Xenpoma

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KSENPOMA (XENPOMA)

Composition:

Active substance: pomalidomide;

1 hard capsule contains pomalidomide 1 mg, 2 mg, 3 mg, or 4 mg;

Excipients:

1 mg hard capsules: anhydrous lactose, pregelatinized starch, sodium stearyl fumarate, hard gelatin capsule size №4 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), FD&C Blue 1 (E 133), erythrosine (E 127), D&C Red 33);

2 mg hard capsules: anhydrous lactose, pregelatinized starch, sodium stearyl fumarate, hard gelatin capsule size №2 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), FD&C Blue 1 (E 133), erythrosine (E 127), D&C Red 33, D&C Yellow 10);

3 mg hard capsules: anhydrous lactose, pregelatinized starch, sodium stearylfumarate, hard gelatin capsule size №2 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), FD&C Blue 1 (E 133), erythrosine (E 127), D&C Red 33, FD&C Red 40 (E 129));

4 mg hard capsules: anhydrous lactose, pregelatinized starch, sodium stearyl fumarate, hard gelatin capsule size №2 (capsule shell composition: gelatin, purified water, titanium dioxide (E 171), FD&C Blue 1 (E 133), erythrosine (E 127), D&C Red 33, D&C Red 28).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

1 mg hard capsules: hard gelatin capsules consisting of a purple cap printed in white ink with " " and "1 mg", and a dark pink body printed in white ink with "520", filled with powder ranging from light yellow to yellow;

2 mg hard capsules: hard gelatin capsules consisting of a purple cap printed in white ink with " " and "2 mg", and an opaque pink body printed in white ink with "519", filled with powder ranging from light yellow to yellow;

3 mg hard capsules: hard gelatin capsules consisting of a purple cap printed in white ink with " " and "3 mg", and an opaque violet body printed in white ink with "518", filled with powder ranging from light yellow to yellow;

4 mg hard capsules: hard gelatin capsules consisting of a purple cap printed in white ink with " " and "4 mg", and an opaque purple body printed in white ink with "517", filled with powder ranging from light yellow to yellow.

Pharmacotherapeutic group.

Immunosuppressants. Other immunosuppressants.

ATC code L04AX06.

Pharmacological Properties.

Pharmacodynamics.

Pomalidomide exerts direct anti-myeloma, anti-angiogenic, and immunomodulatory effects and inhibits the supportive function of stromal cells that promote the growth of multiple myeloma cells. Specifically, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cells, including synergistic activity with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cells, and induces 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, which includes DNA damage-binding protein (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 poly-ubiquitination of various substrate proteins and may partially explain the pleiotropic cellular effects observed during pomalidomide treatment. In the presence of pomalidomide in vitro, substrate proteins Aiolos and Ikaros undergo ubiquitination and subsequent degradation, leading to direct cytotoxic and immunomodulatory effects. In vivo, pomalidomide therapy resulted in reduced levels of Aiolos in patients with relapsed, lenalidomide-resistant multiple myeloma.

Pharmacokinetics.

Absorption

Pomalidomide is absorbed with maximum plasma concentration (Cmax) 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 doses, pomalidomide exhibits an accumulation ratio of 27 to 31% based on AUC.

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

Distribution

Pomalidomide has a mean theoretical volume of distribution (Vd/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 Tmax) following 4 days of 2 mg once-daily dosing. In vitro, binding of pomalidomide enantiomers to plasma proteins in humans 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 who received a single oral dose of [14C]-pomalidomide (2 mg). No metabolites in plasma were detected at concentrations >10% of total or parent-related 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 responsible for 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 have a clinically significant effect on pomalidomide exposure. Concomitant administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole increased mean pomalidomide exposure by 107% (90% CI [91% to 124%]) compared to pomalidomide plus ketoconazole alone. In a second study assessing the impact of a CYP1A2 inhibitor on metabolism, co-administration of fluvoxamine and pomalidomide increased mean pomalidomide plasma concentration by 125% (90% CI [98% to 157%]) compared to pomalidomide alone. If concomitant use of strong CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, or fluvoxamine) with pomalidomide is necessary, the pomalidomide dose should be reduced by 50%. Administration of pomalidomide in smokers (known to induce CYP1A2 via smoking) did not have a clinically significant effect on pomalidomide concentrations compared to non-smokers.

Based on in vitro data, pomalidomide is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes and does not inhibit any known drug transporters. Clinically significant interactions between pomalidomide and other medicinal products are not expected when co-administered with substrates of these pathways.

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.

Following a single oral dose of [14C]-pomalidomide (2 mg) in healthy volunteers, approximately 73% and 15% of the radioactive dose was excreted in urine and feces, respectively, with approximately 2% and 8% of the administered radioactive carbon excreted as unchanged pomalidomide in urine and feces.

Pomalidomide is extensively metabolized prior to elimination, with metabolites primarily excreted in urine. Three major metabolites detected in urine (formed via hydrolysis or hydroxylation followed by glucuronidation) account for approximately 23%, 17%, and 12% of the dose in urine, respectively.

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

Population Pharmacokinetics (PK)

Based on population PK analysis using a two-compartment model, healthy subjects and patients with multiple myeloma had comparable apparent clearance (CL/F) and theoretical 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) being 3.7 and 8 times higher, respectively, than in healthy volunteers.

