Instruction for use: Pomalidomide

Trade name of the drug – Imnovid

The Latin name of the substance Pomalidomide

Pomalidomidum (genus. Pomalidomidi)

Chemical name

(RS) -4-Amino-2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione

Gross formula

C13H11N3O4

Pharmacological groups:

Other antineoplastic agents

Immunosuppressive drugs

The nosological classification (ICD-10)

C90.0 Multiple myeloma: Multiple myeloma; Myeloma

CAS code

19171-19-8

Characteristics of the substance Pomalidomide

Immunomodulating antitumor agent.

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The molecular mass of pologmidomide is 273.24. Pomalidomide is a yellow powder, it has limited or low solubility in organic solvents and low solubility in aqueous solutions at all pH values (about 0.01 mg / ml). Due to the presence of a chiral carbon atom, pomalidomide exists as a racemic mixture of the enantiomers of R (+) and S (-).

Pharmacology

Mode action - Immunomodulating.

Pharmacodynamics

Mechanism of action. Pomalidomide has direct anti-myeloma tumorocidal activity, demonstrates immunomodulatory action and inhibits stromal cells that support the growth of myeloma tumor cells. Pomalidomide selectively inhibits proliferation and causes apoptosis of hematopoietic tumor cells. In addition, pologidomide inhibits the proliferation of multiple myeloma cell lines resistant to lenalidomide, and has synergism with dexamethasone for apoptosis of both sensitive and lenalidomide-resistant tumor cell lines. Pomalidomide enhances cellular immunity with the participation of T cells and natural killers and inhibits the formation of pro-inflammatory cytokines (eg TNF-α and IL-6) by monocytes. Pomalidomide also inhibits angiogenesis, blocking the migration and adhesion of endothelial cells.

Pharmacokinetics

Absorption. After a single oral intake, the absorption of pamildomide is at least 73%, and Cmax is reached after 2-3 hours. Systemic exposure to pamildomide (in terms of AUC) increases almost linearly and in proportion to the dose. With multiple dosing, the degree of accumulation of pamildomide is 27-31% for AUC.

When combined with a high-calorie food with a significant fat content, the rate of suction of pologidomide slows down, the value of Cmax decreases by about 25%, but the total intake practically does not change, the AUC decreases by only 8%. Therefore, pomalidomide can be taken regardless of food intake.

Distribution. The average apparent VSS of pologidomide is in the range of 62-138 liters. After applying pamildomide for 4 days to 2 mg per day, it is found in the seminal fluid of healthy volunteers at a concentration of approximately 67% of the plasma level, which is achieved after 4 hours (approximate Tmax) after taking the drug. In vitro binding of enantiomers of pologmidomide with human plasma proteins is in the range from 12 to 44% and does not depend on concentration.

Biotransformation. In healthy volunteers, after single ingestion of 14C-pologidomide (2 mg), the main component in the blood was pologidomide (approximately 70% of plasma radioactivity). The amount of metabolites did not exceed 10% relative to the parent compound or the total plasma radioactivity level.

Hydroxylation followed by glucuronization or hydrolysis is the main metabolic pathway. In vitro isoenzymes of the cytochrome P450 system CYP1A2 and CYP3A4 were the main enzymes involved in the hydroxylation of pologidomide. The isoenzymes CYP2C19 and CYP2D6 were of less importance. Pamildomide is also a substrate of P-glycoprotein (P-gp) in vitro. Combined use of pamildomide with an active inhibitor of CYP3A4 / 5 and P-gp ketoconazole or with a powerful CYP3A4 / 5 inducer carbamazepine did not have a clinically significant effect on the exposure of pologidomide. The combined use of the active inhibitor of CYP1A2 fluvoxamine in the presence of ketoconazole increased the effect of pamildomide by 104% at a 90% confidence interval (88-122%) compared with the combination of pologidomide + ketoconazole. If an active inhibitor of CYP1A2 (eg ciprofloxacin, enoxacin and fluvoxamine) is used in conjunction with pamalidomide, patients should be carefully monitored to promptly identify unwanted drug reactions.

Based on in vitro data, pamidomide does not induce or inhibit cytochrome P450 isoenzymes, does not inhibit other drug transporters studied. When combining pologmidomide with substrates of such pathways, clinically significant drug interactions are unlikely.

Excretion. The mean T1 / 2 of pologmidomide from plasma was 9.5 hours in healthy volunteers and 7.5 hours in patients with multiple myeloma. The average total clearance (CL / F) of pologidomide is approximately 7-10 l / h.

In healthy volunteers, after a single ingestion of 14C-pologidomide (2 mg), approximately 73 and 15% of the radioactive dose was excreted through the kidneys and intestines. At the same time, about 2% and 8% of the dose of pogalidomide with a carbon label was excreted through the kidneys and intestines in unchanged form.

Pomalidomide is largely biotransformation, and the metabolites formed are mainly excreted through the kidneys. The three main metabolites formed as a result of hydrolysis or hydroxylation followed by glucuronization account for 23, 17 and 12% of the total metabolites in urine, respectively.

The amount of metabolites formed with the participation of cytochrome P450 was approximately 43% of the total radioactivity, and not-CYP-dependent hydrolytic metabolites - 25%. In unmodified form, 10% of pologidomide (2% through the kidneys and 8% through the intestine) is excreted.

Special patient groups

Children and teenagers. Data on the use of pamildomide in children and adolescents (<18 years) do not.

The elderly. There are no data on the pharmacokinetics of pamildomide in elderly patients. Clinical studies did not require dose changes in patients over 65 years of age who received pologiideomide.

Renal insufficiency. Studies of pamildomide in patients with renal insufficiency have not been conducted.

Liver failure. Studies of pamildomide in patients with hepatic insufficiency have not been conducted.

Pre-clinical safety study results

In a toxicological study in rats, pologidomide was well tolerated at doses of 50, 250 and 1000 mg / kg / day with repeated dosing for 6 months. There were no undesirable reactions to the drug with dosing of pamildomide up to 1000 mg / kg / day (175 times higher than the therapeutic dose of 4 mg). Pomalidomide did not show a mutagenic effect and did not cause chromosomal aberrations in human peripheral blood lymphocytes or the formation of micronuclei in polychromatic erythrocytes of bone marrow of rats at doses up to 2000 mg / kg / day. Pomalidomide had a teratogenic effect in both rats and rabbits when applied during the main organogenesis.

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Pharmacodynamics

The ability of pologidomide to prolong the QTc interval was evaluated in a single-center, double-blind, cross-over study (N = 72) using 4 mg of pologidomide, 20 mg of pologidomide, placebo, and 400 mg of moxifloxacin (confirmatory control). After applying pamildomide in doses of 4 and 20 mg, no significant prolonging effect of pologidomide on QTc was observed.

Pharmacokinetics

Absorption. After taking a single oral dose of Cmax, pologmidomide in blood plasma is reached within 2-3 hours. Systemic exposure (AUC) of pologidomide increases approximately in proportion to the dose.

