450 system do not participate in the metabolism of lenalidomide in humans, so metabolic drug interactions with the combined use of lenalidomide and drugs that inhibit the isoenzymes of the cytochrome P450 system are unlikely. Research results in vitro demonstrate the lack of inhibitory effect of lenalidomide on isozymes CYP1A2, CYP2C9, CYP2C19, CYP2D6,CYP2E1, CYP3A or UGT1A1. Thus, it is unlikely that lenalidomide will promote the development of any clinically significant drug interactions with the simultaneous administration of these isoenzymes with substrates.

According to research in vitro Lenalidomide is not a substrate of the human breast cancer resistance protein (BCRP), carriers of the multiple drug resistance protein (MRP) MRP1, MRP2 or MRP3, carriers of organic anions (OAT) OAT1 or OAT3, a polypeptide carrier of organic anions 1B1 (OATP1B1), carriers of organic cations (OCT) of OST1 and OST2, a carrier protein of the family MATE (multidrug and toxin extrusion protein), MATE1 and original carriers of organic cations (OCTN), OCTN1 and OCTN2.

It is not known whether lenalidomide inhibitory properties for energy-dependent vectors BSEP (Bile Salt Export Pump - pump for the export of bile acids), BCRP, MRP2, ОАТ1, ОАТ3, ОАТР1В1, ОАТР1В3 or ОСТ2 in vivo, while that of inhibitory action in vitro in concentrations up to 20 μmol it is not noted.

Excretion

Lenalidomide is practically not metabolized in the body, as 82% of its dose is excreted by the kidneys in an unchanged form. Thus, the renal clearance exceeds the rate of glomerular filtration, however, the excretion process is also of an active nature.

When taken at recommended doses (5-25 mg / day), the half-life of lenalidomide is approximately 3 hours in healthy volunteers and from 3 to 5 hours in patients with multiple myeloma.

Pharmacokinetics the separate groups of patents

Elderly patients

Special clinical studies to assess the pharmacokinetics of lenalidomide in elderly and older patients have not been conducted. Given the increased likelihood of renal dysfunction in the elderly, caution should be exercised in selecting a dose of lenalidomide and perform close monitoring of kidney function while undergoing therapy.

Patients with impaired renal function

Stach does not differ in patients with normal and impaired renal function. In this case, the excretion of lenalidomide slows in proportion to the degree of renal function impairment. The decrease in creatinine clearance (CK) below 50 ml / min is accompanied by an increase AUC. Values AUC approximately 2.5, 4 and 5 times higher in patients with moderate to severe renal insufficiency and terminal renal failure (TSTD), respectively, compared with the group combining patients with normal renal function and patients with mild renal insufficiency. The half-life of lenalidomide rises from approximately 3.5 hours (in patients with QC above 50 ml / min) to approximately 9 hours (in patients with SC less than 50 ml / min). Approximately 30% Lenalidomide is excreted from the body during a 4-hour dialysis session.

Patients with hepatic impairment

Population analysis of pharmacokinetic data of patients with mild hereditary insufficiency showed no effect of mild hepatic insufficiency on the clearance of lenalidomide (exposure in blood plasma).Data on patients with hepatic insufficiency of moderate and severe severity are absent.

Other factors

Population analysis of pharmacokinetic data showed no clinically significant effect of body weight (33-135 kg), sex, race and type of oncohematological disease on lenalidomide clearance in adult patients.

Data on the admission of lenalidomide to breast milk are not available.

Indications:Lenalidomide in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) who received at least one line of therapy.

Contraindications:

- Hypersensitivity to lenalidomide or other components of the drug.

- Pregnancy and the period of breastfeeding.

- Preserved reproductive potential, except in cases when it is possible to comply with all the necessary conditions of the Pregnancy Protection Program specified in the section "Special instructions".

- Impossibility or inability to comply with the necessary contraceptive measures specified in the section "Special instructions".

- Child age (application data not available).

Carefully:

- In elderly patients with renal and / or hepatic insufficiency, as well as in patients with deep vein thrombosis (including in history).

- When combined with drugs that increase the risk of thrombosis, namely, with drugs that have erythropoietic activity, and hormone replacement therapy.

- In patients with hereditary lactose intolerance, lactase deficiency or impaired absorption of glucose-galactose, since the capsules of the drug Lenalidomide-native contain lactose.

