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

Excipients: silicon colloidal dioxide 1.6 mg / 3.2 mg / 4.8 mg / 8.0 mg, lactose monohydrate 37.0 mg / 74.0 mg / 111.0 mg / 185.0 mg; magnesium stearate 0.8 mg / 1.6 mg / 2.4 mg / 4.0 mg, croscarmellose sodium 6.0 mg / 12.0 mg / 18.0 mg / 30.0 mg, cellulose microcrystalline 29.6 mg / 59.2 mg / 88.8 mg / 148.0 mg;

The composition of hard gelatin capsules:

for a dosage of 5 mg:

Capsule body: purified water - 14-15 mg, sodium lauryl sulfate - 0.12 mg, titanium dioxide - 2.05 mg, gelatin - up to 100 mg;

capsule cap: purified water - 14-15 mg, sodium lauryl sulfate - 0.12 mg, titanium dioxide - 2.05 mg, gelatin - up to 100 mg;

for a dosage of 10 mg:

Capsule body: purified water - 14-15 mg, sodium lauryl sulfate - 0.08 mg, titanium dioxide - 0.97524 mg, diamond brilliant blue - 0.2626 mg, gelatin - up to 100 mg; capsule cap: purified water - 14-15 mg, sodium lauryl sulfate - 0.08 mg, titanium dioxide - 0.97524 mg, diamond brilliant blue - 0.2626 mg, gelatin - up to 100 mg; for a dosage of 15 mg:

Capsule body: purified water - 14-15 mg, sodium lauryl sulfate - 0.10 mg, titanium dioxide - 2.05 mg, gelatin - up to 100 mg;

capsule cap: purified water - 14 - 15 mg, sodium lauryl sulfate - 0.10 mg, dye Crimson [Ponso 4R] - 0.7802 mg, dye sunset yellow - 0.0713 mg, titanium dioxide - 0.8065 mg, gelatin - up to 100 mg; for dosage of 25 mg:

Capsule body: purified water - 14-15 mg, sodium lauryl sulfate - 0.10 mg, titanium dioxide - 2.11118 mg, gelatin - up to 100 mg;

cap capsule, purified water - 14-15 mg, sodium lauryl sulfate - 0.10 mg, titanium dioxide - 2.11118 mg, gelatin - up to 100 mg.

Description:

For a dosage of 5 mg - hard gelatin capsules number 3, the body is white, the lid is white.

For the dosage of 10 mg - hard gelatin capsules number 2, the case is blue, the lid is blue.

For dosage of 15 mg - hard gelatin capsules number 1, the body is white, the lid is red.

For the dosage of 25 mg - hard gelatin capsules number 0, the body is white, the lid is white.

The contents of the capsules are a white powder with a yellowish hue of color.

Pharmacotherapeutic group:Immunosuppressive means

ATX: & nbsp

L.04.A.X.04 Lenalidomide

L.04.A.X Other immunosuppressants

Pharmacodynamics:

Mechanism of action

Lenalidomide has antineoplastic, anti-angiogenic, proerythropoietic and immunomodulatory properties. Lenalidomide inhibits the proliferation of certain malignant hematopoietic cells (including multiple myeloma cells (MM) and hematopoietic tumor cells that have cytogenetic defects of the chromosome 5), enhances the immunity mediated by T-lymphocytes and natural killer cells (EC), increases the number of E-T cells, suppresses angiogenesis, blocking the migration and adhesion of endothelial cells and the formation of microvessels, increases the production of fetal hemoglobin Cd34+ stem hematopoietic cells, and inhibits the production of pro-inflammatory cytokines (eg, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) by monocytes. Lenalidomide studied in 2 phase studies III with the newly diagnosed MM and 2 phase studies III with recurrence of refractory MM.

Pharmacokinetics:

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

Absorption

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. The maximum concentration (Cmax) and the area under the "concentration-time" curve (AUC) increase in proportion to the increase in dose. Repeated drug administration does not lead to its cumulation. Lenalidomide can be taken regardless of food intake. FROMmah and AUC increase in proportion with both single and repeated administration of the drug. According to Cmah and AUC Exposure of lenalidomide in MM patients is higher than in healthy volunteers, which is explained by a lower clearance to filtration ratio (CL/F) in patients with MM compared with healthy volunteers.

Distribution

In vitro binding (¹⁴C) -lenalidomide with plasma proteins of MM patients and healthy volunteers was 23% and 29%, respectively.

Lenalidomid is present in the seminal fluid (<0.01% of the dose) after taking it at a dose of 25 mg per day, but is not detected in the seminal fluid of healthy volunteers 3 days after discontinuation of the drug.

Metabolism and excretion

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, therefore, metabolic drug interactions in the joint use of lenalidomide and preparations that inhibit cytochrome P450 isoenzymes are unlikely. Research results in vitro demonstrate the lack of inhibitory effect of lenalidomide on isoenzymes 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 substratum of the human breast cancer resistance protein (BCRP), multidrug resistance protein carriers (MRP) MRP 1, MRP2 or MRP3, carriers of organic anions (OAT) OAT1 and 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 volatile carriers BSEP (Bile Salt Export Pump, pump export of bile acids), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3 or OST2 in vivo, while that of inhibitory action in vitro in concentrations up to 20 μmol it was not noted.

Lenalidomide is practically not metabolized in the body, as 82% of its dose is excreted by the kidneys unchanged. Thus, the renal clearance exceeds the rate of glomerular filtration, however, the elimination process has, to some extent, an active character.

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

Elderly patients

Special clinical studies to assess the pharmacokinetics of lenalidomide in elderly patients have not been conducted. The population analysis, which included the pharmacokinetic data of patients aged 39 to 85 years, did not reveal the effect of age on the clearance of lenalidomide (exposure in plasma). Given the increased likelihood of impaired renal function in the elderly,be careful when choosing a dose of the drug and perform a thorough control of kidney function against the background of therapy.