Paediatric Population

After a single oral dose of pomalidomide in children and young adults with recurrent or progressive primary brain tumors, the median Tmax was 2–4 hours post-dose, corresponding to geometric mean Cmax (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. AUC0–24 and AUC0–inf followed similar trends, with total exposure approximately ranging from 700 to 800 h·ng/mL after the two lower doses and approximately 1200 h·ng/mL after the higher dose. Estimated elimination half-life was approximately 5 to 7 hours.

No clear trends were observed when stratified by age or steroid use, with minimal topological difference (MTD).

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

Pharmacokinetics of orally administered pomalidomide at doses ranging from 1.9 mg/m²/day 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 demonstrated linear and time-invariant pharmacokinetics with moderate variability. Typical values for CL/F, Vc/F, Ka, and absorption lag time were 3.94 L/h, 43.0 L, 1.45 h⁻¹, and 0.454 hours, respectively. Terminal half-life of pomalidomide was 7.33 hours. Except for body surface area (BSA), none of the tested covariates, including age and sex, influenced pomalidomide pharmacokinetics. Although BSA was identified as a statistically significant covariate for CL/F and Vc/F, the impact of BSA on exposure parameters was not considered clinically significant.

Overall, no substantial differences in pharmacokinetic parameters of pomalidomide were observed between children and adults.

Elderly Patients

Based on population pharmacokinetic analysis in healthy volunteers and patients with multiple myeloma, age (within the range of 19–83 years) did not have a significant effect on pomalidomide clearance after oral administration. Dose adjustment was not required in elderly patients (>65 years) receiving pomalidomide in clinical studies.

Renal Impairment

Population pharmacokinetic analysis showed that pomalidomide pharmacokinetic parameters were not substantially altered in patients with renal impairment (defined by creatinine clearance or estimated glomerular filtration rate [eGFR]) compared to patients with normal renal function (CrCl ≥60 mL/min). Mean normalized exposure (AUC) of 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 exposure (AUC) 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 those with normal renal function. Mean normalized exposure (AUC) increased by 35.8% (90% CI [7.5% to 70.0%]) in patients with severe renal impairment requiring dialysis (CrCl <30 mL/min with dialysis requirement) compared to those with normal renal function. Mean changes in pomalidomide exposure in each of these renal impairment groups were not considered clinically significant enough to require dose adjustment.

Hepatic Impairment

Pharmacokinetic parameters were moderately altered in patients with hepatic impairment (classified by Child-Pugh criteria) compared to healthy volunteers. Mean pomalidomide exposure increased by 51% (90% CI [9% to 110%]) in patients with mild hepatic impairment compared to healthy volunteers. Mean pomalidomide exposure increased by 58% (90% CI [13% to 119%]) in patients with moderate hepatic impairment compared to healthy volunteers. Mean pomalidomide exposure increased by 72% (90% CI [24% to 138%]) in patients with severe hepatic impairment compared to healthy volunteers. The mean increases in pomalidomide exposure in each of these hepatic impairment groups were not considered clinically significant enough to require dose adjustment or changes in dosing regimen.

Clinical characteristics.

Indications.

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

Xenpoma in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and whose disease has progressed on the most recent therapy.

Contraindications.

• Pregnancy.
• Women of reproductive potential who do not comply with all necessary pregnancy prevention requirements.
• Male patients unable to comply with required contraceptive measures.
• Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Safety precautions.

Capsules must not be opened or crushed. If pomalidomide powder comes into contact with skin or mucous membranes, they should be immediately and thoroughly washed with soap and water. Healthcare professionals and handling staff must wear disposable gloves when handling the blister or capsule. After completing work with pomalidomide, gloves should be carefully removed to avoid skin contamination, placed in a sealed plastic polyethylene bag, and disposed of according to local requirements. Hands should then be thoroughly washed with soap and water.

Pregnant women or women suspected of being pregnant must not handle the pomalidomide blister or capsule (see section "Special precautions for use").

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Effect of pomalidomide on other medicinal products

Pomalidomide is not expected to cause clinically significant pharmacokinetic interactions with other drugs 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 have a clinically significant effect on 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 metabolic changes, concomitant administration of fluvoxamine and pomalidomide increased the mean blood concentration of pomalidomide by 125% with 90% CI [from 98% to 157%], compared to administration of pomalidomide alone. If concomitant use of strong CYP1A2 inhibitors (e.g., ciprofloxacin, enoxacin, and fluvoxamine) with pomalidomide is necessary, the dose of pomalidomide should be reduced by 50%.

Dexamethasone

Repeated administration of pomalidomide doses up to 4 mg together with dexamethasone at 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 administration of pomalidomide alone.

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

Information on interactions with other medicinal products used in combination with Xenpoma should be sought in the respective product information leaflets.

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 medicinal product with a well-known teratogenic effect in humans, causing severe congenital malformations. Pomalidomide has been shown to be teratogenic when administered during the main organogenesis period in both rats and rabbits.

Pregnancy prevention requirements must be fulfilled for all patients unless there is reliable evidence that the patient does not have reproductive potential.