In patients with multiple myeloma who received pragmadomide at a dose of 4 mg in monotherapy or in combination with dexamethasone, the exposure to pamildomide in the equilibrium state was AUC 400 ng · h / ml and Cmax 75 ng / ml. After repeated administration, the degree of accumulation of pamildomide ranges from 27 to 31%.

Distribution. The average apparent VSS of pologidomide is in the range of 62-138 liters. Pomalidomide is distributed into the seminal fluid of healthy volunteers at a concentration of approximately 67% of the plasma level 4 hours after administration (approximate Tmax) at a dose of 2 mg 1 time per day. Binding to human plasma proteins is 12-44% and does not depend on concentration. Pomalidomide is a substrate of P-gp.

Metabolism. Pomalidomide is metabolized mainly in the liver via CYP1A2 and CYP3A4. In in vitro experiments, CYP1A2 and CYP3A4 have been identified as the main enzymes involved in the CYP-mediated hydroxylation of pologidomide; An additional contribution to this process was made by CYP2C19 and CYP2D6.

Excretion. The mean T1 / 2 of pologmidomide from plasma is approximately 9.5 hours in healthy volunteers and about 7.5 hours in patients with multiple myeloma. The CL / F of pologmidomide is 7-10 l / h.

After a single oral intake of 14C-pomildomide (2 mg) by healthy volunteers, approximately 73 and 15% of the radioactive dose was detected in urine and feces, respectively, including. Approximately 2% and 8% were unchanged.

Drug Interactions

Drugs that inhibit the metabolism of pologidomide

Inhibitors of CYP1A2. The effect of CYP1A2 inhibitors without concomitant use of inhibitors of CYP3A4 and P-gp is unknown. However, the concomitant use of fluvoxamine (a potent inhibitor of CYP1A2) and ketoconazole (a potent inhibitor of CYP3A4 and Pgp) in 12 healthy male volunteers resulted in an increase in exposure to pamildomide (average geometric value of AUCinf) by 146% compared to monotherapy with pologidomide (see p. "Interaction").

Strong inhibitors of CYP3A4 and P-gp. The concomitant use of ketoconazole (a strong inhibitor of CYP3A4 and P-gp) in 16 healthy volunteers (men) resulted in an increase in the exposure of pamildomide (geometric mean of AUCinf) by 19% compared to monotherapy with pomidomide.

Drugs that induce the metabolism of pologidomide

Strong inductors CYP1A2. The concomitant use of pologmidomide with drugs that are inducers of CYP1A2 has not been studied, but it can reduce the exposure of pologidomide.

Strong inductors CYP3A4. The concomitant use of carbamazepine in 16 healthy male volunteers led to a decrease in the exposure of pologidomide (mean geometric value of AUCinf) by 21% compared to monotherapy with pologidomide.

Dexamethasone. Repeated concomitant use of 4 mg amidomide at 4 mg and dexamethasone at doses of 20 to 40 mg (mildly inducible CYP3A4 inducer) in patients with multiple myeloma did not affect the pharmacokinetic parameters of pologidomide compared to monotherapy with pomadidomide.

In vitro, pologidomide does not inhibit or induce CYP450 enzymes involved in drug metabolism and their transporters.

Application of the substance Pomalidomide

Pomalidomide in combination with dexamethasone is indicated for the treatment of adult patients with recurrent and refractory multiple myeloma who received at least two previous courses of treatment, including both lenalidomide and bortezomib, and who had progression of the disease on the background of the last treatment.

Contraindications

Hypersensitivity to pamelidomide, pregnancy and the period of breastfeeding, children under 18 years (due to lack of data on efficacy and safety).

For women: preserved reproductive potential, except when all the necessary conditions of the Pregnancy Protection Program are met (see "Special instructions").

For men: impossibility or inability to comply with the necessary contraceptive measures listed in the section "Special instructions".

Restrictions

Patients with renal and / or hepatic insufficiency, as well as patients with deep vein thrombosis (including in the anamnesis); Patients with the presence of risk factors for thromboembolism (heart or lung disease, high blood pressure or elevated cholesterol in the blood, smokers); Joint admission with drugs that increase the risk of thrombosis, namely with drugs that have erythropoietic activity, and in combination with hormone replacement therapy (see also "Side effects" and "Interaction"); Patients with advanced stage of the disease and / or high tumor burden in connection with the potential risk of developing tumor lysis syndrome (see "Precautions"); Patients with neuropathy (including in the anamnesis).

Pregnancy and breast-feeding

The action category for fetus by FDA is X.

Pomalidomide may have teratogenic effects in humans. The drug is contraindicated during pregnancy and in women with preserved reproductive potential, except for cases of compliance with all conditions for protection from pregnancy (see "Contraindications", "Precautions" and "Special instructions").

It is not established whether pomildomide is excreted in human breast milk. Pomalidomide was found in the milk of rats that were given this drug. Given the potential for undesirable effects of pamildomide on newborns, it is necessary to stop either breastfeeding or taking pologidomide, taking into account the importance of taking this drug for the mother.

Fertility

In animals, poamidomide adversely affects fertility and has a teratogenic effect. Pomalidomide penetrates the placenta and is found in fetal blood (according to data obtained on rabbits).

Side effects of Pomalidomide

Safety Profile Summary

During clinical trials, the most frequent adverse drug reactions (NLR) were violations of the blood and lymphatic system: anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); Among the general disorders, increased fatigue (28.3%), fever (21%) and peripheral edema (13%) prevailed; Among infections and parasitic diseases - pneumonia (10.7%). As a side effect, peripheral neuropathy was registered in 12.3% of patients, and venous embolic and thrombotic disorders (VETN) complications - in 3.3% of patients. The most frequent HLR of the 3rd or 4th degree were abnormalities from the blood and lymphatic system, including neutropenia (41.7%), anemia (27%) and thrombocytopenia (20.7%); Among infections and invasions - pneumonia (9%); Among the common disorders and disorders at the site of administration of the drug - increased fatigue (4.7%), a rise in temperature (3%) and peripheral edema (1.3%). The most frequent serious NLR was pneumonia (9.3%). Of other serious cases of NLR, febrile neutropenia (4%), neutropenia (2%), thrombocytopenia (1.7%) and VETN (1.7%) were recorded.

Undesirable reactions often occurred during the first two cycles of treatment with pomidomide.

NLRs occurring in patients treated with a combination of pamildomide and dexamethasone are presented below in accordance with the classification of lesions of organs and systems of MedDRA organs, taking into account the frequency of all HLR and the frequency of HLR of the 3rd or 4th degree of severity.

The frequency of the NLRs given below was determined in accordance with the following classification: very often (> 1/10); Often (> 1/100, <1/10); Infrequently (> 1/1000, <1/100).

NLR, registered in clinical studies in patients with refractory multiple myeloma on the background of therapy with pamamidomide and dexamethasone

NLR of all degrees of severity

Infectious and parasitic diseases: very often - pneumonia; Often - neutropenic sepsis, bronchopneumonia, bronchitis, acute respiratory infections, acute infectious diseases of the upper respiratory tract, nasopharyngitis.