Pregnancy and lactation:

Lenalidomide is a structural analogue of thalidomide, which has a pronounced teratogenic effect. It is known that the reception of thalidomide by pregnant women causes severe and life-threatening violations of the internal organs of the fetus. Experimental studies on monkeys showed results similar to those previously described for thalidomide. The risk of developing birth defects is very high if lenalidomide is used during pregnancy. Women with a preserved reproductive potential should be treated with lenalidomide during effective treatment with effective methods of contraception.Lenalidomide should be discontinued if a woman is diagnosed with pregnancy and the patient should be referred for advice to a doctor who has experience in monitoring pregnant women for evaluation and clinical recommendations. In a case where a woman who is a partner of a patient receiving lenalidomide treatment is diagnosed as pregnant, the woman is also referred to a specialist in teratology to assess the situation and clinical recommendations.

It is not known whether the lenalidomide in breast milk. In this regard, during treatment with lenalidomide, breastfeeding should be discontinued.

The results of a study of reproductive function performed on rats with lenalidomide at a dose of 500 mg / kg (this dose exceeds the therapeutic doses for humans - 25 mg and 10 mg, approximately 200-500 times, taking into account the surface area of the body), did not demonstrate impairment of fertility or toxicity for the body of parents.

Dosing and Administration:

Treatment with drug Lenalidomide-native It is necessary to spend under supervision of the doctor-chemotherapist.

Lenalidomide-native is intended only for oral administration.

Capsules of the preparation Lenalidomide-native, which can not be opened, broken or chewed, it is recommended to take it every day at the same time before and after eating, swallowing whole and squeezed with water.

The recommended initial dose of the drug Lenalidomide-native is 25 mg orally once a day in 1-21 days of repeated 28-day cycles.

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

The dose should be changed on the basis of clinical and laboratory data. The doctor should carefully select the dose of dexamethasone, taking into account the condition of the patient and the stage of the disease.

If from the moment of missed intake of the drug Lenalidomide-native less than 12 hours have elapsed, the patient may take this missed dose of the drug, and if more than 12 hours pass, the missed dose should not be taken. The next dose of the drug Lenalidomide-native should be taken the next day at the usual time. Lenalidomide treatment should not be started if the absolute number of neutrophils is <1.0 x 10⁹/ l and / or the number of platelets <75 x 10⁹/ l or depending on the infiltration of bone marrow by plasma cells the amount of platelets <30 x 10⁹/ l.

Dose change during treatment or its resumption

Below are the possibilities of dose changes in the development of neutropenia, thrombocytopenia or other types of toxicity of 3 and 4 severity, the relationship of which with the use of lenalidomide can not be excluded.

Table 1. Step-by-step dose reduction

Initial dose	25 mg
Dose of the 1st level	15 mg
Dose Level 2	10 mg
Dose Level 3	5 mg

Table 2. Thrombocytopenia

Number of platelets	Recommendations
Decreased <30 x 10⁹/ l	Stop drug treatment Lenalidomide-native.
Has recovered ≥ 30 x 10⁹/ l	Resume drug treatment Lenalidomide-native in a dose of 1 level 1 time per day.
Each subsequent decrease of <30 x 10⁹/ l	Stop drug treatment Lenalidomide-native.
Has recovered ≥ 30 x 10⁹/ l	Resume drug treatment Lenalidomide-native in a smaller dose (dose of 2 or 3 levels) once a day. Do not use a dose of the drug below 5 mg per day.

Table 3. Neutropenia

Number of neutrophils	Recommendations
Decreased <0.5 x 10⁹/ l	Stop drug treatment Lenalidomide-native.
Has recovered ≥ 0.5 x 10⁹/ l and neutropenia - the only manifestation of toxicity	Resume drug treatment Lenalidomide-native in the initial dose 1 time per day.
Has recovered ≥ 0.5 x 10⁹/ l and there are other manifestations of toxicity	Resume drug treatment Lenalidomide-native in a dose of 1 level 1 time per day.
For each subsequent decrease <0.5 x 10⁹/ l	Stop drug treatment Lenalidomide-native.
Has recovered ≥ 0.5 x 10⁹/ l	Resume drug treatment Lenalidomide-native in a smaller dose (dose of 2 or 3 levels) once a day. Do not use a dose of the drug below 5 mg per day.

Application the separate patient groups

Children and teens

A drug Lenalidomide-native is not recommended for use in children under the age of 18 due to lack of data on efficacy and safety.

