Imnovid^® (Capsules) Instructions for Use

Marketing Authorization Holder

Celgene International, Sarl. (Switzerland)

Manufactured By

Celgene International, Sarl. (Switzerland)

Packaging and Quality Control Release

CELGENE INTERNATIONAL, Sarl. (Switzerland)

Or

PHARMSTANDARD-LEKSREDSTVA, JSC (Russia)

ATC Code

L04AX06 (Pomalidomide)

Active Substance

Pomalidomide (Rec.INN registered by WHO)

Dosage Forms

	Imnovid®	Capsules 1 mg: 21 pcs.
		Capsules 3 mg: 21 pcs.
		Capsules 4 mg: 21 pcs.

Dosage Form, Packaging, and Composition

Capsules gelatin, size 4, with a dark blue opaque cap marked with white ink “POML” and a yellow opaque body marked with black ink “1 mg”; capsule contents – yellow powder.

Excipients: mannitol – 53.68 mg, pregelatinized starch – 70 mg, sodium stearyl fumarate – 0.32 mg.

Capsule shell composition cap – gelatin – 14.915 mg, titanium dioxide – 0.179 mg, indigo carmine – 0.106 mg, white ink*; body – gelatin – 22.566 mg, titanium dioxide – 0.18 mg, yellow iron oxide – 0.054 mg, black ink*.

*composition of capsule marking ink (%, 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%; black ink – shellac (0.45% solution in ethanol) – 59.4%, propylene glycol – 1.3%, ammonium hydroxide (28% solution) – 0.001%, isopropanol – 0.6%, n-butanol – 9.8%, black iron oxide – 24.7%, anhydrous ethanol – 1.1%, purified water – 3.2%.

7 pcs. – blisters (3) – cardboard packs.

Capsules gelatin, size 2, with a dark blue opaque cap marked with white ink “POML” and a green opaque body marked with white ink “3 mg”; capsule contents – yellow powder.

Excipients: mannitol – 75.75 mg, pregelatinized starch – 100.8 mg, sodium stearyl fumarate – 0.45 mg.

Capsule shell composition cap – gelatin – 23.943 mg, titanium dioxide – 0.287 mg, indigo carmine – 0.171 mg, white ink*; body – gelatin – 35.906 mg, titanium dioxide – 0.599 mg, yellow iron oxide – 0.077 mg, indigo carmine – 0.017 mg, white ink*.

*composition of capsule marking ink (%, 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%.

7 pcs. – blisters (3) – cardboard packs.

Capsules gelatin, size 2, with a dark blue opaque cap marked with white ink “POML” and a blue opaque body marked with white ink “4 mg”; capsule contents – yellow powder.

Excipients: mannitol – 101 mg, pregelatinized starch – 134.4 mg, sodium stearyl fumarate – 0.6 mg.

Capsule shell composition cap – gelatin – 23.943 mg, titanium dioxide – 0.287 mg, indigo carmine – 0.171 mg, white ink*; body – gelatin – 35.73 mg, titanium dioxide – 0.815 mg, brilliant blue FCF – 0.056 mg, white ink*.

*composition of capsule marking ink (%, 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%.

7 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Immunomodulator with antitumor activity

Pharmacotherapeutic Group

Other immunosuppressants

Pharmacological Action

Mechanism of action

Pomalidomide has direct anti-myeloma tumoricidal activity, demonstrates immunomodulatory action and inhibits stromal cells that support the growth of myeloma tumor cells.

Pomalidomide selectively inhibits proliferation and induces apoptosis of hematological tumor cells. Furthermore, Pomalidomide inhibits the proliferation of multiple myeloma cell lines resistant to lenalidomide and has synergy with dexamethasone in inducing apoptosis of both lenalidomide-sensitive and resistant tumor cell lines.

Pomalidomide enhances cellular immunity involving T-cells and natural killer cells and inhibits the production of pro-inflammatory cytokines (e.g., TNFα, and interleukin-6, IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking endothelial cell migration and adhesion.

Pharmacokinetics

Absorption

After a single oral dose, the absorption of pomalidomide is at least 73% and its C_max in plasma is reached within 2-3 hours.

The systemic exposure of pomalidomide (by AUC, area under the concentration-time curve) increases almost linearly and proportionally to the dose. With multiple dosing, the accumulation of pomalidomide is 27-31% by AUC.

