Imnovid® (Imnovid®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substancePomalidomidePomalidomide
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  • Imnovid®
    capsules inwards 
    Selden International Sarl     Switzerland
    • Dosage form: & nbspcapsules
    Composition:

    1 capsule with a dosage of 1 mg contains: active substance: pogalidomide 1.0 mg;

    Excipients: mannitol, pregelatinized starch, sodium stearyl fumarate;

    shell capsules: cap - gelatin, titanium dioxide, indigocarmine (E132). white ink *; housing - gelatin, titanium dioxide, iron (III) oxide yellow (E172), black ink *.

    1 capsule with a dosage of 3 mg contains: active substance: pamildomide 3.0 mg;

    Excipients: mannitol, pregelatinized starch, sodium stearyl fumarate;

    shell capsules: cap - gelatin, titanium dioxide, indigocarmine (E132), white ink *; body - gelatin, titanium dioxide, iron (III) oxide yellow (E172), indigo carmine (E132), white ink *.

    1 capsule with a dosage of 4 mg contains: active substance: pologidomide 4.0 mg;

    Excipients: mannitol, pregelatinized starch, sodium stearyl fumarate;

    shell capsules: cap - gelatin, titanium dioxide, indigocarmine (E132), white ink *; housing - gelatin, titanium dioxide, brilliant blue FCF (E133), white ink *.

    * composition of ink for marking the capsule (%, by weight): white ink - shellac (0.45% solution in ethanol); titanium dioxide E171; simethicone; propylene glycol E1520; ammonium hydroxide (28% solution) E527; isopropanol; n-butanol;

    black ink - shellac (0.45% solution in ethanol); propylene glycol E1520; ammonium hydroxide (28% solution) E527; isopropanol; n-butanol; iron oxide black E172; ethanol anhydrous, purified water.

    Description:

    Capsules 1 mg: gelatin capsules No. 4 with a dark blue opaque lid marked with white ink on it "POML" and a yellow opaque case marked with black ink on it "1 mg"; the contents of the capsules are a yellow powder.

    Capsules 3 mg: gelatin capsules No. 2 with a dark blue opaque lid marked with white ink on it "POML" and a green opaque case marked with white ink on it "3 mg"; the contents of the capsules are a yellow powder.

    Capsules 4 mg: gelatin capsules No. 2 with a dark blue opaque lid marked with white ink on it "POML" and a blue opaque case marked with white ink on it "4 mg"; the contents of the capsules are a yellow powder.

    Pharmacotherapeutic group:Immunomodulating agent
    ATX: & nbsp

    L.04.A.X.06   Pomalidomide

    Pharmacodynamics:

    Mechanism of action

    Pomalidomide has a direct anti-myeloma tumor-active activity, demonstrates immunomodulatory action and inhibits stromal cells,supporting the growth of tumor cells of myeloma. Pomalidomide selectively inhibits proliferation and causes apoptosis of hematopoietic tumor cells. Besides, pologidomide inhibits the proliferation of multiple myeloma cell lines resistant to lenalidomide, and has a synergism with dexamethasone in the ability to induce 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, tumor necrosis factor-α, TNF-α, and interleukin-6, IL-6) monocytes. Pomalidomide also inhibits angiogenesis, blocking the migration and adhesion of endothelial cells.

    Pharmacokinetics:

    Absorption

    After a single oral intake, the amount of absorption of pologmidomide is at least 73% and its maximum concentration in the blood plasma (CmOh) is achieved in 2-3 hours. The systemic effect of pologidomide (in terms of AUC, the area under the concentration-time curve) increases almost linearly and in proportion to the dose. With multiple dosing, the degree of accumulation of pamildomide is 27 - 31% by AUC.

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

    Distribution

    Average apparent volume of distribution (Vd/F) pomaladomide at an equilibrium concentration 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 TmOh) after taking the drug. In vitro the binding of the enantiomers of pologmidomide with human blood plasma proteins is in the range of 12% to 44% and is independent of the concentration.

