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Imnovid® [Pomalidomide]

Brand Celgene

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Clinical Pharmacology

Clinico-pharmacological group

Pomalidomide has direct anti-myeloma tumoricidal activity, demonstrates an immunomodulatory effect and inhibits stromal cells that support the growth of myeloma tumor cells. Pomalidomide selectively inhibits proliferation and induces apoptosis of hematological tumor cells. In addition, pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and is synergistic with dexamethasone in its ability to induce apoptosis of both lenalidomide-sensitive and lenalidomide-resistant tumor cell lines. Pomalidomide enhances cellular immunity with the participation of T-cells and natural killer cells and inhibits the formation of pro-inflammatory cytokines (eg, tumor necrosis factor-a, TNF-a, and interleukin-6, IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells.

Indications

- in combination with dexamethasone for the treatment of adult patients with recurrent and refractory multiple myeloma who have received at least two previous courses of treatment, including both lenalidomide and bortezomib, and in which the disease has progressed against the background of the last treatment.

Composition

1 caps
pomalidomide	4 mg

[PRING] mannitol - 101 mg, pregelatinized starch - 134.4 mg, sodium stearyl fumarate - 0.6 mg.

The composition of the capsule shell: cap - gelatin - 23.943 mg, titanium dioxide - 0.287 mg, indigo carmine - 0.171 mg, white ink *; case - gelatin - 35.73 mg, titanium dioxide - 0.815 mg, brilliant blue FCF - 0.056 mg, white ink *.

* ink composition for marking capsules (%, by weight): white ink - shellac (0.45% solution in ethanol) - 52%, titanium dioxide - 30%, simethicone - 0.01%, propylene glycol - 1%, ammonium hydroxide (28% solution ) - 2%, isopropanol - 14%, n-butanol - 1%.

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Dosage and Administration

For oral administration.

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

Immune® should be taken every day at the same time. Capsules must not be opened, cracked or chewed. The capsules of Imnivod® should be swallowed whole with water, regardless of the meal. If the patient has forgotten to take Imovid® on any given day, then the next day he should take the usual dose in accordance with the prescription. The patient should not change the dose of the drug to replenish the dose missed the day before.

The recommended initial dose of the drug Imovid® is 4 mg orally 1 time / day from 1 to 21 days of repeated 28-day cycles.

The recommended dose of dexamethasone is 40 mg orally 1 time / 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 as the disease progresses.

Pomalidomide dose change or treatment interruption

Instructions for interrupting treatment or changing the dose of pomalidomide due to undesirable hematological reactions are presented in the table below:

Instructions for changing the dose pomalidomide

Toxicity	Dose change
Sunbathing
AKN * Interrupt treatment with pomalidomide, perform weekly OAK **
AKN recovered to values ≥1 × 109 / l	Resume treatment with pomalidomide at a dose of 3 mg / day
For each subsequent reduction <0.5 × 109 / l	Discontinue treatment with pomalidomide
AKN recovered to values ≥1 × 109 / l	Resume treatment with pomalidomide at a dose of 1 mg lower than the previous one.
Thrombocytopenia
Platelet count Stop treatment with pomalidomide, perform OAK weekly **
Platelet count recovered to ≥50 × 109 / L	Resume treatment with pomalidomide at a dose of 3 mg / day
For each subsequent reduction. Interrupt treatment with pomalidomide.
Platelet count recovered to ≥50 × 109 / L	Resume treatment with pomalidomide at a dose of 1 mg lower than the previous one.

* AKN - the absolute number of neutrophils; ** KLA - complete blood count.

To start a new treatment cycle with pomalidomide, the neutrophil count should be ≥1 × 109 / L, and the platelet count ≥50 × 109 / L.

In neutropenia, the doctor should consider the possibility of using growth factor drugs.

In case of adverse reactions of grade 3 or 4 associated with pomalidomide, treatment should be stopped and resumed at a dose of 1 mg lower than the previous one, if, according to the evaluation of the attending physician, the severity of the adverse event decreases to 2 or less.