Elderly patients

There was no difference in the efficacy and safety of lenalidomide, depending on age, although the sensitivity to lenalidomide in elderly and elderly patients can not be ruled out. Since elderly and older patients are more likely to have renal dysfunction, the dose of lenalidomide should be carefully chosen, while it is recommended that kidney function be monitored during treatment.

Patients with hepatic impairment

The pharmacokinetics of lenalidomide has not been studied in patients with impaired hepatic function, so it is not possible to provide recommendations for dose changes in this group of patients.

Patients with impaired renal function

Lenalidomide is excreted mainly by the kidneys. In this regard, the risk of toxic reactions can increase with a violation of kidney function. When the drug is prescribed Lenalidomide-native Patients with impaired renal function are advised to follow the recommendations below.

For patients with mild renal insufficiency, a dose change of lenalidomide is not required. The table shows the initial doses of lenalidomide, recommended depending on the severity of renal dysfunction (for patients with moderate and severe renal insufficiency, as well as terminal stage of renal failure).

Table 4. Initial dose of lenalidomide depending on the severity of renal dysfunction

Kidney function status	The recommended dose of the drug is lenalidomide-native (from 1 to 21 days during repeated 28-day cycles)
Renal failure of moderate severity 30 ml / min ≤ KK <50 ml / min	10 mg once a day *
Renal failure of severe severity CK <30 ml / min, no dialysis required	15 mg every other day ** 7.5 mg once daily
Terminal stage of renal insufficiency CK <30 ml / min, dialysis is required	5 mg once a day. On the day of dialysis, the dose of the drug should be taken after the end of the dialysis session.

* The dose of lenalidomide can be increased to 15 mg once a day after 2 cycles of therapy in the absence of response to therapy with good tolerability.

** The dose of lenalidomide can be increased to 10 mg once a day with good tolerability of therapy.

Side effects:

In patients with multiple myeloma receiving lenalidomide in combination with dexamethasone, the most common adverse reactions are: weakness (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhea (38.5%), muscle cramps (33, 4 %), anemia (31.4%), thrombocytopenia (21.5%) and rash (21.2%).

The most severe adverse reactions include:

- Venous thromboembolism (deep vein thrombosis, pulmonary embolism).

- Neutropenia 4 degrees of severity.

Neutropenia and thrombocytopenia are most dependent on the dose of lenalidomide, which allows them to be controlled by reducing the dose of lenalidomide / dexamethasone.

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems. The incidence of adverse reactions is estimated as follows: the occurrence of "very often" -> 10%; "often" -> 1% and <10%, "infrequently" -> 0.1% and <1%, "rarely" -> 0.01% and <0.1%, "very rarely" - <0, 01%, including individual messages, "frequency unknown".

Undesirable reactions (in total)

Violations of the blood and lymphatic system: very often - thrombocytopenia, neutropenia, anemia, hemorrhagic disorders, leukopenia; often - febrile neutropenia, pancytopenia; infrequently - hemolysis, autoimmune hemolytic anemia, hemolytic anemia.

Immune system disorders: infrequently, hypersensitivity reactions.

Disorders from the endocrine system: often - hypothyroidism, hyperthyroidism.

Disorders from the metabolism and nutrition: very often - hypokalemia, decreased appetite; often hypomagnesemia, hypocalcemia, dehydration.

Disorders of the psyche: very often - depression, insomnia; infrequently - loss of libido.

Disturbances from the nervous system: very often - peripheral neuropathy (with the exception of motor neuropathy), dizziness, tremor, taste perversion,headache; often - ataxia, imbalance.

Disturbances on the part of the organ of sight: very often - blurred vision; often - reduced visual acuity, cataract.

Hearing disorders and labyrinthine disorders: often - deafness (including deafness), tinnitus.

Heart Disease: often - atrial fibrillation, bradycardia; infrequent - arrhythmia, lengthening of QT interval, atrial flutter, ventricular extrasystole.

Vascular disorders: very often - thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism); often - arterial hypotension, arterial hypertension, ecchymosis.

Disturbances from the respiratory system, chest and mediastinal organs: very often - shortness of breath, nasopharyngitis, pharyngitis, bronchitis, nosebleeds.

Disorders from the gastrointestinal tract: very often - constipation, diarrhea, nausea, vomiting; often - gastrointestinal bleeding (including rectal, hemorrhoidal, gingival bleeding and bleeding in peptic ulcer), abdominal pain, dry mouth, stomatitis, dysphagia; infrequently - colitis, tiflitis.