    Biotransformation

    In healthy volunteers, after a single oral intake of [14C] -polamidomide (2 mg), the main component in the blood was pologidomide (approximately 70% of the plasma radioactivity level). The amount of metabolites did not exceed 10% relative to the starting 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, appeared to be the main enzymes involved in the hydroxylation of pologidomide. The less important was the isozymes CYP2C19 and CYP2D6. Pomalidomide is also a substrate of P-glycoprotein in vitro. Combined use of pamildomide with an active inhibitor CYP3A4/5 and P-gp ketoconazole or with a powerful inductor CYP3A4/5 carbamazepine had no clinically significant effect on the exposure of pologidomide. Combined use of an active inhibitor CYP1A2 fluvoxamine in the presence of ketoconazole increased the effect of pamildomide by 104% with a 90% confidence interval [88% -122%] compared with the combination of pologidomide-ketoconazole. If an active inhibitor is used in conjunction with pamamidomide CYP1A2 (e.g., ciprofloxacin, enoxacin and fluvoxamine), patients should be carefully monitored for the timely detection of unwanted drug reactions (NLR).

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

    Excretion

    The average half-life of polimedomide from plasma is 9.5 hours in healthy volunteers and 7.5 hours in patients with multiple myeloma. Average overall clearance (CL/F) of the drug is approximately 7-10 l / h.

    In healthy volunteers, after a single oral intake of [14C] -palamidomide (2 mg), approximately 73% and 15% of the radioactive dose were excreted through the kidneys and intestines. At the same time, about 2% and 8% of the dose of polimedomide with a carbon label was excreted through the kidneys and intestines unchanged.

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

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

    Population pharmacokinetics

    Analysis of population pharmacokinetics data using a two-compartment model showed that healthy subjects and patients with multiple myeloma had comparable apparent clearance (CL/F) and the apparent volume of distribution in the central chamber (V2/F). In peripheral tissues pologidomide was absorbed predominantly by tumors with an apparent peripheral clearance of distribution (Q/F) and the apparent peripheral volume of the distribution (V3/F), respectively, 3.7 and 8 times higher than in healthy subjects.

    Children and teens

    There are no data on the use of pamildomide in children and adolescents (<18 years).

    Elderly

    There are no data on the pharmacokinetics of pamildomide in elderly patients. Clinical studies did not require dose changes in patients older than 65 years who received pologidomide (see "Method of administration and dose").

    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 toxicology 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 micronucleation in polychromatic red blood cells of rat 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.

    Indications:

    Imnovid 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, lenalidomide, and bortezomib, and in whom progression of the disease was noted against the background of the last treatment.

    Contraindications:

    - Hypersensitivity to pologidomide or any other components of the drug.

    - Pregnancy and the period of breastfeeding.

    - 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 specified in the section "Special instructions".

    - Children under 18 years of age (due to lack of data on efficiency and safety).

    Carefully:

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

    - In patients with risk factors, thromboembolism (heart or lung disease, high blood pressure or elevated cholesterol in the blood, smokers).

    - 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 drugs").

    - In patients with advanced stage of the disease and / or high tumor burden in connection with the potential risk of developing the syndromelysis of the tumor (see "Special instructions").

    - In patients with neuropathy (including in the anamnesis).

    Pregnancy and lactation:

    Pregnancy

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

    Breastfeeding period

    It is not established whether the pologidomide with human breast milk. Pomalidomide was found in the milk of rats that received the drug. Considering the possibility of undesirable action of pamildomide on newborns, it is necessary to stop either breastfeeding or taking the drug, taking into account the importance of taking this medication for the mother.

    Fertility

    In animals pologidomide has an adverse effect on fertility and teratogenic effect. Pomalidomide penetrates the placenta and is found in fetal blood (according to data obtained on rabbits).

    Dosing and Administration:

    For oral administration.