If undesirable reactions persist after reducing the dose to 1 mg, the drug should be stopped.

Instructions for changing the dose of dexamethasone

Toxicity	Dexamethasone dose change
1-2 degree dyspepsia Dyspepsia ≥3 degrees	Maintain the dose and use histamine blockers (H2) or similar agents. Reduce the dose by one level while maintaining symptoms. Interrupt treatment until symptoms subside. Add histamine blockers (H2) or similar agents and reduce the dose to a single level when resuming treatment.
Edema ≥3 degrees	Use diuretics as needed and reduce the dose by one level.
Confusion and mood changes ≥2 degrees	Interrupt treatment until symptoms resolve. When resuming treatment, reduce the dose by one level.
Muscle weakness ≥2 degrees	Interrupt treatment until muscle weakness is ≤1 degrees. When resuming 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	Stop treatment with dexamethasone until the adverse event values are ≤2 degrees. To resume treatment, reducing the dose by one level.

Dexamethasone dose reduction:

Order of dose reduction (patients aged ≤75 years): initial dose of 40 mg; dose level 1 - 20 mg; Dose Level 2 — 10 mg on days 1, 8, 15, and 22 of each 28-day treatment cycle.

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

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

Features of use in certain groups of patients

Kids and teens

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

Elderly patients

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

Renal dysfunction

Studies pomalidomide in patients with renal insufficiency were not conducted. Patients with moderate or severe renal failure (CC 45 ml / min) were not included in clinical studies. Patients with renal insufficiency should be carefully monitored for the timely detection of unwanted reactions.

Liver function disorders

Studies pomalidomide in patients with liver failure were not conducted, because patients whose total serum bilirubin values exceeded 2.0 mg% were not included in clinical studies. Patients with impaired liver function must be carefully monitored for the timely detection of unwanted reactions.

Adverse reactions

Summary of security profile

During clinical studies, the most frequent adverse reactions were disorders of the blood and lymphatic system: anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); among general disorders, 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 (ETN) complications - in 3.3% of patients. The most frequent adverse reactions of grade 3 or 4 were disorders of the blood and lymphatic system, including neutropenia (41.7%), anemia (27%) and thrombocytopenia (20.7%); among infections and invasions, pneumonia (9%); among the general 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 reactions, febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VETN (1.7%) were recorded.

Adverse reactions occurred more frequently during the first two treatment cycles with pomalidomide.

Undesirable reactions (NLR) that occurred in patients with treatment with a combination of pomalidomide and dexamethasone are presented below in accordance with the classification of lesions of organs and organ systems of MEDDRA, taking into account the frequency of all NLR and the frequency of NLR 3 or 4 severity.

The frequency NLR, below, was determined according to the following classification: very often (> 1/10); often (> 1 / 100,1 / 1000,

NLR, registered in clinical studies in patients with refractory multiple myeloma during therapy with pomalidomide and dexamethasone

