Pomalidomide-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Pomalidomide-Vista (Pomalidomide-Vista)

Composition:

Active substance: pomalidomide;

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

Excipients: microcrystalline cellulose, maltodextrin, sodium stearyl fumarate, hard gelatin capsule (gelatin, titanium dioxide (E 171), red iron oxide (E 172), yellow iron oxide (E 172), indigotine (E 132), erythrosine (E 127)).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

2 mg: hard gelatin capsules, capsule body orange-colored, cap red. "PLM 2" printed in white along the axis of the capsule body. Capsule size 2.

3 mg: hard gelatin capsules, capsule body turquoise-colored, cap red. "PLM 3" printed in white along the axis of the capsule body. Capsule size 2.

4 mg: hard gelatin capsules, capsule body dark blue-colored, cap red. "PLM 4" printed in white along the axis of the capsule body. Capsule size 2.

Pharmacotherapeutic group. Immunosuppressants. Other immunosuppressants.

ATC code L04A X06.

Pharmacological Properties

Pharmacodynamics

Pomalidomide exerts direct anti-myeloma antitumor and immunomodulatory effects and inhibits stromal cell support that promotes the growth of multiple myeloma cells. Specifically, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. Furthermore, pomalidomide inhibits proliferation of lenalidomide-resistant multiple myeloma cells and acts synergistically with dexamethasone in both lenalidomide-sensitive and lenalidomide-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, 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 polyubiquitination of various substrate proteins and may partially explain the pleiotropic cellular effects observed with pomalidomide treatment. In the presence of pomalidomide in vitro, the 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 a 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 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 Cmax 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 (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 a single 2 mg dose on day 4. In vitro, the binding of pomalidomide enantiomers to plasma proteins in human blood 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 predominant metabolic pathways for 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 exposure. Concomitant 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 with ketoconazole alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolic changes, coadministration of fluvoxamine and pomalidomide increased the mean plasma concentration of pomalidomide by 125% (90% CI [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 dose of pomalidomide should be reduced by 50%. Smoking has a clinically significant effect on pomalidomide plasma concentrations compared to non-smokers, as tobacco is known to induce CYP1A2 isoenzymes.

Based on in vitro data, pomalidomide is not an inhibitor or inducer of cytochrome P-450 isoenzymes and does not inhibit any of the drug transporters studied. Clinically significant drug interactions are not expected when pomalidomide is coadministered 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) administered 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 in Specific Populations

Based on population pharmacokinetic analysis 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 distribution was predominantly into tumors, with apparent peripheral 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 administration of 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, with 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 700–800 hour•ng/mL at the lower two doses and approximately 1200 hour•ng/mL at the higher dose. Estimated elimination half-life ranged from approximately 5 to 7 hours.

No clear trends related to age stratification or steroid use were observed at 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 pomalidomide after oral administration at doses 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 pharmacokinetic model with first-order absorption and elimination. Pomalidomide exhibited linear and time-invariant pharmacokinetics with moderate variability. Typical values for CL/F, Vc/F, Ka, and absorption delay 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 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, there is no substantial difference in pharmacokinetic parameters of pomalidomide between children and adults.

Elderly Patients

Based on pharmacokinetic analyses in healthy volunteers and patients with multiple myeloma, age (19–83 years) did not have a significant effect on the clearance of pomalidomide. 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 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 AUC exposure 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 AUC exposure of pomalidomide 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 AUC exposure of pomalidomide 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 those with normal renal function. The mean changes in pomalidomide exposure in each of these renal impairment groups are not of a magnitude requiring 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 to pomalidomide increased by 58% (90% CI [13% to 119%]) in patients with moderate hepatic impairment compared to healthy subjects. Mean exposure to pomalidomide 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 hepatic impairment groups did not result in changes of a magnitude requiring dose or schedule adjustments.

Clinical characteristics.

Indications.

Pomalidomide 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.

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 Programme.
• Male patients unable to comply with the 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 support staff must wear disposable gloves when handling the blister pack or capsule. After completing work with pomalidomide, gloves should be carefully removed to avoid skin contamination, placed into a sealed plastic polyethylene bag, and disposed of according to local requirements. Hands should then be thoroughly washed with soap and water.

Women who are pregnant or suspect they may be pregnant must not handle the pomalidomide blister pack 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 forms of interaction.