    Treatment with the drug should be started and carried out only under the supervision of a physician experienced in the treatment of multiple myeloma.

    Imnovid should be taken every day at the same time. Capsules can not be opened, broken or chewed. Capsules of the preparation Imnovid should be swallowed whole, washed down with water, regardless of food intake. If the patient forgot to take Imnovid on any day, then the next day he should take the usual dose in accordance with the appointment. The patient should not change the dose of the drug to make up for the dose missed the day before.

    Recommended initial dose The drug Imovid is 4 mg orally 1 time per day from 1 to 21 days of repeated 28-day cycles.

    The recommended dose of dexamethasone is 40 mg orally once a day at 1, 8, 15 and 22 days of each 28-day cycle.

    The dosage regimen is maintained or changed depending on the clinical and laboratory data.

    Treatment should be discontinued if the disease progresses.

    Change in the dose of pologidomide or discontinuation of treatment

    Instructions for discontinuing treatment or changing the dose of pamildomide due to unwanted hematologic reactions are presented in the table below:

    Instructions for a change in the dose of pologidomide

    Toxicity

    Dose change

    Neutropenia

    - ACN * <0.5 x 109/ l or febrile neutropenia (fever ≥ 38,5°C and AKN <1 x 109/ l)

    Discontinue treatment with pologidomide, weekly KLA **.

    - AKN recovered to ≥1 × 109/ l

    Resume the treatment with pamildomide at a dose of 3 mg per day.

    - For each subsequent reduction

    <0.5 x 109/ l

    Interrupt the treatment with pomalidomide

    - AKN recovered to ≥1 × 109/ l

    Renew the treatment with pamildomide at a dose of 1 mg lower than the previous one.

    Thrombocytopenia

    - Number of platelets <25 x 109/ l

    Discontinue treatment with pamildomide, take weekly KLA **

    - The platelet count was restored to ≥50 x 109/ l

    Resume the treatment with pamildomide at a dose of 3 mg per day.

    - For each subsequent reduction

    <25 x 109/ l

    Interrupt the treatment with pomalidomide

    - The platelet count was restored to ≥50 x 109/ l

    Renew the treatment with pamildomide at a dose of 1 mg lower than the previous one.

    * ACN is the absolute number of neutrophils; ** UAC - the general or common analysis of a blood

    To start a new cycle of treatment with pamildomide, the amount of neutrophils should be ≥ 1 x 109/ l, and the number of platelets ≥ 50 x 109/ l.

    With neutropenia, the doctor should consider the use of growth factor drugs.

    In case of undesired reactions of grade 3 or 4 associated with pamildomide, treatment should be suspended and resumed at a dose of 1 mg lower than the previous one if the treating physician estimates that the severity of the undesirable phenomenon is reduced to 2 or less.

    If unwanted reactions persist after lowering the dose to 1 mg, the drug should be discontinued.

    Instructions for changing the dose of dexamethasone

    Toxicity

    Change in the dose of dexamethasone

    Indigestion of 1-2 degrees

    Maintain a dose and apply histamine blockers (H2) or similar agents. Reduce the dose by one level while maintaining


    symptoms.

    Dyspepsia ≥3 degrees

    Interrupt treatment until symptoms ease. Add histamine blockers (H2) or


    similar drugs and to reduce the dose by one level with the resumption of treatment.

    Edema ≥3 degree

    Apply diuretics as needed and reduce the dose by one level.

    Confusion and mood changes ≥2 degrees

    Interrupt treatment until symptoms resolve. When you resume treatment, reduce the dose by one level.


    Muscle weakness ≥2 degree

    Interrupt the treatment until the indicator of muscle weakness becomes ≤1 degree.When you resume treatment, reduce the dose by one level.


    Hyperglycemia ≥3 degrees

    Reduce the dose by one level. Use insulin or oral hypoglycemic agents as needed.


    Acute pancreatitis

    Stop treatment with dexamethasone.