Disturbances from the liver and bile ducts: often - deviation of the values of functional liver samples from the norm; infrequently liver failure; frequency unknown - acute hepatic insufficiency, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic / cholestatic hepatitis.

Disturbances from the skin and subcutaneous tissues: very often - a rash; often - hives, hyperhidrosis, dry skin, itching, hyperpigmentation of the skin, eczema, erythema; infrequent - skin color disorder, photosensitivity reaction.

Disturbances from musculoskeletal and connective tissue: very often - muscle cramps, bone pain, pain and discomfort from the osteo-muscular and connective tissue, arthralgia; often - swelling of the joints, muscle weakness, myalgia.

Disorders from the kidneys and urinary tract: often - hematuria, urinary retention, urinary incontinence; infrequently - acquired Fanconi syndrome.

Violations of the genitals and mammary gland: often - erectile dysfunction.

Infectious and parasitic diseases: very often - pneumonia, upper respiratory tract infections; often - sepsis, bacterial, viral and fungal infections (including opportunistic infections), sinusitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently - basioma, squamous cell carcinoma of the skin.

General disorders and disorders at the site of administration: very often - fatigue, swelling (including peripheral), fever, flu-like syndrome (including fever, myalgia, musculoskeletal pain, headache and chills); often - chest pain, lethargy, asthenia.

Undesirable reactions of 3-4 degrees of severity

Violations of the blood and lymphatic system: very often - thrombocytopenia, neutropenia, leukopenia; often - febrile neutropenia, pancytopenia, anemia; infrequently - hypercoagulability, coagulopathy.

Disorders from the metabolism and nutrition: often - hypokalemia, hypocalcemia, hypophosphatemia, hyperglycemia, diabetes mellitus, hyponatremia, hyperuricemia, gout, decreased appetite, weight loss.

Disorders of the psyche: often - depression, insomnia.

Disturbances from the nervous system: often - stroke, dizziness, fainting; infrequently - intracranial hemorrhage, transient ischemic attack, ischemia of the brain.

Disturbances on the part of the organ of sight: often - cataract; infrequently, blindness.

Heart Disease: often - myocardial infarction, myocardial ischemia, atrial fibrillation, heart failure, congestive heart failure, tachycardia.

Vascular disorders: very often - thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism); often - vasculitis; infrequently - ischemia, peripheral ischemia, thrombosis of the intracranial venous sinus.

Disturbances from the respiratory system, chest and mediastinal organs: often - respiratory distress syndrome, dyspnea; frequency unknown - interstitial pneumonitis.

Disorders from the gastrointestinal tract: often - diarrhea, constipation, nausea, abdominal pain; frequency unknown - pancreatitis, perforation of the gastrointestinal tract (including perforation of the diverticulum, small and large intestine).

Disturbances from the skin and subcutaneous tissues: often - a rash; infrequently - angioedema; rarely Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown - leukocytoclastic vasculitis.

Disturbances from musculoskeletal and connective tissue: often - muscle weakness, pain in the bones; infrequently - swelling of the joints.

Disorders from the kidneys and urinary tract: often - kidney failure; infrequently - tubular renal necrosis.

Infectious and parasitic diseases: often - pneumonia, bacterial, viral and fungal infections (including opportunistic infections), sepsis, bronchitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): often acute myeloid leukemia, myelodysplastic syndrome, squamous cell carcinoma of the skin; infrequently - acute T-cell leukemia, basal cell; rarely - lysis of the tumor, basal cell.

General disorders and disorders at the site of administration: often - increased fatigue, fever, asthenia.

Additional Information

Teratogenicity

Lenalidomide is a structural analogue of thalidomide, a substance with an active teratogenic effect and causing severe life-threatening developmental anomalies.

Lenalidomide induced monkey anomalies, similar to those described for thalidomide. If lenalidomide taken during pregnancy, then it is possible to predict a teratogenic effect, so lenalidomide contraindicated in pregnancy.

Neutropenia and thrombocytopenia

The use of a combination of lenalidomide with dexamethasone in patients with multiple myeloma is accompanied by an increase in the frequency of development of grade 4 neutropenia. Febrile neutropenia of the 4th degree of severity in patients taking the combination of lenalidomide with dexamethasone is not infrequent. The use of a combination of lenalidomide with dexamethasone in multiple myeloma is accompanied by an increased likelihood of thrombocytopenia of grade 3 and 4 severity.