When taken with a high-calorie, high-fat meal, the rate of pomalidomide absorption is slowed, the C_max value decreases by approximately 25%, but the overall absorption is practically unchanged, the AUC value decreases by only 8%. Therefore, Pomalidomide can be taken regardless of food intake.

Distribution

The mean apparent volume of distribution (V_d/F) of pomalidomide at steady-state concentration ranges from 62-138 L.

After administration of pomalidomide for 4 days at 2 mg per day, it is detected in the semen of healthy volunteers at a concentration of approximately 67% of the plasma level, which is reached at 4 hours (approximate T_max) after drug intake. In vitro binding of pomalidomide enantiomers to human plasma proteins ranges from 12% to 44% and is concentration-independent.

Biotransformation

In healthy volunteers after a single oral dose of [¹⁴C]-pomalidomide (2 mg), the main component in the blood was Pomalidomide (approximately 70% of the plasma radioactivity level).

The amount of metabolites did not exceed 10% relative to the parent compound or total plasma radioactivity.

Hydroxylation followed by glucuronidation or hydrolysis is the main metabolic pathway. In vitro, cytochrome P450 system isoenzymes, CYP1A2 and CYP3A4, were found to be the main enzymes involved in the hydroxylation of pomalidomide. Isoenzymes CYP2C19 and CYP2D6 were of lesser importance. Pomalidomide is also a substrate of P-glycoprotein in vitro.

Concomitant use of pomalidomide with the potent CYP3A4/5 and Pgp inhibitor ketoconazole or with the potent CYP3A4/5 inducer carbamazepine did not have a clinically significant effect on pomalidomide exposure. Concomitant use of the potent CYP1A2 inhibitor fluvoxamine in the presence of ketoconazole increased pomalidomide exposure by 104% with a 90% confidence interval [88%-122%] compared to the Pomalidomide-ketoconazole combination.

If a potent CYP1A2 inhibitor (e.g., ciprofloxacin, enoxacin, and fluvoxamine) is used concomitantly with pomalidomide, patients should be closely monitored for the timely detection of adverse drug reactions (ADRs).

Based on in vitro data, Pomalidomide does not induce or inhibit cytochrome P450 isoenzymes and does not inhibit other studied drug transporters. When pomalidomide is combined with substrates of such pathways, clinically significant drug interactions are unlikely.

Elimination

The mean T_1/2 of pomalidomide from plasma is 9.5 hours in healthy volunteers and 7.5 hours in patients with multiple myeloma.

The mean total clearance (CL/F) of the drug is approximately 7-10 L/h. In healthy volunteers after a single oral dose of [¹⁴C]-pomalidomide (2 mg), approximately 73% and 15% of the radioactive dose was excreted via the kidneys and intestines, respectively. In this case, about 2% and 8% of the carbon-labeled pomalidomide dose was excreted via the kidneys and intestines unchanged.

Pomalidomide undergoes significant biotransformation, and the resulting metabolites are excreted primarily by the kidneys. Three main metabolites formed by hydrolysis or hydroxylation followed by glucuronidation account for 23%, 17%, and 12% of the total metabolite content in urine, respectively.

The amount of metabolites formed with the involvement of cytochrome P450 was approximately 43% of the total radioactivity level, and non-CYP dependent hydrolytic metabolites accounted for 25%. Pomalidomide is excreted unchanged at 10% (2% via kidneys and 8% via intestines).

Children and adolescents

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

Elderly

There are no data on the pharmacokinetics of pomalidomide in elderly patients.

Clinical studies did not require dose adjustment in patients over 65 years of age receiving Pomalidomide (see “Dosage and Administration”).

Renal impairment

Studies of pomalidomide in patients with renal impairment have not been conducted.

Hepatic impairment

Studies of pomalidomide in patients with hepatic impairment have not been conducted.

Results of preclinical safety studies

In a toxicological study in rats, Pomalidomide was well tolerated at doses of 50, 250, and 1000 mg/kg/day with multiple dosing for 6 months.

