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

Excipients: lactose - 140.0 mg; cellulose microcrystalline - 80,60 mg; croscarmellose sodium - 7.05 mg; magnesium stearate - 2.35 mg; capsule (body / cap): gelatin - up to 100% / up to 100%; titanium dioxide - 0.06591% / 0.02746%; dye azorubin - - / 0.00460%; dye diamond blue - - / 0,02690%.

One 10 mg capsule contains:

active substance: lenalidomide - 10.0 mg;

Excipients: lactose - 290.0 mg; cellulose microcrystalline - 122, 40 mg; croscarmellose sodium - 13.20 mg; magnesium stearate - 4.40 mg; capsule (body / cap): gelatin - up to 100% / up to 100%; titanium dioxide - 0.06591% / 0.02746%; dye quinoline yellow - - / 0.10770%; dye sunset yellow - - / 0,00460%; dye diamond blue - - / 0,09230%.

One 15 mg capsule contains:

active substance: lenalidomide - 15.0 mg;

Excipients: lactose - 288.0 mg; cellulose microcrystalline - 119.40 mg; croscarmellose sodium - 13.20 mg; magnesium stearate - 4.40 mg; capsule (body / cap): gelatin - up to 100% / up to 100%; titanium dioxide - 0.03845% / 0.03845%; dye sunset sunset yellow - 0.19230% / 0.19230%; dye red charming - 0.00850% / 0.00850%.

One capsule of 25 mg contains:

active substance: lenalidomide - 25.0 mg;

Excipients: lactose - 285.0 mg; cellulose microcrystalline - 112.40 mg; croscarmellose sodium - 13.20 mg; magnesium stearate - 4.40 mg; capsule (body / cap): gelatin - up to 100% / up to 100%; titanium dioxide - 0.02197% / 0.02197%; dye quinoline yellow - 0.04000% / 0.04000%; dye azorubin - 0.03770% / 0.03770%; dye red charming - 0,08460% / 0,08460%.

Description:

Capsules 5 mg: hard gelatin capsules No. 2, consisting of a blue lid and a white body; the contents of the capsules are powder from white to pale yellow.

Capsules 10 mg: hard gelatin capsules No. 0, consisting of a lid of green color and a white body; the contents of the capsules are powder from white to pale yellow.

Capsules 15 mg: hard gelatin capsules No. 0, consisting of an orange-colored lid and an orange-colored body; the contents of the capsules are white to pale yellow powder.

Capsules 25 mg: hard gelatin capsules No. 0, consisting of a red lid and a red body; the contents of the capsules are powder from white to pale yellow.

Pharmacotherapeutic group:Immunosuppressive remedy

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 (IMiDsSM), which has both immunomodulatory and anti-angiogenic properties.

Lenalidomide inhibits the secretion of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β, IL-6 and IL-12, from liposaccharide (LPS) -stimulated peripheral mononuclear blood cells (PMCK).

Lenalidomide increases the production of anti-inflammatory cytokine IL-10 from LPS-stimulated PMCC. resulting in inhibition of expression, but not enzymatic activity of cyclooxygenase-2 (COX-2).

Lenalidomide induces T cell proliferation 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, judging by the 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.

Absorption

After ingestion by healthy volunteers lenalidomide quickly absorbed; with the maximum concentration achieved after 0.625-1.5 hours after a single dose. The pharmacokinetic distribution is linear. Maximum concentration (FROM_mOh) 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. FROM_mOh 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 was 22.7% and 29.2%, 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 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 protein substitute for breast cancer resistance (BCRP), carriers of the multiple drug resistance protein (MRP) MRP1, MRP2 or MRP3. carriers of organic anions (OAT) OAT1 and OAT3, carriers of organic cations (OCT) of OST1 and OST2, the transporter 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 for the export of bile acids), BCRP, MRP2, ОАТ1, ОАТЗ, ОАТР1В1, ОАТР1В3 or ОСТ2 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, since 65-85% 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 the drug is approximately 3 hours in healthy volunteers and from 3 to 5 hours in patients with multiple myeloma.

Pharmacokinetics in special clinical cases

Elderly patients

Special clinical studies 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, care should be taken when selecting a dose of the drug and perform careful monitoring of kidney function against the background of therapy.

