Ampomay

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMPOMY (AMPOMY)

Composition:

Active substance: pomalidomide;

1 capsule contains 1 mg or 2 mg or 3 mg or 4 mg of pomalidomide;

Excipients: mannite (E 421), pregelatinized starch, microcrystalline cellulose, sodium stearyl fumarate, hard gelatin capsule (gelatin, titanium dioxide (E 171), black ink (SW-9008) (for 1 mg, 4 mg), red iron oxide (E 172) (for 3 mg), yellow iron oxide (E 172), black iron oxide (E 172) (for 2 mg)).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

1 mg: hard gelatin capsules, size "5", with white opaque cap and white opaque body, marked with "H" on the cap and "P1" on the body, filled with powder ranging from light yellow to almost yellow;

2 mg: hard gelatin capsules, size "4", with white opaque cap and brown opaque body, marked with "H" on the cap and "P2" on the body, filled with powder ranging from light yellow to almost yellow;

3 mg: hard gelatin capsules, size "3", with white opaque cap and pink opaque body, marked with "H" on the cap and "P3" on the body, filled with powder ranging from light yellow to almost yellow;

4 mg: hard gelatin capsules, size "2", with white opaque cap and white opaque body, marked with "H" on the cap and "P4" on the body, filled with powder ranging from light yellow to almost yellow.

Pharmacotherapeutic group. Immunosuppressants. Other immunosuppressants.

ATC code L04AX06.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Pomalidomide exerts direct anti-myeloma and anti-tumor as well as immunomodulatory effects, and inhibits stromal cell support essential for the growth of multiple myeloma cells. Specifically, pomalidomide inhibits proliferation and induces apoptosis in hematopoietic tumor cells. Furthermore, pomalidomide inhibits proliferation of lenalidomide-resistant multiple myeloma cells and acts synergistically with dexamethasone in both lenalidomide-sensitive and -resistant cells to induce tumor cell apoptosis. Pomalidomide enhances T-cell and natural killer (NK) cell-mediated cellular immunity and inhibits the production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking endothelial cell migration and adhesion.

Pomalidomide binds directly to cereblon (CRBN), a component of the E3 ubiquitin ligase complex that includes DNA damage-binding protein 1 (DDB1), Cullin 4 (CUL4), and Roc1 (regulator of cullin 1), and may inhibit auto-ubiquitination of CRBN within the complex. E3 ubiquitin ligases are responsible for polyubiquitination of various substrate proteins, which may partially explain the pleiotropic cellular effects observed during pomalidomide treatment.

In the presence of pomalidomide in vitro, the substrate proteins Aiolos and Ikaros undergo ubiquitination and subsequent degradation, resulting in direct cytotoxic and immunomodulatory effects. In vivo, pomalidomide therapy led to reduced levels of Aiolos in patients with relapsed, lenalidomide-resistant multiple myeloma.

Pharmacokinetics

Absorption

Pomalidomide is absorbed with maximum plasma concentration (C_max) occurring between 2 and 3 hours; at least 73% of the drug is absorbed after a single oral dose. The area under the plasma concentration-time curve (AUC) of pomalidomide increases approximately linearly and proportionally with dose. Following multiple dosing, pomalidomide has an accumulation ratio of 27% to 31% based on AUC.

Concomitant administration with a high-fat, high-calorie meal slows the rate of absorption, reducing the mean C_max in plasma by approximately 27%, but has minimal effect on overall absorption, with only an 8% reduction in mean systemic exposure. Therefore, pomalidomide may be administered regardless of food intake.

Distribution

Pomalidomide has a mean apparent volume of distribution (V_d/F) ranging between 62 and 138 L at steady state. Pomalidomide distributes into semen of healthy volunteers at concentrations approximately 67% of plasma levels 4 hours after dose administration (approximate T_max) following a single 2 mg dose on day 4. In vitro, the binding of pomalidomide enantiomers to human plasma proteins ranges from 12% to 44% and is independent of concentration.

Metabolism

Pomalidomide is the primary circulating component (approximately 70% of plasma radioactivity) in vivo in healthy volunteers receiving a single oral dose of [14C]-pomalidomide (2 mg). No metabolites in plasma were detected at concentrations >10% of the parent compound or total radioactivity.

The major metabolic pathways of excreted radioactivity involve hydroxylation followed by glucuronidation or hydrolysis. In vitro, CYP1A2 and CYP3A4 were identified as the primary enzymes involved in CYP-mediated hydroxylation of pomalidomide, with minor contributions from CYP2C19 and CYP2D6. Pomalidomide is also a substrate of P-glycoprotein (P-gp) in vitro. Concomitant administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole or the strong CYP3A4/5 inducer carbamazepine did not clinically significantly affect pomalidomide’s pharmacokinetics. However, co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole increased the mean exposure to pomalidomide by 107% (90% CI: 91% to 124%) compared to pomalidomide plus ketoconazole alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolism, co-administration of fluvoxamine and pomalidomide increased the mean plasma concentration of pomalidomide by 125% (90% CI: 98% to 157%) compared to pomalidomide alone. When concomitant use of strong CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, and fluvoxamine) with pomalidomide is necessary, a 50% dose reduction of pomalidomide is recommended. Pomalidomide use in patients who smoke has a clinically significant effect on plasma concentrations compared to non-smokers, as tobacco is known to induce CYP1A2 isoenzymes.

Based on in vitro data, pomalidomide is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes and does not inhibit any of the drug transporters studied. Clinically significant drug interactions are not expected when pomalidomide is co-administered with substrates of this metabolic pathway.

Elimination

The mean elimination half-life of pomalidomide is approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. The mean total clearance of pomalidomide (CL/F) is approximately 7–10 L/hour.

After a single oral dose of [14C]-pomalidomide (2 mg) to healthy volunteers, approximately 73% and 15% of the dose is excreted in urine and feces, respectively. Approximately 2% and 8% of the radiolabeled dose is excreted as unchanged pomalidomide in urine and feces, respectively.

Prior to excretion, pomalidomide undergoes extensive metabolism, with metabolites primarily excreted in urine. Three major urinary metabolites (formed via hydrolysis or hydroxylation followed by glucuronidation) account for approximately 23%, 17%, and 12% of the dose, respectively.

Metabolites dependent on CYP enzymes account for approximately 43% of the total excreted dose, while CYP-independent hydrolyzed metabolites account for 25%, and excretion of unchanged pomalidomide accounts for 10% (2% in urine and 8% in feces).

Pharmacokinetics (PK) in Specific Populations

Based on population PK modeling using a two-compartment model, healthy subjects and patients with multiple myeloma had comparable apparent clearance (CL/F) and apparent central volume of distribution (V₂/F). In peripheral tissues, pomalidomide was predominantly taken up by tumors, with apparent peripheral distribution clearance (Q/F) and apparent peripheral volume of distribution (V₃/F) 3.7 and 8 times higher, respectively, than in healthy subjects.

