Pomalidomide-vista
UkraineTable of Contents
INSTRUCTION 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), iron oxide red (E 172), iron oxide yellow (E 172), indigo carmine (E 132), erythrosine (E 127)).
Pharmaceutical form. Hard capsules.
Main physicochemical characteristics:
2 mg: hard gelatin capsules, capsule body orange-colored, cap red. "PLM 2" printed in white along the body axis of the capsule. Capsule size 2.
3 mg: hard gelatin capsules, capsule body turquoise-colored, cap red. "PLM 3" printed in white along the body axis of the capsule. Capsule size 2.
4 mg: hard gelatin capsules, capsule body dark blue-colored, cap red. "PLM 4" printed in white along the body axis of the capsule. Capsule size 2.
Pharmacotherapeutic group. Antineoplastic agents and immunomodulators. Immunosuppressants. Other immunosuppressants. Pomalidomide. ATC code L04AX06.
Pharmacological Properties
Pharmacodynamics
Pomalidomide exerts direct anti-myeloma antitumor and immunomodulatory effects and inhibits the supportive 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 and acts synergistically with dexamethasone—both in 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 the cereblon (CRBN) protein, a component of the E3 ubiquitin ligase complex, which includes DNA damage-binding protein 1 (DDB1), Cullin 4 (CUL4), and Roc1 (Regulator of Cullin-1), and may inhibit auto-ubiquitination of CRBN within the complex. E3 ubiquitin ligases are responsible for polyubiquitination of various substrate proteins and may partially explain the pleiotropic cellular effects observed during pomalidomide treatment. In the presence of pomalidomide in vitro, the substrate proteins Aiolos and Ikaros undergo ubiquitination and subsequent degradation, 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 administered dose is absorbed after a single oral dose. The area under the plasma concentration-time curve (AUC) of pomalidomide increases approximately linearly and proportionally with dose. Following multiple dosing, pomalidomide exhibits an accumulation ratio of 27% to 31% based on AUC.
Concomitant administration of pomalidomide 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, decreasing the mean systemic exposure by only 8%. Therefore, pomalidomide may be administered independently 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 a concentration of approximately 67% of plasma levels 4 hours after dose administration (approximate Tmax) following 4 days of single 2 mg dosing. In vitro, the binding of pomalidomide enantiomers to human plasma proteins ranges from 12% to 44% and is independent of concentration.
Metabolism
Pomalidomide is the primary circulating component (approximately 70% of plasma radioactivity) in vivo in healthy volunteers receiving a single oral dose of [14C]-pomalidomide (2 mg). No metabolites in plasma were detected at concentrations >10% of the parent compound or total radioactivity.
The 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 pomalidomide exposure by 107% (90% CI: 91% to 124%) compared to pomalidomide plus ketoconazole alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolism, coadministration of fluvoxamine and pomalidomide increased the 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, and fluvoxamine) with pomalidomide is necessary, the pomalidomide dose 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 neither an inhibitor nor an 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 volunteers 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 radioactive dose was excreted in urine and feces, respectively. Approximately 2% and 8% of the radiocarbon dose was excreted as unchanged pomalidomide in urine and feces, respectively.
Prior to excretion, pomalidomide undergoes extensive metabolism, with metabolites primarily excreted in urine. The 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 constitute 25%, and excretion of unchanged pomalidomide accounts for 10% (2% in urine and 8% in feces).
Pharmacokinetics in Specific Populations
Population pharmacokinetic analysis using a two-compartment model showed that healthy volunteers and patients with multiple myeloma had comparable apparent clearance (CL/F) and apparent central volume of distribution (V2/F). In peripheral tissues, pomalidomide was predominantly taken up by tumors, with apparent peripheral distribution clearance (Q/F) and apparent peripheral volume of distribution (V3/F) being 3.7 and 8 times higher, respectively, than in healthy volunteers.
Pediatric 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. The geometric mean Cmax (CV %) values were 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 high dose. The estimated elimination half-life was approximately 5 to 7 hours.