Venous thromboembolism

The use of a combination of lenalidomide with dexamethasone in patients with multiple myeloma is associated with an increased risk of developing deep vein thrombosis and pulmonary embolism. The simultaneous administration of erythropoietic agents or the presence of deep vein thrombosis in a history may also increase the risk of thrombotic complications in this group of patients.

Myocardial infarction

In patients receiving lenalidomide, there are cases of the development of myocardial infarction, especially in the presence of known risk factors.

Hemorrhagic complications

Hemorrhagic complications are brought into conformity with systemic-organ classes: violations from the blood and lymphatic system; disorders of the nervous system (intracranial hemorrhage); violations of the respiratory system, chest and mediastinum (nasal bleeding); disorders of the gastrointestinal tract (rectal, hemorrhoidal, gingival bleeding); disorders of the kidneys and urinary tract (hematuria); violations of the vessels (ecchymosis).

Allergic reactions

There are reports of the development of allergic reactions / hypersensitivity reactions. A cross-reaction between lenalidomide and thalidomide is possible.

Severe skin reactions

There are reports of the development of Stevens-Johnson syndrome (SDS) and toxic epidermal necrolysis (TEN). Lenalidomide Do not prescribe to patients who have had severe forms of rash when taking thalidomide in an anamnesis.

Primary malignant tumors of other localization

New malignant neoplasms observed in patients with myeloma after the use of a combination of lenalidomide with dexamethasone, represented mainly basal cell or squamous cell carcinoma of the skin.

Acute myelogenous leukemia

Multiple myeloma

Cases of acute myelogenous leukemia are observed in patients with a newly diagnosed multiple myeloma receiving lenalidomide in combination with melphalan, or immediately after a high dose of melphalan and transplantation of autologous hematopoietic stem cells (autotransfusion).

Disturbances from the liver and bile ducts

There are reports of the following violations from the liver (frequency unknown): acute liver failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic / cholestatic hepatitis.

Rhabdomyolysis

There are reports of rare cases of rhabdomyolysis, in some of them lenalidomide used together with statins.

Thyroid gland diseases

There are reports of cases of hypothyroidism and hyperthyroidism.

Diseases of the gastrointestinal tract

There are reports of the occurrence of perforation of the gastrointestinal tract against the background of lenalidomide. Perforation of the gastrointestinal tract can lead to septic complications and fatal outcome.

Overdose:

A special algorithm for lenalidomide overdose in patients with multiple myeloma has not been developed, in spite of the fact that in studies on determining the dose range, some patients received doses of 150 mg, and in studies of single dose exposure up to 400 mg of lenalidomide. Toxic manifestations, which limited the dose in these studies, were exclusively hematological.

Interaction:

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

Digoxin

Simultaneous administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (FROM_m_Oh digoxin is 114%, a AUC_0-∞ 108%).Thus, against the background of lenalidomide treatment, it is recommended to monitor the concentration of digoxin.

Statins

There is an increased risk of rhabdomyolysis in the case of a joint use of statins and lenalidomide, which can be explained by the summation of the effect of these drugs. Careful clinical and laboratory monitoring is necessary especially during the first weeks of treatment.

Dexamethasone

Simultaneous single or multiple administration of dexamethasone (40 mg / day) does not have a clinically significant effect on the pharmacokinetics of lenalidomide with repeated admission at a dose of 25 mg / day.

Oral contraceptives

Dexamethasone, which is a mandatory component of the lenalidomide therapy regimen, can reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, you must use the means described in the Pregnancy Protection Program, indicated in the section "Special instructions".

Warfarin

There was no mutual influence on the pharmacokinetic parameters of lenalidomide and warfarin. Taking into account the use of dexamethasone in combination with lenalidomide, one can not exclude the influence of the latter on the effects of warfarin.Thus, against a background of combined therapy with lenalidomide and dexamethasone, careful monitoring of the concentration of warfarin is recommended.

Interaction with P-glycoprotein inhibitors (P-gp)

Lenalidomide in vitro is a substrate P-pg, but not an inhibitor P-pg. Simultaneous multiple application of a strong inhibitor P-pg - quinidine (600 mg twice daily), or a mild inhibitor P-pg/ substrate - tamsirolimus (25 mg), does not have a clinically significant effect on the pharmacokinetics of lenalidomide (25 mg / day). The pharmacokinetics of tessirolimus do not change when combined with lenalidomide.