Effect of pomalidomide on other medicinal products

Pomalidomide is not expected to cause clinically significant pharmacokinetic drug interactions 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 of pomalidomide by 107% with a 90% CI [91% to 124%] compared to pomalidomide and ketoconazole therapy alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolic changes, fluvoxamine and pomalidomide were administered concomitantly, resulting in a 125% increase in the mean plasma concentration of pomalidomide with a 90% CI [98% to 157%], compared to pomalidomide alone. If co-administration 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 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 is unknown. Monitoring of warfarin blood levels is recommended during treatment.

Information on other medicinal products used in combination with Pomalidomide-Visto is provided in the respective product information leaflets.

Special precautions for use.

Teratogenicity

Pomalidomide must not be taken during pregnancy, as it has teratogenic effects. Pomalidomide is structurally related to thalidomide. Thalidomide is a known teratogenic medicinal product in humans, causing severe congenital malformations. Pomalidomide has been shown to be teratogenic when administered during the main period of 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 has no reproductive potential.

Criteria for women with no reproductive potential:

Women or female partners of 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 age).
• Premature ovarian failure confirmed by a specialist gynecologist.
• Previous bilateral salpingo-oophorectomy or hysterectomy.
• XY genotype, Turner syndrome, or uterine agenesis.

Counselling

Pomalidomide is contraindicated in women of childbearing 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 duration of treatment, 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 necessity to initiate 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 danger and necessity of preventive measures associated with pomalidomide use.

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

• The patient meets the requirements of the Pregnancy Prevention Programme, including confirmation that she has sufficient 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 patient populations with potentially prolonged drug elimination due to hepatic impairment, all male patients receiving pomalidomide must meet the following conditions:

• The man understands the expected teratogenic risk from sexual activity to 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 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 an expert experienced in teratology for risk assessment and advice.

Contraception

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

• Implant.
• Levonorgestrel-releasing intrauterine system.
• Depot medroxyprogesterone acetate.
• 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 (e.g., desogestrel).

Due to the increased risk of venous thromboembolism in patients with multiple myeloma receiving pomalidomide and dexamethasone, the use of combined oral contraceptive tablets is not recommended. 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 when taken concomitantly with dexamethasone.

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 for 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 testing

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

Before starting treatment

A physician-supervised pregnancy test must be performed during the consultation when pomalidomide is prescribed, or within 3 days prior to the visit, 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 the end 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 any 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.

Hematological complications

Neutropenia is the most frequently observed hematological adverse reaction of Grade 3 or 4 in patients with relapsed/refractory multiple myeloma, followed by anemia and thrombocytopenia. Patients should be monitored for hematological adverse reactions, particularly the development of neutropenia. Patients should also be warned to promptly report any episodes of fever. Physicians should monitor patients for bleeding, including nosebleeds, especially when concomitant medications known to increase bleeding risk are used. 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 required. Patients may require supportive therapy with blood products and/or growth factors.

Thromboembolic complications

Venous thromboembolism (primarily 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 with dexamethasone alone. 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 attention if symptoms such as dyspnea, chest pain, or swelling of an arm or leg occur. Prophylactic anticoagulant therapy (if not contraindicated) (e.g., acetylsalicylic acid, warfarin, heparin, or clopidogrel) is recommended, particularly 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 acetylsalicylic acid or alternative antithrombotic therapy for prophylaxis. 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 before and during pomalidomide treatment is recommended.

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 prior to study start; unstable or poorly controlled angina) were excluded from pomalidomide clinical trials. Adverse reactions related to the cardiovascular system, 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 prior to starting treatment. Close monitoring and appropriate preventive measures should be implemented in case of risk.

Secondary malignancies

Other 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 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 following pomalidomide use. Patients should be informed by their physician about the signs and symptoms of these reactions and advised to seek immediate medical attention if any symptoms occur. Pomalidomide must be discontinued in case of exfoliative or bullous rash or suspicion of Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS. Re-initiation 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 medicinal product should be considered in case of Grade 2–3 rash. Pomalidomide therapy must be permanently discontinued in case 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 consulting their physician.