Criteria for patients without reproductive potential

Women or male patients are considered to have no 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 potential).
• Premature ovarian failure, confirmed by a specialist gynecologist.
• Previous bilateral salpingo-oophorectomy or hysterectomy.
• XY genotype, Turner syndrome, or uterine agenesis.

Counseling

Pomalidomide is contraindicated in women of 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 necessity of effective contraception for at least 4 weeks before starting treatment, throughout the entire treatment duration, and for at least 4 weeks after treatment ends.
• Even if a woman of reproductive age has amenorrhea, all recommendations for effective contraception must be followed.
• The woman must be capable of using effective contraceptive methods.
• The woman is informed and understands the possible consequences of pregnancy and the need for immediate consultation if pregnancy risk arises.
• The woman understands the necessity to start treatment as soon as possible after a negative pregnancy test and after receiving the prescribed medication.
• The woman understands the necessity and agrees to undergo pregnancy testing at least every 4 weeks, except in cases where sterilization via tubal occlusion has been confirmed.
• The woman acknowledges that she understands the danger and necessity of preventive measures associated with pomalidomide use.

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

• The patient fulfills the pregnancy prevention requirements, including confirmation that she has sufficient understanding of the necessity of these actions.
• The patient confirms her agreement to comply with the above conditions.

For male patients taking 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 drug elimination due to hepatic impairment, all male patients taking pomalidomide must fulfill 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 necessity of using a condom during sexual activity with a pregnant woman or a woman of reproductive potential not using effective contraception, throughout the treatment period, during temporary treatment interruption, and for 7 days after temporary or permanent discontinuation of the drug. This also applies to men who have undergone vasectomy, who must use a condom if engaging in sexual intercourse with a pregnant woman or a woman of reproductive potential, as semen may still contain pomalidomide even in the absence of sperm.
• He understands that if his partner becomes pregnant while he is taking pomalidomide or within 7 days after he stops taking it, he must immediately inform his treating physician, and it is also recommended to refer the partner to a specialist or teratologist experienced in teratology for risk assessment and advice.

Contraception

Women of 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 temporary interruption of treatment, unless the patient practices absolute and continuous abstinence, confirmed monthly. If effective contraception is not used, the patient should be referred to an appropriate qualified healthcare provider for counseling on contraceptive methods to initiate contraception. The following options may be considered as effective contraceptive methods:

• Implant.
• Levonorgestrel-releasing intrauterine system.
• Depot medroxyprogesterone acetate.
• Sterilization by tubal occlusion.
• Sexual intercourse only with a partner who has undergone vasectomy; vasectomy must be confirmed by two negative semen analyses.
• Ovulation-inhibiting tablets containing progestogen (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. If a patient is using combined oral contraception, she should switch to one of the effective contraceptive 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 when taken concomitantly with dexamethasone.

Implants and levonorgestrel-releasing intrauterine systems increase the risk of infection during insertion and during irregular vaginal bleeding. Prophylactic antibiotics should be considered for patients with neutropenia. Insertion of copper-releasing intrauterine devices is not recommended due to potential infection risks during insertion and blood loss during menstruation, which may endanger patients with severe neutropenia or pronounced thrombocytopenia.

Pregnancy testing

Women of reproductive potential, as defined above, must undergo medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL, in accordance with local practice and under physician supervision. This requirement applies even to women of reproductive potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, prescription issuance, and medication dispensing should occur on the same day. Dispensing of pomalidomide to women of reproductive age must occur within 7 days after prescription and after a negative physician-supervised pregnancy test.

Prior to starting treatment

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

Monitoring and end of treatment

A physician-supervised pregnancy test should be repeated at least every 4 weeks, including at least 4 weeks after treatment ends, except in cases where sterilization via tubal occlusion has been performed. The pregnancy test should be performed on the day of the visit to the prescribing physician or within 3 days prior to the visit.

Additional safety measures

Patients should be instructed not to give this medication to others and to return unused capsules to their pharmacist upon completion of treatment.

Patients taking pomalidomide must not donate blood, semen, or sperm during treatment (including during dose interruption) and for 7 days after discontinuation of pomalidomide.

Healthcare professionals and caregivers must wear disposable gloves when handling blisters or capsules of the medication. Women who are confirmed or suspected to be pregnant must 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 will provide healthcare professionals with educational materials reinforcing warnings about the expected teratogenic effects of pomalidomide, recommendations for contraception before starting therapy, and instructions regarding the necessity of pregnancy testing. The prescribing physician must inform the patient about the expected risk of teratogenic effects and the necessity of strict pregnancy prevention measures as described in the pregnancy prevention section, and provide the patient with appropriate patient education brochures, patient cards, and/or equivalent applications according to the implemented national patient registry system. The controlled distribution system includes the use of patient cards and/or equivalent tools to control prescribing and/or dispensing of the medication to patients and collection of detailed data on indications for use to monitor off-label use. Ideally, pregnancy testing, prescription issuance, and medication dispensing should occur on the same day. Dispensing of pomalidomide to women of reproductive age must occur within 7 days after prescription and after a negative physician-supervised pregnancy test. For women of reproductive potential, the medication may be prescribed for a maximum of a 4-week treatment period according to approved dosing regimens for the indication, while for all other patients, the medication may be prescribed for a maximum of a 12-week treatment period.