Pediatric Population

After a single oral dose of pomalidomide in children and young adults with recurrent or progressive primary brain tumors, the median T_max was 2–4 hours post-dose, with geometric mean C_max (CV%) values of 74.8 (59.4%), 79.2 (51.7%), and 104 (18.3%) ng/mL at doses of 1.9, 2.6, and 3.4 mg/m², respectively. AUC_0–24 and AUC_0–∞ followed similar trends, with overall exposure approximately 700–800 hour·ng/mL at the two lower doses and approximately 1200 hour·ng/mL at the high dose. Estimated elimination half-life ranged from approximately 5 to 7 hours.

No clear trends related to age stratification or steroid use were observed, with minimal topological difference (MTD).

Overall, data indicate that AUC increased nearly proportionally with increasing pomalidomide dose, whereas increases in C_max were generally less than proportional.

Pharmacokinetics of orally administered pomalidomide at doses ranging from 1.9 to 3.4 mg/m²/day were evaluated in 70 patients aged 4 to 20 years in a pooled analysis of phase 1 and phase 2 studies in recurrent or progressive pediatric brain tumors. Pomalidomide concentration-time profiles were adequately described by a one-compartment PK model with first-order absorption and elimination. Pomalidomide exhibited linear, time-invariant pharmacokinetics with moderate variability. Typical values for CL/F, V_c/F, K_a, and absorption lag time were 3.94 L/h, 43.0 L, 1.45 h⁻¹, and 0.454 h, respectively. The terminal elimination half-life of pomalidomide was 7.33 hours. Except for body surface area (BSA), none of the tested covariates—including age and sex—significantly influenced pomalidomide PK. Although BSA was identified as a statistically significant covariate for CL/F and V_c/F, its impact on exposure parameters was not considered clinically significant.

Overall, there is no substantial difference in PK parameters of pomalidomide between pediatric and adult populations.

Elderly Patients

Based on pharmacokinetic analyses in healthy volunteers and patients with multiple myeloma, age (19–83 years) had no significant effect on pomalidomide clearance. Dose adjustment was not required in elderly patients (>65 years) in clinical studies.

Renal Impairment

Population pharmacokinetic analysis showed that pharmacokinetic parameters of pomalidomide were not significantly affected in patients with impaired renal function (defined by creatinine clearance or estimated glomerular filtration rate [eGFR]) compared to patients with normal renal function (CrCl ≥ 60 mL/min). Mean normalized AUC exposure to pomalidomide was 98.2% (90% CI: 77.4% to 120.6%) in patients with moderate renal impairment (eGFR ≥30 to ≤45 mL/min/1.73 m²) compared to those with normal renal function. Mean normalized AUC exposure was 100.2% (90% CI: 79.7% to 127.0%) in patients with severe renal impairment not requiring dialysis (CrCl < 30 or eGFR < 30 mL/min/1.73 m²) compared to patients with normal renal function. Mean normalized AUC exposure increased by 35.8% (90% CI: 7.5% to 70.0%) in patients with severe renal impairment requiring dialysis (CrCl < 30 mL/min requiring dialysis) compared to patients with normal renal function. The mean changes in pomalidomide exposure in each of these renal impairment groups were not of sufficient magnitude to require dose adjustment.

Hepatic Impairment

Pharmacokinetic parameters were moderately altered in patients with hepatic impairment (defined by Child-Pugh criteria) compared to healthy subjects. Mean pomalidomide exposure increased by 51% (90% CI: 9% to 110%) in patients with mild hepatic impairment compared to healthy subjects. Mean exposure increased by 58% (90% CI: 13% to 119%) in patients with moderate hepatic impairment compared to healthy subjects. Mean exposure increased by 72% (90% CI: 24% to 138%) in patients with severe hepatic impairment compared to healthy subjects. The mean increases in pomalidomide exposure in each of these groups were not of sufficient magnitude to require adjustments in dosing schedule or dose.

Clinical characteristics.

Indications.

Pomalidomide in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy including lenalidomide.

Pomalidomide in combination with dexamethasone is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on the last therapy.

Contraindications.

• Pregnancy.
• Women of childbearing potential who do not meet all the requirements of the Pregnancy Prevention Program (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
• Male patients unable to comply with required contraceptive measures (see section "Special precautions").
• Hypersensitivity to the active substances or to any of the excipients of the medicinal product (see section "Composition").

Special safety precautions.

Capsules must not be opened or crushed. If pomalidomide powder comes into contact with the skin, the skin must be washed immediately and thoroughly with soap and water. If pomalidomide comes into contact with mucous membranes, they should be thoroughly rinsed with water.

Unused medicinal product or waste material must be returned for safe disposal according to local requirements.

Interaction with other medicinal products and other forms of interaction.

Effect of pomalidomide on other medicinal products

Pomalidomide is not expected to cause clinically significant pharmacokinetic interactions with other medicinal products via inhibition or induction of cytochrome P450 or inhibition of transporters when co-administered with substrates of these enzymes or transporters. The potential for such drug interactions, including the potential effect of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been clinically evaluated.

Effect of other medicinal products on pomalidomide

Pomalidomide is partially metabolized by CYP1A2 and CYP3A4/5. Pomalidomide is also a substrate of P-glycoprotein (P-gp). Concomitant administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole or the strong CYP3A4/5 inducer carbamazepine did not clinically affect pomalidomide exposure. Concomitant administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole increased the mean exposure to pomalidomide by 107% with 90% CI [from 91% to 124%] compared to pomalidomide and ketoconazole therapy alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolism, fluvoxamine and pomalidomide were co-administered, resulting in an increase in the mean pomalidomide blood concentration by 125% with 90% CI [from 98% to 157%], compared to pomalidomide alone. If concomitant use of strong CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, and fluvoxamine) with pomalidomide is necessary, the pomalidomide dose should be reduced by 50%.

Dexamethasone

Repeated co-administration of pomalidomide doses up to 4 mg with dexamethasone doses of 20 to 40 mg (considered a weak or moderate inducer of several CYP enzymes, including CYP3A) in patients with multiple myeloma did not affect the pharmacokinetics of pomalidomide compared to pomalidomide alone.

The effect of dexamethasone on warfarin is unknown. Monitoring of warfarin blood levels is recommended during treatment.

For information on other medicinal products used in combination with pomalidomide capsules, refer to the corresponding sections of the instructions.

Special precautions for use.