Renal insufficiency

FROMmah 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 increased by approximately 2.5, 4 and 5 times in patients with moderate to severe renal insufficiency and terminal stage 4 of renal failure (TSTP), respectively, compared with the group combining patients with normal renal function and patients with renal insufficiency of the lung severity. The half-life of lenalidomide increased 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% of the drug was excreted from the body during a 4-hour dialysis session. Recommendations for changing the dose of lenalidomide in patients with renal insufficiency are given in the section "Method of administration and dose".

Liver failure

Population analysis of pharmacokinetic data of patients with mild hepatic insufficiency (total bilirubin> 1 and ≤1.5 x VGN, upper limit of norm, or ACT > VGN) showed no effect of mild hepatic insufficiency on the clearance of lenalidomide (exposure in plasma). Data in patients with hepatic insufficiency of moderate and severe severity were not received.

Other internal 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.

There is no data on lenalidomide intake in breast milk.

Indications:

For the treatment of adult patients with previously untreated multiple myeloma, which does not show transplantation of hematopoietic stem cells.

In combination with dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one line of therapy.

Contraindications:

- Hypersensitivity to lenalidomide or other components of the drug.

- Pregnancy and lactation.

- Preserved fertility potential, except in cases when it is possible to comply with all the necessary conditions of the Pregnancy Protection Program (see "Special instructions"),

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

- Child age (for security reasons).

Carefully:

- In elderly patients with renal insufficiency and / or liver failure (see also "Method of administration and dose"), as well as in patients with deep vein thrombosis (including in history).

- When taken together with drugs that increase the risk of thrombosis, namely, with drugs that have erythropoietic activity and hormone replacement therapy (see also "Adverse effects" and "Interaction with other medicinal products"),

- In patients with hereditary lactose intolerance, lactase deficiency or impaired glucose-galactose absorption, since lenalidomide capsules contain lactose.

Pregnancy and lactation:

Lenalidomide is a structural analogue of thalidomide, which is a known teratogen.It is known that the reception of thalidomide by pregnant women causes severe and life-threatening congenital disorders in the fetus.

Lenalidomide caused malformations in monkeys, similar to the previously described effects of thalidomide. If lenalidomide is used during pregnancy, the risk of developing congenital defects of the fetus is very high (see "Contraindications"). Women of reproductive age should use effective methods of contraception. If the patient becomes pregnant, lenalidomide should be discontinued and the patient should be referred for advice to a doctor who has experience in monitoring pregnant women for examination and clinical recommendations. In case of pregnancy of a woman who is a sexual partner of the patient receiving lenalidomide, it is also referred to a specialist in the field of teratology for examination and clinical recommendations.

Breastfeeding period

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

Fertility

Results of the study of reproductive function,which was performed on rats with lenalidomide at doses up to 500 mg / kg (these doses exceeded the therapeutic doses for humans, 25 mg and 10 mg, approximately 200-500 times the body surface area), showed no impairment of fertility or toxicity for the organism of parents.

The study of the influence of lenalidomide on embryo-fetal development was carried out on monkeys, who received the drug in doses from 0.5 to 4 mg / kg / day. The results of this study showed that lenalidomide caused the development of external defects, including infection of the anus and violation of the development of the upper and lower extremities (curved, shortened, deformed, underdeveloped and / or partially absent limbs, oligochtilia and / or polychaete) in the young monkey females who received the drug during pregnancy.

Dosing and Administration:

Lenalidomide treatment should be performed under the supervision of a chemotherapist. Lenalidomide is intended only for oral administration. Capsules containing lenalidomide, can not be opened, broken or chewed, it is recommended to take them according to the scheme of therapy at the same time before or after eating, swallowing whole and with water.

The first diagnosed MM

Lenalidomide in combination with dexamethasone before the progression of the disease in patients not shown stem cell transplantation (HSCT)

Lenalidomide therapy should not be started if the absolute number of neutrophils (ACH) <1.0 x 10⁹/ l and / or the number of platelets <50 x 10⁹/ l.

Recommended dose

The recommended initial dose of lenalidomide is 25 mg 1 time per day orally from 1 to 21 days of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg 1 time per day orally on days 1, 8, 15 and 22 of the repeated 28-day cycles. Patients may continue with lenalidomide and dexamethasone until the disease progresses or signs of intolerance appear.

The dose should be changed on the basis of clinical and laboratory data (see section "Special instructions"). For patients aged 75 years and older, the initial dose of dexamethasone is 20 mg / day at 1, 8, 15 and 22 days of each 28-day treatment cycle. The recommended dose of lenalidomide for patients with moderate renal insufficiency is 10 mg 1 time per day.

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 lenalidomide can not be ruled out.

Step-by-step dose reduction

	Lenalidomide	Dexamethasone
Initial dose	25 mg	40 mg
Dose of the 1st level	20 mg	20 mg
Dose Level 2	15 mg	12 mg
Dose Level 3	10 mg	8 mg
Dose Level 4	5 mg	4 mg
Dose Level 5	2.5 mg	Not applicable

Thrombocytopenia

Number of platelets	Recommendations
Decreased to <25 x 10⁹/ l	Stop lenalidomide treatment until the end of the cycle^a
Has recovered to ≥ 50 x 10⁹/ l	Resume treatment at a lower dose (in the next cycle, lower the dose by one level)

^a If dose-limiting toxicity (DLT) develops at> 15 day of the cycle, lenalidomide treatment will be interrupted, at least for the remainder of the current 28-day cycle.

Neutropenia

Number of neutrophils	Recommendations
The first decrease to <0.5 x 10⁹/ l	Stop lenalidomide treatment
Has recovered to ≥ 1 x 10⁹/ l and neutropenia - the only manifestation of toxicity	Resume lenalidomide treatment at an initial dose 1 time per day
Has recovered to ≥ 0.5 x 10⁹/ l and there are other dose-dependent, hematological toxicity types besides neutropenia	Resume lenalidomide treatment at a dose of 1 once a day
Each subsequent decline is lower <0,5x10⁹/ l	Stop lenalidomide treatment
Has recovered to ≥ 0.5 x 10⁹/ l	Resume lenalidomide treatment at a dose of the next lower dose level once a day

In the case of neutropenia, the doctor should consider the possibility of prescribing growth factor preparations to the patient.