No clear trends related to age stratification or steroid use were observed at the minimal topological difference (MTD).
Overall, data indicate that AUC increases nearly proportionally with increasing pomalidomide dose, whereas increases in Cmax are generally less than proportional.
Pharmacokinetics of orally administered pomalidomide at doses ranging from 1.9 to 3.4 mg/m²/day were evaluated in 70 patients aged 4 to 20 years in a pooled analysis of phase 1 and phase 2 studies in recurrent or progressive pediatric brain tumors. Pomalidomide concentration-time profiles were adequately described by a one-compartment pharmacokinetic 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 lag time were 3.94 L/h, 43.0 L, 1.45 h⁻¹, and 0.454 h, respectively. The terminal elimination half-life of pomalidomide was 7.33 hours. Except for body surface area (BSA), none of the tested covariates—including age and sex—significantly influenced pomalidomide 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 significantly affect pomalidomide clearance. Dose adjustment was not required in elderly patients (>65 years) in clinical studies.
Renal Impairment
Population pharmacokinetic analysis showed that pharmacokinetic parameters of pomalidomide were not significantly affected in patients with renal impairment (defined by creatinine clearance or estimated glomerular filtration rate [eGFR]) compared to patients with normal renal function (CrCl ≥ 60 mL/min). The mean normalized 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. The mean normalized 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 patients with normal renal function. The mean normalized AUC 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 volunteers. Mean pomalidomide exposure increased by 51% (90% CI: 9% to 110%) in patients with mild hepatic impairment compared to healthy volunteers. Mean exposure increased by 58% (90% CI: 13% to 119%) in patients with moderate hepatic impairment compared to healthy volunteers. Mean 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 groups were not 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 regimen 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 treatment regimens including lenalidomide and bortezomib, and who have demonstrated disease progression on the most recent therapy.
Contraindications
- Pregnancy.
- Women of childbearing potential who do not comply with all requirements of the Pregnancy Prevention Program.
- 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 the skin or mucous membranes, they should be immediately and thoroughly washed with soap and water. Healthcare professionals and support staff should wear disposable gloves when handling the blister pack or capsule. After completing work with pomalidomide, gloves should be carefully removed to avoid skin contact, placed into a sealed polyethylene plastic 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 Warnings and Precautions for Use").
Any unused medicinal product or waste material must be disposed of according to local requirements.
Unused capsules must be returned to the healthcare facility at the end of treatment.
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 enzymes 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-gp. Concomitant administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole or the strong CYP3A4/5 inducer carbamazepine did not clinically affect pomalidomide exposure. Concomitant administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole increased the mean exposure to pomalidomide by 107% with a 90% CI [91% to 124%], compared to pomalidomide and ketoconazole alone. In a second study evaluating the impact of a CYP1A2 inhibitor on metabolism, co-administration of fluvoxamine and pomalidomide resulted 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 pomalidomide dose should be reduced by 50%.
Dexamethasone
Repeated administration of pomalidomide doses up to 4 mg together with dexamethasone at 20 to 40 mg (considered a weak or moderate inducer of several CYP enzymes, including CYP3A) in patients with multiple myeloma did not affect the pharmacokinetics of pomalidomide compared to pomalidomide alone.
The effect of dexamethasone on warfarin is unknown. Monitoring of warfarin blood levels is recommended during treatment.
Special precautions for use
Teratogenicity
Pomalidomide must not be used during pregnancy, as it has teratogenic effects. Pomalidomide is structurally related to thalidomide. Thalidomide is a well-known medicinal product with teratogenic effects 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 lacks reproductive potential.
Criteria for women without reproductive potential:
Women patients or female partners of male patients are considered to lack reproductive potential if they meet at least one of the following criteria:
- Age ≥ 50 years and natural amenorrhea for ≥1 year (amenorrhea due to cancer therapy or during breastfeeding does not exclude reproductive age).