Hematological complications

The most common grade 3 or 4 hematological adverse reaction in patients with relapsed/refractory multiple myeloma was neutropenia, followed by anemia and thrombocytopenia in order of frequency. 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 signs of bleeding, including epistaxis, especially when concomitant use of medications known to increase bleeding risk is present. Complete blood counts should be performed at the start of therapy, weekly for the first 8 weeks of therapy, and monthly thereafter. Dose adjustments may be necessary. 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 prior 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 arms or legs occur. Anticoagulant therapy (if not contraindicated), such as acetylsalicylic acid, warfarin, heparin, or clopidogrel, is recommended, especially in patients with additional risk factors for thrombotic complications. The decision on prophylactic 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 treatment.

Peripheral neuropathy

Patients with peripheral neuropathy ≥ grade 2 were excluded from clinical trials with pomalidomide. 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 of study start; unstable or poorly controlled angina) were excluded from pomalidomide clinical trials. Adverse cardiac events, including congestive heart failure, pulmonary edema, and atrial fibrillation, 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.

Tumor lysis syndrome

Patients at highest risk of tumor lysis syndrome are those with high tumor burden before starting treatment. Close monitoring and appropriate preventive measures should be implemented when risk is present.

Secondary primary malignancy

Cases of secondary primary malignancies, such as non-melanoma skin cancer, have been reported in patients receiving pomalidomide. Physicians should carefully monitor patients before and during treatment using standard oncological screening to detect possible secondary primary malignancies and initiate appropriate treatment if necessary.

Allergic reactions and severe skin reactions

Angioedema, anaphylactic reactions, and severe dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and DRESS syndrome, have been reported with pomalidomide use. Patients should be counseled on the signs and symptoms of such reactions and instructed to seek immediate medical help if these symptoms occur. Pomalidomide must be discontinued in cases of exfoliative or bullous rash or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or DRESS syndrome; and must not be restarted after discontinuation due to these reactions. Patients with a history of serious allergic reactions to thalidomide or lenalidomide were excluded from clinical trials. Such patients have a higher risk of hypersensitivity reactions and must not take pomalidomide. In cases of grade 2–3 rash, temporary or permanent discontinuation of the drug should be considered. Pomalidomide therapy must be permanently discontinued in cases of angioedema or anaphylactic reaction.

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 medications that may cause dizziness or confusion without prior consultation with their physician.

Interstitial lung disease (ILD)

Cases of ILD and related events, including pneumonia, have been reported after pomalidomide use. A thorough evaluation of patients with acute onset or unexplained worsening of pulmonary symptoms is necessary to rule out ILD. Pomalidomide use should be temporarily discontinued during investigation of these symptoms, and appropriate treatment initiated if ILD is confirmed. Pomalidomide therapy should be resumed only after careful benefit-risk assessment.

Hepatic impairment

Marked increases in alanine aminotransferase (ALT) and bilirubin levels have been observed in patients taking pomalidomide. Cases of hepatitis requiring discontinuation of pomalidomide therapy have also been reported. Regular 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. Testing for hepatitis B virus should be performed before starting pomalidomide therapy. Patients with positive hepatitis B virus (HBV) tests are recommended to consult a physician experienced in hepatitis B treatment. Caution should be exercised when treating patients previously infected with hepatitis B virus, including those with positive anti-HBc but negative HBsAg, with pomalidomide in combination with dexamethasone.

These patients should be closely monitored for possible signs and symptoms of active HBV infection throughout the treatment period.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with pomalidomide use. PML cases have occurred from several months to several years after starting pomalidomide therapy. PML cases have generally been reported in patients who were also receiving dexamethasone or had prior treatment with other immunosuppressive chemotherapeutic agents. 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 testing for JC virus (JCV) DNA by polymerase chain reaction (PCR), or brain biopsy with JCV testing. A negative JCV PCR does not exclude PML. If an alternative diagnosis cannot be established, additional monitoring and evaluation may be required.

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

Sodium content

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

The medicinal product contains lactose as an excipient; therefore, if the patient has been diagnosed with intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

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 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, the patient should be referred to a physician specialized or experienced in teratology for fetal risk assessment and advice. Pomalidomide penetrates into human semen. As a precaution, all male patients taking pomalidomide must use condoms throughout the entire treatment period, during dose interruption, and for 7 days after treatment discontinuation, if the partner is pregnant or of reproductive age and not using other contraceptive methods.

Pregnancy

The teratogenic effect of pomalidomide in humans is probable. Pomalidomide is contraindicated during pregnancy and in women of reproductive potential, except when all pregnancy prevention conditions are fulfilled.

Breastfeeding

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

Fertility

It has been established that pomalidomide negatively affects fertility and has teratogenic effects in animals. Pomalidomide crosses the placenta and has been detected in fetal blood after administration to pregnant rabbits.

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Method of Administration and Dosage

Treatment should be initiated and monitored under the supervision of physicians experienced in the treatment of multiple myeloma.

Dosing should be continued or modified based on clinical and laboratory findings.

Combination Therapy

• Pomalidomide in combination with bortezomib and dexamethasone

The recommended starting dose of pomalidomide is 4 mg orally once daily on days 1 to 14 of each 21-day treatment cycle.