If the dose of lenalidomide has been lowered due to the development of hematologic DLT, it can subsequently be increased (up to the initial dose) at the discretion of the attending physician if prolongation of lenalidomide / dexamethasone therapy resulted in improved bone marrow function (no DLT for at least 2 consecutive cycles, and АЧН ≥1,5 х 10⁹/ l and the number of platelets ≥100 x 10⁹/ l at the beginning of a new cycle under the current dosing regime).

Lenalidomide in combination with melphalan and prednisolone followed by maintenance monotherapy in patients not shown by TSCC

Do not start lenalidomide therapy if ACCH <1.5 x 10⁹/ l and / or the number of platelets <75 x 10⁹/ l.

Recommended dose

Recommended primary The dose of lenalidomide is 10 mg once daily for 1 to 21 days of repeated 28-day cycles (totaling up to 9 cycles), and melphalan 0.18 mg / kg and prednisolone-2 mg / kg orally for 1-4 days repeated 28-day cycles. Patients who completed 9 complete cycles or who can not receive combination therapy due to intolerance are prescribed lenalidomide monotherapy at a dose of 10 mg once daily for 1 to 21 days of repeated 28-day cycles until the disease progresses. The dose should be changed on the basis of clinical and laboratory data (see section "Special instructions").

Dose change during treatment or its resumption

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

Step-by-step dose reduction

	Lenalidomide	Melphalan	Prednisolone
Initial dose	10 mg^a	0.18 mg / kg	2 mg / kg
Dose of the 1st level	7.5 mg	0.14 mg / kg	1 mg / kg
Dose Level 2	5 mg	0.10 mg / kg	0.5 mg / kg
Dose Level 3	2.5 mg	-	0.25 mg / kg

^a if neutropenia is the only manifestation of toxicity,it is necessary to add a colony-stimulating factor (G-CSF) to therapy and continue treatment with lenalidomide at the same dose.

Thrombocytopenia

Number of platelets	Recommendations
Decreased to <25 x 10⁹/ l	Suspend lenalidomide treatment
Has recovered to ≥ 25 x 10⁹/ l	Resume lenalidomide and melphalan in a dose of 1 level
For each subsequent decrease <30 x 10⁹/ l	Suspend lenalidomide treatment
Has recovered to ≥ 30 x 10⁹/ l	Resume lenalidomide treatment in a smaller dose (dose of 2-3 levels) 1 time per day

Neutropenia

Number of neutrophils	Recommendations
The first decrease to <0.5 x 10⁹/ l^a	Stop lenalidomide treatment
Has recovered to ≥ 0.5 x 10⁹/ l and neutropenia - the only manifestation of toxicity	Resume lenalidomide treatment at an initial dose 1 time per day
Has recovered to ≥ 0.5 x 10⁹/ l and there is another hematologic DLT besides neutropenia	Resume lenalidomide treatment at a dose of 1 once a day
Each subsequent decline is below <0.5 x 10⁹/ l	Stop lenalidomide treatment
Has recovered to ≥ 0.5 x 10⁹/ l	Resume lenalidomide treatment at a dose of the next lower level 1 time per day

^a Assign G-CSF if the patient does not receive this therapy.On the first day of the next cycle, continue treatment G-CF and melphalan in the previous dose provided that neutropenia - the only manifestation of DLT. Otherwise, in the next cycle, apply lenalidomide in a dose of the next lower level.

In the case of neutropenia, the doctor should consider the possibility of prescribing growth factor preparations to the patient.

MM in patients who received at least one line of therapy

Recommended initial dose lenalidomide is 25 mg orally once a day in 1-21 days of repeated 28-day cycles.

Dexamethasone 40 mg is prescribed once a day at 1-4, 9-12 and 17-20 days of each 28 day cycle in the first 4 cycles of therapy, followed by 40 mg once daily on 1-4 days of each subsequent 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 less than 12 hours have elapsed since the missed admission of lenalidomide, the patient may take the missed dose of the drug, and if more than 12 hours pass, the missed dose should not be taken.The next dose of lenalidomide should be taken the next day, at the usual time.

Lenalidomide should not be started if ACCH <1.0 x 10⁹/ l and / or the number of platelets <75x10⁹/ 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

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

Thrombocytopenia

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

Neutropenia

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

In the case of neutropenia, the physician should consider the possibility of prescribing growth factor preparations to the patient.

All patients

When developing with the treatment of lenalidomide other types of toxicity of 3 or 4 degrees, treatment should be suspended. Treatment can be resumed at a dose of the next, lower level with a decrease in the severity of toxicity to ≤ 2 degrees, depending on the doctor's decision.

Suspension or discontinuation of lenalidomide should be considered with a skin rash of grade 2 or grade 3. The use of lenalidomide should be discontinued with angioneurotic edema, rash grade 4,exfoliative or bullous rash, or with suspected Stevens-Johnson syndrome (SDS) or toxic epidermal necrolysis (TEN). Treatment should not be resumed after the cessation of these reactions.

Children and teens

Lenalidomide is not recommended for use in children under the age of 18 for safety reasons (see section "Special instructions").

Elderly patients

The results of a study of the pharmacokinetics of lenalidomide in elderly patients are presented in the section "Pharmacokinetics." In clinical trials lenalidomide was prescribed to patients with MM at the age of 91 years. In patients with newly diagnosed MM at age 75 and older who received lenalidomide, serious 13 adverse drug reactions (NLR) and NIRs that led to discontinuation of treatment were noted more often (see section "Special instructions"). Before the appointment of treatment for patients with newly diagnosed MM at the age of 75 years and older, a thorough examination should be carried out (see section "Special instructions").

The first diagnosed MM

For patients older than 75 years who received lenalidomide in combination with dexamethasone, the initial dose of dexamethasone is 20 mg / day at 1, 8, 15 and 22 days of each 28-day treatment cycle.In clinical trials of newly diagnosed MM in patients not shown by THSC, combined therapy with lenalidomide was tolerated worse in patients older than 75 years compared with young patients. Older patients were more likely to stop taking the drug because of individual intolerance (grade 3 or grade 4 NLR and severe NLR) than patients under the age of 75 years (see "Special instructions").