Patients with renal insufficiency

FROM_m_Oh 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 have increased approximately in 2,5, 4 and 5 times at patients with a renal insufficiency of an average degree of gravity,severe renal failure and terminal stage of renal failure, respectively, compared with the group that unites 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% of the drug was excreted from the body during a 4-hour dialysis session. Recommendations for changing the dose of the drug Metiblastan® in patients with renal insufficiency are given in the section "Method of administration and dose".

Patients with hepatic insufficiency

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 on patients with hepatic insufficiency of moderate to severe severity have not been obtained.

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 for clearance of lenalidomide in adult patients.

Indications:

Lenalidomide in combination with dexamethasone is indicated 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 the period of breastfeeding.

- 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".

- Children's age (not enough clinical experience of application).

Carefully:

In elderly patients with renal 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 "Side effect" and "Interaction with other medicinal products").

In patients with hereditary lactose intolerance, lactase deficiency or impaired absorption of glucose-galactose, as the capsules of the drug Metiblastan® contain lactose.

Pregnancy and lactation:

Pregnancy

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 (see "Contraindications"). Women of reproductive age should be treated with effective methods of contraception during the treatment with Metiblastan®. 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 sexual 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.

Breastfeeding period

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

Fertility

The results of a study of reproductive function 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, taking into account the body surface area), did not demonstrate impairment of fertility or toxicity for the body of parents.

Dosing and Administration:

Treatment with Metiblastan® should be performed under the supervision of a chemotherapist.

Lenalidomide is intended only for oral administration.

Capsules of the drug Metiblastan®, which can not be opened, broken or chewed, are recommended to be taken every day at the same time before or after eating, swallowing whole and with water.

The recommended initial dose of Metiblastan® 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 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 less than 12 hours have elapsed since the missed dose of Metiblastan®, 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 Metiblastan® 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 changing the dose for the development of neutropenia,thrombocytopenia or other types of toxicity of 3 and 4 severity, the relationship of which with the use of the drug Metiblastan® can not be ruled out.

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 treatment with Metilblast®
Has recovered ≥30 x 10⁹/ l	To resume treatment with Metiblastan ® at a dose of 1 level 1 time per day
Each subsequent decrease of <30 x 10⁹/ l	Stop treatment with Metilblast®
Has recovered ≥30 x 10⁹/ l	To resume treatment with Metiblastan ® 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 treatment with Metilblast®
Has recovered ≥0.5 х 10⁹/ l and neutropenia - the only manifestation of toxicity	To resume treatment with Metiblastan® in the initial dose once a day
Has recovered ≥0.5 х 10⁹/ l and there are other manifestations of toxicity	To resume treatment with Metiblastan ® at a dose of 1 level 1 time per day
For each subsequent decrease less than <0.5 x 10⁹/ l	Stop treatment with Metilblast®
Has recovered ≥0.5 х 10⁹/ l	To resume treatment with Metiblastan ® 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.

Children and teens

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

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 administered to patients with multiple myeloma before the age of 86 years. 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 elderly patients are more likely to have impaired renal function, the dose of the drug should be carefully selected, while monitoring of renal function is recommended during treatment.

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.

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 prescribing Metiblastan® to patients with impaired renal function, it is recommended that the following guidelines be followed.

For patients with mild renal impairment, there is no need to change the dose of Metiblastan®. The table shows primary dose of the drug, recommended depending on the degree of renal dysfunction (for patients with moderate to severe severity of renal failure, as well as terminal stage of renal failure).

Initial dose of lenalidomide depending on the severity of renal dysfunction

Kidney function status	The recommended dose of Metiblastan® (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 severe severity CK <30 ml / min, no dialysis required	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 a dialysis session.

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

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

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.

Side effects:

In patients with multiple myeloma who received lenalidomide in combination with dexamethasone, the most frequent adverse reactions were: neutropenia (39.4%), fatigue (27.2%), constipation (23.5%), decreased appetite (23.1%), muscle cramps (20 , 1%), thrombocytopenia (18.4%), asthenia (17.6%), anemia (17.0%), diarrhea (14.2%), and rash (10.2%).

The most serious adverse reactions 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 them to be successfully controlled by reducing the dose of Metiblastan® / dexamethasone.

Frequency of side effects: very often (≥ 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to <1/1000), very rarely (<1/10000), the frequency is not established (there is currently no evidence of the incidence of adverse reactions).