Special instructions:

Lenalidomide treatment should be performed under the supervision of an experienced hematologist or chemotherapist.

Pregnancy Protection Program

Strict adherence to all requirements of the Pregnancy Protection Program should apply to both women and men.

For women with unsaved reproductive potential

A female patient or woman who is a partner of a male patient is not considered fertile in the presence of at least one of the following factors:

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

- early failure of the ovaries, confirmed by a gynecologist;

- bilateral salpingo-oophorectomy or hysterectomy in history;

- genotype XY, Turner's syndrome, anatomical defect of the uterus;

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

Lenalidomide in women with preserved reproductive potential contraindicated in those cases if the following conditions are not met:

- a woman should be aware of the possible teratogenic effects of lenalidomide on an unborn baby;

- a woman should understand the need for continuous use of effective contraceptive methods within 4 weeks prior to treatment, during treatment and 4 weeks after lenalidomide treatment;

- even in the case of amenorrhea, a woman must comply with all the rules of effective contraception;

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

- a woman should know and understand the possible consequences of pregnancy, as well as the need for urgent treatment for advice when a pregnancy is suspected;

- a woman should understand the need to comply with all the rules of effective contraception against lenalidomide, which can be started immediately after receiving negative pregnancy test results;

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

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

Application in men

Data from the study of the pharmacokinetics of lenalidomide in male volunteers indicate that lenalidomide may be contained in the seminal fluid of patients during treatment at extremely low concentrations and is not determined 3 days after discontinuation of the drug in healthy volunteers. As a precaution, given the possible reduction in the rate of elimination of lenalidomide in certain patient groups (in patients with impaired renal function), in all male patients receiving lenalidomide, the following conditions must be met:

- a man should understand the possible risk of teratogenic action of lenalidomide in sexual contact with a pregnant woman or a woman with a preserved reproductive potential;

- a man should understand the need for condoms (even after a vasectomy) in sexual contact with pregnant women or women with a reproductive potential that does not use reliable contraceptive methods during treatment and within 1 week after the suspension of treatment and / or completion of treatment;

- a man should understand that if his partner becomes pregnant during his treatment with lenalidomide or immediately after stopping lenalidomide therapy, he should immediately inform his / her treating doctor about this and that his partner is advised to seek advice from a teratologist.

The doctor prescribing treatment with the drug Lenalidomide-native women with preserved reproductive potential must make sure that the patient meets all the requirements of the Pregnancy Protection Program, including confirmation that she understands the situation adequately, and obtains the patient's consent to be bound by all the conditions of the above-mentioned Program.

Contraceptive rules

Women with preserved reproductive potential should use one of the highly effective methods of contraception within 4 weeks before the start of treatment,during lenalidomide therapy and within 4 weeks after the end of treatment, even in the event of interruptions in treatment. Exception is made only by patients who abstain from heterosexual relations throughout the specified period, which is documented monthly. If the patient does not have an effective method of contraception, she should be referred to a gynecologist for the method of effective contraception.

The highly effective methods of contraception include:

- subcutaneous hormonal implants;

- intrauterine systems that release levonorgestrel;

- depot preparations medroxyprogesterone acetate;

- ligation of the fallopian tubes;

- partner vasectomy (confirmed by two negative seminal fluid analyzes);

- progesterone-containing pills that inhibit ovulation (eg, desogestrel).

Admission of combined oral contraceptives is not indicated in patients with multiple myeloma due to an increased risk of thromboembolic complications during the treatment with lenalidomide and dexamethasone. For effective contraception these patients are recommended to use one of the methods listed above.An increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives. The effectiveness of hormonal contraceptives can be reduced with the simultaneous administration of dexamethasone.

Patients with neutropenia using as a contraceptive subcutaneous hormonal implants or intrauterine systems that release levonorgestrel, it is necessary to prophylaxisally prescribe antibiotics in connection with an increased risk of infectious complications at the time of installation of these therapeutic systems.

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

Pregnancy tests (sensitivity of at least 25 mIU / mL) should be performed in the presence of a physician for all women with preserved reproductive potential, including those that completely and continuously refrain from heterosexual relationships.After patients use an effective method of contraception for 4 or more weeks, the tests are performed on the day of treatment or 3 days before the visit to the treating doctor, and then every 4 weeks, including after the end of lenalidomide. The test results should confirm the absence of pregnancy in the patient against lenalidomide treatment.