System organ class	Adverse reactions (total), frequency	Adverse reactions 3-4 severity, frequency
Infectious and parasitic diseases	Very often: pneumonia. Often: neutropenic sepsis, bronchopneumonia, bronchitis, ARVI, acute infectious diseases of the upper respiratory tract, nasopharyngitis.	Often: neutropenic sepsis, pneumonia, bronchopneumonia, ARVI, acute infectious diseases of the upper respiratory tract. Infrequently: bronchitis.
Violations of the blood and lymphatic system	Very often: neutropenia, thrombocytopenia, leukopenia, anemia. Often: febrile neutropenia.	Very often: neutropenia, thrombocytopenia, anemia.Often: febrile neutropenia, leukopenia.
Metabolic and nutritional disorders	Very often: decreased appetite. Often: hyperkalemia, hyponatremia.	Often: hyperkalemia, hyponatremia. Infrequently: decrease in appetite.
Mental disorders	Often: confusion.	Often: confusion.
Nervous system disorders	Often: inhibition, peripheral sensory neuropathy, dizziness, tremor.	Often: lethargy. Infrequently: peripheral sensory neuropathy, dizziness, tremor.
Disturbances from an organ of hearing and labyrinth disturbances	Often: vertigo.	Often: vertigo.
Vascular disorders	Often: deep vein thrombosis.	Infrequently: deep vein thrombosis.
Disorders of the respiratory system, organs of the chest and mediastinum	Very often: shortness of breath, cough. Often: pulmonary embolism.	Often: shortness of breath. Infrequently: pulmonary thromboembolism, cough.
Gastrointestinal disorders	Very often: diarrhea, nausea, constipation. Often: vomiting.	Often: diarrhea, vomiting, constipation. Infrequently: nausea.
Disorders of the liver and biliary tract	Infrequently: hyperbilirubinemia.	Infrequently: hyperbilirubinemia.
Violations of the skin and subcutaneous tissue	Often: rash, pruritus.	Often: rash.
Disorders of the musculoskeletal and connective tissue	Very often: bone pain, muscle spasms.	Often: bone pain. Infrequently: muscle cramps.
Kidney and urinary tract disorders	Often: renal failure, urinary retention.	Often: renal failure. Infrequently: urine retention.
Violations of the genitals and mammary glands	Often: pain in the pelvic area.	Often: pain in the pelvic area.
General disorders and disorders at the site of administration	Very often: fatigue, fever, peripheral edema.	Often: fatigue, fever, peripheral edema.
Laboratory and instrumental data	Often: neutropenia, leukopenia, thrombocytopenia, increased alanine aminotransferase activity.	Often: neutropenia, leukopenia, thrombocytopenia, increased alanine aminotransferase activity.

Description of individual adverse reactions

Teratogenicity

Pomalidomide is structurally similar to thalidomide, a well-known teratogen for humans, which causes severe, life-threatening birth defects. The teratogenic effect of pomalidomide was found during the period of primary organogenesis in its use in rats and rabbits. When pomalidomide is used during pregnancy in humans, a manifestation of its teratogenic effect is likely (see "Contraindications" and "Special Instructions").

Neutropenia and Thrombocytopenia

Neutropenia was registered in 45.3% of patients receiving pomalidomide in combination with dexamethasone in a low dose (Pom + LD-Dex). Neutropenia 3 or 4 severity occurred in 41.7% of patients taking Pom + LD-Dex, while neutropenia was rarely serious (2.0% of patients), did not lead to discontinuation of treatment, caused discontinuation of treatment in 21.0% of patients, and the reason for reducing the dose in 7.7% of patients.

Febrilpaya neutropenia (FN) was noted in 6.7% of patients with Pom + LD-Dex. All manifestations were grade 3 and 4. FN was recognized as serious in 4.0% of patients, was the cause of interruption in treatment in 3.7% of patients, the cause of dose reduction in 1.3% of patients. None of the patients had completely stopped the treatment. Thrombocytopenia was recorded in 27.0% of patients receiving Pom + LD-Dex. Thrombocytopenia of 3 or 4 severity was in 20.7% of patients, while thrombocytopenia was regarded as serious in 1.7% of patients, caused a dose reduction in 6.3%, interruption of treatment in 8% and discontinuation of treatment in 0.7% of patients.

Infections

Infections were the most frequent non-hematological manifestation of toxicity: they were registered in 55.0% of patients with Pom + LD-Dex. About half of these infections were 3 or 4 degrees.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, the infections were serious, and in 2.7% of patients they were fatal (grade 5). 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 complications

Venous embolic or thrombotic complications (ETOs) were detected in 3.3% of patients who received Pom + LD-Dex. These complications of grade 3 or 4 were noted in 1.3% of patients, and in 1.7% of patients with ETO were considered serious. ETO was not accompanied by fatal outcome and did not require discontinuation of treatment.