Adverse reactions observed in clinical and postrepresentation studies in patients with multiple myeloma, who received lenalidomide at combination with dexamethasone

System-Organ Class	Adverse reactions (in total), frequency		Adverse reactions of 3-4 degrees of severity, frequency
Infectious and parasitic diseases	Often: pneumonia, upper respiratory tract infections, lower 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), sepsis, bronchitis.
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Infrequently: basal cell carcinoma, squamous cell carcinoma^{^}.		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: trhombocytopenia^{^}, neutropenia^{^}, anemia, hemorrhagic disorders ^, leukopenia.		Often: thrombocytopenia^{^}, neutropenia^{^}, leukopenia.
	Often: febrile neutropenia, pancytopenia, leukopenia, lymphopenia. Infrequently: hemolysis, autoimmune hemolytic anemia, hemolytic anemia.		Often: febrile neutropenia, 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: hyperglycemia, weight loss, decreased appetite, hypocalcemia, hypokalemia. Often: hypomagnesemia, dehydration.			Often: hypokalemia, hyperglycemia, hypocalcemia, diabetes mellitus, hypophosphatemia, hyponatremia, 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 (with the exception of motor neuropathy), dizziness, tremor, taste perversion, 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: blurred vision, cataract. Often: decreased visual acuity.			Often: cataract. Infrequently: blindness.
Violations fromhearing and labyrinthine violations		Often: deafness (including deafness), tinnitus. Infrequently: hearing loss, pain in the ears.			-
Heart Disease		Often: atrial fibrillation, bradycardia. Infrequently: arrhythmia, lengthening interval QT, atrial flutter, ventricular extrasystole.		Often: myocardial infarction (including acute myocardial infarction)^{^}, 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. Frequency unknown: interstitial pneumonitis.
Disorders from the gastrointestinal tract		Often: constipation, diarrhea, nausea, vomiting, indigestion. Often: gastrointestinal bleeding (including rectal, hemorrhoidal, gingival bleeding and bleeding in peptic ulcer), dry mouth, stomatitis, dysphagia. Infrequently: colitis, tiflitis.		Often: diarrhea, constipation, nausea, abdominal pain, vomiting. Frequency unknown: pancreatitis ***.
Disturbances from the liver and bile ducts		Often: deviation 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: liver failure. 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: skin color disorder, photosensitivity reaction. Rarely: Stevens-Johnson syndrome, toxic epidermal necrolysis.		Often: rash. Infrequently: angioedema edema**. Rarely:* Stevens-Johnson * ^ toxic epidermal necrolysis * ^. Frequency unknown: leukocytoclastic vasculitis ***.
Musculoskeletal system disorders		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, pain in the bones. Infrequently: swelling of the joints.
Disorders from the kidneys and urinary tract		Often: kidney failure (including acute). Often: hematuria, urinary retention, incontinence Infrequently: acquired Fanconi syndrome.		Infrequently: tubular renal necrosis.
Violations of the genitals and mammary glands		Often: erectile disfunction,
Congenital, hereditary and genetic disorders		Infrequently: chromosomal abnormalities.
General violations and violations at the site of introduction		Often: increased fatigue, swelling (including peripheral), fever, asthenia, flu-like syndrome (including fever, 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.
Injuries, intoxication and complications manipulations		Often: fall, bruise.

^{^} Details are provided at the end of this section.

*** Post-marketing research data

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 (see "Contraindications" and "Special instructions").

Neutropenia and thrombocytopenia

Use of a combination of lenalidomide and dexamethasone in patients with multiple myeloma was accompanied by an increase in the incidence of neutropenia 4 severity (at 5.1% of patients receiving lenalidomide with dexamethasone, compared with 0.6% in patients taking the combination of dexamethasone and placebo).Febrile neutropenia of 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 use of a combination of lenalidomide with dexamethasone in multiple myeloma was accompanied by an increased likelihood 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 multiple myeloma has been associated with an increased risk of developing deep vein thrombosis and pulmonary embolism (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 brought into conformity with systemic-organ classes: violations from 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 had severe forms of rash when taking thalidomide in an anamnesis.

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 compared with the control, represented mainly basal cell or squamous cell carcinoma of the skin.

Acute myelogenous leukemia

Cases of acute myelogenous leukemia have been observed in clinical studies of newly diagnosed multiple myeloma in patients who received lenalidomide in combination with melphalan or immediately after a high dose of melphalan and transplantation of autologous hematopoietic stem cells (ASCT) (see "Special instructions").