On the part of the blood and lymphatic system: very often - neutropenia, thrombocytopenia, leukopenia, anemia; Often - febrile neutropenia.

From the side of metabolism and nutrition: very often - a decrease in appetite; Often - hyperkalemia, hyponatremia.

From the nervous system: often - inhibition, peripheral sensory neuropathy, dizziness, tremor.

Disorders of the psyche: often confusion.

From the side of the hearing organ and labyrinthine disturbances: often - vertigo.

From the side of the vessels: often - deep vein thrombosis.

From the respiratory system, chest and mediastinum: very often - shortness of breath, cough; Often - thromboembolism of the pulmonary artery.

From the digestive tract: very often - diarrhea, nausea, constipation; Often - vomiting.

From the side of the liver and bile ducts: infrequently - hyperbilirubinemia.

From the skin and subcutaneous tissues: often - a rash, itchy skin.

From the musculoskeletal system and connective tissue: very often - pain in the bones, muscle spasm.

From the side of the kidneys and urinary tract: often - kidney failure, urinary retention.

From the genitals and mammary glands: often - pain in the pelvic region.

General disorders and disorders at the injection site: very often - increased fatigue, fever, peripheral edema.

Changes in laboratory indicators: often - neutropenia, leukopenia, thrombocytopenia, increased ALT activity.

NLR 3-4 degrees of severity

Infectious and parasitic diseases: often - neutropenic sepsis, pneumonia, bronchopneumonia, acute respiratory infections, acute infectious diseases of the upper respiratory tract; Infrequently bronchitis.

On the part of the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia; Often - febrile neutropenia, leukopenia.

From the side of metabolism and nutrition: often - hyperkalemia, hyponatremia; Infrequent - loss of appetite.

Disorders of the psyche: often confusion.

From the nervous system: often - retardation; Infrequently - peripheral sensory neuropathy, dizziness, tremor.

From the side of the hearing organ and labyrinthine disturbances: often - vertigo.

From the side of the vessels: infrequently - deep vein thrombosis.

From the respiratory system, chest and mediastinum: often - shortness of breath; Infrequently - thromboembolism of the pulmonary artery, cough.

From the digestive tract: often - diarrhea, vomiting, constipation; Infrequently - nausea.

From the side of the liver and biliary tract: infrequently - hyperbilirubinemia.

From the skin and subcutaneous tissues: often - a rash.

From the musculoskeletal system and connective tissue: often - pain in the bones; Infrequently - muscle spasm.

From the side of the kidneys and urinary tract: often - kidney failure.

From the genitals and mammary glands: often - pain in the pelvic region.

General disorders and disorders at the injection site: often - increased fatigue, fever, peripheral edema.

Changes in laboratory indicators: often - neutropenia, leukopenia, thrombocytopenia, increased ALT activity.

Description of selected NLRs

Teratogenicity. Pomalidomide is structurally similar to thalidomide, a known teratogen for a person that causes severe, life-threatening birth defects. There was a teratogenic effect of pologidomide during the main organogenesis when it was used in rats and rabbits. When applying pamildomide during pregnancy, people are likely to have a teratogenic effect (see "Contraindications" and "Precautions").

Neutropenia and thrombocytopenia. Neutropenia was recorded in 45.3% of patients receiving pologidomide in combination with low-dose dexamethasone. Neutropenia of the 3rd or 4th degree of severity occurred in 41.7% of patients taking pologidomide in combination with dexamethasone in a low dose, with neutropenia rarely serious (2% of patients), did not lead to cessation of treatment, caused a break in Treatment in 21% of patients and the cause of dose reduction in 7.7% of patients.

Febrile neutropenia (FN) was noted in 6.7% of patients on a background of pologidomide combined with dexamethasone in a low dose. All manifestations were of the 3rd and 4th degree of severity. FN was recognized as serious in 4% of patients, caused a break in treatment in 3.7% of patients, the cause of dose reduction in 1.3% of patients. None of the patients completely cured the treatment.

Thrombocytopenia was reported in 27% of patients receiving pologidomide in combination with low-dose dexamethasone. Thrombocytopenia of the 3rd or 4th degree of severity was in 20.7% of patients, with thrombocytopenia regarded as serious in 1.7% of patients, caused a dose reduction in 6.3%, a break in treatment in 8%, and discontinuation of treatment In 0.7% of patients.

Infections. Infections were the most common nonhematological manifestation of toxicity: they were registered in 55% of patients with pomaladomide in combination with low-dose dexamethasone. Approximately half of these infections were of the 3rd or 4th degree of severity. The most frequent complications were pneumonia and upper respiratory tract infections (in 10.7 and 9.3% of patients, respectively). In 24.3% of cases, infections were severe, and 2.7% of patients were fatal (grade 5). Infections required discontinuation of treatment in 2% of patients, interruption of treatment in 14.3% and dose reduction in 1.3% of patients.

Thromboembolic complications. VETN were detected in 3.3% of patients receiving pologidomide in combination with low-dose dexamethasone. VETN of the 3rd or 4th degree of severity was noted in 1.3% of patients, in 1.7% of patients with VETN were recognized as serious. VETN were not accompanied by a fatal outcome and did not require the cessation of treatment.

Prophylactic use of acetylsalicylic acid (or other antiplatelet agents in high-risk patients) was mandatory. In the absence of contraindications, treatment with anticoagulants was also recommended.

Peripheral neuropathy. Peripheral neuropathy, mostly of the 1st or 2nd degree of severity, was noted in 12.3% of patients with pomaladomide in combination with low-dose dexamethasone. Reactions of the 3rd or 4th degree of severity were registered in 1% of patients.

Serious peripheral neuropathies did not develop, and treatment in this regard was discontinued in 0.3% of patients.

The median time to the manifestation of peripheral neuropathy was 2.1 weeks with fluctuations from 0.1 to 48.3 weeks.

The median time before resolution of this complication was 22.4 weeks.

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The following side effects are discussed in more detail in other sections of this description:

- risk to the fetus (see "Precautions" and "Special instructions");

- Venous and arterial thromboembolism (see "Precautions" and "Special instructions");

- hematological toxicity (see "Precautions");

- hepatotoxicity (see "Precautions");

- Hypersensitivity reactions (see "Precautions");

- dizziness and confusion (see "Precautions");

- Neuropathy (see "Precautions");

- risk of secondary malignant neoplasms (see "Precautions");

- Tumor lysis syndrome (see "Precautions").

Experience in clinical trials

Multiple myeloma

Since clinical studies have been conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies can not be directly compared with the frequency in other studies and may not reflect the incidence of side effects in clinical practice.

Study 1 evaluated the data of 219 patients (safety assessment population) who received a combination of pamildomide in combination with low-dose dexamethasone (112 patients) or only pamamidomide (107 patients). The average number of treatment cycles was 5. Due to adverse reactions, 67% of patients in this study were forced to discontinue treatment with one of the two drugs. 42% of patients in this study were forced to reduce the dose of one of these two drugs due to adverse reactions. 11% of patients were forced to discontinue treatment due to adverse reactions.