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

Peripheral Neuropathy

Peripheral neuropathy, mainly 1 or 2 degrees of severity, was observed in 12.3% of patients with Pom + LD-Dex. Reactions of 3 or 4 severity were registered in 1.0% of patients.

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

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

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

- hypersensitivity to pomalidomide or any other components of the drug;

- pregnancy and breastfeeding;

- for women: preserved childbearing potential, unless all necessary conditions are met for the Pregnancy Protection Program (see "Special instructions");

- for men: the inability or inability to comply with the necessary contraceptive measures specified in the section "Special instructions";

- children's age up to 18 years (and due to the lack of data on efficacy and safety).

Carefully

- in patients with renal and / or hepatic insufficiency (see also "Dosage and administration"), as well as in patients with deep vein thrombosis (including, and anamnesis);

- in patients with risk factors for thromboembolism (heart or lung disease, increased blood pressure or elevated blood cholesterol, smokers);

- when taken together with drugs that increase the risk of thrombosis, namely, with drugs with erythropoietic activity, and hormone replacement therapy (see also "Side effects" and "Interaction with other drugs");

- in patients with a common stage of the disease and / or high tumor burden due to the potential risk of developing tumor lysis syndrome (see "Special Instructions");

- in patients with neuropathy (including and in history).

Drug interactions

Influence of the drug Imovid® on other medicines

Pomalidomide is believed to cause no clinically significant pharmacokinetic drug interactions associated with the inhibition or induction of cytochrome P450 isoenzymes, or the activation or inhibition of transport systems when used together with the substrates of these enzymes or transporters. The possibility of such drug interactions, including the effect of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been clinically evaluated (see "Side Effects" and "Special Instructions").

Effect of Other Drugs on Imnavid®

Pomalidomide is partially metabolized by isoenzymes CYP1A2 and CYP3A4 / 5 and is a substrate for P-glycoprotein. The combined use of pomalidomide with an active CYP3A4 / 5 inhibitor and P-gp ketoconazole or with a powerful inducer of CYP3A4 / 5 carbamazepine did not have a clinically significant effect on pomalidomide. The combined use of the active CYP1A2 inhibitor fluvoxamine in the presence of ketoconazole increased the effect of pomalidomide by 104% at a 90% confidence interval [88% -122%] in comparison with the combination pomalidomide-ketoconazole. If an active CYP1A2 inhibitor (for example, ciprofloxacin, enoxacin and fluvoxamine) is used together with pomalidomide, then in such patients it is necessary to carefully monitor adverse events.

Dexamethasone

Combination therapy with pomalidomide in repeated doses up to 4 mg and dexamethasone in doses of 20-40 mg {weak-moderate inducer of some CYP enzymes, including CYP3A) in patients with multiple myeloma was not accompanied by impaired pomalidomide pharmacokinetics compared to pomalidomide monotherapy.

The effect of dexamethasone on warfarin has not been studied, so it is recommended to carefully monitor the concentration of warfarin during the combination therapy.

Pregnancy and Lactation

Pregnancy

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

Breastfeeding period

It is not established whether pomalidomide is excreted in human breast milk. Pomalidomide was found in the milk of rats, which were administered the drug. Given the potential undesirable effects of pomalidomide on newborns, either breastfeeding or taking the drug should be discontinued, taking into account the importance of taking this drug for the mother.

Special instructions

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

Pregnancy prevention program

Strict observance of all the requirements of the Pregnancy Protection Program should apply to all patients, unless their lack of childbearing potential is reliably proven.