In combination with bortezomib and dexamethasone, pomalidomide should be administered according to Table 1. The recommended 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 pomalidomide in combination with bortezomib and dexamethasone should continue until disease progression or until unacceptable toxicity occurs.

Recommended dosing schedule for pomalidomide 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)*
Cycle 9 and subsequent cycles	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)*

* See Special populations for use in patients aged >75 years.

Dose modification or temporary interruption 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 temporary interruption or dose reduction of pomalidomide due to pomalidomide-related adverse reactions are provided in Table 2, and dose levels are defined in Table 3.

Dose modification guidelines for pomalidomide∞

Table 2

Toxicity	Dose adjustment
Neutropenia* ANC** < 0.5 x 109/L or febrile neutropenia (fever ≥38.5 °C and ANC** < 1 x 109/L)	Temporarily discontinue pomalidomide treatment until the end of the cycle. Perform CBC*** weekly.
ANC** returns to ≥ 1 x 109/L	Resume pomalidomide treatment at a dose one level lower than the previous dose.
For each subsequent decrease < 0.5 x 109/L	Temporarily discontinue pomalidomide treatment.
ANC** returns to ≥ 1 x 109/L	Resume pomalidomide treatment at a dose one level lower than the previous dose.
Thrombocytopenia Platelet count < 25 x 109/L	Temporarily discontinue pomalidomide treatment until the end of the cycle. Perform CBC*** weekly.
Return to level ≥ 50 x 109/L	Resume pomalidomide treatment at a dose one level lower than the previous dose.
For each subsequent decrease < 25 x 109/L	Temporarily discontinue pomalidomide treatment.
Return to level ≥ 50 x 109/L	Resume pomalidomide treatment at a dose one level lower than the previous dose.
Rash Rash of grade 2–3	Consider the need for temporary discontinuation or permanent discontinuation of pomalidomide.
Rash of grade 4 or blistering (including angioedema, anaphylactic reaction, exfoliative or bullous dermatitis, or if Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is suspected)	Permanently discontinue treatment.
Other Other pomalidomide-related adverse reactions ≥ grade 3	Temporarily discontinue pomalidomide treatment until the end of the cycle. In the next cycle, resume pomalidomide treatment at a dose one level lower than the previous dose (adverse reactions must resolve or improve to ≤ grade 2 before reinitiating the drug).

∞ 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

Dosing level	Oral pomalidomide dose
Initial dose	4 mg
Dose level-1	3 mg
Dose level-2	2 mg
Dose level-3	1 mg

∞ Dose modification guidelines 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%.

Dose adjustment or temporary interruption of bortezomib

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

Dose adjustment or temporary interruption of dexamethasone

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

Dexamethasone dose modification guidelines

Table 4

Toxicity	Dose adjustment
Grade 1–2 dyspepsia	Continue recommended dose and treat with an H2-receptor blocker or analogue. Reduce dose by one level if symptoms persist.
Grade ≥3 dyspepsia	Temporarily discontinue therapy until symptoms are controlled. Add an H2-receptor blocker or analogue and resume treatment at a dose one level lower than the previous dose.
Edema > grade 3	Consider adding a diuretic to therapy and reduce the drug dose by one level from the previous dose.
Disorientation and mood disturbances ≥ grade 2	Temporarily discontinue therapy until symptoms resolve. Resume treatment at a dose one level lower than the previous dose.
Muscle weakness ≥ grade 2	Temporarily discontinue treatment until muscle weakness symptoms improve to ≤ grade 1. Resume treatment at a dose one level lower than the previous dose.
Hyperglycemia ≥ grade 3	Reduce drug dose by one level. Initiate insulin or oral hypoglycemic agents as needed.
Acute pancreatitis	Permanently discontinue dexamethasone from the treatment regimen.
Other dexamethasone-related adverse reactions ≥ grade 3	Discontinue dexamethasone therapy until adverse reactions resolve to ≤ grade 2. Resume treatment at a dose one level lower than the previous dose.

If recovery from the toxic effect lasts longer than 14 days, dexamethasone administration should be resumed at a dose one level lower than the previous dose.

Dexamethasone dose reduction

Table 5

Dosing level	Age ≤ 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)	Age > 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 cannot 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 is 4 mg, administered orally once daily on days 1 to 21 of each 28-day treatment 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 toxic effects occur.

Dose adjustment or temporary discontinuation of lenalidomide

Guidelines for temporary interruption of therapy or dose reduction to reduce the risk of adverse reactions associated with lenalidomide are provided in Tables 2 and 3.

Dexamethasone dose adjustment

Guidelines for dose modification to reduce the risk of adverse reactions associated with dexamethasone are provided in Table 4. Guidelines for dose reduction to reduce the risk of adverse reactions associated with dexamethasone are provided in Table 6. However, decisions regarding discontinuation/resumption of dosing should be made at the physician's discretion in accordance with the current medical product information.

Dexamethasone dose reduction

Table 6

Dosing level	Age ≤ 75 years Day 1, 8, 15, 22 of each 28-day cycle	Age >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

Discontinue dexamethasone if the patient cannot 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

Pomalidomide in combination with bortezomib and dexamethasone

Dose adjustment of pomalidomide is not required.