MM in patients who received at least one line of therapy

The percentage of patients aged 65 years and older receiving lenalidomide / dexamethasone or placebo / dexamethasone was comparable. There was no difference in the efficacy and safety of lenalidomide depending on age, although it is impossible to exclude a greater sensitivity to the drug of patients of the older age group. Since in elderly patients the probability of renal dysfunction is higher, the dose of the drug should be selected very carefully, while during the treatment it is recommended to monitor the kidney function.

Patients with impaired renal function

Lenalidomide is excreted mainly by the kidneys. In this regard, as the degree of impairment of renal function increases, tolerance to therapy decreases (see section "Special instructions").It is recommended to carefully select the dose of the drug and monitor the function of the kidneys.

For patients with mild renal insufficiency, a dose change of lenalidomide is not required. The following changes in the dosage regimen are recommended at the beginning of therapy and during its continuation, depending on the degree of severity of renal dysfunction (for patients with moderate to severe renal insufficiency and TSSN). Phase III studies with TSRP (QC <30 mL / min, requiring dialysis) were not performed.

Initial dose of lenalidomide depending on the severity of renal dysfunction

Kidney function status	The recommended dose of lenalidomide (1 to 21 days during repeated 28-day cycles)
Renal insufficiency of moderate severity 30 ml / min ≤ KK <50	10 mg once a day *
Renal failure of severe severity	7.5 mg once a day 15 mg every other day
Terminal stage of renal failure (TSPN) 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 the drug can be increased to 15 mg 1 time per day after 2 cycles of therapy in the absence of response to therapy, but its good tolerability.

After the initiation of lenalidomide treatment, subsequent dose changes in patients with impaired renal function should be based on individual tolerability of treatment as previously indicated.

Patients with hepatic impairment

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

Side effects:

The first diagnosed MM in patients who received lenalidomide in combination with low doses of dexamethasone

Serious NLR, more often observed (≥5%) with lenalidomide in combination with a low dose of dexamethasone, were

- pneumonia (9.8%)

- renal insufficiency (including acute) (6.3%)

From NLR were observed more often: diarrhea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash ( 24.3%), a decrease in appetite (23.1%), cough (22.7%), hyperthermia (21.4%), and muscle spasms (20.5%).

The first diagnosed MM in patients who received lenalidomide in combination with melphalan and prednisolone

Serious NLR, more often (≥5%) observed when taking melphalan, prednisolone and lenalidomide, were:

- febrile neutropenia (6.0%)

- anemia (5.3%)

Of the NLRs, neutropenia (83.3%), anemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%), constipation (34.0%), diarrhea (33.3% %), rash (28.9%), hyperthermia (27.0%), peripheral edema (25.0%), cough (24.0%), decreased appetite (23.7%) and asthenia (22.0%) %).

MM in patients who received at least one line of therapy

In patients with MM who received lenalidomide in combination with dexamethasone, the most common were the following NLR: fatigue (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 NLRs registered with lenalidomide / dexamethasone compared with placebo / dexamethasone were:

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

- Neutropenia 4 degrees of severity.

Neutropenia and thrombocytopenia showed the greatest dependence on the dose of the drug, which allows to successfully control them by reducing the dose of lenalidomide / dexamethasone. The frequency of the NLRs given below was determined by according to the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000), the frequency is unknown (can not be determined from available data).

Table 1.NLR, noted in clinical and post-registration studies in patients with MM who received lenalidomide in combination with dexamethasone or with melphalan and prednisolone