For women without childbearing potential:

A female patient or female sexual partner of a male patient is NOT considered capable of childbearing if at least one of the listed factors is present:

- age ≥50 years and duration of natural amenorrhea ≥1 years *;

- early ovarian failure, confirmed by a gynecologist;

- bilateral salpingoophorectomy or hysterectomy in history;

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

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

Counseling

The use of pomalidomide in women with preserved childbearing potential is contraindicated if one of the following statements is incorrect:

A woman should:

- understand the possibility of teratogenic action of pomalidomide on the fetus;

- understand the need for continuous use of effective contraceptive methods for 4 weeks before the start of treatment, during treatment and 4 weeks after the end of treatment with pomalidomide;

- 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;

- know and understand the possible consequences in the event of pregnancy while receiving pomalidomide, as well as the need for an urgent consultation for suspected pregnancy;

- understand the need to comply with all the rules of effective contraception against pomalidomide, which can be started immediately after receiving negative results of the pregnancy test;

- be aware of the need to carry out the test on children and perform it every 4 weeks;

- confirm that he understands the risk and the necessary precautions associated with taking pomalidomide.

A physician must ensure that a woman with preserved childbearing potential:

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

- I agree with the above conditions.

Use for men

These pharmacokinetic studies of pomalidomide in male volunteers suggest that pomalidomide may be contained in the patient's seminal fluid.As a precautionary measure, all men taking pomalidomide should observe the following conditions:

A man should:

- to understand the possible risk of teratogenic action of pomalidomide during sexual contact with a pregnant woman or a woman with preserved childbearing potential;

- understand the need to use condoms during sexual contact with a pregnant woman or a woman with preserved childbearing potential who does not use reliable contraceptive methods during the treatment period and for 7 days after stopping and / or completing the treatment. Even after a vasectomy, a man should use a condom during sexual contact with a pregnant woman, since even in the absence of spermatozoids, his sperm may contain pomalidomide;

- understand that if his partner became pregnant during his treatment with pomalidomide or within 7 days after stopping treatment with pomalidomide, he should immediately inform his attending physician about this, and his partner is advised to consult a teratologist for examination and consultation.

Contraception 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 end of treatment with pomalidomide even in case of a break in treatment. The exception is made by patients who for a long time completely abstain from sexual relations, which is confirmed monthly. If the patient does not choose an effective method of contraception, it should be sent to a gynecologist to select a method of contraception and start using it.

Examples of highly effective contraceptive methods include:

- subcutaneous hormonal implants;

- intrauterine systems that produce levonorgestrel;

- depot drugs medroxyprogesterone acetate;

- tubal ligation;

- sexual relations with a partner who underwent a vasectomy; vasectomy is confirmed by two negative semen analyzes;

- progesterone-containing tablets that inhibit ovulation (for example, desogestrel).

Reception of combined oral contraceptives is not recommended for patients with multiple myeloma due to the increased risk of thromboembolic complications during treatment with pomalidomide and dexamethasone. If the patient is using combined oral contraceptives, she should be transferred to one of the effective methods of contraception listed above. Increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptives. The effectiveness of hormonal contraceptive drugs can be reduced while dexamethasone is given.

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 given prophylactic antibiotics.

The use of intrauterine systems that emit 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 may increase the severity of neutropenia or thrombocytopenia.

Pregnancy tests

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

According to the recommendations, the pregnancy test, the prescription and delivery of the drug should be carried out on the same day.A woman with preserved childbearing potential should receive pomalidomide no later than 7 days after prescribing treatment.

Before 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 pomalidomide or 3 days before the visit to the attending physician. The test should confirm the absence of the patient's pregnancy at the time of the start of the administration of pomalidomide.

During and after treatment

A 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.

Men

Pomalidomide is found in human seminal fluid during treatment with this drug. As a precautionary measure, and taking into account those groups of patients who can prolong the elimination o

Brand name: Imnovid®
Active ingredient: Pomalidomide
Dosage form: Gelatin capsules, 2, with a dark blue opaque cap with a white ink "POML" printed on it and a blue opaque body with a white ink "4 mg" applied on it; the contents of the capsules are yellow powder.
Manufacturer: Celgene
Country of Origin: Great Britain