- Premature ovarian failure confirmed by a specialist gynecologist.
- Previous bilateral salpingo-oophorectomy or hysterectomy.
- XY genotype, Turner syndrome, uterine agenesis.
Consultation
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 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 of starting treatment as soon as possible after pomalidomide is dispensed, following a negative pregnancy test result.
- The woman understands the necessity and agrees to undergo pregnancy testing at least every 4 weeks, except in cases where tubal sterilization has been confirmed.
- The woman acknowledges that she understands the risks and the necessity of preventive measures associated with pomalidomide use.
The prescribing physician must ensure that women of reproductive age meet the following conditions:
- The patient complies with the requirements of the Pregnancy Prevention Programme, including confirmation that she has adequate understanding of the necessity of these measures.
- The patient acknowledges the above-mentioned 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 for a pregnant woman or a woman of reproductive potential.
- The man understands the necessity of using a condom during sexual intercourse with a pregnant woman or a woman of reproductive age who is not using effective contraception, throughout the entire treatment period, during treatment interruptions, and for 7 days after treatment has been interrupted 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 with 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. It is also recommended to refer the partner to a specialist or teratology expert for risk assessment and counseling.
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 dose interruptions, unless the patient commits to complete and continuous abstinence each month. 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. Examples of effective contraceptive methods include:
- 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 (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 currently using combined oral contraception, they 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. Patients, especially those with neutropenia, should carefully consider the possibility of prophylactic antibiotic use. Insertion of copper-releasing intrauterine devices is not recommended due to potential infection risks during insertion and menstrual blood loss, which may pose risks for patients with severe neutropenia or pronounced thrombocytopenia.
Pregnancy diagnosis
According to local practice, women of reproductive potential, as defined above, must undergo medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL. This requirement also applies to women of reproductive potential who practice complete and permanent abstinence. Ideally, pregnancy testing, prescription, and drug dispensing should occur on the same day. Dispensing of pomalidomide to women of reproductive age should occur within 7 days of prescription and after a negative pregnancy test result.
Before starting treatment
A pregnancy test should be performed under medical supervision during the consultation when pomalidomide is prescribed, or within 3 days prior to the visit if the patient has been using effective contraceptive methods 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 medically 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 unused capsules to the healthcare facility at the end of treatment.
Patients receiving pomalidomide must not donate blood, semen, or sperm during treatment (including during dose interruptions) and for 7 days after discontinuation of pomalidomide therapy.
Healthcare professionals and caregivers should use disposable gloves when handling blisters or capsules.
Pregnant women or women who suspect they may be pregnant should not handle blisters or capsules.
Educational materials, prescribing and dispensing restrictions
To assist patients in avoiding the effects of pomalidomide on the fetus, the marketing authorization holder must provide healthcare professionals with educational materials to reinforce the warnings regarding the teratogenicity of pomalidomide, recommend contraception before starting therapy, and explain the necessity of pregnancy testing. The physician must inform both male and female patients about the risk of teratogenic effects of pomalidomide and the necessity of strict pregnancy prevention measures according to the Pregnancy Prevention Programme. The physician must provide the patient with an educational brochure and a patient card and/or equivalent document according to the implemented national patient card system. A national controlled dispensing system has been established in cooperation with each national competent authority. The controlled dispensing system includes the use of a patient card and/or equivalent document to monitor prescribing and/or dispensing, and to collect detailed prescription data for careful monitoring of misuse within the national territory. Ideally, pregnancy testing, treatment prescription, and drug dispensing should occur on the same day. Dispensing of pomalidomide to women with preserved reproductive potential should occur no later than 7 days after treatment prescription and after a negative physician-supervised pregnancy test.
Prescriptions for women of reproductive age may be issued for a maximum treatment duration of 4 weeks according to approved dosing regimens, while prescriptions for all other patients may be issued for a maximum treatment duration of 12 weeks.