No adverse reactions to the drug were noted when pomalidomide was dosed up to 1000 mg/kg/day (which is 175 times higher than the therapeutic dose of 4 mg). Pomalidomide did not show mutagenic action and did not cause chromosomal aberrations in human peripheral blood lymphocytes or micronucleus formation in rat bone marrow polychromatic erythrocytes at doses up to 2000 mg/kg/day. Pomalidomide had a teratogenic effect in both rats and rabbits when administered during the main period of organogenesis.

Indications

• In combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and who have demonstrated disease progression on the last therapy.

ICD codes

Dosage Regimen

For oral administration.

Treatment with the drug should be initiated and conducted only under the supervision of a physician experienced in the treatment of multiple myeloma.

Imnovid^® should be taken every day at the same time.

The capsules should not be opened, broken, or chewed. Imnovid^® capsules should be swallowed whole with water, regardless of meals. If a patient forgets to take Imnovid^® on any day, the next day they should take the usual dose as prescribed. The patient should not change the drug dose to make up for the missed dose from the previous day.

The recommended starting dose of Imnovid^® is 4 mg orally once daily from day 1 to day 21 of repeated 28-day cycles.

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

The dosing regimen is maintained or changed based on clinical and laboratory data.

Treatment should be discontinued upon disease progression.

Pomalidomide dose modification or treatment interruption

Instructions for treatment interruption or pomalidomide dose modification due to adverse hematological reactions are presented in the table below.

Instructions for pomalidomide dose modification

* ANC – absolute neutrophil count; ** CBC – complete blood count.

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

In case of neutropenia, the physician should consider the use of growth factor preparations.

For Grade 3 or 4 adverse reactions related to pomalidomide, treatment should be suspended and resumed at a dose 1 mg lower than the previous dose if, in the treating physician’s assessment, the severity of the adverse event decreases to Grade 2 or less.

If adverse reactions persist after dose reduction to 1 mg, drug administration should be discontinued.

Instructions for dexamethasone dose modification

Dexamethasone dose reduction

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

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

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

Special considerations for specific patient groups

Children and adolescents

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

Elderly patients

Dose adjustment of pomalidomide in patients over 65 years of age is not required. For patients over 75 years of age, the starting dose of dexamethasone is 20 mg once on days 1, 8, 15, and 22 of each 28-day treatment cycle.

Renal impairment

Studies of pomalidomide in patients with renal impairment have not been conducted. Patients with moderate or severe renal impairment (CrCl 45 ml/min) were not included in clinical studies. Patients with renal impairment should be closely monitored for the timely detection of adverse reactions.

Hepatic impairment

Studies of pomalidomide in patients with hepatic impairment have not been conducted, as patients with total serum bilirubin values exceeding 2.0 mg% were not included in clinical studies. Patients with hepatic impairment should be closely monitored for the timely detection of adverse reactions.

Adverse Reactions

Brief assessment of the safety 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%), pyrexia (21%) and peripheral edema (13%) predominated; among infections and parasitic diseases – pneumonia (10.7%). As an adverse effect, peripheral neuropathy was registered in 12.3% of patients, and venous embolic and thrombotic (VET) complications – in 3.3% of patients.

The most frequent Grade 3 or 4 adverse reactions were disorders of the blood and lymphatic system, including neutropenia (41.7%), anemia (27%) and thrombocytopenia (20.7%); among infections and infestations – pneumonia (9%); among general disorders and administration site conditions – fatigue (4.7%), pyrexia (3%) and peripheral edema (1.3%). The most frequent serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VET (1.7%).

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

Adverse reactions (ARs) that occurred in patients treated with the combination of pomalidomide and dexamethasone are listed below according to the MedDRA system organ class classification, with the frequency of all ARs and the frequency of grade 3 or 4 ARs.

The frequency of ARs listed below was determined according to the following classification: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100).

ARs reported in clinical trials in patients with refractory multiple myeloma treated with pomalidomide and dexamethasone

Description of selected adverse reactions

Teratogenicity

Pomalidomide is structurally similar to thalidomide, a known human teratogen that causes severe, life-threatening birth defects. Pomalidomide has been shown to be teratogenic in rats and rabbits when administered during the period of major organogenesis. If used during human pregnancy, pomalidomide is likely to exhibit teratogenic effects (see “Contraindications” and “Special Precautions”).