    Other adverse events ≥ 3 degrees due to dexamethasone

    Interrupt treatment with dexamethasone until the values ​​of undesirable events become ≤2 degrees. Resume the treatment, lowering the dose by one level.






    Decrease in the dose of dexamethasone:

    The order of dose reduction (patients ≤ 75 years of age): initial dose of 40 mg; dose of 1 level - 20 mg; dose level 2 - 10 mg at 1, 8, 15 and 22 day of each 28-day treatment cycle.

    The order of dose reduction (patients older than 75 years): an initial dose of 20 mg; dose of 1 level - 12 mg; dose level 2 - 8 mg at 1.8, 15 and 22 days of each 28-day treatment cycle.

    If the toxic effects persist for more than 14 days, the dose of dexamethasone should be reduced by one level.

    Peculiarities of application in separate groups of patients

    Children and teens

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

    Elderly patients

    Change in the dose of pamildomide in patients older than 65 years is not required.For patients older than 75 years, the initial dose of dexamethasone is 20 mg once every 1, 8, 15 and 22 days of each 28-day treatment cycle.

    Renal impairment

    Studies of pamildomide in patients with renal insufficiency have not been conducted. Patients with moderate or severe renal insufficiency (creatinine clearance <45 mL / min) were not included in the clinical studies. Patients with renal insufficiency should be carefully monitored for the timely detection of unwanted reactions.

    Dysfunction of the liver

    Studies of pamildomide in patients with hepatic insufficiency have not been carried out, since. patients with total serum bilirubin values ​​exceeding 2.0 mg% were not included in the clinical trials. Patients with impaired liver function should be carefully monitored for the timely detection of unwanted reactions.

    Side effects:

    Safety Profile Summary

    During clinical trials, the most frequent adverse reactions were violations of the blood and lymphatic system: anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); Among the common disorders, fatigue prevailed (28.3%), fever (21%) and peripheral edema (13%); 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) - in 3.3% of patients. The most frequent adverse reactions of grade 3 or 4 were violations of the blood and lymphatic system, including neutropenia (41.7%), anemia (27%) and thrombocytopenia (20.7%); among infections and invasions - pneumonia (9%); among common disorders and disorders at the injection site - fatigue (4.7%), fever (3%) and peripheral edema (1.3%). The most frequent serious adverse reaction was pneumonia (9.3%). Of the other serious adverse events, febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VETN (1.7%) were recorded. Undesirable reactions often occurred during the first two cycles of treatment with pomidomide.

    The adverse reactions (NLR) that occurred in patients treated with a combination of pamildomide and dexamethasone are presented below in accordance with the classification of lesions of organs and organ systems MEDDRA taking into account the frequency of all NLRs and the frequency of NLR 3 or 4 severity.

    The frequency of the NLRs given below was determined according to 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 pologidomide and

    dexamethasone

    System-Organic

    grade

    Adverse reactions (in total), frequency

    Adverse reactions of 3-4 degrees of severity, frequency

    Infectious and

    parasitic

    diseases

    Often: pneumonia. Often: neutropenic sepsis, bronchopneumonia, bronchitis, acute respiratory infections, acute infectious diseases of the upper respiratory tract, nasopharyngitis.

    Often: neutropenic sepsis, pneumonia, bronchopneumonia, acute respiratory infections, acute infectious diseases of the upper respiratory tract.

    Infrequently: bronchitis.

    Violations of the blood and lymphatic system

    Often: neutropenia, thrombocytopenia, leukopenia, anemia.

    Often: febrile neutropenia. pancytopenia *

    Often: neutropenia, thrombocytopenia, anemia.

    Often: febrile neutropenia, leukopenia, pancytopenia *.

    Disorders from the metabolism and nutrition

    Often: decreased appetite.

    Often: hyperkalemia,

    hyponatremia,

    hyperuricemia.

    Infrequently: tumor lysis syndrome.

    Often: hyperkalemia,

    hyponatremia,

    hyperuricemia.