Hematological complications
Neutropenia is the most commonly observed hematological adverse reaction (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 neutropenia. Patients should also be warned to report episodes of fever promptly. 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 during the first 8 weeks of treatment, 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, arterial 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. 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 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 medicinal products that may increase the risk of thromboembolic complications should be used with caution.
Thyroid disorders
Cases of hypothyroidism have been reported. Concomitant 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 reactions related to the cardiovascular system, including congestive heart failure, pulmonary edema, and atrial fibrillation, have been reported, mainly in patients with pre-existing cardiac conditions 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. In such cases, close monitoring and appropriate preventive measures should be implemented when risk is present.
Other primary 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 examinations to detect other primary malignancies and initiate appropriate treatment as indicated.
Allergic reactions and severe skin reactions
Angioedema and severe dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported after pomalidomide use. 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 use must be discontinued in cases of exfoliative or bullous rash or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS. Therapy should not be resumed after resolution of the reaction. Patients with a history of serious allergic reactions to thalidomide or lenalidomide were excluded from clinical trials. Such patients are at high risk of hypersensitivity reactions and must not take pomalidomide. Discontinuation of the drug should be considered in cases of grade 2–3 rash. Permanent discontinuation of pomalidomide therapy is required in cases of angioedema.
Dizziness and confusion
Cases of dizziness and confusion have been reported after pomalidomide use. Patients should avoid situations where dizziness or confusion could be problematic and should not use other medicinal products that may cause dizziness or confusion without consulting a physician.
Interstitial lung disease (ILD)
Cases of ILD and related events, including pneumonia, have been reported after pomalidomide use. A careful evaluation of patients with acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. Pomalidomide therapy should be interrupted during investigation of these symptoms, and appropriate treatment should be initiated if ILD is confirmed. Pomalidomide therapy may be resumed only after careful benefit-risk assessment.
Hepatic disorders
Marked increases in alanine aminotransferase (ALT) and bilirubin levels have been observed in patients receiving pomalidomide. Cases of hepatitis requiring discontinuation of pomalidomide therapy have also been reported. Clinical monitoring of liver function is recommended throughout 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, necessitating discontinuation of pomalidomide therapy. HBV status should be determined before starting pomalidomide therapy. Patients with positive HIV infection test are advised to consult a physician experienced in hepatitis B management. Caution should be exercised when treating with pomalidomide in combination with dexamethasone in patients with prior HBV infection, including those with positive anti-HBc but negative HBsAg. These patients should be monitored for signs and symptoms of active HBV throughout therapy.
Progressive multifocal leukoencephalopathy (PML)
Cases of progressive multifocal leukoencephalopathy, including fatal cases, have been reported with pomalidomide use. PML cases have occurred from several months to several years after starting pomalidomide therapy. PML cases have typically 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 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.
Evaluation of PML should be based on neurological examination, brain magnetic resonance imaging, 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., it can be considered 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 counseling. If a woman becomes pregnant from a man taking pomalidomide, it is recommended to refer the patient to a physician specialized or experienced in teratology for fetal risk assessment and counseling. Pomalidomide penetrates into human semen. As a precautionary measure, all male patients taking pomalidomide must use condoms throughout the entire treatment period, during treatment interruptions, and for 7 days after treatment discontinuation if the sexual partner is a pregnant woman or a woman of reproductive age not using highly effective contraceptive methods.
Pregnancy
Pomalidomide is expected to have teratogenic effects in humans. Pomalidomide is contraindicated during pregnancy and in women of reproductive age, except when all conditions for pregnancy prevention 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 risk of adverse reactions in breastfed children, a decision must be made whether to discontinue breastfeeding or pomalidomide therapy, taking into account the benefits of breastfeeding for the child and the benefits 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 affect reaction speed when driving or operating machinery
Pomalidomide has a minor or moderate influence on the ability to drive or operate machinery. Cases of fatigue, 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.
Dosage and Administration
Treatment should be initiated and supervised by physicians experienced in the management of multiple myeloma.
