Revlimid - instructions for use, doses, side effects, contraindications

Excipients: lactose 147.0 mg, microcrystalline cellulose 40.0 mg, croscarmellose sodium 6.0 mg, magnesium stearate 2.0 mg; capsule (body / lid): titanium dioxide 2.9079% / 2.9079%, gelatin qsp 100% / qsp 100%; black ink (TekPrint™SW-9008/SW-9009): shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia water, potassium hydroxide, iron dye oxide black.

1 capsule 10 mg contains:

active substance: lenalidomide 10.0 mg;

Excipients: lactose 294.0 mg, microcrystalline cellulose 80.0 mg, croscarmellose sodium 12.0 mg, magnesium stearate 4.0 mg; capsule (body / cap): indigo carmine dye FD&c Blue 2 0.0000% / 0.0468%, iron dye oxide yellow 0.1294% / 0.2113%, titanium dioxide 2.11816% / 1.6371%, gelatin qsp 100%/ qsp 100%; black ink (TekPrint™SW-9008/SW-9009): shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia water, potassium hydroxide, iron dye oxide black.

1 capsule 15 mg contains:

active substance: lenalidomide 15.0 mg;

Excipients: lactose 289.0 mg, microcrystalline cellulose 80.0 mg, croscarmellose sodium 12.0 mg, magnesium stearate 4.0 mg; capsule (body / cap): indigo carmine dye FD&c Blue 2 0.0000% / 0.0427%, titanium dioxide 2.9079% / 1.9565%, gelatin qsp 100% / qsp 100%; black ink (TekPrint™SW-9008/SW-9009): shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia water, potassium hydroxide, iron dye oxide black.

1 capsule 25 mg contains:

active substance: lenalidomide 25.0 mg;

Excipients: lactose 200.0 mg, microcrystalline cellulose 159.0 mg, croscarmellose sodium 12.0 mg, magnesium stearate 4.0 mg; capsule (body / lid): titanium dioxide 2.9079% / 2.9079%, gelatin qsp 100% / qsp 100%; black ink (TekPrint™SW-9008/SW-9009): shellac, ethanol, isopropanol, butanol, propylene glycol, water, ammonia water, potassium hydroxide, iron dye oxide black.

Description:

Capsules 5 mg: opaque hard gelatin capsules No. 2 cylindrical forms, consisting of a body and a lid of white or almost white, with a black mark "5 mg" (on the body) and "REV" (on the lid); the contents of the capsules are powder from almost white to pale yellow.

Capsules 10 mg: opaque hard gelatin capsules No. 0 cylindrical Forms consisting of a pale yellow body and a blue-green lid, marked black in color "10 mg" (on the body) and "REV" (on the lid); the contents of the capsules are powder from almost white to pale yellow.

Capsules 15 mg: opaque hard gelatin capsules No. 0 cylindrical Forms consisting of a white or almost white body and a blue lid with a black marking "15 mg" (on the body) and "REV" (on the lid); the contents of the capsules are powder from almost white to pale yellow.

Capsules 25 mg: opaque hard gelatin capsules No. 0 cylindrical forms, consisting of a body and a lid of white or almost white color, with a black marking "25 mg" (on the body) and "REV" (on the lid); the contents of the capsules are powder from almost white to pale yellow.

Pharmacotherapeutic group:Immunomodulating agent

ATX: & nbsp

L.04.A.X.04 Lenalidomide

L.04.A.X Other immunosuppressants

Pharmacodynamics:

Lenalidomide is the leading compound of a new class of immunomodulators (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 liposaccharides (LPS) - stimulated peripheral mononuclear blood cells (PMCC).

Lenalidomide increases the production of anti-inflammatory cytokine IL-10 from LPS-stimulated PMCC. as a result of which the expression, but not the enzymatic activity of cyclooxygenase-2 (COX-2), is inhibited.

Lenalidomide induces the proliferation of T cells and increases the synthesis of IL-2 and interferon-1 y. 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.

Clinical effectiveness and safety of Revlimid was confirmed by the results of two multicenter randomized phase III trials in which patients with multiple myeloma received Revlimid together with dexamethasone or one dexamethasone as a second line of therapy. For all the efficacy criteria, including the percentage of complete and partial responses, combined therapy with Rewlimide and dexamethasone was superior to monotherapy with dexamethasone.

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 The exposure of lenalidomide in patients with multiple myeloma is higher than in healthy volunteers, which is explained by a lower ratio of clearance to filtration (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 23% and 29%, respectively.