Information on the concomitant use of bortezomib with pomalidomide is provided in the relevant section of the current summary of product characteristics.

For patients aged >75 years, the starting 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 aged >75 years, the starting 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 x ULN (upper limit of normal) were excluded from clinical trials. Hepatic impairment has minimal impact on the pharmacokinetics of pomalidomide. No initial dose adjustment of pomalidomide is required for 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 temporary interruption of pomalidomide treatment should be considered as necessary.

Renal impairment

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

Method of administration

Oral use.

The 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 scheduled the following day. Patients should not adjust the dose to compensate for a missed dose from previous days.

It is recommended to press only one edge of the capsule to push it out of the blister, thereby reducing the risk of capsule deformation or breakage.

Information on other medicinal products used in combination with XENPOZYME is provided in the respective summaries of product characteristics.

Children

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

Apart from the approved indications, the use of pomalidomide has been studied in children aged 4 to 18 years with recurrent or progressive brain tumors; however, study results did not allow a conclusion that the benefit of such use outweighs the risks. Available information is provided in the sections "Adverse reactions" and "Pharmacological properties". There is no appropriate use of pomalidomide in children aged 0–17 years 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; no serious adverse reactions related to overdose were observed. Studies have shown that pomalidomide is removed by haemodialysis.

In case of overdose, supportive therapy is recommended.

Adverse Reactions

Pomalidomide in combination with bortezomib and dexamethasone

The most frequently observed hematologic and lymphatic system disorders were neutropenia (46.8%), thrombocytopenia (36.7%), and anemia (28.4%). The most commonly reported adverse reaction was peripheral sensory neuropathy (47.8%). The most common grade 3 or 4 adverse reactions were hematologic and lymphatic system disorders: neutropenia (41.7%), thrombocytopenia (27.3%), and anemia (14.0%). The most frequently reported serious adverse reaction was pneumonia (11.5%). Other serious adverse reactions included pyrexia (4.0%), lower respiratory tract infections (2.9%), pulmonary embolism (2.9%), influenza (2.9%), and acute kidney injury (2.9%).

Pomalidomide in combination with dexamethasone

In clinical studies, the most frequently reported adverse reactions involved the 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 thromboembolic events (VTE) 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, such as 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 thromboembolic events (1.7%).

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

List of adverse reactions in tabular form

Pomalidomide in combination with bortezomib and dexamethasone

In the randomized trial CC-4047-MM-007, 278 patients received pomalidomide, bortezomib, and dexamethasone (Pom+Btz+Dex arm) (see section "Dosage and administration").

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 for grade 3 and 4 adverse reactions.

The frequency of adverse reactions for the combination therapy Pom + Btz + Dex (any grade) is defined according to current conventions: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1000 and < 1/100).

All adverse reactions (AR) reported in the MM-007 clinical trial for patients receiving pomalidomide in combination with bortezomib and dexamethasone are listed below.

Table 7

System organ class/Precferred term	All adverse reactions/frequency	Grade 3–4 adverse reactions/frequency
Infections and infestations	Very common Pneumonia, bronchitis, upper respiratory tract infections, viral upper respiratory tract infection Common Sepsis, septic shock, Clostridium difficile-induced colitis, respiratory tract infections, lower respiratory tract infections, pulmonary infection, influenza, bronchiolitis, urinary tract infections	Very common Pneumonia Common Sepsis, septic shock, Clostridium difficile-induced colitis, bronchitis, upper respiratory tract infections, lower respiratory tract infections, pulmonary infection, influenza, bronchiolitis, urinary tract infections
Benign, malignant and unspecified neoplasms (incl. cysts and polyps)	Common Basal cell carcinoma
Blood and lymphatic system disorders	Very common Neutropenia, thrombocytopenia, leukopenia, anemia Common Febrile neutropenia, lymphopenia	Very common Neutropenia, thrombocytopenia, anemia Common Febrile neutropenia, leukopenia, lymphopenia
Metabolism and nutrition disorders	Very common Hypokalemia, hyperglycemia Common Hypomagnesemia, hypocalcemia, hypophosphatemia, hyperkalemia, hypercalcemia	Common Hypokalemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypophosphatemia, hyperkalemia, hypercalcemia
Psychiatric disorders	Very common Insomnia Common Depression	Common Depression, insomnia
Nervous system disorders	Very common Peripheral sensory neuropathy, dizziness, tremor Common Syncope, peripheral sensorimotor neuropathy, paresthesia, dysgeusia	Common Syncope, peripheral sensory neuropathy, peripheral sensorimotor neuropathy Uncommon Dizziness, tremor
Eye disorders	Common Cataract	Common Cataract
Cardiac disorders	Common Atrial fibrillation	Common Atrial fibrillation
Vascular disorders	Common Deep vein thrombosis, hypotension, hypertension	Common Hypotension, hypertension Uncommon Deep vein thrombosis
Respiratory, thoracic and mediastinal disorders	Very common Dyspnea, cough Common Pulmonary embolism	Common Pulmonary embolism, dyspnea
Gastrointestinal disorders	Very common Diarrhea, vomiting, nausea, constipation Common Abdominal pain, upper abdominal pain, stomatitis, dry mouth, abdominal distension	Common Diarrhea, vomiting, abdominal pain, constipation Uncommon Upper abdominal pain, stomatitis, nausea, abdominal distension
Skin and subcutaneous tissue disorders	Common Rash	Common Rash
Musculoskeletal and connective tissue disorders	Very common Muscle weakness, back pain Common Bone pain, muscle spasms	Common Muscle weakness, back pain Uncommon Bone pain
Renal and urinary disorders	Common Acute renal failure, chronic renal failure, urinary retention	Common Acute renal failure, chronic renal failure, urinary retention
General disorders and administration site conditions	Very common Fatigue, pyrexia, peripheral edema Common Non-cardiac chest pain, edema	Common Fatigue, pyrexia, non-cardiac chest pain, peripheral edema, edema
Investigations	Common Increased ALT levels, weight decreased	Common Weight decreased Uncommon Increased ALT levels
Injury, poisoning and procedural complications	Common Fall	Uncommon Fall