The prescribed dose should be continued or adjusted based on clinical and laboratory findings.
Combination Therapy
- Lenalidomide in combination with bortezomib and dexamethasone
The recommended initial dose of lenalidomide is 4 mg orally once daily on days 1 to 14 of each 21-day cycle.
Lenalidomide is administered in combination with bortezomib and dexamethasone (see Table 1). The initial 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 unacceptable toxicity occurs.
Table 1
Recommended dosing regimen for Pomalidomide-Vista 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 neutrophil count must be > 1 x 10⁹/L and the platelet count must be > 50 x 10⁹/L.
Guidelines for interruption or reduction of dose to manage adverse reactions related to pomalidomide are provided in Table 2, and dose levels are defined in Table 3.
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 of grade 2–3 |
Consider dose modification or discontinuation of pomalidomide. |
| Rash of grade 4 or blistering (including angioedema, anaphylactic reaction, exfoliative or bullous rash, or if Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) is suspected) |
Permanently discontinue treatment. |
| Other Other pomalidomide-related adverse reactions ≥ grade 3 |
Interrupt pomalidomide treatment until the end of the cycle. In the next cycle, resume pomalidomide 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). |
Dose modification instructions 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 |
The 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, treatment with the medicinal product must be discontinued.
Strong CYP1A2 inhibitors
If strong CYP1A2 inhibitors, such as ciprofloxacin, enoxacin, and fluvoxamine, are coadministered with pomalidomide, the pomalidomide dose should be reduced by 50%.
Dosage adjustment or discontinuation of bortezomib
For instructions on temporary interruption or dose reduction of bortezomib, physicians should refer to the appropriate product information for the medicinal product containing bortezomib.
Dosage 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 product information for the medicinal product.
Table 4
Dexamethasone dosage modification guidelines
| Toxicity |
Dose adjustment |
| Mild to moderate dyspepsia (Grade 1–2) |
Maintain dose and treat with H2-receptor blockers or analogs. Reduce dose by one level if symptoms persist. |
| Severe dyspepsia (Grade ≥ 3) |
Temporarily interrupt treatment until symptoms are controlled. Add H2-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 resolve. Resume therapy 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 therapy 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 if needed. |
| Acute pancreatitis |
Exclude dexamethasone from the treatment regimen. |
| Other dexamethasone-related adverse reactions ≥ Grade 3 |
Discontinue dexamethasone therapy until adverse reaction manifestations decrease to ≤ Grade 2. Resume therapy at a dose one level lower than the previous dose. |
If recovery from the toxic effect takes more than 14 days, the dose of dexamethasone will be restored to one level lower than the previous dose.
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 physician should determine whether to continue the remaining medicinal products.
- Pomalidomide in combination with dexamethasone
The recommended starting dose of Pomalidomide-Vista is 4 mg. Administer 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 until the occurrence of unacceptable toxicity.
Dose modification or discontinuation of pomalidomide
Guidelines for temporary interruption or dose reduction to manage pomalidomide-related adverse reactions are provided in Tables 2 and 3.
Dexamethasone dose modification
Guidelines for dose adjustment to manage dexamethasone-related adverse reactions are provided in Table 4. Guidelines for dose reduction to manage dexamethasone-related adverse reactions are provided in Table 6. However, decisions regarding discontinuation or re-initiation of dosing should be made at the physician's discretion in accordance with the current medical instructions for the medicinal product.
Table 6
Dexamethasone dose reduction
| Dose level |
≤ 75 years Day 1, 8, 15, 22 of each 28-day cycle |
>75 years Day 1, 8, 15, 22 of each 28-day cycle |
| Initial dose |
40 mg |
20 mg |
| Dose level – 1 |
20 mg |
12 mg |
| Dose level – 2 |
10 mg |
8 mg |
Dexamethasone should be discontinued if the patient 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
Dose adjustment of pomalidomide is not required.