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 be carefully evaluated to exclude ILD. Pomalidomide therapy should be discontinued during investigation of these symptoms, and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide therapy should 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. 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 in patients previously infected with hepatitis B virus (HBV) after pomalidomide therapy in combination with dexamethasone. Some of these cases led to acute liver failure, requiring discontinuation of pomalidomide therapy. The presence of hepatitis B virus should be determined before starting pomalidomide therapy. Patients with positive HIV infection test are recommended to consult a physician experienced in hepatitis B management. Caution should be exercised when treating patients previously infected with HBV, including patients with positive anti-HBc but negative HBsAg, when using 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 (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 concurrently receiving dexamethasone or had prior immunosuppressive chemotherapy. Physicians should regularly monitor patients and consider PML in the differential diagnosis of patients with new or progressive neurological, cognitive, or behavioral signs or 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 assessment should be based on neurological examination, brain MRI, cerebrospinal fluid analysis 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 (0.24 mg, 0.36 mg, 0.48 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 from 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 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 treatment if the partner is pregnant or of reproductive age and not using other forms of contraception.

Pregnancy

Pomalidomide is expected to have teratogenic effects in humans. Pomalidomide is contraindicated during pregnancy and in women of reproductive potential unless all conditions for preventing pregnancy are fulfilled.

Breastfeeding

There are no data confirming the passage of the medicinal product into human breast milk. Pomalidomide has been detected in the milk of lactating rats after administration. Due to the potential for 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 a negative effect on fertility and teratogenic effects in animals. Pomalidomide crosses the placenta and has been detected in fetal blood after administration to pregnant rabbits.

Ability to influence 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, 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, operate machinery, or perform hazardous tasks during treatment.

Method of administration and dosage.

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

A specific dose is continued or modified based on clinical and laboratory findings.

Combination therapy

• Lenalidomide in combination with bortezomib and dexamethasone

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

Lenalidomide is 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 toxicity occurs.

Table 1

Recommended dosing regimen of lenalidomide in combination with bortezomib and dexamethasone

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)*

Subsequent cycle 9	Day (of the 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 absolute neutrophil count must be > 1 x 10⁹/L and platelet count must be > 50 x 10⁹/L.

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

Table 2

Dose modification guidelines for pomalidomide

Toxicity	Dose modification
Neutropenia* ANC** <0.5 x 109/L or febrile neutropenia (fever ≥38.5 °C and ANC** <1 x 109/L)	Interrupt 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	Interrupt 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	Interrupt pomalidomide treatment until the end of the cycle. Perform CBC*** weekly.
Platelet count returns to ≥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	Interrupt pomalidomide treatment.
Platelet count returns to ≥50 x 109/L	Resume pomalidomide treatment at a dose one level lower than the previous dose.
Rash Rash grade 2-3	Consider dose modification or discontinuation of pomalidomide.
Rash grade 4 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 completion of the cycle. In the next cycle, resume pomalidomide treatment at a dose one level lower than the previous dose (adverse reactions must be resolved or improved to ≤ grade 2 prior to resuming therapy).

The 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.

Table 3

Pomalidomide dose reduction

Dose level	Oral pomalidomide dose
Starting 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%.

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.

Table 4

Dexamethasone dose modification guidelines

Toxicity	Dose adjustment
Grade 1-2 dyspepsia	Maintain dose and treat with H2 histamine receptor blockers or analogs. Reduce dose by one level if symptoms persist.
Grade ≥3 dyspepsia	Temporarily interrupt treatment until symptoms become manageable. 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	Consider adding diuretics to therapy and reduce the drug dose by one level from the previous dose.
Disorientation and mood changes ≥ grade 2	Interrupt treatment until symptoms are resolved. Resume treatment at a dose one level lower than the previous dose.
Muscle weakness ≥ grade 2	Interrupt 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. Add insulin or oral hypoglycemic agents to therapy as needed.
Acute pancreatitis	Exclude dexamethasone from the treatment regimen.
Other dexamethasone-related adverse reactions ≥ 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 resumed at one level lower than the previous dose.

Table 5

Reduction of dexamethasone dose

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

Dexamethasone should be discontinued if the patient is unable to tolerate a dose of 8 mg at age ≤ 75 years or a dose of 4 mg at age >75 years.

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

• Pomalidomide in combination with dexamethasone

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

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

Treatment with pomalidomide in combination with dexamethasone should continue until disease progression or the occurrence of toxic effects.

Dose modification or discontinuation of pomalidomide

Instructions for temporary interruption of therapy or dose reduction to manage pomalidomide-related adverse reactions are provided in Tables 2 and 3.

Dexamethasone dose modification

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

Table 6

Dexamethasone dose reduction

Dose level	≤ 75 years Days 1, 8, 15, 22 of each 28-day cycle	>75 years Days 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 concomitant use of bortezomib with pomalidomide is provided in the relevant section of the current Summary of Product Characteristics.