Pomalidomide in combination with dexamethasone

In the randomized CC-4047-MM-003 study, 302 patients with relapsed and refractory multiple myeloma received pomalidomide 4 mg once daily on days 1–21 of each 28-day cycle in combination with low-dose weekly dexamethasone.

Adverse reactions observed in patients receiving pomalidomide in combination with dexamethasone are listed below in Table 8 by system organ class (SOC), frequency of all adverse reactions, and for adverse reactions of grade 3 or 4.

The frequency of adverse reactions is as observed in the group of patients who received pomalidomide and dexamethasone in study CC-4047-MM-003 (n=302). Within each SOC and frequency grouping, adverse reactions are listed in order of decreasing severity. Frequencies are defined according to the following criteria: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); frequency not known (cannot be estimated from available data).

Common adverse reactions reported in the MM-003 clinical trial in patients receiving pomalidomide in combination with dexamethasone

Table 8

System organ class/Preferred term	All common adverse reactions/Frequency	Grade 3-4 common adverse reactions/Frequency
Infections and infestations	Very common Pneumonia (bacterial, viral and fungal infections, including opportunistic infections) Common Neutropenic sepsis, bronchopneumonia, bronchitis, respiratory tract infections, upper respiratory tract infections, nasopharyngitis, herpes zoster	Common Neutropenic sepsis, pneumonia (bacterial, viral and fungal infections, including opportunistic infections), bronchopneumonia, respiratory tract infections, upper respiratory tract infections Uncommon Bronchitis, herpes zoster
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Uncommon Basal cell carcinoma, squamous cell carcinoma of the skin	Uncommon Basal cell carcinoma, squamous cell carcinoma of the skin
Blood and lymphatic system disorders	Very common Neutropenia, thrombocytopenia, leukopenia, anemia Common Febrile neutropenia	Very common Neutropenia, thrombocytopenia, anemia Common Febrile neutropenia, leukopenia
Metabolism and nutrition disorders	Very common Decreased appetite Common Hyperkalemia, hyponatremia	Common Hyperkalemia, hyponatremia Uncommon Decreased appetite
Psychiatric disorders	Common Confusional state	Common Confusional state
Nervous system disorders	Common Decreased level of consciousness, peripheral sensory neuropathy, dizziness, tremor	Common Decreased level of consciousness Uncommon Peripheral sensory neuropathy, dizziness, tremor
Ear and labyrinth disorders	Common Dizziness	Common Dizziness
Vascular disorders	Common Deep vein thrombosis	Uncommon Deep vein thrombosis
Respiratory, thoracic and mediastinal disorders	Very common Dyspnea, cough Common Pulmonary embolism	Common Dyspnea Uncommon Pulmonary embolism, cough
Gastrointestinal disorders	Very common Diarrhea, nausea, constipation Common Vomiting, gastrointestinal hemorrhage	Common Diarrhea, vomiting, constipation Uncommon Nausea, gastrointestinal hemorrhage
Hepatobiliary and biliary disorders	Uncommon Hyperbilirubinemia	Uncommon Hyperbilirubinemia
Skin and subcutaneous tissue disorders	Common Rash, pruritus	Common Rash
Musculoskeletal and connective tissue disorders	Very common Bone pain, muscle spasms	Common Bone pain Uncommon Muscle spasms
Renal and urinary disorders	Common Renal failure, urinary retention	Common Renal failure Uncommon Urinary retention
Reproductive system and breast disorders	Common Pelvic pain	Common Pelvic pain
General disorders and administration site conditions	Very common Fatigue, pyrexia, peripheral edema	Common Fatigue, pyrexia, peripheral edema
Investigations	Common Decreased neutrophil count, decreased white blood cell count, decreased platelet count, increased ALT level	Common Decreased neutrophil count, decreased white blood cell count, decreased platelet count, increased ALT level

In addition to the adverse reactions listed above identified in the main clinical trials, the table 9 below has been compiled based on data collected during the post-marketing period.