Pomalidomide in combination with bortezomib and dexamethasone
For patients >75 years of age, the initial dose of dexamethasone is:
- Days 1 to 8 cycles: 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
For patients >75 years of age, the initial dose of dexamethasone is:
- 20 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle.
Hepatic impairment
Patients with 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. Initial dose adjustment of pomalidomide is not required in patients with hepatic impairment as defined by Child–Pugh criteria. However, patients with hepatic impairment should be closely monitored for adverse reactions, and dose reduction or interruption of pomalidomide therapy should be considered if necessary.
Renal impairment
Dose adjustment of pomalidomide in patients with renal impairment is not necessary. 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, regardless of food intake. Capsules must not be opened, broken, or chewed. Capsules should be swallowed whole, preferably with water. If a patient misses a dose of pomalidomide on any given day, the prescribed dose should be taken as scheduled on the following day. Patients must not adjust the dose to compensate for a missed dose from previous days.
It is recommended to press only one end of the capsule to remove it from the blister pack, thereby minimizing the risk of capsule deformation or breakage.
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. Current available data are presented in the sections “Pharmacological properties” and “Adverse reactions”.
Overdose
Administration of pomalidomide at a single dose of 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 (54.0%), thrombocytopenia (39.9%), and anemia (32.0%).
Other commonly reported adverse reactions included peripheral sensory neuropathy (48.2%), fatigue (38.8%), diarrhea (38.1%), constipation (38.1%), and peripheral edema (36.3%).
The most common grade 3 or 4 adverse reactions were hematologic and lymphatic system events: neutropenia (41.7%), thrombocytopenia (28.1%), and anemia (15.1%). The most frequently reported serious adverse reaction was pneumonia (12.2%). Other serious adverse reactions included pyrexia (4.3%), lower respiratory tract infection (3.6%), influenza (3.6%), pulmonary embolism (3.2%), atrial fibrillation (3.2%), and acute kidney injury (2.9%).
- Pomalidomide in combination with dexamethasone
In clinical trials, the most frequently reported adverse reactions were hematologic and lymphatic system disorders, including anemia (45.7%), neutropenia (45.3%), and thrombocytopenia (27%); general disorders and administration site conditions such as fatigue (28.3%), pyrexia (21%), and peripheral edema (13%); and infections and infestations including pneumonia (10.7%). Peripheral neuropathy was reported in 12.3% of patients and venous or thrombotic embolic events (VTE) in 3.3% of patients. The most frequently reported grade 3 or 4 adverse reactions were hematologic 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 common serious adverse reaction reported was pneumonia (9.3%). Other serious adverse reactions included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%), and venous or thrombotic embolic reactions (1.7%).
Adverse reactions generally occur during the first two cycles of pomalidomide treatment.
List of adverse reactions in tabular form
Adverse reactions observed in patients receiving pomalidomide in combination with bortezomib and dexamethasone, and pomalidomide in combination with dexamethasone, are listed in Table 7 by system organ class, frequency of all adverse reactions, and frequency of grade 3 and 4 adverse reactions.
The frequency of adverse reactions is defined according to current conventions: very common (≥ 1/10); common (≥ 1/100 and < 1/10); uncommon (≥ 1/1,000 and < 1/100); and frequency not known (cannot be estimated based on available data).