    Infrequently: loss of appetite, tumor lysis syndrome *.

    Disorders of the psyche

    Often: confusion of consciousness.

    Often: confusion of consciousness.

    Disturbances from the nervous system

    Often: inhibition, peripheral sensory neuropathy, dizziness, tremor, intracranial bleeding *.

    Infrequently: stroke*.

    Often: retardation.

    Infrequently: peripheral sensory neuropathy, dizziness, tremor, stroke *, intracranial hemorrhage *.

    Hearing disorders and labyrinthine disorders

    Often: Vertigo.

    Often: Vertigo.

    Vascular disorders

    Often: deep vein thrombosis.

    Infrequently: deep vein thrombosis.

    Heart Disease

    Often: heart failure *, atrial fibrillation *, myocardial infarction *.

    Often: heart failure, atrial fibrillation.

    Infrequently: myocardial infarction.

    Immune system disorders

    Often: angioedema, hives *.

    Infrequently: angioedema, hives *.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: shortness of breath, cough.

    Often: thromboembolism of the pulmonary artery, epistaxis *, interstitial lung disease *.

    Often: dyspnea.

    Infrequently: thromboembolism of the pulmonary artery, cough, nosebleeds *, interstitial lung disease *.

    Disorders from the gastrointestinal tract

    Often: diarrhea, nausea, constipation.

    Often: vomiting.

    Often: diarrhea, vomiting, constipation.

    Infrequently: nausea.

    Disturbances from the liver and bile ducts

    Infrequently:

    hyperbilirubinemia,

    hepatitis*.

    Infrequently: hyperbilirubinemia.

    Disturbances from the skin and subcutaneous tissues

    Often: rash, itchy skin.

    Often: rash.

    Disturbances from musculoskeletal and connective tissue

    Often: pain in the bones, muscle spasms.

    Often: pain in the bones. Infrequently: muscle spasms.

    Disorders from the kidneys and urinary tract

    Often: renal failure, urinary retention.

    Often: renal insufficiency.

    Infrequently: retention of urine.

    Violations from

    the sex

    organs and dairy

    glands

    Often: pain in the pelvic area.

    Often: pain in the pelvic area.

    General disorders

    and violations in place

    introduction of

    Often: fatigue,

    temperature increase,

    peripheral edema.

    Often: fatigue, fever, peripheral edema.

    Laboratory and

    instrumental

    data

    Often: neutropenia,

    leukopenia,

    thrombocytopenia, increased

    activity

    alanine aminotransferase,

    increase in concentration

    of uric acid in plasma

    blood *.

    Often: neutropenia, leukopenia, thrombocytopenia, increased activity

    alanine aminotransferase.

    Infrequently: increase in the concentration of uric acid in the blood plasma *.

    Identified in the post-marketing period with the frequency determined in clinical trials

    Description of individual adverse reactions

    Teratogenicity

    Pomalidomide is structurally similar to thalidomide, a known teratogen for a person that causes severe, life-threatening birth defects. The teratogenic effect of pamildomide in the period of the main organogenesis in its use in rats and rabbits was detected. When applying pamildomide during pregnancy, people are likely to have a teratogenic effect (see "Contraindications" and "Special instructions").

    Neutropenia and thrombocytopenia

    Neutropenia was recorded in 45.3% of patients receiving pologidomide in combination with dexamethasone in a low dose (Pom + LD-Dex). Neutropenia of grade 3 or 4 occurred in 41.7% of patients, with neutropenia rarely serious (2.0% of patients), did not lead to discontinuation of treatment was the cause of treatment interruption in 21.0% of patients and cause dose reduction in 7.7% of patients.