Teratogenicity

Pomalidomide must not be used during pregnancy as it has teratogenic effects. Pomalidomide is structurally related to thalidomide. Thalidomide is a well-known medicinal product with human teratogenic effects, causing severe congenital malformations. Pomalidomide has been shown to be teratogenic when administered during the period of major organogenesis in both rats and rabbits.

The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient lacks reproductive potential.

Criteria for women without reproductive potential

Women or female partners of male patients are considered to lack reproductive potential if they meet at least one of the following criteria:

• Age ≥ 50 years and natural amenorrhea for ≥ 1 year (amenorrhea due to cancer therapy or during breastfeeding does not exclude reproductive age).
• Premature ovarian failure confirmed by a specialist gynaecologist.
• Previous bilateral salpingo-oophorectomy or hysterectomy.
• XY genotype, Turner syndrome, uterine agenesis.

Counselling

Pomalidomide is contraindicated in women with reproductive potential unless all of the following conditions are met:

• The woman understands the expected teratogenic risk to the unborn child.
• The woman understands the need for effective contraception at least 4 weeks before starting treatment, throughout the entire treatment period, and for at least 4 weeks after treatment ends.
• Even if a woman of reproductive age has amenorrhea, all recommendations regarding effective contraception must be followed.
• The woman must be capable of using effective contraceptive methods.
• The woman has been informed and understands the possible consequences of pregnancy and the need for prompt consultation in case of pregnancy risk.
• The woman understands the need to start treatment as soon as possible after a negative pregnancy test and prescription of pomalidomide.
• The woman understands the necessity and agrees to undergo pregnancy testing at least every 4 weeks, except in cases where tubal sterilization has been confirmed.
• The woman acknowledges that she understands the risks and the need for preventive measures associated with the use of pomalidomide.

The prescribing physician must ensure that women of reproductive age meet the following conditions:

• The patient complies with the requirements of the Pregnancy Prevention Programme, including confirmation that she has adequate understanding of the necessity of these measures.
• The patient acknowledges the above conditions.

For male patients receiving pomalidomide, pharmacokinetic data have shown that the drug is present in semen during treatment. As a precautionary measure, and considering special populations with potentially prolonged elimination periods due to hepatic impairment, all male patients taking pomalidomide must meet the following conditions:

• The man understands the expected teratogenic risk from sexual activity for a pregnant woman or a woman of reproductive potential.
• The man understands the need to use a condom during sexual activity with a pregnant woman or a woman of reproductive age who is not using effective contraception, throughout the treatment period, during treatment interruptions, and for 7 days after treatment has been interrupted and/or discontinued. This also applies to men who have undergone vasectomy, who must use a condom if engaging in sexual contact with a pregnant woman or a woman of reproductive potential, as semen may still contain pomalidomide even in the absence of spermatozoa.
• He understands that if his partner becomes pregnant while he is taking pomalidomide or within 7 days after he stops taking pomalidomide, he must immediately inform his treating physician, and it is also recommended to refer the partner to a specialist or teratology expert for risk assessment and advice.

Contraception

Women with reproductive potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and for at least 4 weeks after therapy with pomalidomide, even during dose interruptions, unless the patient commits to complete and continuous abstinence monthly. If effective contraception is not used, the patient should be referred to an appropriate qualified healthcare provider for consultation on contraceptive methods to initiate contraception.

Examples of effective contraceptive methods:

• Implant.
• Levonorgestrel-releasing intrauterine system.
• Medroxyprogesterone acetate depot.
• Tubal sterilization.
• Sexual intercourse only with a partner who has undergone vasectomy; vasectomy must be confirmed by two negative semen analyses.
• Ovulation-inhibiting tablets containing progesterone (i.e., desogestrel).

Due to the increased risk of venous thromboembolism in patients with multiple myeloma receiving pomalidomide and dexamethasone, the use of combined oral contraceptives is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If a patient is currently using combined oral contraception, the patient should switch to one of the effective methods listed above. The risk of venous thromboembolism persists for 4–6 weeks after discontinuation of combined oral contraceptives. The effectiveness of contraceptive steroids may be reduced during concomitant use of the drug with dexamethasone (see section "Interaction with other medicinal products and other forms of interaction").

Implants and levonorgestrel-releasing intrauterine systems increase the risk of infection during insertion and during irregular vaginal bleeding. Prophylactic use of antibiotics should be considered in patients with neutropenia.

Insertion of copper-releasing intrauterine devices is not recommended due to potential risks of infection during insertion and blood loss during menstruation, which may endanger patients with severe neutropenia or pronounced thrombocytopenia.

Pregnancy diagnosis

According to local practice, women with reproductive potential, as defined above, must undergo physician-monitored pregnancy tests with a minimum sensitivity of 25 mIU/mL. This requirement also applies to women with reproductive potential who practice complete and permanent abstinence. Ideally, pregnancy testing, prescription, and dispensing of the medicinal product should occur on the same day. Dispensing of pomalidomide to women of reproductive age must occur within 7 days of prescription.

Before starting treatment

A physician-supervised pregnancy test should be performed during the consultation when pomalidomide is prescribed, or within 3 days prior to the visit, after the patient has used effective contraceptive methods for at least 4 weeks. The test must confirm that the patient is not pregnant before starting pomalidomide therapy.

Monitoring and completion of treatment

A physician-supervised pregnancy test should be repeated at least every 4 weeks, including at least 4 weeks after completion of treatment, except in cases of confirmed sterilization. The pregnancy test should be performed on the day of the physician visit or within 3 days prior to the visit.

Additional safety measures

Patients should be instructed not to give this medicinal product to others and to return unused capsules to their pharmacist at the end of treatment.

Patients receiving pomalidomide must not donate blood, semen, or spermatozoa during treatment (including during dose interruptions) and for 7 days after discontinuation of pomalidomide therapy.

Healthcare professionals and caregivers should wear disposable gloves when handling blisters or capsules. Pregnant women or women who suspect they may be pregnant should not handle blisters or capsules.

Educational materials, prescribing and dispensing restrictions

To help patients avoid the effects of pomalidomide on the fetus, the marketing authorization holder for this medicinal product must provide healthcare professionals with educational materials containing information to reinforce the warning about the expected teratogenic effects of pomalidomide, recommend contraception before starting treatment, and explain the need for pregnancy testing. The physician must inform patients (men and women) about the expected teratogenic risk and strict pregnancy prevention measures as outlined in the Pregnancy Prevention Programme and provide patients with the appropriate patient education brochure, patient card, and/or equivalent document according to the implemented national patient card system. A national controlled dispensing system has been established in cooperation with each national competent authority. The controlled dispensing system includes the use of a patient card and/or equivalent document to monitor prescription and/or dispensing, as well as collection of detailed prescription data for careful monitoring of misuse within the national territory. Ideally, pregnancy testing, prescription, and receipt of the drug should occur on the same day. Dispensing of pomalidomide to women of reproductive age must occur no later than 7 days after therapy prescription and a negative pregnancy test performed in the presence of a physician. Dispensing of the medicinal product to women with preserved fertility should not exceed 4 weeks of treatment; for all other patient categories, dispensing should not exceed 12 weeks.