Table 7
Adverse reactions recorded during clinical studies and post-marketing surveillance
| Combination of treatments |
Pomalidomide/ bortezomib/dexamethasone |
Pomalidomide/ dexamethasone |
||
| System organ class / Preferred term |
All adverse reactions |
Grade 3–4 adverse reactions |
All adverse reactions |
Grade 3–4 adverse reactions |
| Infections and infestations |
||||
| Pneumonia |
very common |
very common |
- |
- |
| Pneumonia (bacterial, viral and fungal infections, including opportunistic infections) |
- |
- |
very common |
common |
| Bronchitis |
very common |
common |
common |
uncommon |
| Upper respiratory tract infection |
very common |
common |
common |
common |
| Viral upper respiratory tract infection |
very common |
- |
- |
- |
| Sepsis |
common |
common |
- |
- |
| Septic shock |
common |
common |
- |
- |
| Neutropenic sepsis |
- |
- |
common |
common |
| Pseudomembranous colitis |
common |
common |
- |
- |
| Bronchopneumonia |
- |
- |
common |
common |
| Respiratory tract infections |
common |
common |
common |
common |
| Infections of lower respiratory tract |
common |
common |
- |
- |
| Lung infection |
common |
uncommon |
- |
- |
| Influenza |
very common |
common |
- |
- |
| Bronchiolitis |
common |
common |
- |
- |
| Urinary tract infections |
very common |
common |
- |
- |
| Nasopharyngitis |
- |
- |
common |
- |
| Herpes zoster |
- |
- |
common |
uncommon |
| Hepatitis B reactivation |
- |
- |
frequency unknown* |
frequency unknown* |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
||||
| Basal cell carcinoma |
common |
uncommon |
- |
- |
| Basal cell skin cancer |
- |
- |
uncommon |
uncommon |
| Squamous cell skin cancer |
- |
- |
uncommon |
uncommon |
| Blood and lymphatic system disorders |
||||
| Neutropenia |
very common |
very common |
very common |
very common |
| Thrombocytopenia |
very common |
very common |
very common |
very common |
| Leukopenia |
very common |
common |
very common |
common |
| Anemia |
very common |
very common |
very common |
very common |
| Febrile neutropenia |
common |
common |
common |
common |
| Lymphopenia |
common |
common |
- |
- |
| Pancytopenia |
- |
- |
common* |
common* |
| Immune system disorders |
||||
| Angioedema |
- |
- |
common* |
uncommon* |
| Urticaria |
- |
- |
common* |
uncommon* |
| Anaphylactic reaction |
frequency unknown* |
frequency unknown* |
- |
- |
| Organ rejection in parenchymal organ transplantation |
frequency unknown* |
- |
- |
- |
| Endocrine disorders |
||||
| Hypothyroidism |
uncommon* |
- |
- |
- |
| Metabolism and nutrition disorders |
||||
| Hypokalemia |
very common |
common |
- |
- |
| Hyperglycemia |
very common |
common |
- |
- |
| Hypomagnesemia |
common |
common |
- |
- |
| Hypocalcemia |
common |
common |
- |
- |
| Hypophosphatemia |
common |
common |
- |
- |
| Hyperkalemia |
common |
common |
common |
common |
| Hypercalcemia |
common |
common |
- |
- |
| Hyponatremia |
- |
- |
common |
common |
| Decreased appetite |
- |
- |
very common |
uncommon |
| Hyperuricemia |
- |
- |
common* |
common* |
| Tumor lysis syndrome |
- |
- |
uncommon* |
uncommon* |
| Psychiatric disorders |
||||
| Insomnia |
very common |
common |
- |
- |
| Depression |
common |
common |
- |
- |
| Confusion |
- |
- |
common |
common |
| Nervous system disorders |
||||
| Peripheral sensory neuropathy |
very common |
common |
common |
uncommon |
| Dizziness |
very common |
uncommon |
common |
uncommon |
| Tremor |
very common |
uncommon |
common |
uncommon |
| Syncope |
common |
common |
- |
- |
| Peripheral sensorimotor neuropathy |
common |
common |
- |
- |
| Paraesthesia |
common |
- |
- |
- |
| Dysgeusia |
common |
- |
- |
- |
| Decreased level of consciousness |
- |
- |
common |
common |
| Intracranial hemorrhage |