Neutropenia and thrombocytopenia

Neutropenia was reported in 45.3% of patients receiving Pomalidomide in combination with low-dose dexamethasone (Pom+LD-Dex). Grade 3 or 4 neutropenia occurred in 41.7% of patients taking Pom+LD-Dex; neutropenia was rarely serious (2.0% of patients), did not lead to treatment discontinuation, was the reason for treatment interruption in 21.0% of patients, and was the reason for dose reduction in 7.7% of patients.

Febrile neutropenia (FN) was noted in 6.7% of patients on Pom+LD-Dex. All events were grade 3 and 4. FN was considered serious in 4.0% of patients, was the reason for treatment interruption in 3.7% of patients, and was the reason for dose reduction in 1.3% of patients. No patient discontinued treatment completely. Thrombocytopenia was reported in 27.0% of patients receiving Pom+LD-Dex. Grade 3 or 4 thrombocytopenia occurred in 20.7% of patients; thrombocytopenia was considered serious in 1.7% of patients, led to dose reduction in 6.3%, treatment interruption in 8%, and treatment discontinuation in 0.7% of patients.

Infections

Infections were the most common non-hematological toxicity: they were reported in 55.0% of patients treated with Pom+LD-Dex. Approximately half of these infections were grade 3 or 4. The most common complications were pneumonia and upper respiratory tract infections (in 10.7% and 9.3% of patients, respectively). In 24.3% of cases, infections were serious, and in 2.7% of patients they were fatal (grade 5). Infections led to treatment discontinuation in 2.0% of patients, treatment interruption in 14.3%, and dose reduction in 1.3% of patients.

Thromboembolic complications

Venous thromboembolic or thrombotic complications (VTET) were identified in 3.3% of patients receiving Pom+LD-Dex. These complications of grade 3 or 4 were noted in 1.3% of patients; VTET was considered serious in 1.7% of patients. VTET were not fatal and did not require treatment discontinuation.

Prophylactic use of acetylsalicylic acid (or other anticoagulants in patients at high risk) was mandatory. Treatment with anticoagulants was also recommended if there were no contraindications.

Peripheral neuropathy

Peripheral neuropathy, mainly grade 1 or 2, was observed in 12.3% of patients treated with Pom+LD-Dex. Grade 3 or 4 reactions were reported in 1.0% of patients.

No serious peripheral neuropathies developed, and treatment was discontinued for this reason in 0.3% of patients.

The median time to onset of peripheral neuropathy was 2.1 weeks, ranging from 0.1 to 48.3 weeks.

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

Contraindications

• Hypersensitivity to pomalidomide or any other component of the drug;
• Pregnancy and breastfeeding;
• For women: preserved reproductive potential, except when all necessary conditions of the Pregnancy Prevention Program are met (see “Special Precautions”);
• For men: inability or failure to comply with the necessary contraceptive measures specified in the “Special Precautions” section;
• Children under 18 years of age (due to lack of data on efficacy and safety).

With caution

• In patients with renal and/or hepatic impairment (see also “Dosage and Administration”), and in patients with deep vein thrombosis (including history);
• In patients with risk factors for thromboembolism (heart or lung disease, high blood pressure or high blood cholesterol, smokers);
• When used concomitantly with drugs that increase the risk of thrombosis, namely, drugs with erythropoietic activity and hormone replacement therapy (see also “Adverse Reactions” and “Drug Interactions”);
• In patients with advanced disease and/or high tumor burden due to the potential risk of tumor lysis syndrome (see “Special Precautions”);
• In patients with neuropathy (including history).

Use in Pregnancy and Lactation

Pregnancy

Pomalidomide may be teratogenic in humans. The drug is contraindicated during pregnancy and in women with preserved reproductive potential, except when all conditions of pregnancy prevention are met (see “Contraindications” and “Special Precautions”).

Breastfeeding period

It is not known whether Pomalidomide is excreted in human breast milk. Pomalidomide was detected in the milk of rats administered the drug. Given the potential for adverse effects of pomalidomide on newborns, either breastfeeding or drug administration should be discontinued, taking into account the importance of the drug for the mother.

Fertility

In animals, Pomalidomide has adverse effects on fertility and is teratogenic. Pomalidomide crosses the placenta and is detected in fetal blood (according to data obtained in rabbits).