Hematological complications

The most commonly observed hematological adverse reactions of grade 3 or 4 in patients with relapsed/refractory multiple myeloma are neutropenia, followed by anemia and thrombocytopenia. Patients should be monitored for hematological adverse reactions, particularly neutropenia. Patients should also be warned to report episodes of fever promptly. Physicians should monitor patients for bleeding, including nosebleeds, especially when concomitant medicinal products known to increase bleeding risk are used (see section "Adverse reactions"). Complete blood counts should be performed at the beginning of therapy, weekly during the first 8 weeks of therapy, and monthly thereafter. Dose adjustments may be required (see section "Method of administration and dosage"). Patients may require supportive therapy with blood products and/or growth factors.

Thromboembolic complications

Venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) may occur in patients receiving pomalidomide in combination with bortezomib and dexamethasone or in combination with dexamethasone. Patients with known risk factors for thromboembolism, including previous thrombosis, should be closely monitored. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia). Patients and physicians should be vigilant for signs and symptoms of thromboembolism. Patients should seek medical help if symptoms such as dyspnea, chest pain, or swelling of an arm or leg occur. Anticoagulant therapy (if not contraindicated) is recommended (e.g., acetylsalicylic acid, warfarin, heparin, or clopidogrel), especially in patients with additional risk factors for thrombotic complications. The decision on preventive measures should be made after careful assessment of individual patient risk factors. In clinical trials, patients received prophylactic acetylsalicylic acid or alternative antithrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic complications, including thromboembolism. Therefore, erythropoietic agents and other agents that may increase the risk of thromboembolic complications should be used with caution.

Thyroid disorders

Cases of hypothyroidism have been reported. Comorbid conditions affecting thyroid function should be assessed before starting treatment. Monitoring of thyroid function is recommended before and during pomalidomide therapy.

Peripheral neuropathy

Patients with pre-existing peripheral neuropathy ≥ grade 2 were excluded from pomalidomide clinical trials. Caution should be exercised when considering pomalidomide therapy in such patients.

Severe cardiac dysfunction

Patients with significant cardiac dysfunction (NYHA class III or IV heart failure; myocardial infarction within 12 months prior to study start; unstable or poorly controlled angina) were excluded from pomalidomide clinical trials. Adverse cardiac reactions, including congestive heart failure, pulmonary edema, and atrial fibrillation (see section "Adverse reactions"), have been reported, primarily in patients with pre-existing cardiac disease or cardiac risk factors. Appropriate caution should be exercised when prescribing pomalidomide to such patients, including periodic monitoring for signs or symptoms of cardiovascular disease.

Tumour lysis syndrome (TLS)

Patients at highest risk of tumour lysis syndrome are those with high tumour burden before starting treatment. Close monitoring and appropriate preventive measures should be taken in such cases.

Secondary primary malignancies (SPM)

Other primary malignancies, such as non-melanoma skin cancer, have been reported in patients receiving pomalidomide (see section "Adverse reactions"). Physicians should carefully monitor patients before and during treatment using standard oncological screening for other primary malignancies and initiate treatment as indicated.

Allergic reactions and severe skin reactions

Angioedema and severe dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported after pomalidomide use (see section "Adverse reactions"). Patients should be informed by their physician about the signs and symptoms of these reactions and instructed to seek immediate medical attention if any symptoms occur. Pomalidomide use must be discontinued in cases of exfoliative or bullous rash or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS. Reinitiation of therapy after resolution of the reaction is not recommended. Patients with a history of serious allergic reactions to thalidomide or lenalidomide were excluded from clinical trials. Such patients are at high risk of hypersensitivity reactions and must not take pomalidomide. Discontinuation of the drug should be considered in cases of grade 2–3 rash. Pomalidomide therapy must be permanently discontinued in cases of angioedema.

Dizziness and confusion

Cases of dizziness and confusion have been reported after pomalidomide use. Patients should avoid situations where dizziness or confusion could be problematic and should not use other medicinal products that may cause dizziness or confusion without physician consultation.

Interstitial lung disease (ILD)

Cases of ILD and related events, including pneumonia, have been reported after pomalidomide use. Patients with acute onset or unexplained worsening of pulmonary symptoms should undergo careful evaluation to exclude ILD. Pomalidomide therapy should be interrupted during investigation of these symptoms, and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide therapy may be resumed only after careful benefit-risk assessment.

Hepatic disorders

Marked increases in alanine aminotransferase (ALT) and bilirubin levels have been observed in patients receiving pomalidomide (see section "Adverse reactions"). Cases of hepatitis requiring discontinuation of pomalidomide therapy have also been reported. Continuous monitoring of clinical liver function parameters is recommended during the first 6 months of treatment and after discontinuation of therapy.

Infections

Reactivation of hepatitis B has been rarely reported after pomalidomide therapy in combination with dexamethasone in patients previously infected with hepatitis B virus (HBV). Some of these cases led to acute liver failure, requiring discontinuation of pomalidomide therapy. HBV status should be determined before starting pomalidomide therapy. Patients with positive HIV infection test are advised to consult a physician experienced in hepatitis B management. Caution should be exercised when treating patients previously infected with HBV, including those with positive anti-HBc but negative HBsAg, with pomalidomide in combination with dexamethasone. These patients should be monitored for signs and symptoms of active HBV throughout therapy.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy, including fatal cases, have been reported with pomalidomide use. PML cases have been reported from several months to several years after starting pomalidomide therapy. Cases were generally reported in patients who were concurrently receiving dexamethasone or had previously received other immunosuppressive chemotherapy. Physicians should regularly monitor patients and consider PML in the differential diagnosis of patients with new or progressive neurological, cognitive, or behavioral symptoms. Patients should also be advised to inform their partner or caregiver about their treatment, as they may notice symptoms the patient is unaware of.

PML evaluation should be based on neurological examination, brain MRI, cerebrospinal fluid analysis for JC virus (JCV) DNA by PCR, or brain biopsy with JCV testing. A negative JCV PCR does not exclude PML. If an alternative diagnosis cannot be established, further monitoring and evaluation may be necessary.