Disorders from the side of the liver

The following liver abnormalities were detected (frequency not established): acute liver failure 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 have been reported 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 multiple myeloma is not currently developed, despite the fact that in studies to determine the range of doses, some patients received doses up to 150 mg and in single dose studies - 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, 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 (C_mOh digoxin was 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 joint use of statins and lenalidomide, which can be explained by the summation of the actions 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 administration at a dose of 25 mg / day.

Oral contraceptives

Dexamethasone, which is an obligatory component of the treatment regimen with the drug Metiblastan®, can reduce the effectiveness of oral contraceptives. To effectively prevent pregnancy, use the means indicated in the Pregnancy Protection Program (see "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 the background of combined therapy with lenalidomide and dexamethasone, careful monitoring is recommendedconcentration of warfarin.

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 twice daily), or a mild inhibitor P-gp/ substrate, tamsirolimus (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:

Treatment with Metiblastan® 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 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 the 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's syndrome, anatomical defect of the uterus

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

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

Female

- must be aware of the possible teratogenic effects of Metiblastan® on unborn child;

- should understand the need for continuous use of effective contraceptive methods for 4 weeks prior to treatment, during treatment and 4 weeks after treatment with Metiblastan®;

- even in the case of amenorrhea must comply with all the rules of 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 to comply with all the rules of effective contraception against the background of taking Metablastan ®, which can be started immediately after receiving negative test results forpregnancy;

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

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

Application in men:

Data from the study of the pharmacokinetics of lenalidomide in male volunteers indicate that lenalidomide can be contained in the seminal fluid of patients during the treatment period at extremely low concentrations, 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 lenalidomide excretion in specific patient groups (in patients with impaired renal function), the following conditions must be met in all male patients taking Methybastane®:

Man

- should understand the possible risk of teratogenic action of the drug Metiblastan® in sexual contact with a pregnant woman or a woman with a preserved childbearing potential;

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

- should understand that if his partner became pregnant during his treatment with Metablastan® or immediately after discontinuing therapy with the drug

Metiblastan®, he must immediately inform his / her own attending physician about this, and that his partner is advised to seek advice from a teratologist.

The doctor who prescribes treatment with Metiblastan® women with preserved reproductive potential should

- make sure that the patient meets all conditions Pregnancy prevention programsincluding confirmation that she adequately understands the situation;

- To obtain the patient's consent to the obligatory observance by her of 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 treatment with Metiblastan® 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 patient should immediately begin using the effective method of contraception.

The highly effective methods of contraception include:

- Subcutaneous hormonal implants;

- Intrauterine devices that release 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 multiple myeloma due to an increased risk of thromboembolic complications during the treatment with the drug Metilblast® 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.

Tests for pregnancy (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 the 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 attending physician, and then every 4 weeks, even after the end of the Methiblastan® drug. The results of the test should confirm the absence of pregnancy in the patient against the background of treatment with the drug Metiblastan®.

Male patients should use condoms during the entire course of treatment with the drug Metilblast®, during the interruption of treatment and within 1 week after discontinuation of treatment if the sexual partner is a pregnant woman or a woman with a preserved childbearing potential that does not use highly effective methods of contraception (even if the man suffered a vasectomy).

Additional precautions

Patients should not transfer Metiblastan® to others. 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 Metilblast® and within 1 week after the end.

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

To help patients prevent lenalidomide from affecting the fetus, the holder of the registration certificate will provide all the necessary training materials to medical personnel in order to strengthen the warning about teratogenicity of lenalidomide, recommend contraception before starting therapy and explain the need for a pregnancy test. The physician should inform male and female patients of the teratogenic risk of lenalidomide and strict measures to prevent 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.Ideally, a pregnancy test, treatment appointment and drug delivery should occur on the same day. Delivery of lenalidomide to women of reproductive age should occur within 7 days after the appointment of therapy and receive 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 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) (see "Side effect").

Venous and arterial thromboembolism

Against the background of combined therapy with the drug Metiblastan® and dexamethasone, there is an increase in the frequency of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism)and arterial thromboembolic events (mainly myocardial infarction and stroke) in patients with multiple myeloma (cm. '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 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 heparin or warfarin. The decision to prescribe antithrombotic therapy should be taken after a thorough assessment of individual risk factors.

If the patient has symptoms of thromboembolism, it is necessary to stop lenalidomide treatment and prescribe a 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 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 myelosuppressive drugs.