Lenalidomide is present in the seminal fluid (<0.01% of the dose) after taking it at a dose of 25 mg per day, but not determined in 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, so metabolic drug interactions in the joint use of lenalidomide and drugs that inhibit the isoenzymes of the cytochrome P450 system. 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)l. MRP2 or MRP3. carriers of organic anions (OLT) ОАТ1 and ОАТЗ. a polypeptide-carrier of organic anions 1B1 (OATP1B1), a carrier 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 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 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 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, ns revealed the influence 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.

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 about 2.5. 4 and 5 times in patients with moderate to severe renal insufficiency and terminal stage of renal failure, respectively, compared with the group combining patients with normal renal function and patients with mild renal insufficiency. The half-life of lenalidomide rises from approximately 3.5 hours (in patients with QC above 50 ml / min) to approximately 9 hours (in patients with SC less than 50 ml / min). Approximately 30% of the preparation was excreted from the body during a 4-hour dialysis session. Recommendations for changing the dose of Revlimide 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 (N=16, total bilirubin> 1 and <1.5 x VGN. the upper limit of the 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 and 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 on lenalidomide clearance in adult patients.

There is no data on lenalidomide intake in breast milk.

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 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".

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

Carefully:

In the elderly, in 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 the anamnesis).

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, lactose deficiency or impaired glucose-galactose absorption, since Revlimate capsules contain lactose.

Pregnancy and lactation:

Lalalidomide is a structural analogue of thalidomide, which possesses pronounced teratogenic action. 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 Revlimide is used during pregnancy (see "Contraindications"). Women of reproductive age should be treated with effective methods of contraception during the treatment with Revlimate. The use of 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 of 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. Due with this, during lenalidomide treatment, 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 Revlimide should be done under the supervision of a chemotherapist.

Revlimate is intended only for oral administration.

Rewlimide Capsules, which can not be opened,break or chew, it is recommended to take every day at the same time before or after eating, swallowing whole and squeezed with water.

Recommended initial dose Revlimide is 25 mg orally once a day in 1-21 days of repeated 28-day cycles. Dexamethasone in a dose of 40 mg 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 Revlimide, 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 Revlimid should be taken the next day, at the usual time.

Lenalidomide treatment should not be initiated if the absolute number of neutrophils is <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 number of platelets <30 x 10⁹/ l.

Dose change during treatment or its resumption

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

- Incremental 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 Rewlimide
Recovered> 30 x 10⁹/ l	Resume treatment with Revlimid at a dose of 1 level 1 time per day
Each subsequent decrease of <30 x 10⁹/ l	Stop treatment with Rewlimide
Recovered> 30 x 10⁹/ l	Resume treatment with Rewlimide in a smaller dose (dose of 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 Rewlimide
Recovered> 0.5 x 10⁹/ l and neutropenia - the only manifestation of toxicity	Restore Rewlimide treatment at an initial dose 1 time per day
Recovered> 0.5 x 10⁹/ l and there are other manifestations of toxicity	Resume treatment with Revlimid at a dose of 1 level 1 time per day
For each subsequent decrease less than <0.5 x 10⁹/ l	Stop treatment with Rewlimide
Recovered> 0.5 x 10⁹/ l	Resume treatment Rewlimide 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

Revlimid 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. Percentage of patients aged 65 years and over who received

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 disrupt the function of the night, the dose of the drug should be selected very carefully, while during the treatment it is recommended to monitor the kidney function.

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 functions of the nights

Lenalidomide is excreted mainly by the kidneys. In this regard, the risk of toxic reactions can increase with a violation of kidney function. When administering Revlimid, patients with impaired renal function are recommended to follow the recommendations below.

For patients with mild renal insufficiency, no dose change of Revlimide is required. In the table are presented primary doses recommended in relation to the severity of renal dysfunction (for patients with moderate to severe renal insufficiency, 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 Revlimide (1 to 21 days during repeated 28-day cycles)

Renal failure of moderate severity 30 ml / min <KK <50 ml / min		10 mg once a day *
Renal failure of severe severity CK <30 ml / min, not required dialysis		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 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 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: weakness (43.9%), neutropenia (42.2%), constipation (40.5%), diarrhea (38.5%), muscle cramps (33.4 %), anemia (31.4%), thrombocytopenia (21.5%) and rash (21,2%).