Study 2 evaluated data from 450 patients (safety assessment population) who were treated with a combination of pamildomide in combination with low-dose dexamethasone (300 patients) or high-dose dexamethasone (150 patients). The average number of treatment cycles for a combination of pamildomide in combination with dexamethasone in a low dose was 5. Using a combination of pamildomide in combination with dexamethasone in a low dose, 67% of patients stopped receiving pamildomide, the median time before the first suspension was 4.1 weeks. 27% of patients were forced to reduce the dose of pologidomide, the average time to the first dose reduction was 4.5 weeks. 8% of patients discontinued the use of pamildomide because of adverse reactions.

Adverse reactions observed in Study 1 (regardless of the mention of the connection with the use of pologidomide) (data as of March 1, 2013)

The data given below (monomethacinamide versus a combination of pamildomide in combination with low-dose dexamethasone) are classified according to systems and organs in preferred terms. The first group of digits after each term (before the comma) is the total number of adverse reactions that occurred with a frequency of ≥10% in Study 1 with only pamidomide (N = 107, 61 of all 107 patients randomized only to pologidomide, Dexamethasone) and a combination of pologidomide in combination with dexamethasone in a low dose (N = 112). The second group of digits (after the decimal point) - similar data on adverse reactions of the 3rd or 4th degree of severity, noted in ≥5% of patients (asterisk "*" marked adverse reactions, severe cases of which were observed in at least 2 patients in each Group of participants receiving pologidomide). In brackets - the data in% of the number of participants in the tests.

The number of patients with at least one adverse reaction was 107 (100%) and 112 (100%), 98 (91.6%) and 102 (91.1%).

On the part of the blood and lymphatic system: neutropenia * 57 (53.3%) and 55 (49.1%), 51 (47.7%) and 46 (41.1%); Anemia * 41 (38.3%) and 47 (42%), 25 (23.4%) and 24 (21.4%); Thrombocytopenia * 28 (26.2%) and 26 (23.2%), 24 (22.4%) and 21 (18.8%); Leukopenia 14 (13.1%) and 22 (19.6%), 7 (6.5%) and 11 (9.8%); Febrile neutropenia * <10% and <10%, 6 (5.6%) and 3 (2.7%); Lymphopenia 4 (3.7%) and 17 (15.2%), 2 (1.9%) and 8 (7.1%).

General disorders and disorders at the site of administration: increased fatigue and asthenia * 62 (57.9%) and 70 (62.5%), 13 (12.1%) and 19 (17%); Peripheral edema 27 (25.2%) and 19 (17%), 0 (0%) and 0 (0%); Hyperthermia * 25 (23.4%) and 36 (32.1%), <5% and <5%; Fever 11 (10.3%) and 14 (12.5%), 0 (0%) and 0 (0%).

From the digestive tract: constipation * 38 (35.5%) and 41 (36.6%), <5% and <5%; Diarrhea 37 (34.6%) and 40 (35.7%), <5% and <5%; Vomiting * 15 (14%) and 16 (14.3%), <5% and 0 (0%).

From the musculoskeletal system and connective tissue: back pain * 37 (34.6%) and 36 (32.1%), 15 (14%) and 11 (9.8%); Musculoskeletal pain in the chest 25 (23.4%) and 22 (19.6%), <5% and 0 (0%); Muscle spasms 23 (21.5%) and 22 (19.6%), <5% and <5%; Arthralgia 18 (16.8%) and 17 (15.2%), <5% and <5%; Muscle weakness 15 (14%) and 15 (13.4%), 6 (5.6%) and 4 (3.6%); Pain in the bones of 13 (12.1%) and 8 (7.1%), <5% and <5%; Musculoskeletal pain 13 (12.1%) and 19 (17%), <5% and <5%; Pain in the extremities 8 (7.5%) and 16 (14.3%), 0 (0%) and <5%.

Infections and invasions: infection of the upper respiratory tract 40 (37.4%) and 32 (28.6%), <5% and <5%; Pneumonia * 30 (28%) and 38 (33.9%), 21 (19.6%) and 32 (28.6%); Urinary tract infection * 11 (10.3%) and 19 (17%), 2 (1.9%) and 10 (8.9%); Sepsis * <10% and <10%, 6 (5.6%) and 5 (4.5%).

From the side of metabolism and eating disorders: a decrease in appetite 25 (23.4%) and 21 (18.8%), <5% and 0 (0%); Hypercalcemia * 23 (21.5%) and 13 (11.6%), 11 (10.3%) and 1 (0.9%); Hypokalemia 13 (12.1%) and 13 (11.6%), <5% and <5%; Hyperglycemia 12 (11.2%) and 17 (15.2%), <5% and <5%; Hyponatremia 12 (11.2%) and 14 (12.5%), <5% and <5%; Dehydration * <10% and <10%, 5 (4.7%) and 6 (5.4%); Hypocalcemia 6 (5.6%) and 13 (11.6%), 0 (0%) and <5%.

On the part of the respiratory system, chest and mediastinal organs: dyspnea * 38 (35.5%) and 50 (44.6%), 8 (7.5%) and 14 (12.5%); Cough 18 (16.8%) and 25 (22.3%), 0 (0%) and 0 (0%); Nasal bleeding 18 (16.8%) and 12 (10.7%), <5% and 0 (0%); Productive cough 10 (9.3%) and 14 (12.5%), 0 (0%) and 0 (0%); Oropharyngeal pain 6 (5.6%) and 12 (10.7%), 0 (0%) and 0 (0%).

From the side of the nervous system: dizziness 24 (22.4%) and 20 (17.9%), <5% and <5%; Peripheral neuropathy 23 (21.5%) and 20 (17.9%), 0 (0%) and 0 (0%); Headache 16 (15%) and 15 (13.4%), 0 (0%) and <5%; Tremor 11 (10.3%) and 15 (13.4%), 0 (0%) and 0 (0%).

From the skin and subcutaneous tissues: rash 22 (20.6%) and 18 (16.1%), 0 (0%) and <5%; Itching 16 (15%) and 10 (8.9%), 0 (0%) and 0 (0%); Dry skin 10 (9.3%) and 12 (10.7%), 0 (0%) and 0 (0%); Hyperhidrosis 8 (7.5%) and 18 (16.1%), 0 (0%) and 0 (0%); Night sweats 5 (4.7%) and 14 (12.5%), 0 (0%) and 0 (0%).

Changes in laboratory indicators: an increase in the level of creatinine in the blood * 20 (18.7%) and 11 (9.8%), 6 (5.6%) and 3 (2.7%); Decrease in body weight 16 (15%) and 10 (8.9%), 0 (0%) and 0 (0%); An increase in body weight of 1 (0.9%) and 12 (10.7%), 0 (0%) and 0 (0%).

Mental disorders: anxiety 14 (13.1%) and 8 (7.1%), 0 (0%) and 0 (0%); Confusion of consciousness * 13 (12,1%) and 15 (13,4%), 6 (5,6%) and 3 (2,7%); Insomnia 7 (6.5%) and 18 (16.1%), 0 (0%) and 0 (0%).