The risk of developing grade 4 neutropenia in patients with multiple myeloma with simultaneous prescription of the drug Metilblast® and dexamethasone is very high (5.1% in the group receiving Metylbastan ® / dexamethasone, 0.6% in the placebo / dexamethasone group). Episodes of febrile neutropenia of 4 severity are infrequent (0.6% in the group receiving Metilblast® / dexamethasone, relatively 0.0% in the placebo / dexamethasone group).A high incidence of grade 3 and 4 thrombocytopenia is observed in patients with multiple myeloma with concomitant administration of Metiblastan® and dexamethasone (9.9% and 1.4%, respectively, in patients treated with Metiblastan® / dexamethasone versus 2.3 % and 0.0% - on the background of treatment placebo / 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 are capable of increasing the tendency to bleeding (see "Venous and arterial thromboembolism" and "Side effects, hemorrhagic complications" ).

Infectious diseases with / without neutropenia

When taking Metablastan®, it is possible to develop infectious diseases, including pneumonia. Less than one third of patients, infection of the 3rd degree of severity developed in the absence of neutropenia. It is necessary to carefully monitor the condition of patients at risk of infectious diseases. If there are first signs of infection (cough, fever, etc.), you need to see a doctor to prevent the development of the disease and the occurrence of complications.

Renal insufficiency

Given the primary isolation of the drug Metilblastan® by the kidneys, patients with renal failure need to carefully monitor the status of kidney function and the dose of the drug Metiblastan® (see "Method of administration and dose").

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 the thyroid function before starting treatment and its regular monitoring against the background of the use of the drug Metiblastan®.

Peripheral Neuropathy

It is impossible to exclude the possibility of neurotoxic action of the drug Metiblastan® during its long reception, taking into account the structural similarity of the molecules of the drug Metiblastan® and thalidomide, which is known for its pronounced neurotoxic side effect.

Tumor lysis syndrome

Due to the pronounced anti-neoplastic activity of the drug Metiblastan®, 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 (see "Side effect"). Due to the fact that there are scientific publications on possible cross-reactions between lenalidomide and thalidomide, 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). If eczoliative or bullous skin rashes occur, or suspected development of SS or TENS, 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 can not be administered to patients,who have a history of indication of severe skin reactions against the background of 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, patients with newly diagnosed multiple myeloma who received Metiblastan® experienced a 4-fold increase (7%) of cases of PID compared with the control group (1.8%).

From cases of invasive PID in patients receiving combined treatment with Metiblastan® and melphalan, or immediately after the use of high doses of melphalan and autologous stem cell transplantation, cases of acute myeloid leukemia, myeloid dysplasia syndrome and solid tumors were noted. Cases of development

B-cell tumors (including Hodgkin's lymphoma) were noted in clinical studies when Metiblastan® was used after stem cell transplantation. The risk of developing an AML should be considered before prescribing Metiblastan®. Doctors should carefully examine patients using standard diagnostic methods to detect PALA before deciding whether to prescribe Methiblastan® or during the entire treatment period with Metiblastan®. Treatment should be conducted according to generally accepted recommendations.

Disorders from the side of the liver

Hepatic insufficiency, including death, has been reported in patients treated with lenalidomide in combination with dexamethasone: acute liver failure, 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 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 failure to avoid reaching plasma concentrations that may increase the risk of hematologic side effects 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.

Cataract

A higher incidence of cataracts was observed in patients who received lenalidomide in combination with dexamethasone, especially with prolonged use. Regular monitoring of the visual function is recommended.

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

Some of the side effects of Metiblastan®,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 appear, one should refrain from performing these activities.

Form release / dosage:

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

Packaging:

For 7 capsules in a blister of PVC-PTFE film / aluminum foil.

For 1, 3 or 4 blisters, along with instructions for medical use, put in a pack of cardboard.

For 18, 24, 30 or 40 blisters together with an equal number of instructions for medical use are placed in a pack of cardboard (for hospitals).

Storage conditions:

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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003551

Date of registration:11.04.2016 / 11.05.2016

Expiration Date:11.04.2021

The owner of the registration certificate:Laboratory Tutor SAASIFAALaboratory Tutor SAASIFAA Argentina

Manufacturer: & nbsp

Laboratorio TUTEUR S.A.C.I.F.I.A. Argentina

Representation: & nbspGENPHA LTD.GENPHA LTD.Russia

Information update date: & nbsp07.05.2018

Illustrated instructions

Instructions

Methylbastan® (Methylbastan®)