The most serious adverse reactions were:

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

- Neutropenia of the 4th degree 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 Revlimide / dexamethasone. The incidence of adverse reactions listed below was determined 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 established with the available data).

Adverse reactions observed in clinical and post-test 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	Very often: pneumonia, upper respiratory tract infections. Often: sepsis, bacterial, viral and fungal infections (including opportunistic), sinusitis.	Often: pneumonia, bacterial, viral and fungal infections (including opportunistic).
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Infrequent: basal cell carcinoma of the skin.	Rarely: lysis syndrome, tumors *.
Violations of the blood and lymphatic system	Very often: thrombocytopenia, neutropenia, anemia, hemorrhagic disorders, leukopenia. Often: pancytopenia. Infrequently: hemolysis, autoimmune hemolytic anemia, hemolytic anemia.	Very often: Thrombocytopenia, neutropenia, leukopenia. Often: febrile neutropenia, anemia. Infrequent: hypercoagulation, coagulopathy.
Immune system disorders	Infrequent: hypersensitivity reactions ^.	-
Disorders from the endocrine system	Often: hypothyroidism, hyperthyroidism.	-
Disorders from the metabolism and nutrition	Very often: hypokalemia, decreased appetite. Often: hypomagnesemia, hypocalcemia, dehydration.	Often: hypokalemia, hypocalcemia, hypophosphatemia.
Disorders of the psyche	Infrequently: loss of libido.	Often: depression.
Disturbances from the nervous system	Very often: peripheral neuropathy (with the exception of 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	Very often: blurred vision. Often: reduced visual acuity, cataract.	Often: cataract. Infrequently: blindness.
Hearing disorders and labyrinthine disorders	Often: deafness (including deafness), tinnitus.	-
Heart Disease	Often: atrial fibrillation, bradycardia. Infrequent: arrhythmia, lengthening of the QT interval, atrial flutter, ventricular extrasystole.	Often: myocardial infarction, atrial fibrillation, congestive heart failure, tachycardia.
Vascular disorders	Very often: thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism). Often: arterial hypotension, arterial hypertension, ecchymosis.	Very often: thromboembolic disorders (mainly deep vein thrombosis and pulmonary embolism). Infrequent: ischemia, peripheral ischemia, thrombosis of the intracranial venous sinus.
Disturbances from the respiratory system, chest and mediastinal organs	Very often: dyspnea, nasopharyngitis, pharyngitis, bronchitis, nosebleeds ^.	Often: respiratory distress syndrome. Unknown: interstitial pneumonitis *.
Disorders from the gastrointestinal tract	Very often: constipation, diarrhea, nausea, vomiting. Often: gastrointestinal bleeding (including rectal, hemorrhoidal, gingival bleeding and bleeding in peptic ulcer), abdominal pain, dry mouth, stomatitis, dysphagia. Infrequently: colitis, tiflitis.	Often: diarrhea, constipation, nausea. Unknown: pancreatitis *, perforation of the gastrointestinal tract (including perforation of the diverticulum, small and large intestine).
Disturbances from the liver and bile ducts	Often: deviation of the values of functional liver samples from normal. Infrequently: hepatic impairment . Unknown: acute liver failure ^ , toxic hepatitis ^, cytolytic hepatitis ^ , cholestatic hepatitis ^ , mixed cytolytic / cholestatic hepatitis ^ *.	Often: deviation of the values of functional liver samples from normal. Infrequently: hepatic impairment . Unknown: acute hepatic insufficiency ^ , toxic hepatitis ^ *.
Disturbances from the skin and subcutaneous tissues	Very often: rash. Often: urticaria, hyperhidrosis, dry skin, skin itching, hyperpigmentation of the skin, eczema. Infrequent: skin color disorder, photosensitivity reaction.	Often: rash. Infrequently: angioedema. Rarely: Stevens-Johnson syndrome ^ , toxic epidermal necrolysis ^ . Unknown: leukocytoclastic vasculitis *.
Disorders from the musculoskeletal system	Very often: muscle cramps, bone pain, pain and discomfort from the osteomuscular and connective tissue. Often: swelling of the joints.	Often: muscle weakness, pain in the bones. Infrequent: swelling of the joints.
Disorders from the kidneys and urinary tract	Often: hematuria, urinary retention, incontinence. Infrequently: acquired Fanconi syndrome.	Often: kidney failure. Infrequently: tubular renal necrosis.
Violations of the genitals and mammary glands	Often: erectile dysfunction.	-
General disorders and disorders at the site of administration	Very often: increased fatigue, swelling (including peripheral), fever, flu-like syndrome (including fever, myalgia, musculoskeletal pain, headache and chills). Often: chest pain, lethargy.	Often: increased fatigue.