From the kidney and urinary tract: renal failure 16 (15%) and 11 (9.8%), 9 (8.4%) and 8 (7.1%).

The adverse reactions observed in Study 2 (data as of March 1, 2013)

The data presented below (a combination of pamildomide in combination with low-dose dexamethasone versus dexamethasone in a high dose) are classified according to systems and organs in preferred terms. The first group of digits after each term (before the comma) is the total number of adverse reactions that occurred with a frequency of ≥5% with a combination of pamildomide combined with low-dose dexamethasone (N = 300) and at least 2% more often than with treatment Dexamethasone in a high dose (N = 150). The second group of digits (after the decimal point) - similar data on adverse reactions of the 3rd or 4th degree of severity, noted in ≥1% of patients with a combination of pamildomide combined with dexamethasone in a low dose and at least 1% more often than When treated with high-dose dexamethasone. In brackets - the data in% of the number of participants in the tests. The asterisk "*" marked adverse reactions, the severe cases of which were observed in at least 3 patients in the group of participants who received pamidomide in combination with low-dose dexamethasone, and occurred at a frequency of at least 1% higher than in the group receiving dexamethasone In a high dose. The percentage marked "**" did not meet the criteria that should be considered a side effect of pamildomide in this category of cases (ie all adverse reactions or third-degree or fourth-degree adverse reactions).

The number of patients with at least one adverse reaction was 297 (99%) and 149 (99.3%), 259 (86.3%) and 127 (84.7%).

On the part of the blood and lymphatic system: neutropenia * 154 (51.3%) and 31 (20.7%), 145 (48.3%) and 24 (16%); Thrombocytopenia 89 (29.7%) ** and 44 (29.3%) **, 66 (22%) ** and 39 (26%) **; Leukopenia 38 (12.7%) and 8 (5.3%), 27 (9%) and 5 (3.3%); Febrile neutropenia * 28 (9.3%) and 0 (0%), 28 (9.3%) and 0 (0%).

General disorders and disorders at the site of administration: increased fatigue and asthenia 140 (46.7%) and 64 (42.7%), 26 (8.7%) ** and 18 (12%) **; Hyperthermia * 80 (26.7%) and 35 (23.3%), 9 (3%) ** and 7 (4.7%) **; Peripheral edema 52 (17.3%) and 17 (11.3%), 4 (1.3%) ** and 3 (2%) **; Pain 11 (3.7%) ** and 3 (2%) **, 5 (1.7%) and 1 (0.7%).

Infections and invasions: upper respiratory tract infection * 93 (31%) and 19 (12.7%), 9 (3%) and 1 (0.7%); Pneumonia * 58 (19.3%) and 20 (13.3%), 47 (15.7%) and 15 (10%); Neutropenic sepsis * 3 (1%) ** and 0 (0%) **, 3 (1%) and 0 (0%).

On the part of the digestive tract: diarrhea 66 (22%) and 28 (18.7%), 3 (1%) ** and 2 (1.3%) **; Constipation 65 (21.7%) and 22 (14.7%), 7 (2.3) and 0 (0%); Nausea 45 (15%) and 17 (11.3%), 3 (1%) ** and 2 (1.3%) **; Vomiting 23 (7.7%) and 6 (4%), 3 (1%) and 0 (0%).

From the musculoskeletal system and connective tissue: back pain * 59 (19.7%) and 24 (16%), 15 (5%) and 6 (4%); Bone pain * 54 (18%) and 21 (14%), 22 (7.3%) and 7 (4.7%); Muscle spasms 46 (15.3%) and 11 (7.3%), 1 (0.3%) ** and 1 (0.7%) **; Arthralgia 26 (8.7%) and 7 (4.7%), 2 (0.7%) ** and 1 (0.7%) **; Pain in the extremities 20 (6.7%) ** and 9 (6%) **, 6 (2%) and 0 (0%).

On the part of the respiratory system, chest and mediastinal organs: dyspnea * 76 (25.3%) and 25 (16.7%), 17 (5.7%) and 7 (4.7%); Cough 60 (20%) and 15 (10%), 2 (0.7%) ** and 1 (0.7%) **; COPD * 5 (1.7%) ** and 0 (0%) **, 4 (1.3%) and 0 (0%).

From the side of the nervous system: peripheral neuropathy 52 (17.3%) and 18 (12%), 5 (1.7%) ** and 2 (1.3%) **; Dizziness 37 (12.3%) and 14 (9.3%), 4 (1.3%) ** and 2 (1.3%) **; Headache 23 (7.7%) and 8 (5.3%), 1 (0.3%) ** and 0 (0%) **; Tremor 17 (5.7%) and 2 (1.3%), 2 (0.7%) ** and 0 (0%) **; Depressive level of consciousness 5 (1.7%) ** and 0 (0%) **, 3 (1%) and 0 (0%).

From the side of metabolism and eating disorders: a decrease in appetite 38 (12.7%) and 12 (8%), 3 (1%) ** and 2 (1.3%) **; Hypokalemia 28 (9.3%) ** and 12 (8%) **, 12 (4%) and 4 (2.7%); Hypocalcemia 12 (4%) ** and 9 (6%) **, 5 (1.7%) and 1 (0.7%).

From the skin and subcutaneous tissues: rash 23 (7.7%) and 2 (1.3%), 3 (1%) and 0 (0%); Itching 22 (7.3%) and 5 (3.3%), 0 (0%) ** and 0 (0%) **; Hyperhidrosis 15 (5%) and 1 (0.7%), 0 (0%) ** and 0 (0%) **.

Changes in laboratory indicators: a decrease in the number of neutrophils 15 (5%) and 1 (0.7%), 14 (4.7%) and 1 (0.7%); A decrease in the number of platelets 10 (3.3%) ** and 3 (2%) **, 8 (2.7%) and 2 (1.3%); A decrease in the number of white blood cells 8 (2.7%) ** and 1 (0.7%) **, 8 (2.7%) and 0 (0%); Increase in ALT 7 (2.3%) ** and 2 (1.3%) **, 5 (1.7%) and 0 (0%); Increase in the level of AST 4 (1.3%) ** and 2 (1.3%) **, 3 (1%) and 0 (0%); A decrease in the number of lymphocytes 3 (1%) ** and 1 (0.7%) **, 3 (1%) and 0 (0%).

From the kidney and urinary tract: renal failure 31 (10.3%) ** and 18 (12%) **, 19 (6.3%) and 8 (5.3%).

Injuries, intoxications and complications resulting from the procedure: hip fracture * 5 (1.7%) ** and 1 (0.7%) **, 5 (1.7%) and 1 (0.7%).

On the part of the reproductive system and breast disease: pain in the pelvis 6 (2%) ** and 3 (2%) **, 4 (1.3%) and 0 (0%).

Other adverse reactions

The following are not the above-mentioned adverse reactions in patients with multiple myeloma receiving pologidomide, which should be considered due to their importance.