If PML is suspected, further use should be suspended until PML is ruled out. If PML is confirmed, pomalidomide use must be permanently discontinued.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Women of reproductive age/contraception in men and women

Women of reproductive age must use effective contraceptive methods. If a woman becomes pregnant during pomalidomide therapy, treatment must be discontinued, and the patient should be referred to a physician specialized or experienced in teratology for fetal risk assessment and advice. If a woman becomes pregnant by a man taking pomalidomide, it is recommended to refer the patient to a physician specialized or experienced in teratology for fetal risk assessment and advice. Pomalidomide penetrates into human semen. As a precautionary measure, all male patients taking pomalidomide must use condoms throughout the entire treatment period, during dose interruptions, and for 7 days after discontinuation of therapy if the partner is pregnant or of reproductive age and not using other forms of contraception (see sections "Contraindications", "Special precautions for use").

Pregnancy

Teratogenic effects of pomalidomide in humans are expected. Pomalidomide is contraindicated during pregnancy and in women of reproductive potential unless all conditions for pregnancy prevention are met (see sections "Contraindications", "Special precautions for use").

Breastfeeding

There are no data confirming the passage of the medicinal product into human breast milk. Pomalidomide was detected in the milk of lactating rats after administration. Due to the potential risk of adverse reactions in breastfed infants, a decision must be made whether to discontinue breastfeeding or pomalidomide therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Pomalidomide has been shown to have negative effects on fertility and teratogenic effects in animals. Pomalidomide crossed the placenta and was detected in fetal blood after administration to pregnant rabbits.

Ability to affect reaction speed when driving or operating machinery.

Pomalidomide has a minor or moderate influence on the ability to drive or operate machinery. Cases of fatigue, somnolence, confusion, and dizziness have been reported after pomalidomide use. If these adverse reactions occur during therapy, patients should be instructed not to drive, operate machinery, or perform hazardous tasks during treatment.

Dosage and Administration

Treatment should be initiated and supervised by physicians experienced in the management of multiple myeloma.

A specific dose should be continued or modified based on clinical and laboratory findings (see section "Special Warnings and Precautions for Use").

• Lenalidomide in combination with bortezomib and dexamethasone

The recommended starting dose of lenalidomide is 4 mg orally once daily on days 1–14 of a 21-day cycle.

Lenalidomide should be administered in combination with bortezomib and dexamethasone (see Table 1). The starting dose of bortezomib is 1.3 mg/m² administered intravenously or subcutaneously once daily on the days specified in Table 1. The recommended dose of dexamethasone is 20 mg orally once daily on the days specified in Table 1.

Treatment with lenalidomide in combination with bortezomib and dexamethasone should continue until disease progression or until unacceptable toxicity occurs.

Recommended dosing regimen for Ampray

in combination with bortezomib and dexamethasone

Table 1

Cycles 1-8	Day (of 21-day cycle)
	1		2		3		4		5		6		7		8		9		10		11		12		13		14		15		16		17		18		19		20		21
Pomalidomide (4 mg)
Bortezomib (1.3 mg/m²)
Dexamethasone (20 mg)*
From cycle 9 onwards	Day (of 21-day cycle)
	1	2		3		4		5		6		7		8		9		10		11		12		13		14		15		16		17		18		19		20		21
Pomalidomide (4 mg)
Bortezomib (1.3 mg/m²)
Dexamethasone (20 mg)*

*For patients > 75 years of age (see Special patient populations).

Dose modification or discontinuation of pomalidomide

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

Guidelines for interruption or reduction of dose to manage adverse reactions related to pomalidomide are provided in Table 2, and dose levels are defined in Table 3.

Dose modification guidelines for pomalidomide∞

Table 2

Toxicity	Dose modification
Neutropenia* ANC** < 0.5 × 109/L or febrile neutropenia (fever ≥ 38.5 °C and ANC** < 1 × 109/L)	Interrupt pomalidomide treatment until the end of the cycle. Perform weekly CBC***.
ANC** returns to ≥ 1 × 109/L	Resume pomalidomide at a dose level one level lower than the previous dose.
For each subsequent decrease < 0.5 × 109/L	Interrupt pomalidomide treatment.
ANC** returns to ≥ 1 × 109/L	Resume pomalidomide at a dose level one level lower than the previous dose.
Thrombocytopenia Platelet count < 25 × 109/L	Interrupt pomalidomide treatment until the end of the cycle. Perform weekly complete blood count (CBC)***.
ANC** returns to ≥ 50 × 109/L	Resume pomalidomide at a dose level one level lower than the previous dose.
For each subsequent decrease < 25 × 109/L	Interrupt pomalidomide treatment.
ANC** returns to ≥ 50 × 109/L	Resume pomalidomide at a dose level one level lower than the previous dose.
Rash Grade 2–3 rash	Consider dose modification or discontinuation of pomalidomide.
Grade 4 rash or blistering (including angioedema, exfoliative or bullous rash, or if Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) is suspected)	Permanently discontinue treatment.
Other Other pomalidomide-related adverse reactions ≥ Grade 3	Interrupt pomalidomide treatment until the end of the cycle. In the next cycle, resume pomalidomide at a dose one level lower than the previous dose (adverse reactions must be resolved or improved to ≤ Grade 2 before resuming therapy).

∞ Dose modification guidelines in this table apply to pomalidomide in combination with bortezomib and dexamethasone, and to pomalidomide in combination with dexamethasone.

*In the case of neutropenia, the physician should consider the use of growth factors.

**ANC – absolute neutrophil count.

***CBC – complete blood count.

Pomalidomide dose reduction∞

Table 3

Dose level	Pomalidomide oral dose
Initial dose	4 mg
Dose level-1	3 mg
Dose level-2	2 mg
Dose level-3	1 mg

∞ Dose modification instructions in this table apply to pomalidomide in combination with bortezomib and dexamethasone, and to pomalidomide in combination with dexamethasone.

If adverse reactions occur after dose reduction to 1 mg, the drug should be discontinued.

Strong CYP1A2 inhibitors

If strong CYP1A2 inhibitors such as ciprofloxacin, enoxacin, and fluvoxamine are used concomitantly with pomalidomide, the pomalidomide dose should be reduced by 50% (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

Dose adjustment or discontinuation of bortezomib

For instructions on temporary interruption or dose reduction of bortezomib, physicians should refer to the appropriate summary of product characteristics for the medicinal product containing bortezomib.

Dose adjustment or discontinuation of dexamethasone

Instructions for temporary interruption or dose reduction of dexamethasone are provided in Tables 4 and 5 below. However, decisions regarding temporary interruption or resumption of dosing should be made at the physician's discretion, in accordance with the relevant summary of product characteristics for the medicinal product.