    Febrile neutropenia (FN) was noted in 6.7% of patients in the background Pom + LD-Dex. All manifestations were 3 and 4 degrees of severity. FN recognized as serious in 4.0% of patients, was the cause of the 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 27.0% of patients who received Pom + LD-Dex. Thrombocytopenia 3 or 4 severity was 20.7% of patients with thrombocytopenia is regarded as a serious in 1.7% of patients, the dose caused a decrease in 6.3% suspension of the treatment in 8% and termination of treatment at 0.7 % of patients.

    Infections

    Infections were the most frequent non-hematologic manifestation of toxicity: they were registered in 55.0% of patients treated Pom + LD-Dex. About half of these infections were 3 or 4 degrees 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 (5 severity). Infections required discontinuation of treatment in 2.0% of patients, interruption of treatment in 14.3% and dose reduction in 1.3% of patients.

    Thromboembolic disorders

    Venous embolic or thrombotic disorders (VETN) were detected in 3.3% of patients who received Pom + LD-Dex. These violations of 3 or 4 severity were noted in 1.3% of patients. In 1.7% of patients, VETN are 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 anticoagulants in patients with high risk) was mandatory. In the absence of contraindications, treatment with anticoagulants was also recommended.

    Peripheral Neuropathy

    Peripheral neuropathy, mostly 1 or 2 degrees of severity, was noted in 12.3% of patients in treatment Pom + LD-Dex. Reactions of 3 or 4 severity were recorded in 1.0% 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.

    Overdose:

    Iminovid 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 pimildomide are absent. It is not known whether pologidomide and its metabolites to dialysis. In case of an overdose, supportive therapy is recommended.

    Interaction:

    Influence of Imnovid on other medications

    It is believed that pologidomide does not cause clinically significant pharmacokinetic drug interactions associated with the inhibition or induction of cytochrome P450 isoenzymes, or the 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 combined oral contraceptives, was not clinically evaluated (see "Side effects" and "Special instructions").

    The effect of other drugs on Imnidid

    Pomalidomide is partially metabolized by isoenzymes CYP1A2 and CYP3A4/5 and is a substrate for P-glycoprotein. Combined use of pamildomide with an active inhibitor CYP3A4/5 and P-gp ketoconazole or with a powerful inducer CYP3A4/5 Carbamazepine did not clinically significant effect on the action of pologidomide. Combined use of an active inhibitor 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 pomidomid-ketoconazole. If the active inhibitor CYP1A2 (e.g., ciprofloxacin, enoxacin and fluvoxamine) are used in conjunction with pamalidomide, then in such patients it is necessary to carefully monitor undesirable phenomena.

    Dexamethasone

    Combined therapy with pamildomide in repeated doses up to 4 mg and dexamethasone at doses of 20-40 mg (a weak-moderate inducer of some enzymes CYP, including CYP3A) in patients with multiple myeloma was not accompanied by a violation of the pharmacokinetics of pamildomide compared with monotherapy with pamildomide.

    Effect of dexamethasone on warfarin has not been studied, therefore it is recommended that the concentration of warfarin be carefully monitored against a combination therapy.

    Special instructions:

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

    Pregnancy Protection Program

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

    For women without childbearing 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 listed factors:

    - Age ≥ 50 years and duration of natural amenorrhea ≥ 1 year *

    - Early ovarian failure, confirmed by a gynecologist

    - Bilateral salpingo-oophorectomy or hysterectomy in anamnesis

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

    - Amenorrhea due to antitumor therapy or during breastfeeding does not exclude the presence of genital potential.

    Counseling

    The use of pamildomide in women with preserved reproductive potential is contraindicated in the event that one of the following statements is incorrect:

    Female must

    - Understand the possibility of teratogenicity of pamildomide on the fetus

    - Understand the need for continued use of effective contraceptive methods for 4 weeks before the start of treatment, during treatment and 4 weeks after the end of treatment with pologidomide

    - 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 taking pamildomide, as well as the need for urgent treatment for advice in case of a suspected pregnancy

    - understand the need for an immediate start of taking pamildomide after receiving negative pregnancy test results

    - be aware of the need for a pregnancy test and perform it every 4 weeks, except for women with confirmed surgical sterilization

    - to confirm that he understands the risk and necessary precautions associated with taking pamildomide

    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.