Use in Hepatic Impairment

Use with caution in patients with hepatic impairment. Studies of pomalidomide in patients with hepatic impairment have not been conducted, as patients with total serum bilirubin values exceeding 2.0 mg% were not included in clinical trials. Patients with impaired liver function should be closely monitored for timely detection of adverse reactions.

Use in Renal Impairment

Use with caution in patients with renal impairment. Studies of pomalidomide in patients with renal impairment have not been conducted. Patients with moderate or severe renal impairment (CrCl 45 ml/min) were not included in clinical trials. Patients with renal impairment should be closely monitored for timely detection of adverse reactions.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated due to the lack of clinical data on efficacy and safety.

Geriatric Use

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

Special Precautions

Treatment with Imnovid^® should be initiated and conducted under the supervision of an experienced hematologist or oncologist.

Pregnancy Prevention Program

Strict adherence to all requirements of the Pregnancy Prevention Program must apply to all patients unless the absence of reproductive potential is reliably proven.

For women without reproductive potential

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

• Age ≥50 years and duration of natural amenorrhea ≥1 year*;
• Premature ovarian failure confirmed by a gynecologist;
• History of bilateral salpingo-oophorectomy or hysterectomy;
• XY genotype, Turner syndrome, anatomical defect of the uterus;
• Amenorrhea due to anticancer therapy or during breastfeeding does not exclude the presence of reproductive potential.

Counseling

The use of pomalidomide in women with preserved reproductive potential is contraindicated unless one of the following statements is true:

The woman must

• Understand the potential teratogenic effect of pomalidomide on the fetus;
• Understand the need for continuous use of effective contraceptive methods for 4 weeks before starting treatment, during treatment, and for 4 weeks after discontinuation of pomalidomide treatment;
• Even in case of amenorrhea, comply with all rules of effective contraception;
• Be capable of complying with all rules of effective contraception;
• Know and understand the possible consequences in case of pregnancy during pomalidomide administration, as well as the need for immediate consultation if pregnancy is suspected;
• Understand the need to comply with all rules of effective contraception while on pomalidomide, which can be started immediately after receiving negative pregnancy test results;
• Be aware of the need for pregnancy testing and perform it every 4 weeks;
• Confirm that she understands the risks and necessary precautions associated with taking pomalidomide.

The physician must ensure that the woman with preserved reproductive potential

• Meets all conditions of the Pregnancy Prevention Program, including an adequate level of understanding of its requirements;
• Agrees with the above conditions.

Use in men

Pharmacokinetic data from male volunteers indicate that Pomalidomide may be present in the patient’s semen. As a precaution, all men taking Pomalidomide must comply with the following conditions:

The man must

• Understand the potential risk of teratogenic effects of pomalidomide during sexual intercourse with a pregnant woman or a woman with preserved reproductive potential;
• Understand the need to use condoms during sexual intercourse with a pregnant woman or a woman with preserved reproductive potential not using reliable contraception, during treatment and for 7 days after interruption and/or completion of treatment. Even after vasectomy, a man must use a condom during sexual intercourse with a pregnant woman, because even in the absence of sperm, his semen may contain Pomalidomide;
• Understand that if his partner becomes pregnant during his treatment with pomalidomide or within 7 days after discontinuation of pomalidomide therapy, he must immediately inform his treating physician, and his partner is advised to consult a teratologist for examination and counseling.

Contraception rules

Women with preserved reproductive potential must use one highly effective method of contraception for 4 weeks before starting treatment, during treatment, and for 4 weeks after discontinuation of pomalidomide treatment, even in case of treatment interruption. The exception is patients who have been completely abstinent from sexual relations for a long time, confirmed monthly. If an effective method of contraception has not been selected for the patient, she should be referred to a gynecologist for selection and initiation of a contraceptive method.

Examples of highly effective contraceptive methods include:

• Subcutaneous hormonal implants;
• Levonorgestrel-releasing intrauterine systems;
• Depot preparations of medroxyprogesterone acetate;
• Tubal ligation;
• Sexual relations with a partner who has undergone vasectomy; vasectomy must be confirmed by two negative semen analyses;
• Progesterone-containing pills that inhibit ovulation (e.g., desogestrel).

The use 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 a patient uses combined oral contraceptives, she should be switched to one of the effective contraceptive methods listed above. The increased risk of thromboembolism persists for 4-6 weeks after discontinuation of combined contraceptive use. The effectiveness of hormonal contraceptives may be reduced with concomitant administration of dexamethasone.