Dexamethasone dose modification instructions

Table 4

Toxicity	Dose modification
Dyspepsia Grade 1–2	Maintain dose and treat with H2-histamine receptor blockers or analogs. Reduce dose by one level if symptoms persist.
Dyspepsia ≥ Grade 3	Temporarily interrupt treatment with the medicinal product until symptoms are controlled. Add H2-histamine receptor blockers or analogs to therapy and resume treatment at a dose one level lower than the previous dose.
Edema > Grade 3	If necessary, add diuretics to therapy and reduce the dose of the medicinal product by one level from the previous dose.
Disorientation and mood changes ≥ Grade 2	Interrupt treatment with the medicinal product until symptoms resolve. Resume treatment at a dose one level lower than the previous dose.
Muscle weakness ≥ Grade 2	Interrupt treatment with the medicinal product until symptoms of muscle weakness improve to ≤ Grade 1. Resume treatment at a dose one level lower than the previous dose.
Hyperglycemia ≥ Grade 3	Reduce the dose of the medicinal product by one level. If needed, add insulin or oral hypoglycemic agents to therapy.
Acute pancreatitis	Exclude dexamethasone from the treatment regimen.
Other adverse reactions due to dexamethasone ≥ Grade 3	Discontinue dexamethasone therapy until manifestations of adverse reactions improve to ≤ Grade 2. Resume treatment at a dose one level lower than the previous dose.

If recovery from the toxic effect takes more than 14 days, the dose of dexamethasone will be restored to one level lower than the previous dose.

Reduction of dexamethasone dose

Table 5

Dose level	≤ 75 years Dose (cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle; cycle ≥ 9: days 1, 2, 8, 9 of a 21-day cycle)	> 75 years Dose (cycles 1-8: days 1, 2, 4, 5, 8, 9, 11, 12 of a 21-day cycle; cycle ≥ 9: days 1, 2, 8, 9 of a 21-day cycle)
Initial dose	20 mg	10 mg
Dose level-1	12 mg	6 mg
Dose level-2	8 mg	4 mg

Discontinue dexamethasone if the patient is unable to tolerate a dose of 8 mg in patients ≤ 75 years of age or a dose of 4 mg in patients > 75 years of age.

If any component of the treatment regimen is discontinued, the continued use of the remaining medicinal products should be determined by the physician.

Lenalidomide in combination with dexamethasone

The recommended starting dose of the medicinal product Ampomay is 4 mg, administered orally once daily on days 1 to 21 of a 28-day cycle.

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

Treatment with lenalidomide in combination with dexamethasone should be continued until disease progression or until unacceptable toxicity occurs.

Dose modification or discontinuation of lenalidomide

Guidelines for temporary interruption or dose reduction to manage adverse reactions related to lenalidomide are provided in Tables 2 and 3.

Dexamethasone dose modification

Guidelines for dose adjustment to manage adverse reactions related to dexamethasone are provided in Table 4. Guidelines for dose reduction to manage adverse reactions related to dexamethasone are provided in Table 6. However, decisions regarding discontinuation or resumption of dosing should be made at the physician's discretion in accordance with the current product information for medical use.

Dexamethasone dose reduction

Table 6

Dose level	≤ 75 years Day 1, 8, 15, 22 of each 28-day cycle	> 75 years Day 1, 8, 15, 22 of each 28-day cycle
Initial dose	40 mg	20 mg
Dose level-1	20 mg	12 mg
Dose level-2	10 mg	8 mg

Dexamethasone should be discontinued if the patient is unable to tolerate a dose of 10 mg at age ≤ 75 years or a dose of 8 mg at age > 75 years.

Special patient populations

Elderly patients

Dose adjustment of pomalidomide is not required.

Pomalidomide in combination with bortezomib and dexamethasone.

For patients > 75 years of age, the initial dose of dexamethasone is:

• Doses in cycles 1 to 8: 10 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.
• For cycle 9 and subsequent cycles: 10 mg once daily on days 1, 2, 8, and 9 of each 21-day cycle.

Pomalidomide in combination with dexamethasone

Dose adjustment of pomalidomide is not required.

For patients > 75 years of age, the initial dose of dexamethasone is:

• 20 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle.

Hepatic impairment

Patients with total serum bilirubin > 1.5 × ULN (upper limit of normal) were excluded from clinical trials. Hepatic dysfunction has minimal impact on the pharmacokinetics of pomalidomide. Initial dose adjustment of pomalidomide is not required in patients with hepatic impairment as defined by Child-Pugh criteria. However, patients with hepatic impairment should be monitored more closely for the occurrence of adverse reactions, and dose reductions or treatment interruptions with pomalidomide may be necessary.

Renal impairment

Dose adjustment of pomalidomide in patients with renal impairment is not required. On days when patients undergo hemodialysis, the dose of pomalidomide should be administered after hemodialysis.

Method of administration

Oral administration.

Pomalidomide hard capsules should be taken orally at the same time each day. The capsules must not be opened, broken, or chewed. The capsules should be swallowed whole, preferably with water, with or without food. If a patient misses a dose of pomalidomide on any given day, the prescribed dose should be taken as planned the following day. Patients should not alter the dose to compensate for a missed dose in previous days.

It is recommended to press only one end of the capsule when removing it from the blister pack, thereby minimizing the risk of capsule deformation or breakage.

Pediatric population

There are no data on the use of pomalidomide in children under 18 years of age for the indication multiple myeloma.

Overdose

Administration of pomalidomide at single doses up to 50 mg in healthy volunteers and multiple daily doses of 10 mg in patients with multiple myeloma has been studied, without identification of serious adverse reactions related to overdose. Studies have shown that pomalidomide is removed by hemodialysis.

In case of overdose, supportive therapy is recommended.

Adverse reactions.

Summary of safety profile

• Pomalidomide in combination with bortezomib and dexamethasone

The most frequently reported hematologic and lymphatic system disorders were neutropenia (54.0%), thrombocytopenia (39.9%), and anemia (32.0%). Other commonly reported adverse reactions included peripheral sensory neuropathy (48.2%), fatigue (38.8%), diarrhea (38.1%), constipation (38.1%), and peripheral edema (36.3%). The most common grade 3 or 4 adverse reactions were blood and lymphatic system disorders, including neutropenia (47.1%), thrombocytopenia (28.1%), and anemia (15.1%). The most frequently reported serious adverse reaction was pneumonia (12.2%). Other serious adverse reactions included pyrexia (4.3%), lower respiratory tract infection (3.6%), influenza (3.6%), pulmonary embolism (3.2%), atrial fibrillation (3.2%), and acute kidney injury (2.9%).