    Application in men:

    Data from studies of the pharmacokinetics of pologidomide in male volunteers indicate that pologidomide may be contained in the patient's seminal fluid. As a precautionary measure, all men taking pologidomide, must comply with the following conditions:

    Man must

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

    - understand the need for condoms to be used in sexual intercourse with a pregnant woman or a woman with a preserved reproductive potential that does not use reliable contraceptive methods during the treatment period and within 7 days after the 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 pologidomide.

    - understand that if his partner became pregnant during his treatment with pomildomide or within 7 days after discontinuing therapy with pamildomide. he should immediately inform your doctor about it, and his partner is recommended to see a teratologist-doctor for examination and consultation.

    Contraceptive rules:

    Women with preserved childbearing 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 abstain from sexual relations, which is confirmed on a monthly basis. If the patient does not have an effective method of contraception, she should be referred to the gynecologist for the choice of the method of contraception and the beginning of its use.

    Examples of highly effective methods of contraception include:

    - Subcutaneous hormonal implants.

    - Intrauterine devices that release levonorgestrel.

    - Depot preparations medroxyprogesterone acetate.

    - Ligation of fallopian tubes.

    - Sexual relationships with a partner who underwent a vasectomy; The vasectomy is confirmed by two negative analyzes of the seminal fluid.

    - Progesterone-containing pills that inhibit ovulation (for example, desogestrel).

    The use of combined oral contraceptives is not recommended for patients with multiple myeloma due to an increased risk of thromboembolic complications during treatment with pamildomide and dexamethasone. If a patient uses combined oral contraceptives, she should be transferred to one of the effective methods of contraception listed above. The 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.

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

    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.

    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, prescribing and dispensing of the drug should be conducted on the same day. A woman with a preserved childbearing potential should receive pologidomide not later than 7 days after the appointment of treatment.

    Before treatment begins

    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 should be repeated every 4 weeks, including 4 weeks after the end of treatment, except for women with confirmed surgical sterilization. Tests are performed on the day of the visit or within 3 days before the visit to the attending physician.

    Men's

    Pomalidomide is found in the seminal fluid of a person during treatment with this drug. As a precaution, and taking into account the group of patients in whom the possibility of extension of time of elimination of the drug, such as patients with renal failure, all the men taking pologidomideIncluding undergoing a vasectomy should use condoms throughout the course of treatment, during treatment interruptions, and for 7 days after cessation of treatment if their partner - a pregnant woman or a woman with a stored childbearing potential not using contraception.

    Male patients are not allowed to be semen or sperm donors throughout the treatment period (including breaks in treatment) and for 7 days after receiving the pomalidomida.

    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 donate blood, semen, or sperm throughout the 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 pamelidomide 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 starting therapy, and guidance on conducting the necessary pregnancy tests. The physician should inform the patient of the possible teratogenic risk of pologidomide and severe preventive measures in accordance with the Pregnancy Protection Program and provide the patient 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 cards and / or an equivalent instrument to monitor the prescriptions and / or dispensing of the drug. Conducting a pregnancy test, prescribing and issuing a drug is recommended to be carried out 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 result of a pregnancy test 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 - not more than 12 weeks.

    Hematologic complications

    In patients with recurrent / resistant multiple myeloma, neutropenia is most commonly reported in the group of adverse events of grade 3 or 4; the following in frequency - anemia and thrombocytopenia. Patients need to monitor unwanted hematologic reactions, especially neutropenia. Patients should be informed of 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 - during the first 8 weeks, then - once a month. You may need to change the dose of pamildomide (see "Method of administration and dose"), use of blood substitutes and / or growth factor preparations.