System-Organic grade	Adverse reactions (in total), frequency	Adverse reactions of 3-4 degrees of severity, frequency
Infectious and parasitic diseases	Often: pneumonia, upper respiratory tract infections, bacterial, viral and fungal infections (including opportunistic infections), nasopharyngitis, pharyngitis, bronchitis. Often: sepsis, sinusitis.	Often: pneumonia, bacterial, viral and fungal infections (including opportunistic infections), sepsis, bronchitis.
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Infrequently: basal cell carcinoma of the skin.	Often: acute myeloid leukemia, myelodysplastic syndrome, squamous cell carcinoma *. Infrequently:* acute T-cell leukemia, basiolioma, tumor lysis syndrome ***.
Violations of the blood and lymphatic system	Often: neutropenia, thrombocytopenia, anemia, hemorrhagic disorders, and leukopenia. Often: febrile neutropenia, pancytopenia. Infrequently: hemolysis, autoimmune hemolytic anemia, hemolytic anemia.	Often: thrombocytopenia, neutropenia, leukopenia. Often: febrile pancytopenia, hemolytic anemia. Infrequently: hypercoagulation, coagulopathy.
Immune system disorders	Infrequently: hypersensitivity reactions.	-
Disorders from the endocrine system	Often: hypothyroidism, hyperthyroidism ***.	-
Disorders from the metabolism and nutrition	Often: hypokalemia, hyperglycemia, hypocalcemia, decreased appetite, weight loss. Often: hypomagnesemia. hyperuricemia. dehydration.	Often: hypokalemia, hyperglycemia, hypocalcemia, diabetes mellitus, hypophosphatemia. hyponatremia, hyperuricemia, gout, decreased appetite, weight loss.
Disorders of the psyche	Often: depression, insomnia. Infrequently: loss of libido.	Often: depression, insomnia.
Disturbances from the nervous system	Often: peripheral neuropathy (except motor neuropathy), dizziness, tremor perversion of taste, headache. Often: ataxia, imbalance.	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, blurred vision. Often: decreased visual acuity.	Often: cataract. Infrequently: blindness.
Hearing disorders and labyrinthine disorders	Often: deafness (including deafness), tinnitus.	-
Heart Disease	Often: atrial fibrillation, bradycardia. Infrequently: arrhythmia, lengthening of the QT interval, atrial flutter, ventricular extrasystole.	Often: myocardial infarction (including acute myocardium), atrial fibrillation, congestive heart failure, tachycardia, heart failure, myocardial ischemia.
Vascular disorders	Often: thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism). Often: decrease and increase of arterial pressure, ecchymosis.	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: shortness of breath, nosebleeds.	Often: respiratory distress syndrome, dyspnea. Frequency unknown: interstitial pneumonitis ***.
Disorders from the gastrointestinal tract	Often: constipation, diarrhea, abdominal pain, nausea, vomiting, indigestion. Often: gastrointestinal bleeding (including rectal, hemorrhoidal, gingival hemorrhage and bleeding in peptic ulcer), dry mouth, stomatitis, dysphagia. Infrequently: colitis, tiflitis.	Often: diarrhea, constipation, abdominal pain, nausea, vomiting. Frequency unknown: pancreatitis ***.
Disturbances from the liver and bile ducts	Often: deviation of the values of functional liver samples from normal. Infrequently: hepatic impairment. Frequency unknown: acute hepatic insufficiency * ^, toxic hepatitis * ^, cytolytic hepatitis * ^, cholestatic hepatitis * ^, mixed cytolytic / cholestatic hepatitis *** ^.	Often: Cholestasis, deviation of the values of functional liver samples from normal. Infrequently: hepatic impairment. Frequency unknown: acute hepatic insufficiency * ^, toxic hepatitis * ^.
Disturbances from the skin and subcutaneous tissues	Often: rash, itchy skin. Often: urticaria, hyperhidrosis, dry skin, hyperpigmentation of the skin, eczema, erythema. Infrequently: a skin color disorder, a photosensitization reaction.	Often: rash. Infrequently: angioedema. *** Rarely: Stevens-Johnson syndrome *, toxic epidermal necrolysis * ^. Frequency unknown: leukocytoclastic vasculitis ***.
Disorders from the musculoskeletal system	Often: muscle cramps, bone pain, pain and discomfort from the osteomuscular and connective tissue, arthralgia. Often: muscle weakness, swelling of the joints, myalgia.	Often: muscle weakness, bone pain Infrequently: swelling of the joints.
Disorders from the kidneys and urinary tract	Often: kidney failure (including acute). Often: hematuria, urinary retention, urinary incontinence. Infrequently: acquired Fanconi syndrome.	Infrequently: tubular renal necrosis.
Violations of the genitals and mammary glands	Often: erectile disfunction.	-
General disorders and disorders at the site of administration	Often: increased fatigue, swelling (including peripheral), fever, asthenia, flu-like syndrome (including fever, cough, myalgia, musculoskeletal pain, headache and chills). Often: pain in the chest, lethargy.	Often: increased fatigue, fever, asthenia.
Laboratory and instrumental data	Often: increase in the concentration of C-reactive protein.
Trauma, intoxication and complications of manipulation	Often: fall, bruise.

^ For more information, see the end of this section.

* - Squamous cell carcinoma was noted in clinical trials in patients with MM who had previously been treated with lenalidomide / dexamethasone compared to the control group

** - Squamous cell carcinoma was recorded in a clinical trial in patients with newly diagnosed MM who received lenalidomide / dexamethasone compared with the control group

***- post-registration data

Additional Information

Teratogenicity

Lenalidomide is a structural analogue of thalidomide - a substance with an active teratogenic effect and causing severe life-threatening anomalies development in humans.Lenalidomide induced monkey anomalies, similar to those described for thalidomide. If lenalidomide enters the body during pregnancy, it is possible to predict its teratogenic effect, so lenalidomide contraindicated in pregnancy (see "Contraindications" and "Special instructions"),

Neutropenia and thrombocytopenia

The first diagnosed MM in patients who received lenalidomide in combination with such doses of dexamethasone

The combination of lenalidomide with low doses of dexamethasone in patients with newly diagnosed MM is associated with a reduced incidence of grade 4 neutropenia. Febrile neutropenia of grade 4 was not infrequent.

The combination of lenalidomide with low doses of dexamethasone in patients with newly diagnosed MM is associated with a reduced incidence of grade 3 and 4 thrombocytopenia.

The first diagnosed MM in patients who received lenalidomide in combination with melphalan and prednisolone

The combination of lenalidomide with melphalan and prednisolone in patients with newly diagnosed MM is associated with a higher incidence of grade 4 neutropenia.Episodes of febrile neutropenia of grade 4 were observed more often.

The combination of lenalidomide with melphalan and prednisolone in patients with newly diagnosed MM is associated with a higher incidence of grade 3 and 4 thrombocytopenia.

MM in patients who received at least one line of therapy

The use of a combination of lenalidomide with dexamethasone in patients with MM was accompanied by an increase in the frequency of development of grade 4 neutropenia (in 5.1% of patients taking lenalidomide with dexamethasone, compared with 0.6% in patients taking the combination of dexamethasone and placebo). Febrile neutropenia 4 degrees of severity in patients taking the combination of lenalidomide with dexamethasone, was infrequent - 0.6% (in patients taking the combination of dexamethasone and placebo - 0.0%).

The combination of lenalidomide with dexamethasone in MM was accompanied by an increase in the probability of thrombocytopenia 3 and 4 severity (9.9% and 1.4%, respectively, in patients taking lenalidomide with dexamethasone, relative to 2.3% and 0.0% in patients taking the combination of dexamethasone and placebo).

Venous thromboembolism

The use of a combination of lenalidomide with dexamethasone in patients with MM was associated with an increased risk of developing deep vein thrombosis and pulmonary embolism, while in combination with melphalan and prednisolone this risk was lower (see "Interaction with Other Drugs"). 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 who took lenalidomide, there were cases of myocardial infarction, especially in the presence of known risk factors.

Hemorrhagic complications

Hemorrhagic complications are indicated in accordance with the system-organ classification: violations of the blood and lymphatic system; disorders of the nervous system (intracranial hemorrhage); from the respiratory, thoracic and mediastinal (nasal bleeding); from the gastrointestinal tract (rectal, hemorrhoidal, gingival bleeding); from the kidneys and urinary tract (hematuria); from the side 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 should not be given to patients who have a history of severe rash when taking thalidomide.