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

• Cycles 1 to 8: 10 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.
• From cycle 9 onwards: 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 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 serum total 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 adjustment of the initial dose of pomalidomide is required in patients with hepatic impairment as defined by Child-Pugh criteria. However, patients with hepatic impairment should be closely monitored for the occurrence of adverse reactions, and dose reductions or interruption of pomalidomide therapy 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 use.

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 scheduled the following day. Patients must not alter the dose to compensate for a missed dose from previous days.

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

Information on other medicinal products used in combination with Pomalidomide-Vista is provided in the respective Summary of Product Characteristics.

Paediatric population

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

Apart from registered indications, 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 data are presented in the sections "Adverse Reactions" and "Pharmacological Properties". There is no established use of pomalidomide in children aged 0–17 years for the indication of 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

• 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 frequent adverse reactions of Grade 3 or 4 severity were hematologic and lymphatic system disorders: neutropenia (41.7%), thrombocytopenia (27.3%), and anemia (14.0%). The most commonly reported serious adverse reaction was pneumonia (11.5%). Other serious adverse reactions included pyrexia (4.0%), lower respiratory tract infection (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, 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 embolism (VTE) occurred in 3.3% of patients. The most commonly reported adverse reactions of Grade 3 or 4 severity 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 thrombotic embolism reactions (1.7%).

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

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 "Posology and method of administration").

Adverse reactions observed in patients receiving pomalidomide in combination with bortezomib and dexamethasone are listed in Table 7 by System Organ Class (SOC), overall frequency of all adverse reactions, and frequency of Grade 3 and Grade 4 adverse reactions.

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

Table 7
All adverse reactions (ARs) reported in the MM-007 clinical trial in patients receiving pomalidomide in combination with bortezomib and dexamethasone

System organ class / Preferred 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, pseudomembranous colitis, respiratory tract infections, lower respiratory tract infections, pulmonary infection, influenza, bronchiolitis, urinary tract infections	Very common Pneumonia Common Sepsis, septic shock, pseudomembranous colitis, bronchitis, upper respiratory tract infections, lower respiratory tract infections, pulmonary infection, influenza, bronchiolitis, urinary tract infections
Benign, malignant and unspecified neoplasms (including 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 trial CC-4047-MM-003, 302 patients with relapsed and refractory multiple myeloma received pomalidomide 4 mg administered once daily for 21 days of each 28-day cycle in combination with low-dose dexamethasone weekly.

Adverse reactions observed in patients receiving pomalidomide in combination with dexamethasone are listed below in Table 8 by System Organ Class (SOC), overall 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 trial 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 current conventions: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); frequency not known (cannot be estimated from the available data).

Table 8

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

System organ class/Preferred term	All common adverse reactions/Frequency	3-4 grade 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 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 levels	Common Decreased neutrophil count, decreased white blood cell count, decreased platelet count, increased ALT levels

In addition to the adverse reactions listed above identified in the main clinical trials, the following Table 9 is derived from data collected during the post-marketing period.

Table 9

Reports of consistent adverse reactions occurring during the post-marketing period with pomalidomide therapy

System organ class/Preferred 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, solid organ transplant rejection	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 Nose bleed, Upper respiratory tract infection	Uncommon Nose bleed, upper respiratory tract infection
Hepatobiliary disorders	Uncommon Hepatitis
Skin and subcutaneous tissue disorders	Frequency unknown Drug reaction with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis, Stevens-Johnson syndrome	Frequency unknown Drug reaction with eosinophilia and systemic symptoms (DRESS), 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 known human teratogen causing severe congenital birth defects. 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 of the medicinal product 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 discontinuation of pomalidomide therapy in any patient and was mostly non-serious.

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

In patients receiving pomalidomide combination therapy in 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 pomalidomide therapy interruption 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" and "Dosage and administration").

Infection

Infection was the most common non-hematological toxic manifestation.

In patients receiving pomalidomide combination therapy in 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 in 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 reported as serious adverse reactions in 1.7–4.4% of patients, with no fatal events reported. Venous thromboembolic complications were associated with discontinuation of pomalidomide therapy 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 within 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). 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 12.9% of patients, pomalidomide in 1.8%, 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 reported, and therapy discontinuation due to peripheral neuropathy occurred in 0.3% of patients.

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.

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

Paediatric population

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

High-density polyethylene (HDPE) bottles with a polypropylene child-resistant closure. 21 capsules in a bottle, 1 bottle in a cardboard box.

7 capsules in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sandoz Spain, S.L.

Manufacturer's address and place of business.

C/Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.