Male patients should use condoms throughout the course of treatment with the drug Lenalidomide-native, during a break in treatment and within 1 week after discontinuation of treatment if the sexual partner is a pregnant woman or a woman with a preserved reproductive potential that does not use highly effective methods of contraception (even if the man has had a vasectomy).

Additional precautions

Patients should not transmit the drug Lenalidomide-native to other persons. The unused medication should be returned to the medical institution at the end of the treatment.

Patients are not allowed to donate blood or sperm as a donor throughout the treatment with the drug Lenalidomide-native and within 1 week after its termination.

Limitations in the appointment and dispensing of the drug

The physician should inform male and female patients about the teratogenic risk of lenalidomide and strict measures for the prevention of pregnancy, as indicated in the Pregnancy Protection Program, and provide patients with a training brochure, patient card and / or equivalent instrument in accordance with the national patient card system. A controlled distribution system includes the use of patient records and / or an equivalent instrument to monitor the designation and / or dispensing of the drug and to collect detailed data relevant to the indication, in order to closely monitor the use of unapproved indications in the Russian Federation. The pregnancy test, treatment and lenalidomide delivery should take place on the same day, but lenalidomide may be given to women with preserved reproductive potential within 7 days after the appointment of therapy and receiving a negative result of a pregnancy test performed under the supervision of a doctor. Women with preserved reproductive potential lenalidomide can be issued / discharged for a maximum of up to 4 weeks, while for other patients - for up to 12 weeks.

Cardiovascular diseases

Myocardial infarction

There are reports of cases of myocardial infarction in patients taking lenalidomide, in particular, in individuals who have risk factors for cardiovascular disease. In case of presence of risk factors, including in the first place thromboses in the anamnesis, it is necessary to monitor the condition of patients, and also take actions aimed at possible reduction of the influence of risk factors (smoking, hypertension, hyperlipidemia).

Venous and arterial thromboembolism

Combined therapy with lenalidomide and dexamethasone marked an increase in the frequency 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 observe patients who have risk factors for thromboembolism, including thrombosis in the anamnesis. Steps should be taken to address possible risk factors, such as smoking, hypertension, hyperlipidemia.The greatest prognostic value has thromboembolic complications in the anamnesis, concomitant therapy with erythropoietin, hormone replacement therapy. Thus, drugs with erythropoietic activity, as well as other drugs that may increase the risk of developing thrombosis (eg, hormone replacement therapy), should be administered with caution to patients with multiple myeloma taking lenalidomide along with dexamethasone. Concentration of hemoglobin above 120 g / l suggests the cessation of therapy with erythropoietin.

Physicians and patients should carefully evaluate the clinical signs that indicate possible thromboembolism. Patients should be warned about the need to seek immediate medical attention in the event of symptoms such as shortness of breath, chest pain, swelling of the upper or lower extremity.

For 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 taken after a thorough assessment of individual risk factors.

If a patient develops symptoms of thromboembolism, it is necessary to stop lenalidomide treatment and prescribe standard anticoagulant therapy. After the patient's condition stabilizes on anticoagulant therapy, and the symptoms of thromboembolism are eliminated, lenalidomide can be re-started at the same dose with a favorable benefit / risk ratio. The patient should continue anticoagulant therapy throughout the further treatment with lenalidomide.

Neutropenia and thrombocytopenia

Severe dose-limiting toxic phenomena of lenalidomide are neutropenia and thrombocytopenia. An extended blood test, including the determination of the number of leukocytes, blood counts, platelet counts, hemoglobin, hematocrit, should be performed before therapy, every week during the first 8 weeks of lenalidomide therapy and then monthly for monitoring cytopenia. With the development of neutropenia, a reduction in the dose of lenalidomide may be required. In the case of development of neutropenia, the administration of growth factor drugs is advisable.Patients should be informed of the need to inform the doctor in a timely manner about any temperature increases. It should be used with caution lenalidomide with other mielodepressive drugs.

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

Episodes of febrile neutropenia of 4 severity are recorded infrequently. A high incidence of grade 3 and 4 thrombocytopenia is observed in patients with multiple myeloma with concomitant administration of lenalidomide and dexamethasone. It is recommended to carefully monitor both the doctor and the patient the symptoms of increased bleeding, including petechiae and hemoptysis, especially in cases when concomitant medications can increase the tendency to bleeding.