From the heart: myocardial infarction, atrial fibrillation, stenocardia, congestive heart failure.

From the side of the hearing organ and labyrinthine disturbances: vertigo.

From the gastrointestinal tract: pain in the abdomen.

General disorders and disorders at the site of administration: deterioration of the general physical condition, non-cardiac pain in the thorax, polyorganism disorders.

From the hepatobiliary system: hyperbilirubinemia.

Infections and invasions: pneumonia caused by Pneumocystis jiroveci, respiratory syncytial virus infection, neutropenic sepsis, bacteremia, pneumonia caused by respiratory syncytial virus, cellulitis, urosepsis, septic shock, colitis associated with Clostridium difficile, pneumonia streptococcal, focal pneumonia, viral Infection, infection of the lungs.

Changes in laboratory indicators: increased ALT level, lowering of hemoglobin level.

Injuries, intoxications and complications resulting from the procedure: falling, compression fracture, compression fracture of the spine.

From the side of metabolism and eating disorders: hyperkalemia, developmental lag.

From the nervous system: a depressive level of consciousness, fainting.

Mental disorders: a change in mental state.

From the side of the kidneys and urinary tract: urinary retention, hyponatremia.

On the part of the reproductive system and breast disease: pain in the pelvic region.

On the part of the respiratory system, chest and mediastinal organs: interstitial lung disease, pulmonary embolism, respiratory disorders, bronchospasm.

Vascular disorders: hypotension.

Post-marketing research

In postmarketing studies of pamidomide, conducted around the world, the following adverse reactions were identified: pancytopenia, tumor lysis syndrome (SLO), allergic reactions (eg angioedema, urticaria), hepatic enzyme elevation, hepatic insufficiency (including death). Since these reactions are detected spontaneously in a population of an unidentified size, it is not always possible to unambiguously estimate their frequency or unambiguously associate their occurrence with the use of drugs.

Interaction

Effect of pologidomide on other drugs

It is believed that pologidomide does not cause clinically significant pharmacokinetic drug interactions associated with inhibition or induction of cytochrome P450 isoenzymes or activation or inhibition of transport systems, when combined with the substrates of these enzymes or transports. The possibility of such drug interactions, including the effect of pologidomide on the pharmacokinetics of COCs, was not clinically evaluated (see "Side Effects" and "Precautions").

Influence of other drugs on pologidomide

Pomalidomide is partially metabolized by the isoenzymes CYP1A2 and CYP3A4 / 5 and is a substrate of P-gp. Combined use of pamildomide with the active inhibitor CYP3A4 / 5 and P-gp ketoconazole or with the powerful inducer CYP3A4 / 5 carbamazepine clinically significantly did not affect the action of pologidomide. The combined use of the active inhibitor of CYP1A2 fluvoxamine in the presence of ketoconazole increased the effect of pamildomide by 104% at a 90% confidence interval (88-122%) compared with the combination of pologidomide + ketoconazole. If an active inhibitor of CYP1A2 (eg ciprofloxacin, enoxacin and fluvoxamine) is used in conjunction with pamildomide, then such patients should carefully monitor NLP.

Dexamethasone

Combined therapy with pamalidomide in repeated doses up to 4 mg and dexamethasone in doses of 20-40 mg (a mildly inducible inducer of some CYP isoenzymes, including CYP3A) in patients with multiple myeloma was not accompanied by a violation of the pharmacokinetics of pologidomide compared to monotherapy with pologidomide.

The effect of dexamethasone on warfarin has not been studied, therefore it is recommended that the concentration of warfarin be closely monitored against a background of combination therapy.

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Pomalidomide is metabolized mainly by CYP1A2 and CYP3A, in addition it is a substrate of P-gp.

Drugs that can increase the concentration of pomeledomide in blood plasma

Inhibitors of CYP1A2. Exposure of pamildomide increases when combined with a strong inhibitor of CYP1A2 (fluvoxamine) in the presence of a strong inhibitor of CYP3A4 / 5 and P-gp (ketoconazole). Ketoconazole in the absence of an inhibitor of CYP1A2 does not increase the exposure of pologidomide. Combined use of strong inhibitors of CYP1A2 (eg ciprofloxacin and fluvoxamine) should be avoided. If the simultaneous use of strong inhibitors of CYP1A2 in the presence of strong inhibitors of CYP3A4 and P-gp is required, the dose of pologidomide should be reduced by 50%.

The effect of the CYP1A2 inhibitor in the absence of inhibitors of CYP3A4 and P-gp has not been studied. Toxic effects should be monitored if CYP1A2 inhibitors are added to treatment without the combined use of an inhibitor of CYP3A4 and P-gp, and if necessary, reduce the dose.

Drugs that can reduce the concentration of pomeledomide in blood plasma

Smoking. Tobacco smoke can reduce the exposure of pamildomide due to the induction of CYP1A2. Patients should be warned about a possible decrease in the effectiveness of pologidomide in smoking.

Inductors CYP1A2. The combined use of pamildomide with inducers of CYP1A2 has not been studied, but it can reduce the exposure of pologidomide.

Overdose

Pomalidomide in high single doses up to 50 mg in healthy volunteers and in doses of 10 mg with repeated daily dosing in patients with multiple myeloma did not cause serious undesirable effects due to overdose.

Specific recommendations for the treatment of an overdose of pologidomide are absent. It is not known whether pomildomide and its metabolites are being taken out by dialysis. In case of an overdose, supportive therapy is recommended.

Routes of administration

Inside.

Precautionary measures

Treatment with pomeledomide should be started and carried out under the supervision of an experienced hematologist or chemotherapist.

Hematologic complications. In patients with recurrent / resistant multiple myeloma, neutropenia is most commonly reported in the 3rd- or 4th-degree NLR group; The following in frequency - anemia and thrombocytopenia. Patients need to monitor unwanted hematologic reactions, especially neutropenia. Patients should be informed about the need to report temperature increases in a timely manner. Doctors should monitor patients for symptoms of increased bleeding, including nasal bleeding, especially with concomitant therapy with drugs that increase the risk of bleeding. A complete blood test should be performed before the treatment, then weekly for the first 8 weeks, then 1 time per month. You may need to change the dose of pamildomide, the use of blood substitutes and / or growth factor preparations.

Thromboembolic complications. Venous thromboembolic complications (mainly deep vein thrombosis and pulmonary embolism) and arterial thrombotic disorders developed in patients with pologidomide in combination with dexamethasone. Patients with risk factors for thromboembolism, including previous thromboses, should be carefully monitored. It is necessary to take all possible measures to minimize risk factors (for example, smoking, hypertension, hyperlipidemia). Patients and doctors should monitor the signs and symptoms of thromboembolism. Patients should be warned that they should seek medical help for symptoms such as shortness of breath, chest pain, swelling of the hands and feet. In the absence of contraindications, treatment with anticoagulants (such as acetylsalicylic acid, warfarin, heparin or clopidogrel) is recommended, especially in patients with additional risk factors for thrombosis.