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

The use of copper-releasing intrauterine systems is generally not recommended due to the high risk of infectious complications at the time of insertion and increased blood loss during menstruation, which may exacerbate neutropenia or thrombocytopenia.

Pregnancy tests

According to accepted practice, pregnancy tests with a minimum sensitivity of 25 mIU/ml should be performed under medical supervision for all women with preserved reproductive potential, including those who are completely and long-term abstinent from sexual relations.

According to recommendations, the pregnancy test, prescription, and dispensing of the drug should be performed on the same day. A woman with preserved reproductive potential should receive Pomalidomide no later than 7 days after the treatment is prescribed.

Before starting 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 treating physician on the day pomalidomide is prescribed or within 3 days before the visit to the treating physician. The test must confirm that the patient is not pregnant at the time of starting pomalidomide.

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 treating physician.

Men

Pomalidomide is detected in human semen during treatment with this drug. As a precaution and taking into account those patient groups in which drug elimination time may be prolonged, such as patients with renal impairment, all men taking Pomalidomide, including those who have undergone vasectomy, must use condoms throughout the course of treatment, during treatment interruptions, and for 7 days after discontinuation of treatment if their partner is a pregnant woman or a woman with preserved reproductive potential not using contraception.

Patients are not permitted to donate blood, semen, or sperm during the entire treatment period (including treatment interruptions) and for 7 days after completion of pomalidomide administration.

Additional precautions

Patients should not transfer the drug to other persons. At the end of treatment, unused drug is recommended to be returned to the medical institution. Patients are not permitted to donate blood, semen, or sperm during the entire treatment period (including treatment interruptions) and for 7 days after completion of pomalidomide administration.

Educational materials, prescribing and dispensing restrictions

To help patients avoid fetal exposure to pomalidomide, the marketing authorization holder will provide healthcare professionals with educational materials on precautions regarding the potential teratogenicity of pomalidomide, contraceptive methods prior to initiation of therapy, and guidance on conducting necessary pregnancy tests. The physician must inform the patient about the potential teratogenic risk of pomalidomide and the strict pregnancy prevention measures in accordance with the Pregnancy Prevention Program, and provide the patient with an educational brochure, patient card, and/or equivalent tool in accordance with the national patient card system. The controlled distribution system includes the use of patient cards and/or an equivalent tool to control prescriptions and/or dispensing of the drug and to collect detailed data related to prescriptions in order to carefully monitor cases of use for indications not registered in the Russian Federation.

It is recommended that the pregnancy test, prescription, and dispensing of the drug be performed on the same day. Dispensing of pomalidomide to women with preserved reproductive potential should occur no later than 7 days after therapy is prescribed and a negative pregnancy test result is obtained under medical supervision.

Dispensing of the drug to women with preserved reproductive potential should be for no more than 4 weeks of treatment, and for all other patient categories – for no more than 12 weeks.

Hematological complications

In patients with relapsed/refractory multiple myeloma, neutropenia is the most frequently reported Grade 3 or 4 adverse event; followed in frequency by anemia and thrombocytopenia. Patients should be monitored for hematological adverse reactions, especially neutropenia. Patients should be informed of the need to promptly report fever. Physicians should monitor patients for signs and symptoms of bleeding, including epistaxis, especially during concomitant therapy with medications that increase the risk of hemorrhage. A complete blood count should be performed prior to treatment initiation, then weekly for the first 8 weeks, and then monthly thereafter. Dose modification of pomalidomide (see “Dosage and Administration”), use of blood product support, and/or growth factors may be required.

Thromboembolic complications

Venous thromboembolic events (primarily deep vein thrombosis and pulmonary embolism) and arterial thrombotic disorders have been reported in patients treated with pomalidomide in combination with dexamethasone. Patients with known risk factors for thromboembolism, including prior thrombosis, should be carefully monitored. All possible measures should be taken to minimize risk factors (e.g., smoking, hypertension, hyperlipidemia). Patients and physicians should be vigilant for signs and symptoms of thromboembolism. Patients should be warned to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Anticoagulant prophylaxis (such as acetylsalicylic acid, warfarin, heparin, or clopidogrel) is recommended in the absence of contraindications, especially in patients with additional thrombotic risk factors.