    Thromboembolic complications

    Venous thromboembolic disorders (mainly deep vein thrombosis and pulmonary arterial thromboembolism - PE) and thrombotic arterial thrombotic disorders (myocardial infarction and stroke) developed in patients treated with pamildomide in combination with dexamethasone. Patients with risk factors for thromboembolism, including previous thromboses, should be closely monitored. It is necessary to take all possible measures to minimize risk factors (for example, smoking, hypertension, hyperlipidemia). Patients and physicians 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), 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 agents is accompanied by a risk of thrombotic complications, including thromboembolism. Therefore, erythropoietic preparations, as well as other agents that may increase the risk of thromboembolism, should be used with caution.

    Peripheral Neuropathy

    Patients with peripheral neuropathy ≥ 2 degrees of severity were not included in the clinical studies of pamildomide. When deciding on the appointment of treatment with pamildomide, such patients need to be cautious.

    Severe dysfunction of the heart

    Patients with severe cardiac function impairment (congestive heart failure [Class III or IV NYHA]; myocardial infarction within 12 months before the start of the study; unstable or poorly controlled angina) were not included in the clinical studies of pamildomide. Complications in the form of heart failure, including congestive heart failure and pulmonary edema (see section "Side effect") were noted mainly in patients with pre-existing heart failure or risk factors for heart disease. When deciding whether to prescribe treatment with pologidomide, such patients need to be cautious, including regular examinations to detect symptoms of heart failure.

    Tumor lysis syndrome

    The greatest risk of tumor lysis syndrome 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 site

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

    Allergic reactions

    Angioneurotic edema and severe skin reactions were recorded. Patients with severe allergic reactions to thalidomide or lenalidomide in the anamnesis was not included in clinical studies of pamildomide. Such patients may have an increased risk of developing hypersensitivity reactions and should not receive pologidomide. Consideration should be given to the possibility of interrupting or stopping treatment with pamildomide in the case of a skin rash of 2-3 degree of severity. With the development of angioedema, skin rash of 4 severity, exfoliative or bullous skin rash pologidomide should be canceled.

    Dizziness and confusion

    There are reports of dizziness and confusion in the background of pologidomide. Patients should avoid situations where dizziness and confusion may present a problem, and not take other medicines,which can cause the same violations, without prior medical advice.

    Interstitial lung disease (PID)

    IZL and other similar phenomena, including cases of pneumonitis, were observed against a background of treatment with pamildomide. Patients with acute symptoms or unexplained worsening of pulmonary symptoms should undergo a thorough examination to exclude CLD. In the course of this examination, treatment with pamildomide should be suspended, and with the confirmation of the diagnosis of IZL, appropriate therapy is prescribed. Treatment with pamildomide can be resumed only after a thorough evaluation of the benefits and risks.

    Diseases of the liver

    A marked increase in the activity of alanine aminotransferase and bilirubin concentrations was noted in patients taking pologidomide (see section "Side effect"). Registered, also, cases of hepatitis, which led to the cessation of treatment with pomildomide. Regular monitoring of liver function is recommended during the first 6 months of therapy with pomadedomide, and subsequently - according to clinical indications.

    Precautions for disposal and handling

    Capsules can not be opened or broken.If 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 medicinal product and contaminated materials must be disposed of in accordance with the established requirements. After the end of treatment, it is recommended to return the unused medication to a medical institution.

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

    The imovid has little or moderate influence on the ability to drive a car or machinery. Some side effects of Imnovid, such as fatigue, blocking, confusion and dizziness, can adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. When such undesirable phenomena appear, one should refrain from performing these activities.

    Form release / dosage:

    Capsules 1 mg, 3 mg, 4 mg.

    Packaging:

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

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

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002985
    Date of registration:07.05.2015 / 11.07.2016
    Expiration Date:07.05.2020
    The owner of the registration certificate:Selden International SarlSelden International Sarl Switzerland
    Manufacturer: & nbsp
    Representation: & nbspSeldzhen International Holdings Corporation Seldzhen International Holdings Corporation USA
    Information update date: & nbsp13.10.2016
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