Primary malignant tumors of other localization

* New malignant neoplasms noted in clinical studies in patients with myeloma after using a combination of lenalidomide with dexamethasone to compared with the control, represented, mainly, basal cell or squamous cell carcinoma of the skin.

Acute myeloid leukemia (AML)

Cases of AML were observed in clinical studies of newly diagnosed MM in patients who received lenalidomide in combination with melphalan or immediately after a high dose of melphalan and THSC (see "Specific guidance"), AML was not observed in clinical trials in patients with newly diagnosed MM who received lenalidomide in combination with low doses of dexamethasone when compared with thalidomide in combination with melphalan and prednisolone.

Disorders from the side of the liver

In the post-registration period, the following liver abnormalities were recorded (frequency unknown): acute hepatic insufficiency and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic / cholestatic hepatitis.

Rhabdomyolysis

Rare cases of rhabdomyolysis were noted, in some of them lenalidomide used together with statins.

Thyroid gland diseases

There were reports of cases of hypothyroidism and hyperthyroidism (see section "Special instructions: Diseases of the thyroid gland").

Diseases of the gastrointestinal tract

Perforation of the gastrointestinal tract was recorded against lenalidomide. Perforation of the gastrointestinal tract can lead to septic complications and fatal outcome.

Overdose:

A special plan of action for an overdose of lenalidomide in patients with MM is currently not developed, despite the fact that in studies on determining the dose range, some patients received doses of up to 150 mg, and in studies of single dose exposure up to 400 mg of the drug.Toxic manifestations, which limited the dose in these studies, were exclusively hematological.

In case of an overdose, symptomatic maintenance therapy is recommended.

Interaction:

Erythropoietic medicines, as well as other agents that may increase the risk of thrombosis, for example, drugs for hormone replacement therapy, should be used with caution in patients with MM who are taking lenalidomide in combination with dexamethasone.

Oral contraceptives: There was no study of drug interaction with oral contraceptives. Lenalidomide is not an inducer of cytochrome system enzymes. In the study in vitro on human hepatocytes lenalidomide in different concentrations did not induce isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, against the background of monotherapy with lenalidomide, induction is not expected, leading to a decrease in the effectiveness of drugs, including hormonal contraceptives. but dexamethasone, being a weak / moderate isoenzyme inducer CYP3A4, probably affects other enzymes, as well as transporters.It is impossible to exclude the possibility of reducing the effectiveness of oral contraceptives on the background of therapy. Therefore, effective measures should be taken to protect against pregnancy (see sections on "Use during pregnancy and during breastfeeding" and "Special instructions").

Warfarin: no effect of lenalidomide in the dose of 10 mg, taken repeatedly, on the pharmacokinetic parameters R- and S-warfarin at its single admission. Simultaneous single use of warfarin in a dose of 25 mg with lenalidomide did not affect the pharmacokinetics of the latter. However, it is not known whether there is interaction in clinical use (concomitant therapy with dexamethasone). Dexamethasone is a weak / moderate inducer of enzymes, and its effect on warfarin is unknown. A careful monitoring of the concentration of warfarin during lenalidomide therapy is recommended.

Digoxin: simultaneous appointment of lenalidomide at a dose of 10 mg / day increased the plasma exposure of digoxin (0.5 mg, once) by 14% with CI (Trust Interval) 90% [0.52% -28.2%]. It is not known whether this effect will be different in the clinical situation (higher doses of lenalidomide and concomitant therapy with dexamethasone).Therefore, 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 the 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 in 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 its repeated administration at a dose of 25 mg / day.

Interaction with P-glycoprotein inhibitors (P-gp): lenalidomide in vitro is a substrate P-gp, but not inhibitors P-gp. Simultaneous multiple application of a strong inhibitor P-gp quinidine (600 mg 2 times per day) or a moderate inhibitor of P- gp/ substrate temsirolimus (25 mg) had no clinically significant effect on the pharmacokinetics of lenalidomide (25 mg / day). The pharmacokinetics of tessirolimus did not change when combined with lenalidomide.

Special instructions:

Lenalidomide treatment should be started and carried out 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 unserved fertility potential:

A female patient or woman, a sexual 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 anamnesis

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

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

The use of lenalidomide in women with preserved reproductive potential is contraindicated in cases where the following conditions are not met: a woman

- should know about the likely teratogenic effect of lenalidomide on the fetus

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

- even in the case of amenorrhea, follow recommendations to use effective contraception

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

- should know and understand the possible consequences of pregnancy, as well as the need for urgent treatment for advice in case of suspected pregnancy

- should understand the need for emergency treatment with lenalidomide immediately after receiving negative pregnancy test results

- should be aware of the need for a test and perform a pregnancy test every 4 weeks, except for patients who have undergone sterilization by ligation of the fallopian tubes

- must confirm that he understands the risk of possible undesirable consequences and the need for their prevention during the treatment with lenalidomide.

Application in men:

Data from the study of 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 determined 3 days after discontinuation of the drug in healthy volunteers (see."Pharmacological action, pharmacokinetics"). As a precaution, given the possible reduction in the rate of elimination of lenalidomide in specific groups of patients (in patients with impaired renal function), for all men taking lenalidomide, the following conditions must be met: Man

- should understand the possible risk of teratogenic effects of lenalidomide in sexual contact with a pregnant woman or a woman with a preserved childbearing potential

- should understand the need to use condoms (even after a previous vasectomy) with sexual contact with pregnant women or women with preserved reproductive potential not using reliable contraceptive methods during the treatment period and within 1 week after stopping treatment and / or completing treatment

- should understand that if his partner becomes pregnant during his treatment with lenalidomide or soon after the cessation of lenalidomide therapy, he should immediately inform his or her attending physician about it, and his partner is recommended to seek a consultation and consultation with a teratologist.

A doctor who prescribes treatment with lenalidomide to women with preserved reproductive potential should

- make sure that the patient meets all conditions Pregnancy prevention programs, including confirmation that she adequately understands the situation

- to obtain the consent of the patient for mandatory compliance with 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 for 4 weeks before the start of treatment, during therapy and for 4 weeks after the end of lenalidomide therapy, even during treatment interruptions. Exception is made by patients who throughout the specified period abstain from heterosexual relations, 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 patient should immediately start using the effective method of contraception.