Reported common adverse reactions occurring during post-marketing period with pomalidomide therapy

Table 9

System Organ Class/Precise Term	All adverse reactions/frequency	Grade 3-4 adverse reactions/frequency
Infections and infestations	Frequency unknown Hepatitis B reactivation	Frequency unknown Hepatitis B reactivation
Blood and lymphatic system disorders	Common Pancytopenia	Common Pancytopenia
Immune system disorders	Common Angioedema, urticaria Frequency unknown Anaphylactic reaction, rejection of transplanted solid organ	Uncommon Angioedema, urticaria Frequency unknown Anaphylactic reaction
Endocrine disorders	Uncommon Hypothyroidism
Metabolism and nutrition disorders	Common Hyperuricemia Uncommon Tumor lysis syndrome	Common Hyperuricemia Uncommon Tumor lysis syndrome
Nervous system disorders	Common Intracranial hemorrhage Uncommon Stroke	Uncommon Stroke, intracranial hemorrhage
Cardiac disorders	Common Heart failure, atrial fibrillation, myocardial infarction	Common Heart failure, atrial fibrillation Uncommon Myocardial infarction
Respiratory, thoracic and mediastinal disorders	Common Nosebleed, interstitial lung disease	Uncommon Nosebleed, interstitial lung disease
Hepatobiliary disorders	Uncommon Hepatitis
Skin and subcutaneous tissue disorders	Frequency unknown Drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, Stevens- Johnson syndrome	Frequency unknown Drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, Stevens-Johnson syndrome
Investigations	Common Increased blood uric acid level	Uncommon Increased blood uric acid level

Description of selected adverse reactions

Teratogenicity

Pomalidomide is structurally related to thalidomide. Thalidomide is a medicinal product with a known teratogenic effect in humans, which causes severe congenital malformations. Pomalidomide has been shown to be teratogenic when administered during the main period of organogenesis in both rats and rabbits. If pomalidomide is used during pregnancy, teratogenic effects on humans are expected.

Neutropenia and thrombocytopenia

In patients receiving pomalidomide combination therapy in clinical studies, neutropenia was observed in 46.8% of patients (of which 41.7% were grade 3 or 4). Neutropenia did not lead to interruption of pomalidomide therapy in any patient and was mostly non-serious.

Febrile neutropenia was reported in 3.2–6.7% of patients, of whom 1.8–4.0% were considered serious.

In patients receiving pomalidomide combination therapy during clinical studies, thrombocytopenia occurred in 27.0–36.7% of patients. Grade 3 or 4 thrombocytopenia occurred in 20.7–27.3% of patients, leading to interruption of pomalidomide therapy in 0.7% of patients and considered serious in 0.4–1.7%.

Neutropenia and thrombocytopenia occurred more frequently during the first two cycles of pomalidomide treatment (see sections "Special precautions for use" and "Method and dose of administration").

Infection

Infection was the most common non-hematological toxic manifestation.

In patients receiving pomalidomide combination therapy during clinical studies, infection occurred in 55.0–80.2% of patients (of which 24.0–30.9% were grade 3 or 4). Upper respiratory tract infections and pneumonia were the most common infectious manifestations. Fatal infections (grade 5) occurred in 2.7–4.0% of patients. Infections led to discontinuation of pomalidomide therapy in 2.0–2.9% of patients.

Thromboembolic complications

Prophylaxis with acetylsalicylic acid (and other anticoagulants for patients at high risk) was mandatory for all patients in clinical studies. Anticoagulant therapy is recommended (if not contraindicated).

In patients receiving pomalidomide combination therapy during clinical studies, venous thromboembolic complications occurred in 3.3–11.5% of patients (of which 1.3–5.4% were grade 3 or 4). Venous thromboembolic complications were recorded as serious adverse reactions in 1.7–4.3% of patients, with no fatal reactions reported. Discontinuation of pomalidomide therapy due to venous thromboembolic complications occurred in up to 1.8% of patients.

Peripheral neuropathy

• Pomalidomide in combination with bortezomib and dexamethasone

Patients with pre-existing peripheral neuropathy ≥ grade 2 with pain lasting more than 14 days prior to randomization were excluded from clinical studies. Peripheral neuropathy was observed in 55.4% of patients (of which 10.8% were grade 3; 0.7% grade 4). Duration-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 12.9% of patients, pomalidomide in 1.8% of patients, and dexamethasone in 2.2–8.9% of patients, respectively. See also the respective Summary of Product Characteristics for bortezomib.

• Pomalidomide in combination with dexamethasone

Patients with pre-existing peripheral neuropathy ≥ grade 2 were excluded from clinical studies. 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 discontinuation due to peripheral neuropathy occurred in 0.3% of patients.

Bleeding/hemorrhage

Hemorrhagic disorders have been reported following pomalidomide administration, 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.

Allergic 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 following pomalidomide administration. Patients with a history of severe rashes associated with lenalidomide or thalidomide should not receive pomalidomide therapy.

Pediatric population

Adverse reactions reported in pediatric patients (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 medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as 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.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

21 capsules in a container with a child-resistant cap, 1 container in a cardboard box; 100 capsules in a container with a child-resistant cap, 1 container in a cardboard box; 7 capsules in a blister, 3 blisters in a cardboard box; 10 capsules in a blister, 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Dr. Reddy’s Laboratories Ltd, FTO-7.

Manufacturer’s address and location of operations.

Plot No. R1-R9, Phase - III, SEZ, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India.

To report an adverse reaction or lack of efficacy during use of the medicinal product, call (24/7):

+380 44 207 51 97 or +380 50 414 39 39; or send an email to: [email protected].