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

* Post-registration 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 in monkeys the appearance of congenital anomalies, similar to those described for thalidomide. If lenalidomide is 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 dexamethasone relative to 2? 3% and 0.0% in patients treated with a combination of dexamethasone and placebo).

Venous thromboembolism

Use of a combination of lenalidomide with dexamethasone in multiple myeloma patients was accompanied by an increased risk of deep vein thrombosis and pulmonary embolism (see. "Interaction with other medicinal products"). 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 system,organs of the chest and mediastinum (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 Do not prescribe to patients who have had severe forms of rash when taking thalidomide in an anamnesis.

Primary malignant tumors of other localization

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

Acute myelogenous leukemia

- Multiple myeloma

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 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 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 currently not developed,that in studies to determine the range of doses, some patients received doses 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 multiple myeloma, taking lenalidomide in combination with dexamethasone.

Digoxin

Simultaneous administration of lenalidomide with digoxin is accompanied by an increase in the plasma concentration of digoxin (Cmdigoxin was 114%, a AUC₀-_∞ 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 effect of these drugs.Careful clinical and laboratory monitoring is necessary, especially during the first treatment session.

Dexamethasone

Simultaneous single or multiple administration of dexamethasone (40 mg / day) nc has 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 Revlimide, 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 a background of combined therapy with lenalidomide and dexamethasone, careful monitoring of the concentration of warfarin is recommended. Interaction with inhibitors of P-glycoprotein (P-gp) Lenalidomide in vitro is a substrate of P-gp, but not of P-gp inhibitors.Simultaneous multiple application of a potent inhibitor of P-gp, quinidine (600 mg twice daily), or a moderate P-gp / substrate inhibitor, 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 Revlimid 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 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 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 childbearing potential is contraindicated in cases where the following conditions are not met:

female

- must To know about the possible teratogenic effect of Revlimid on unborn child

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

- even in the case of amenorrhea, it 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 Revlimid. which can be started immediately after receiving negative results of the pregnancy test

- 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 Rewlimide

Application in men:

Data from the study of the pharmacokinetics of lenalidomide in male volunteers indicate that lenalidomide may be contained in the seminal fluid of patients during treatment in 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 special groups of patients (in patients with impaired renal function), the following conditions must be met in all male patients taking Revlimide:

Man

- should understand the possible risk of teratogenic action of the drug Revlimid in sexual contact with a pregnant woman or a woman with a preserved reproductive potential should understand the need for using condoms (even after a vasectomy) with sexual contact with pregnant women or women with preserved reproductive potential not using reliable methods of contraception during the treatment period, and within 1 week after the suspension of treatment and / or completion of treatment

- should understand that if his partner becomes pregnant during his treatment with Revlimid or immediately after the cessation of Rewlimid therapy, he should immediately inform his or her attending physician about this and that his partner is advised to seek advice from a teratologist.

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

The highly effective methods of contraception include:

- Subcutaneous hormonal implants;

- Intrauterine 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 treatment with Rewlimide and dexamethasone. For effective contraception, this patients are encouraged to use one of the methods listed above. An increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives.

The effectiveness of hormonal contraceptives can be reduced with the simultaneous administration of dexamethasone.

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

The use of intrauterine systems that release copper is generally not recommended due to a high risk of developing infectious complications at the time of implantation and increased blood loss during menstruation, which may increase the severity of neutropenia or thrombocytopenia in the patient. Pregnancy tests (sensitivity of at least 25 mIU / mL) should be performed in the presence of a physician for all women with preserved reproductive potential, including those that completely and continuously refrain from heterosexual 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 attending physician, and then every 4 weeks, including after the completion of Rewlimid.The results of the test should confirm the absence of pregnancy in the patient against the background of treatment with Rewlimide.

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

Additional precautions

Patients should not transfer Revlimid 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 Revlimid and within 1 week after the end.

Teaching materials, restrictions in appointment and extradition preparation

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 warnings about the 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. Lenalidomide delivery to women of reproductive age should occur within 7 days after the appointment of therapy and receive a negative result of a pregnancy test, 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

Combined therapy Revlimid and dexamethasone marked increase in the incidence of venous thromboembolism (primarily deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (mainly myocardial infarction and stroke) in patients 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 in 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 limb.