The decision to take prophylactic measures should be made after a careful assessment of individual patient risk factors. In clinical trials, patients received prophylactic acetylsalicylic acid or other antithrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic complications, including thromboembolism. Consequently, erythropoietic drugs, as well as other agents that may increase the risk of thromboembolism, should be used with caution.

Peripheral neuropathy

Patients with peripheral neuropathy of Grade 2 or higher severity were not included in the pomalidomide clinical trials. Caution should be exercised when considering treatment with pomalidomide in such patients.

Severe cardiac impairment

Patients with severe cardiac impairment (congestive heart failure [NYHA Class III or IV]; myocardial infarction within 12 months prior to study initiation; unstable or poorly controlled angina) were not included in the pomalidomide clinical trials. Caution should be exercised when considering treatment with pomalidomide in such patients.

Tumor lysis syndrome

The risk of tumor lysis syndrome is highest in patients with a high tumor burden at the start of treatment. These patients should be closely monitored with appropriate prophylactic measures.

Second primary malignancies

Second primary malignancies have been reported in patients treated with Pomalidomide. The physician should carefully examine patients before and during treatment using standard cancer screening for detection of second primary malignancies and institute appropriate treatment if necessary.

Allergic reactions

Patients with a history of serious allergic reactions to thalidomide or lenalidomide were not included in the pomalidomide clinical trials. Such patients may have an increased risk of hypersensitivity reactions and should not receive Pomalidomide.

Dizziness and confusion

Dizziness and confusion have been reported with pomalidomide. Patients should avoid situations where dizziness or confusion could be a problem, and should not take other medications that may cause similar effects without prior medical consultation.

Disposal and handling precautions

Capsules should not be opened or broken. If pomalidomide powder contacts the skin, it should be washed immediately with soap and water. If pomalidomide comes into contact with mucous membranes, they should be rinsed thoroughly with water. Unused medicinal product and materials contaminated with it should be disposed of in accordance with established requirements. At the end of treatment, it is recommended to return any unused drug to the medical facility.

Effect on ability to drive and operate machinery

Imnovid^® has minor to moderate influence on the ability to drive and use machines. Some adverse effects of Imnovid^®, such as fatigue, somnolence, confusion, and dizziness, may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions. If such adverse events occur, patients should refrain from these activities.

Overdose

Imnovid^® in single doses up to 50 mg in healthy volunteers and in doses of 10 mg with repeated daily administration in patients with multiple myeloma did not cause serious adverse events due to overdose. There are no specific recommendations for the treatment of pomalidomide overdose. It is not known whether Pomalidomide and its metabolites are dialyzable. In case of overdose, supportive therapy is recommended.

Drug Interactions

Effect of Imnovid^® on other medicinal products

Pomalidomide is not considered to cause clinically significant pharmacokinetic drug interactions associated with inhibition or induction of cytochrome P450 isoenzymes, or activation or inhibition of transport systems, when co-administered with 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 “Adverse Reactions” and “Special Instructions”).

Effect of other medicinal products on Imnovid^®

Pomalidomide is partially metabolized by CYP1A2 and CYP3A4/5 isoenzymes and is a substrate for P-glycoprotein. Concomitant administration of pomalidomide with the potent CYP3A4/5 and Pgp inhibitor ketoconazole or with the potent CYP3A4/5 inducer carbamazepine did not clinically significantly affect the effect of pomalidomide. Concomitant administration of the potent CYP1A2 inhibitor fluvoxamine in the presence of ketoconazole increased pomalidomide exposure by 104% with a 90% confidence interval [88%-122%] compared to the Pomalidomide-ketoconazole combination. If a potent CYP1A2 inhibitor (e.g., ciprofloxacin, enoxacin, and fluvoxamine) is used concomitantly with pomalidomide, such patients should be carefully monitored for adverse events.

Dexamethasone

Combination therapy with pomalidomide in repeated doses up to 4 mg and dexamethasone in doses of 20-40 mg (a weak or moderate inducer of some CYP enzymes, including CYP3A) in patients with multiple myeloma did not alter the pharmacokinetics of pomalidomide compared to pomalidomide monotherapy.

The effect of dexamethasone on warfarin has not been studied, so careful monitoring of warfarin concentration is recommended during combination therapy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.