• Pomalidomide in combination with dexamethasone

In clinical studies, the most commonly reported adverse reactions were blood and lymphatic system disorders, including anemia (45.7%), neutropenia (45.3%), and thrombocytopenia (27%); general disorders and administration site conditions such as fatigue (28.3%), pyrexia (21%), and peripheral edema (13%); and infections and infestations including pneumonia (10.7%). Peripheral neuropathy was reported in 12.3% of patients and venous or thrombotic embolic events in 3.3% of patients. The most frequently reported grade 3 or 4 adverse reactions were blood and lymphatic system disorders, including neutropenia (41.7%), anemia (27%), and thrombocytopenia (20.7%); infections and infestations, including pneumonia (9%); and general disorders and administration site conditions, including fatigue (4.7%), pyrexia (3%), and peripheral edema (1.3%). The most commonly reported serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%), and venous or thrombotic embolic events (1.7%).

Adverse reactions usually occur during the first 2 treatment cycles with pomalidomide.

List of adverse reactions in tabular form

Adverse reactions observed in patients receiving pomalidomide in combination with bortezomib and dexamethasone are listed in Table 7 by system organ class (SOC), frequency of all adverse reactions, and frequency of grade 3 and 4 adverse reactions.

The frequency of adverse reactions is defined according to current conventions: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100).

Adverse reactions (AR) recorded during clinical trials and post-marketing surveillance

Table 7

Combination of treatment	Pomalidomide/ bortezomib/dexamethasone		Pomalidomide/ dexamethasone
System organ class/ preferred term	All adverse reactions	Grade 3–4 adverse reactions	All adverse reactions	Grade 3–4 adverse reactions
Infections and infestations
Pneumonia	Very common	Very common	-	-
Pneumonia (bacterial, viral and fungal infections, including opportunistic infections)	-	-	Very common	Common
Bronchitis	Very common	Common	Common	Uncommon
Upper respiratory tract infection	Very common	Common	Common	Common
Viral upper respiratory tract infection	Very common	-	-	-
Sepsis	Common	Common	-	-
Septic shock	Common	Common	-	-
Neutropenic sepsis	-	-	Common	Common
Pseudomembranous colitis	Common	Common	-	-
Bronchopneumonia	-	-	Common	Common
Respiratory tract infections	Common	Common	Common	Common
Infections of lower respiratory tract	Common	Common	-	-
Lung infection	Common	Uncommon	-	-
Influenza	Very common	Common	-	-
Capillary bronchitis	Common	Common	-	-
Urinary tract infections	Very common	Common	-	-
Nasopharyngitis	-	-	Common	-
Herpes zoster	-	-	Common	Uncommon
Reactivation of hepatitis B	-	-	Frequency unknown*	Frequency unknown*
Benign, malignant and unspecified neoplasms (including cysts and polyps)
Basal cell carcinoma	Common	Uncommon	-	-
Basal cell carcinoma of the skin	-	-	Uncommon	Uncommon
Squamous cell carcinoma of the skin	-	-	Uncommon	Uncommon
Blood and lymphatic system disorders
Neutropenia	Very common	Very common	Very common	Very common
Thrombocytopenia	Very common	Very common	Very common	Very common
Leukopenia	Very common	Common	Very common	Common
Anemia	Very common	Very common	Very common	Very common
Lymphopenia	Common	Common	-	-
Pancytopenia	-	-	Common*	Common*
Immune system disorders
Angioedema	-	-	Common*	Uncommon*
Urticaria	-	-	Common*	Uncommon*
Anaphylactic reaction	Frequency unknown*	Frequency unknown*	-	-
Rejection of parenchymal organ transplant	Frequency unknown*	-	-	-
Endocrine disorders
Hypothyroidism	Uncommon*	-	-	-
Metabolism and nutrition disorders
Hypokalemia	Very common	Common	-	-
Hyperglycemia	Very common	Common	-	-
Hypomagnesemia	Common	Common	-	-
Hypocalcemia	Common	Common	-	-
Hypophosphatemia	Common	Common	-	-
Hyperkalemia	Common	Common	Common	Common
Hypercalcemia	Common	Common	-	-
Hyponatremia	-	-	Common	Common
Decreased appetite	-	-	Very common	Uncommon
Hyperuricemia	-	-	Common*	Common*
Tumor lysis syndrome	-	-	Uncommon*	Uncommon*
Psychiatric disorders
Insomnia	Very common	Common	-	-
Depression	Common	Common	-	-
Confusional state	-	-	Common	Common
Nervous system disorders
Peripheral sensory neuropathy	Very common	Common	Common	Uncommon
Dizziness	Very common	Uncommon	Common	Uncommon
Tremor	Very common	Uncommon	Common	Uncommon
Syncope	Common	Common	-	-
Peripheral sensorimotor neuropathy	Common	Common	-	-
Paresthesia	Common	-	-	-
Dysgeusia	Common	-	-	-
Decreased level of consciousness	-	-	Common	Common
Intracranial hemorrhage	-	-	Common*	Uncommon*
Stroke	-	-	Uncommon*	Uncommon*
Eye disorders
Cataract	Common	Common	-	-
Ear and labyrinth disorders
Dizziness	-	-	Common	Common
Cardiac disorders
Atrial fibrillation	Very common	Common	Common*	Common*
Heart failure	-	-	Common*	Common*
Myocardial infarction	-	-	Common*	Uncommon*
Vascular disorders
Deep vein thrombosis	Common	Uncommon	Common	Uncommon
Hypotension	Common	Common	-	-
Hypertension	Common	Common	-	-
Respiratory, thoracic and mediastinal disorders
Dyspnea	Very common	Common	Very common	Common
Cough	Very common	-	Very common	Uncommon
Pulmonary embolism	Common	Common	Common	Uncommon
Nosebleed	-	-	Common*	Uncommon*
Interstitial lung disease (ILD)	-	-	Common*	Uncommon*
Gastrointestinal disorders
Diarrhea	Very common	Common	Very common	Common
Vomiting	Very common	Common	Common	Common
Nausea	Very common	Uncommon	Very common	Uncommon
Constipation	Very common	Common	Very common	Common
Abdominal pain	Very common	Common	-	-
Upper abdominal pain	Common	Uncommon	-	-
Stomatitis	Common	Uncommon	-	-
Dry mouth	Common	-	-	-
Abdominal distension	Common	Uncommon	-	-
Gastrointestinal hemorrhage	-	-	Common	Uncommon
Hepatobiliary disorders
Hyperbilirubinemia	-	-	Uncommon	Uncommon
Hepatitis	-	-	Uncommon*	-
Skin and subcutaneous tissue disorders
Rash	Very common	Common	Common	Common
Pruritus	-	-	Common	-
Drug reaction with eosinophilia and systemic symptoms	-	-	Frequency unknown*	Frequency unknown*
Toxic epidermal necrolysis	-	-	Frequency unknown*	Frequency unknown*
Stevens-Johnson syndrome	-	-	Frequency unknown*	Frequency unknown*
Musculoskeletal and connective tissue disorders
Muscle weakness	Very common	Common	-	-
Back pain	Very common	Common	-	-
Bone pain	Common	Uncommon	Very common	Common
Muscle spasms	Very common	-	Very common	Uncommon
Renal and urinary disorders
Acute kidney injury	Common	Common	-	-
Chronic kidney failure	Common	Common	-	-
Urinary retention	Common	Common	Common	Uncommon
Kidney failure	-	-	Common	Common
Reproductive system and breast disorders
Pelvic pain	-	-	Common	Common
General disorders and administration site conditions
Fatigue	Very common	Common	Very common	Common
Pyrexia	Very common	Common	Very common	Common
Peripheral edema	Very common	Common	Very common	Common
Non-cardiac chest pain	Common	Common	-	-
Edema	Common	Common	-	-
Investigations
Increased ALT levels	Common	Common	Common	Common
Weight decreased	Common	Common	-	-
Decreased neutrophil count	-	-	Common	Common
Decreased white blood cell count	-	-	Common	Common
Decreased platelet count	-	-	Common	Common
Increased blood uric acid	-	-	Common*	Uncommon*
Injury, poisoning and procedural complications
Fall	Common	Common	-	-