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

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

Neutropenia and thrombocytopenia

Severe dose-limiting toxic phenomena of lenalidomide are neutropenia and thrombocytopenia. An extensive blood test, including determination of the number of leukocytes, blood formulas, platelet counts, hemoglobin, hematocrit should be performed before the beginning therapy, every week for the first 8 weeks of lenalidomide therapy and, subsequently, monthly for the monitoring of cytopenia. In the development of neutropenia, a decrease in the vine 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 risk of developing grade 4 neutropenia in patients with multiple myeloma with the simultaneous administration of Revlimate and dexamethasone is very high (5.1% in the Rewlimide / dexamethasone group relative to 0.6% in the placebo / dexamethasone group). Episodes of febrile neutropenia of the 4th severity level are infrequent (0.6% in the group treated with Revlimid / Dexamethasone, 0.0% in the placebo / dexamethasone group). A high incidence of thrombocytopenia of grade 3 and 4 was observed in patients with multiple myeloma with the simultaneous administration of Revlimid and dexamethasone (9.9% and 1.4%, respectively, in patients treated with Rewlimide / dexamethasone, relative to 2.3% and 0, 0% against treatment placebo / dexamethasone). It is recommended that careful monitoring by the doctor and physician,and symptoms of increased bleeding, including petechia and hemoptysis, especially when simultaneously used drugs are capable of increasing tendency to bleeding (see. "venous and arterial thrombosis" and "Side effect, hemorrhagic complications").

Renal insufficiency

Given the preferential allocation Revlimid kidneys in patients with renal failure need to carefully monitor the status of renal function and dose Revlimid (cm. "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 during treatment with Revlimid.

Peripheral Neuropathy

It is impossible to exclude the possibility of neurotoxic action

Revlimid during prolonged his admission, given the structural similarity of molecules Revlimid and thalidomide, which is known for its severe neurotoxic side effects.

Tumor lysis syndrome

In connection with the expressed antineoplastic activity Revlimid may develop tumor lysis syndrome, especially in patients with large tumor mass. These patients should be monitored appropriately, and the use of conventional preventive measures.

Allergic reactions

There have been reports of cases of allergic reaction / hypersensitivity reactions (see. "Side effects"), in connection with the fact that there are scientific publications on possible cross-reaction between lenalidomide and thalidomide should carefully monitor the condition of patients who have a history of Indication of allergic reactions during treatment with thalidomide.

Severe skin reactions

There are reports of cases of Stevens-Johnson syndrome (SDS) and toxic epidermal necrolysis (TEN). When the ekfoliativnyh or bullous rash on the skin, or suspected development of SSc or heater should immediately to stop the use of 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 studies, a higher incidence of primary malignant tumors was observed 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 multiple myeloma receiving Revlimide, an increase in 4-fold (7%) of cases of PID compared with the control group (1.8%) was noted. From invasive subleases in patients receiving combined treatment with Revlimide 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 are noted. Cases of development of B-cell tumors (including Hodgkin's lymphoma) were noted inclinical studies, when Revlimid was used after stem cell transplantation.

The risk of developing an AML should be considered before prescribing Revalimid. Doctors should carefully examine patients using standard diagnostic methods to detect PALL before deciding to prescribe Rewlimid. and during the entire period of treatment with Rewlimide. 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. Mechanisms of severe drug hepatotoxicity remain unknown, although In some cases, the previous viral disease of the liver, the initial increase in the activity of liver enzymes and, possibly, the treatment with antibiotics can be risk factors.

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.

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

Some side effects of Revlimid, such as dizziness, weakness, drowsiness and blurred vision, can adversely affect the ability to drive and perform potentially dangerous activities requiring increased attention 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 planar cell package (blister) [laminated film (PVC / Aclar®) / aluminum foil].

For 3 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

In a dry place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003870/09

Date of registration:22.05.2009

The owner of the registration certificate:Selden International SarlSelden International Sarl Switzerland

Manufacturer: & nbsp

CELGENE INTERNATIONAL, Sarl. Switzerland

PENN PHARMACEUTICAL SERVICES, Ltd. United Kingdom

Representation: & nbspSeldzhen International Holdings Corporation Seldzhen International Holdings Corporation USA

Information update date: & nbsp10.11.2015

Illustrated instructions

Instructions

Revlimate (Revlimid)