The decision to conduct preventive measures is taken after a thorough assessment of the risk factors for each patient. In clinical trials, patients received prophylactic acetylsalicylic acid or other antithrombotic therapy. The use of erythropoietic drugs is accompanied by a risk of thrombotic complications, including thromboembolism. Therefore, erythropoietic drugs, as well as other drugs that can increase the risk of thromboembolism, should be used with caution.

Peripheral neuropathy. Patients with peripheral neuropathy> 2-nd degree of severity were not included in the clinical studies of pologidomide. When deciding on the appointment of treatment with pamildomide, such patients need to be cautious.

Severe dysfunction of the heart. Patients with severe cardiac dysfunction (congestive heart failure (NYHA class III or IV), myocardial infarction within 12 months prior to the study, unstable or poorly controlled angina pectoris) were not included in the clinical studies of pologidomide. When deciding on the appointment of treatment with pamildomide, such patients need to be cautious.

Tumor lysis syndrome (SLO). The greatest risk of OA is present in patients with a large tumor burden at the time of treatment initiation. These patients should be carefully monitored with appropriate preventive measures.

Primary tumors of other localization. The formation of primary malignant tumors of other localization was registered in patients receiving pologidomide. The physician should carefully examine patients before and during treatment with standard methods of screening neoplasms to identify the primary tumor of another location and, if necessary, prescribe appropriate treatment.

Allergic reactions. Patients with severe allergic reactions to thalidomide or lenalidomide in the anamnesis were not included in the clinical studies of pamildomide. Such patients may have an increased risk of developing hypersensitivity reactions and should not receive pamildomide.

Dizziness and confusion. There are reports of dizziness and confusion on the background of pologidomide. Patients should avoid situations where dizziness and confusion may present a problem, and do not take other drugs that can cause the same disorders without prior medical advice.

Precautions for disposal and handling. Capsules of pologidomide can not be opened or broken. When the powder of pologidomide gets on the skin, it must be washed immediately with soap and water. When contact with pimildomide with mucous membranes, they should be thoroughly rinsed with water.

Unused polysaccharide and contaminated materials should be disposed of in accordance with established requirements. Upon termination of treatment, unused drugs are recommended to be returned to a medical institution.

Impact on the ability to drive and work with machinery. Pomalidomide has little or moderate influence on the ability to drive or operate machinery. Some of the side effects of pamelidomide, such as fatigue, confusion, confusion and dizziness, can adversely affect the ability to drive and carry out potentially dangerous activities requiring increased attention and speed of psychomotor reactions. When such undesirable phenomena appear, one should refrain from these activities.

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Embryo and fetotoxicity

Pomalidomide is an analogue of thalidomide and is contraindicated for use in pregnancy. Thalidomide is a known teratogen for a person who causes severe birth defects or death of an embryo and fetus. The use of pamildomide is allowed only through participation in the Pregnancy Protection Program (see "Special instructions").

Women with preserved reproductive potential should avoid pregnancy while taking pamildomide and for at least 4 weeks after completion of therapy.

Women should decide to abstain from sexual relations or use 2 reliable methods of contraception 4 weeks before starting treatment with pamidomide, during therapy, during treatment interruptions and for 4 weeks after the abolition of therapy with pamildomide.

Before the start of therapy, two negative pregnancy tests should be obtained. The first test should be performed no later than 10-14 days and the second one no later than 24 hours before the appointment of pomaladomide therapy, then weekly for the first month and then every month for women with a regular menstrual cycle or every 2 weeks for women with irregular menstrual cycles.

The men. Pomalidomide is defined in the seminal fluid of patients who received this drug. Therefore, men should always use latex or synthetic condoms during sexual intercourse with women with preserved childbearing potential during taking pologidomide and up to 28 days after completion of therapy, even if they were subjected to a vasectomy. Men taking pologidomide should not be sperm donors.

Blood donation. Patients should not be blood donors during the period of treatment with pomidomide and another 1 month after completion of this drug, Blood can be given to a pregnant patient whose fetus should not be exposed to the action of pamildomide.

VTE and arterial thromboembolism

In patients receiving pologidomide, cases of VTE (deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (myocardial infarction and stroke) were observed. In Study 2, in which anticoagulant therapy was prescribed, thromboembolism occurred in 8% of patients who received a combination of pamildomide in combination with low-dose dexamethasone and 3.3% of patients receiving high-dose dexamethasone. VTE occurred in 4.7% of patients receiving pologidomide in combination with low-dose dexamethasone, and 1.3% receiving high-dose dexamethasone. Cases of arterial thromboembolism include the definition of arterial thromboembolism, ischemic cerebrovascular conditions, and IHD. Such cases occurred in 3% of patients receiving pologidomide in combination with low-dose dexamethasone, and in 1.3% of patients receiving high-dose dexamethasone.

Patients with existing risk factors, including previous thromboses, may be more at risk for developing VTE and arterial thromboembolism, and measures should be taken to minimize these factors (for example, hyperlipidemia, hypertension, smoking). It is recommended to prevent thrombosis and choose a lifestyle based on the risk factors available to the individual patient.

Hematologic Toxicity

In studies 1 and 2, neutropenia was the most common adverse reaction of the 3rd to 4th degree in patients receiving pologidomide in combination with dexamethasone in a low dose, followed by anemia and thrombocytopenia. Neutropenia of any severity was noted in 51% of patients in both studies. The proportion of neutropenia of grade 3-4 was 46%, and the proportion of febrile neutropenia was 8%.

Hematological toxicity, especially neutropenia, should be monitored. A complete blood test should be done weekly for the first 8 weeks and then on a monthly basis. It may take a break in treatment or dose adjustment.

Hepatotoxicity

In patients receiving pologidomide, there were cases of hepatic insufficiency, including lethal ones. There was also an increase in the level of ALT and bilirubin. The liver function should be monitored on a monthly basis. If the level of hepatic enzymes increases, the treatment should be stopped and clinical evaluation performed. After restoring the indices to the initial values, therapy in a reduced dose can be considered.

Hypersensitivity reactions

There have been reports of angioedema and severe dermatological reactions. In cases of angioedema, exfoliation of the skin, bloating or any other severe dermatological reactions, it is necessary to stop the use of pamildomide and not resume treatment.

Dizziness and confusion

In studies 1 and 2, 14% and 7% of patients, respectively, experienced dizziness and confusion in patients who received pamildomide in combination with low-dose dexamethasone; Similar cases of the 3rd or 4th degree of severity - in 1 and 3% of patients, respectively. Patients should be instructed to avoid situations in which dizziness or confusion may present a problem and not take other drugs that can cause dizziness or confusion without proper medical attention.

Neuropathy

In studies 1 and 2, among patients receiving pologidomide in combination with low-dose dexamethasone, neuropathy was noted in 18% of patients, approximately 12% of patients experienced peripheral neuropathy. In Study 2, grade 3 neuropathy was noted in 2% of patients. There were no cases of neuropathic adverse reactions of the 4th degree of severity in both studies.

The risk of developing a primary tumor of another location

When studying polymidomide as a drug, undergoing clinical trials that do not relate to multiple myeloma, cases of acute myelogenous leukemia are noted.