Renal insufficiency

Given the primary allocation of lenalidomide by the kidneys, patients with renal insufficiency should carefully monitor the status of kidney function and the dose of lenalidomide.

Thyroid gland diseases

There are reports of cases of hypothyroidism and hyperthyroidism. Before the start of treatment, it is necessary to evaluate concomitant diseases that can affect the function of the thyroid gland. It is recommended to evaluate thyroid function before treatment and its regular monitoring against lenalidomide.

Peripheral Neuropathy

It is impossible to exclude the possibility of neurotoxic action of the drug Lenalidomide-native at its long reception, taking into account the structural similarity of lenalidomide and thalidomide molecules, which is known for its pronounced neurotoxic undesirable reaction.

Tumor lysis syndrome

In connection with 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 monitored appropriately and the use of conventional preventive measures.

Allergic reactions

There are reports of cases of allergic reactions / reactions of hypersensitivity. Due to the fact that there are scientific publications on possible cross-reactions between lenalidomide and thalidomide,it is necessary to carefully monitor the condition of patients who have a history of allergic reactions during treatment with thalidomide.

Severe skin reactions

There are reports of cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. When exfoliative and bullous rashes on the skin or suspected development of SSD and TEN, lenalidomide should be discontinued immediately, and treatment should not be resumed after the disappearance of skin manifestations.

The need for a break or cancellation of lenalidomide should be considered in case of appearance of other types of skin reactions depending on their severity. Lenalidomide Do not administer to patients who have a history of severe skin reactions with thalidomide.

The development of primary malignant tumors of other localization (PODL)

There is evidence of a higher incidence of primary malignant tumors of another location in patients who were previously treated with lenalidomide and dexamethasone. Non-invasive subleases included basal cell carcinoma and squamous cell carcinoma.Most of the invasive podlas were solid tumors.

In patients with newly diagnosed multiple myeloma receiving lenalidomide, there is an increase in cases of AML. From cases of invasive podlacillosis in patients receiving combined treatment with lenalidomide and melphalan, or immediately after applying high doses of melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia, myeloid dysplasia syndrome and solid tumors are noted. Cases of development of B-cell tumors (including Hodgkin's lymphoma) are noted with the use of lenalidomide after stem cell transplantation.

The risk of developing an AML should be considered before prescribing the drug Lalalidomide-native. Doctors should carefully examine patients using standard diagnostic methods to detect PALL both before deciding on the appointment of lenalidomide and during the entire treatment with lenalidomide. Treatment should be conducted according to generally accepted recommendations.

Disorders from the side of the liver

Hepatic insufficiency, including fatal cases, is noted in patients,receiving lenalidomide in combination with dexamethasone: acute hepatic insufficiency, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis and mixed cytolytic / cholestatic hepatitis. The mechanisms of severe drug hepatotoxicity remain unknown, although in some cases, a previous viral disease of the liver, an initial increase in the activity of liver enzymes, and possibly antibiotic treatment may be a risk factor.

Deviations in liver function evaluation results are often recorded, but they are usually asymptomatic and reversible after discontinuation of therapy. After recovery to baseline, therapy can be resumed at a lower dose. Lenalidomide it is important to adjust the dose of the drug in patients with renal failure to avoid reaching plasma concentrations that may increase the risk of hematologic adverse reactions or hepatotoxicity. It is recommended to monitor liver function especially in the presence of concomitant viral disease of the liver or indication of it in an anamnesis or with the use of lenalidomide in combination with drugs,causing violations of the liver.

Effect on the ability to drive transp. cf. and fur:

Some adverse reactions that develop when using lenalidomide, such as dizziness, weakness, drowsiness and blurred vision, may adversely affect the ability to drive and perform potentially hazardous activities that require high concentration and psychomotor speed reactions. When these undesirable reactions appear, one should refrain from performing these activities.

Form release / dosage:

Capsules, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 25 mg.

Packaging:

7 capsules in blisters of aluminum foil laminated and printed films and polyvinyl chloride.

By capsule 21 vials of polyethylene terephthalate, polyethylene sealed with lids.

3 blisters or 1 bottle together with instructions for use in a cardboard pack.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003788

Date of registration:17.08.2016

Expiration Date:17.08.2021

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Lenalidomide-native (Lenalidomide-nativ)