* Adverse reactions reported during post-marketing use

Description of selected adverse reactions

The frequency of adverse reactions in this section was obtained from clinical trials in patients who received treatment with pomalidomide in combination with bortezomib and dexamethasone (Pom+Btz+Dex) or with dexamethasone (Pom+Dex).

Teratogenicity

Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen causing severe congenital malformations. Pomalidomide has been shown to be teratogenic when administered during the period of major organogenesis in both rats and rabbits. If pomalidomide is used during pregnancy, teratogenic effects on humans are expected (see section "Special precautions for use").

Neutropenia and thrombocytopenia

Neutropenia was observed in 54.0% of patients receiving combination therapy with pomalidomide, bortezomib, and dexamethasone (Pom+Btz+Dex) (of which 47.1% were grade 3 or 4). Neutropenia led to interruption of pomalidomide therapy in 0.7% of all patients and was mostly non-serious.

Febrile neutropenia was reported in 3.2% of patients receiving (Pom+Btz+Dex) and in 6.7% of patients receiving (Pom+Dex), of which 1.8% (Pom+Btz+Dex) and 4.0% (Pom+Dex) were considered serious (see sections "Special precautions for use" and "Dosage and administration").

Thrombocytopenia occurred in 39.9% of patients receiving combination therapy (Pom+Btz+Dex) and in 6.7% of patients (Pom+Dex). Grade 3 or 4 thrombocytopenia occurred in 28.1% (Pom+Btz+Dex) and 20.7% (Pom+Dex) of patients, leading to discontinuation of pomalidomide therapy in 0.7% (Pom+Btz+Dex) of patients and considered serious in 0.7% (Pom+Btz+Dex) and 1.7% (Pom+Dex) of patients (see sections "Special precautions for use" and "Dosage and administration").

Neutropenia and thrombocytopenia occurred more frequently during the first two cycles of treatment with pomalidomide either in combination with bortezomib and dexamethasone or with dexamethasone.

Infections

Infection was the most common non-hematological toxic effect.

Infectious events occurred in 83.1% of patients receiving combination therapy (Pom+Btz+Dex) and in 55.0% of patients (Pom+Dex) (of which 34.9% (Pom+Btz+Dex) and 24.0% (Pom+Dex) were grade 3 or 4). Upper respiratory tract infections and pneumonia were the most common manifestations of infections. Fatal infections (grade 5) occurred in 4.0% (Pom+Btz+Dex) and 2.7% (Pom+Dex) of patients. Infections led to discontinuation of pomalidomide therapy in 3.6% (Pom+Btz+Dex) and 2.0% (Pom+Dex) of patients.

Thromboembolic complications

Prophylaxis with acetylsalicylic acid (and other anticoagulants for patients at high risk) was mandatory for all patients in clinical trials. Anticoagulant therapy is recommended (if not contraindicated) (see section "Special precautions for use").

Venous thromboembolic complications occurred in 12.2% of patients receiving combination therapy (Pom+Btz+Dex) and in 3.3% of patients (Pom+Dex) (of which 5.8% (Pom+Btz+Dex) and 1.3% (Pom+Dex) were grade 3 or 4). Venous thromboembolic complications were reported as serious adverse reactions in 4.7% (Pom+Btz+Dex) and 1.7% (Pom+Dex) of patients. No fatal events were recorded. Venous thromboembolic complications were associated with discontinuation of pomalidomide therapy in up to 2.2% (Pom+Btz+Dex) of patients.

Peripheral neuropathy

• Pomalidomide in combination with bortezomib and dexamethasone

Patients with pre-existing peripheral neuropathy ≥ grade 2 with pain within 14 days prior to randomization were excluded from clinical trials. Peripheral neuropathy was observed in 55.4% of patients (of which 10.8% were grade 3; 0.7% grade 4). Time-adjusted exposure rates were comparable across treatment groups. Approximately 30% of patients who developed peripheral neuropathy had a history of neuropathy at study entry. Peripheral neuropathy led to discontinuation of bortezomib in approximately 14.4% of patients, pomalidomide in 1.8%, and dexamethasone in 1.8% and 8.9% of the respective patient groups.

• Pomalidomide in combination with dexamethasone

Patients with pre-existing peripheral neuropathy ≥ grade 2 were excluded from clinical trials. Peripheral neuropathy was observed in 12.3% of patients (of which 1.0% were grade 3 or 4). No serious peripheral neuropathy reactions were recorded, and therapy interruption due to peripheral neuropathy occurred in 0.3% of patients (see section "Special precautions for use").

Bleeding

Hemorrhagic disorders have been reported following administration of pomalidomide, particularly in patients with risk factors such as concomitant use of medicinal products that increase the risk of bleeding. Hemorrhagic complications included epistaxis, intracranial hemorrhage, and gastrointestinal bleeding.

Hypersensitivity reactions and severe skin reactions

Angioedema, anaphylactic reactions, and severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported after administration of pomalidomide. Patients with a history of severe rash associated with lenalidomide or thalidomide should not receive pomalidomide therapy (see section "Special precautions for use").

Pediatric population

Adverse reactions reported in children (aged 4 to 18 years) with recurrent or progressive brain tumors were consistent with the known safety profile of pomalidomide in adult patients (see section "Pharmacological properties").

Reporting suspected adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

7 capsules in a blister; 3 blisters in a cardboard box or 21 capsules in a container; 1 container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of its business operations.

Unit-V, Block-VB, TSIIC Formulation SEZ, Sy. No 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.