The highly effective methods of contraception include:

- Subcutaneous hormonal implants;

- Intrauterine devices, allotting levonorgestrel;

- Depot preparations medroxyprogesterone acetate;

- Ligation of fallopian tubes;

- Vasectomy of the partner (confirmed by two negative analyzes of seminal fluid);

- Progesterone-containing pills that inhibit ovulation (for example, desogestrel). The use of combined oral contraceptives is not indicated in patients with MM due to an increased risk of thromboembolic complications with combined therapy with lenalidomide. 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 test (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 who completely and continuously refrain from heterosexual relations. 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 within 4 weeks after completion of treatment, except for those patients who have been confirmed to be sterilized by ligation of the fallopian tubes. The results of the test should confirm the absence of pregnancy in the patient at the time of initiation of therapy.

Male patient should use condoms during the entire course of treatment, during a break in treatment and within 1 week after the cessation of treatment if his sexual partner is a pregnant woman or a woman with a preserved childbearing potential,not using highly effective methods of contraception (even if a man underwent a vasectomy).

Additional precautions

Patients should not transmit lenalidomide 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 lenalidomide and within 1 week after the end.

Teaching materials, restrictions in the appointment and dispensing of the drug

To help patients prevent the effects of lenalidomide on the fetus, the holder of the registration certificate will provide medical personnel with training materials to justify warnings about the teratogenicity of lenalidomide, recommend contraception before starting therapy, and explain the need for pregnancy tests. The physician should inform male and female patients about the risk of developing a teratogenic effect of lenalidomide and strict measures to prevent pregnancy in accordance with the Pregnancy Protection Program.The physician must provide the patient with a training brochure and patient card, as well as other equivalent instructions in accordance with the state patient card system. A controlled distribution system includes the use of patient cards and / or an equivalent instrument to control the appointment and / or dispensing of the drug and to collect detailed data relevant to the indication, in order to closely monitor the use of the indications not approved by the Russian Federation. Ideally, a pregnancy test, treatment appointment and drug delivery should occur on the same day. Lenalidomide delivery to women with preserved reproductive potential should occur no later than 7 days after the appointment of therapy and the receipt of a negative test result for pregnancy, performed under the supervision of a doctor. To women of reproductive age 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 with risk factors for cardiovascular disease and during the first 12 months of combined use with dexamethasone. In case of presence of risk factors, including, first of all, thromboses in the anamnesis, it is necessary to monitor the patients' condition, 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. Venous thromboembolism was less often observed with lenalidomide in combination with melphalan and prednisolone for the first time diagnosed with MM and with monotherapy of myelodysplastic syndrome (see "Interaction with other drugs" and "Side effect"). Therefore, it is necessary to observe patients who have risk factors for thromboembolism, including thrombosis in the anamnesis.Steps should be taken to eliminate 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 the patient with MM 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 such symptoms like 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 heparins or warfarin. The decision to prescribe antithrombotic therapy should be take after a thorough assessment of individual risk factors.

If a patient has symptoms of thromboembolism, it is necessary to stop treatment lenalidomide and prescribe a standard anticoagulant therapy. After The patient's condition is stabilized by anticoagulant therapy, and symptoms thromboembolism will be eliminated, you can start lenalidomide again 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 extensive blood test, including the determination of the number of leukocytes, blood counts, platelet counts, hemoglobin, hematocrit should be performed before the therapy, every week during the first 8 weeks of lenalidomide therapy and then monthly for the monitoring of cytopenia. With the development of neutropenia, a dose reduction of the drug may be required (see "Method of administration and dose").In the case of development of neutropenia, the use 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 first diagnosed MM in patients receiving lenalidomide in combination with low doses of dexamethasone

Neutropenia of grade 4 was less common in patients who received lenalidomide in combination with low doses of dexamethasone than in the control group (8.5% for continuous treatment or treatment for 18 four-week cycles group lenalidomide / dexamethasone, compared with 15% in the group receiving melphalan / prednisone / thalidomide (MAT), see the "Side effect" section). Episodes of febrile neutropenia of grade 4 occurred at the same frequency in the lenalidomide / dexamethasone group and in the comparison group (0.6 % in patients treated with lenalidomide / dexamethasone compared with 0.7% in the group receiving MAT cm. to "Side effect"). Patients should be advised to report promptly febrile episodes, a dose reduction may be required (see the "Dosage and Administration" section).

Thrombocytopenia of grade 3 or 4 was less observed in the lenalidomide / dexamethasone group than in the comparison group (8.1% versus 11.1%, respectively). Patients and doctors are advised to observe the signs and symptoms of bleeding, including petechiae and nosebleeds, especially in cases when concomitant medications are capable of increasing the tendency to bleeding (see "Side effect, Hemorrhagic complications").

The first diagnosed MM in patients receiving lenalidomide in combination with melphalan and prednisolone

The use of lenalidomide with melphalan and prednisolone in clinical trials in patients with newly diagnosed MM was accompanied by a higher frequency of grade 4 neutropenia. Episodes of febrile neutropenia of grade 4 were rare. The use of lenalidomide with melphalan and prednisolone in patients with MM was accompanied by a higher incidence of grade 3 and 4 thrombocytopenia. Patients and doctors are recommended to observe the signs and symptoms of bleeding,including petechiae and nasal bleeding, especially in cases when concomitantly used medications are capable of increasing the tendency to bleeding (see section "Side effects." Hemorrhagic complications ").