Tumor lysis syndrome (SLO)

In patients receiving pologidomide, there may be an OA; This risk exists for patients with a high tumor burden prior to the appointment of pologidomide. Such patients should be under constant monitoring and appropriate precautions should be taken.

Special instructions

Pregnancy Protection Program

Strict adherence to all the requirements of the Pregnancy Protection Program should apply to all patients if the lack of genital potential is not reliably proven.

For women without childbearing potential

Women who are being treated or who are the sexual partner of the patient are NOT considered fertile in the presence of at least one of the listed factors:

- age ≥50 years and duration of natural amenorrhea ≥1 years (amenorrhea due to antitumor therapy or during breastfeeding does not exclude the presence of genital potential);

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

- bilateral salpingo-oophorectomy or hysterectomy in the anamnesis;

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

Counseling

The use of pamildomide in women with preserved reproductive potential is contraindicated in the event that one of the following conditions is not feasible.

A woman should:

- Understand the possibility of teratogenic effect of pamildomide on the fetus;

- Understand the need for continuous use of effective methods of contraception for 4 weeks before the start of treatment, during treatment and 4 weeks after the end of treatment with pamildomide;

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

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

- To know and understand the possible consequences in the event of pregnancy on the background of receiving pamildomide, as well as the need for urgent treatment for advice in case of suspected pregnancy;

- Understand the need to comply with all the rules of effective contraception against a background of pologidomide, the reception of which can be started immediately after receiving negative results of the pregnancy test

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

- to confirm that he understands the risk and necessary precautions associated with the use of pamildomide.

The doctor should make sure that a woman with a preserved childbearing potential:

- meets all the conditions of the Pregnancy Prevention Program, including an adequate level of understanding of its requirements;

- agrees with the above conditions.

Use in men

Data from studies of the pharmacokinetics of pologmidomide in volunteers (men) indicate that pologiadomide can be contained in the patient's semen. As a precautionary measure, all men taking pomidomid should comply with the following conditions.

A man must:

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

- Understand the need to use condoms for sexual contact with a pregnant woman or a woman with a preserved childbearing potential that does not use reliable contraceptive methods during the treatment period and within 7 days after suspension and / or completion of treatment. Even after a vasectomy, a man should use a condom with sexual contact with a pregnant woman, since in the absence of spermatozoa, his semen may contain pamildomide;

- Understand that if a partner becomes pregnant during his treatment with pamildomide or within 7 days after discontinuing therapy with pamildomide, he should immediately inform his / her treating doctor about it, and the partner is recommended to consult a teratologist for examination and consultation.

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 treatment and for 4 weeks after the termination of treatment with pamildomide even in the event of a break in treatment. The exception is made by patients who for a long time completely refrain from sexual relations, which is confirmed on a monthly basis. If the patient does not have an affective method of contraception, she should be referred to a gynecologist for the method of contraception and the beginning of its use.

Examples of highly effective methods of contraception include:

- subcutaneous hormonal implants;

- intrauterine systems that release levonorgestrel;

- depot preparations of medroxyprogesterone acetate;

- ligation of the fallopian tubes;

- Sexual relationships with a partner who underwent a vasectomy; Vasectomy is confirmed by two negative seminal fluid analyzes;

- Progesterone-containing tablets that inhibit ovulation (eg, desogestrel).

Admission COC is not recommended for patients with multiple myeloma due to an increased risk of thromboembolic complications in the background of treatment with pamildomide and dexamethasone. If the patient uses COC, it should be transferred to one of the effective methods of contraception listed above. The increased risk of thromboembolism persists for 4-6 weeks after cessation of COC administration. The effectiveness of hormonal contraceptives can be reduced with the simultaneous administration of dexamethasone.

Subcutaneous hormonal implants or intrauterine systems that release levonorgestrel are associated with an increased risk of infectious complications at the time of their placement and with irregular vaginal bleeding. Patients with neutropenia using these methods of contraception should be prophylactically prescribed antibiotics.

The use of intrauterine systems that release copper is generally not recommended due to the high risk of developing infectious complications at the time of implantation and increased blood loss during menstruation, which can exacerbate pronounced neutropenia or thrombocytopenia.

Tests for pregnancy

In accordance with accepted practice, pregnancy tests with a minimum sensitivity of 25 mIU / ml should be performed under the supervision of a doctor by all women with preserved reproductive potential, including those who completely and permanently abstain from sexual relations.

According to the recommendations, the pregnancy test, the appointment and delivery of pamidomide should be conducted on the same day. A woman with a preserved childbearing potential should receive pamildomide not later than 7 days after the appointment of treatment.

Before the start of treatment. After the patient has used an effective method of contraception for 4 or more weeks, the test is performed under the supervision of the attending physician on the day of appointment of pamildomide or 3 days before the visit to the attending physician. The test should confirm the patient's absence of pregnancy at the time of the onset of taking pologidomide.

During and after treatment. The pregnancy test under medical supervision should be repeated every 4 weeks, including 4 weeks after the end of treatment. Tests are performed on the day of the visit or within 3 days before the visit to the attending physician.

The Men

Pomalidomide is found in the human semen during treatment with this drug. As a precautionary measure and taking into account those groups of patients who may prolong the time for elimination of pamidomide, such as patients with renal insufficiency, all men taking pamidomide, including those who have had a vasectomy, should use condoms throughout the course of treatment, during breaks in Treatment and within 7 days after cessation of treatment if their partner is a pregnant woman or a woman with a preserved childbearing potential who does not use contraception.

Patients are not allowed to be donors of blood, semen or semen during the entire treatment period (including interruptions in treatment) and within 7 days after the completion of pologidomide.

Additional precautions

Patients should not transfer the drug to others. After the end of treatment, it is recommended to return the unused medication to a medical institution. Patients are not allowed to be donors of blood, semen or semen during the entire treatment period (including interruptions in treatment) and within 7 days after the completion of pologidomide.

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

To help patients avoid the effects of pamildomide on the fetus, the holder of the registration certificate will provide medical personnel with training materials on precautionary measures regarding the likely teratogenicity of pamildomide, the methods of contraception before the start of therapy, and guidelines for conducting the necessary pregnancy tests. The physician should inform the patient of the possible teratogenic risk of pamildomide and severe pregnancy prevention measures in accordance with the Pregnancy Protection Program and provide the patient with a training brochure, a patient card and / or an equivalent control method in accordance with the national patient card system. A controlled distribution system includes the use of patient cards and / or an equivalent way to monitor the prescriptions and / or dispensing of the drug and to collect detailed data relating to prescriptions in order to closely monitor cases of use by indications not registered in the Russian Federation.

The pregnancy test, prescribing and dispensing of the drug is recommended in one day. The delivery of pomamidomide to women with preserved reproductive potential should occur no later than 7 days after the appointment of therapy and receive a negative test result for pregnancy, performed under the supervision of a doctor.

The drug should be given to women with preserved reproductive potential for no more than 4 weeks of treatment, for all other categories of patients - no more than 12 weeks.