MM in patients who received at least one line of therapy

The risk of developing grade 4 neutropenia in patients with MM with simultaneous administration of lenalid and dexamethasone is very high (5.1% in the group treated with lenalidomide / dexamethasone versus 0.6% in the placebo / dexamethasone group). Episodes of febrile neutropenia of 4th severity are rare (0.6% in the group receiving lenalidomide / dexamethasone, 0.0% in the placebo / dexamethasone group). Patients should be advised to report febrile episodes immediately, a dose reduction may be required (see "Dosage and Administration"). With the development of neutropenia should consider the appropriateness of the patient's appointment of a growth factor. A high incidence of grade 3 and 4 thrombocytopenia is observed in MM patients with concomitant administration of lenalidomide and dexamethasone (9.9% and 1.4%, respectively, with lenalidomide / dexamethasone,relative to 2,3% and 0,0% - against the background of placebo / dexamethasone treatment). It is recommended that careful monitoring by both the doctor and the patient of symptoms of increased bleeding, including petechiae and nasal bleeding, especially in cases when concomitantly used medications are capable of increasing 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 the development of infections, including pneumonia. A higher infection rate was observed with lenalidomide in combination with dexamethasone, rather than with MPT. Infections> 3 degrees of severity developed in conditions of neutropenia less than one-third of patients. Patients with known risk factors for infection should be closely monitored. All patients are advised to immediately consult a doctor at the first sign of infection (eg, cough, fever, etc.), which allows for early treatment to reduce severity.

Renal insufficiency

Considering the primary allocation of lenalidomide by the kidneys,In patients with renal insufficiency, the status of kidney function and the dose of lenalidomide should be carefully monitored (see "Dosage and Administration").

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

The molecule of lenalidomide is structurally similar to the molecule of thalidomide, which is known for its ability to cause severe peripheral neuropathy. Nevertheless, there was no increased incidence of peripheral neuropathy in the long-term use of lenalidomide in the treatment of newly diagnosed MM.

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 carefully monitored with appropriate preventive measures.

Allergic reactions

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

Severe skin reactions

There are reports of cases of Stevens-Johnson syndrome (SDS) and toxic epidermal necrolysis (TEN). When exfoliative or bullous rashes on the skin, or suspected development of SDS or TENS should immediately stop using lenalidomide, the treatment of which should not be renewed even 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)

In clinical trials, a higher incidence of primary malignant tumors 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). Non-invasive subleases included basal cell carcinoma and squamous cell carcinoma. Most of the invasive podlas were solid tumors.

In clinical trials in patients with newly diagnosed MM who were not shown to have TSCAs who received lenalidomide in combination with melphalan and prednisolone to progression (1.75 per 100 person-years), there was an increase in the incidence of hematologic GAD (acute myelogenous leukemia, myelodysplastic syndrome) by 4.9 times compared with melphalan in combination with prednisolone (0.36 per 100 person -years).

An increase in the incidence of solid PID was 2.12 times in patients who received 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).

In patients who received lenalidomide in combination with dexamethasone to progression or for 18 months, the incidence of hematologic PID did not increase (0.16 per 100 person-years) compared with the use of MAT (0.79 per 100 person-years).

The increase in the incidence of solid PID is 1.3 times in patients who received lenalidomide in combination with dexamethasone to progression or in for 18 months (1.58 per 100 person-years) compared with receiving MAT (1.19 per 100 person-years).

In clinical trials in patients with newly diagnosed MM who had been shown to have a TSCT, an increase in the incidence of hematologic GAD was observed in those patients who received lenalidomide immediately after a high dose of melphalan and autologous TSCC, compared to patients receiving placebo (1.27 to 1.56 compared to 0.46 to 0.53 per 100 person-years, respectively). Cases of B-cell malignancies (including Hodgkin's lymphoma) observed in clinical trials were found in patients who received lenalidomide in the period after TSCC.

The risk of developing hematologic GAD should be considered before lenalidomide is administered both in combination with melphalan, and after using a high dose of melphalan and TSCC.Doctors should carefully examine patients using standard diagnostic methods to detect PID before and during therapy. Treatment should be conducted according to generally accepted recommendations.

Disorders from the side of the liver

Hepatic insufficiency, including cases with fatal outcome, was registered in patients who received lenalidomide in the combined therapy: 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.

Functional liver abnormalities were often recorded, but they were usually asymptomatic and reversible after discontinuation of therapy. After recovery to baseline, 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 insufficiency in order to avoid reaching concentrations in the blood plasma that may increase the risk of hematologic NLR or hepatotoxicity. It is recommended to monitor liver function, especially if there is a concomitant viral disease of the liver or a history of it, or when lenalidomide is used in combination with drugs that cause liver dysfunction.

Patients with newly diagnosed MM

In patients over the age of 75 years, with stage III according to the international staging system (ISS), with the sum of points on the scale ECOG ≤ 2 or CC <60 ml / min, a higher level of intolerance was observed (grade 3 or grade 4 NLP, severe NLR, discontinuation of treatment) with lenalidomide in combination. Before the appointment of lenalidomide in combination with other drugs, you should carefully evaluate the tolerability of this therapy in elderly patients, taking into account the age, stage III ISS, ECOG ≤ 2 or KK <60 ml / min (see section "Method of administration and dose" and "Side effect").

Cataract

With a higher frequency, cataracts were noted in patients who received lenalidomide in combination with dexamethasone, especially with prolonged therapy. Regular monitoring of vision is recommended.

Unused Capsules

Patients should be warned that they never give their medication to other patients, and at the end of the course of therapy, unused capsules are returned to the treating doctor.

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

Some of the side effects of lenalidomide, such as dizziness, weakness, drowsiness and blurred vision can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration and speed of psychomotor reactions. When these undesirable phenomena are described, one should refrain from carrying out these activities.

Form release / dosage:

Capsules 5 mg, 10 mg, 15 mg, 25 mg.

Packaging:

Primary packaging of medicinal product

For 7 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 7 or 21 capsules in a polymer can of polyethylene with a cover pulled with the control of the first opening. Free space is filled with cotton wool.Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

Secondary packaging of medicinal product

For 1 or 3 contour squares, together with the instructions for use, they are placed in a pack of cardboard for consumer containers.

On 1 bank together with the instruction on application place in a pack from a cardboard for consumer tare.

Storage conditions:

In the original packaging of the manufacturer at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004259

Date of registration:25.04.2017

Expiration Date:25.04.2022

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp05.03.2018

Illustrated instructions

Instructions

Lenalidomide (Lenalidomide)