- |
- |
common* |
uncommon* |
| Stroke |
- |
- |
uncommon* |
uncommon* |
| Eye disorders |
||||
| Cataract |
common |
common |
- |
- |
| Ear and labyrinth disorders |
||||
| Dizziness |
- |
- |
common |
common |
| Cardiac disorders |
||||
| Atrial fibrillation |
very common |
common |
common* |
common* |
| Heart failure |
- |
- |
common* |
common* |
| Myocardial infarction |
- |
- |
common* |
uncommon* |
| Vascular disorders |
||||
| Deep vein thrombosis |
common |
uncommon |
common |
uncommon |
| Arterial hypotension |
common |
common |
- |
- |
| Arterial hypertension |
common |
common |
- |
- |
| Respiratory, thoracic and mediastinal disorders |
||||
| Dyspnea |
very common |
common |
very common |
common |
| Cough |
very common |
- |
very common |
uncommon |
| Pulmonary embolism |
common |
common |
common |
uncommon |
| Nose bleed |
- |
- |
common* |
uncommon* |
| Interstitial lung disease (ILD) |
- |
- |
common* |
uncommon* |
| Gastrointestinal disorders |
||||
| Diarrhea |
very common |
common |
very common |
common |
| Vomiting |
very common |
common |
common |
common |
| Nausea |
very common |
uncommon |
very common |
uncommon |
| Constipation |
very common |
common |
very common |
common |
| Abdominal pain |
very common |
common |
- |
- |
| Upper abdominal pain |
common |
uncommon |
- |
- |
| Stomatitis |
common |
uncommon |
- |
- |
| Dry mouth |
common |
- |
- |
- |
| Abdominal distension |
common |
uncommon |
- |
- |
| Gastrointestinal hemorrhage |
- |
- |
common |
uncommon |
| Hepatobiliary disorders |
||||
| Hyperbilirubinemia |
- |
- |
uncommon |
uncommon |
| Hepatitis |
- |
- |
uncommon* |
- |
| Skin and subcutaneous tissue disorders |
||||
| Rash |
very common |
common |
common |
common |
| Pruritus |
- |
- |
common |
- |
| Drug reaction with eosinophilia and systemic symptoms (DRESS) |
- |
- |
frequency unknown* |
frequency unknown* |
| Toxic epidermal necrolysis |
- |
- |
frequency unknown* |
frequency unknown* |
| Stevens-Johnson syndrome |
- |
- |
frequency unknown* |
frequency unknown* |
| Musculoskeletal and connective tissue disorders |
||||
| Muscle weakness |
very common |
common |
- |
- |
| Back pain |
very common |
common |
- |
- |
| Bone pain |
common |
uncommon |
very common |
common |
| Muscle spasms |
very common |
- |
very common |
uncommon |
| Renal and urinary disorders |
||||
| Acute kidney injury |
common |
common |
- |
- |
| Chronic kidney disease |
common |
common |
- |
- |
| Urinary retention |
common |
common |
common |
uncommon |
| Kidney failure |
- |
- |
common |
common |
| Reproductive system and breast disorders |
||||
| Pelvic pain |
- |
- |
common |
common |
| General disorders and administration site conditions |
||||
| Fatigue |
very common |
common |
very common |
common |
| Pyrexia |
very common |
common |
very common |
common |
| Peripheral edema |
very common |
common |
very common |
common |
| Non-cardiac chest pain |
common |
common |
- |
- |
| Edema |
common |
common |
- |
- |
| Investigations |
||||
| Increased ALT levels |
common |
common |
common |
common |
| Weight decreased |
common |
common |
- |
- |
| Decreased neutrophil count |
- |
- |
common |
common |
| Decreased white blood cell count |
- |
- |
common |
common |
| Decreased platelet count |
- |
- |
common |
common |
| Increased blood uric acid |
- |
- |
common* |
uncommon* |
| Injury, poisoning and procedural complications |
||||
| Fall |
common |
common |
- |
- |
* Adverse reactions have been reported during post-marketing use.
Description of selected adverse reactions
The frequency of adverse reactions in this section was obtained from clinical trials in patients receiving treatment with pomalidomide in combination with bortezomib and dexamethasone (Pom + Btz + Dex) or with dexamethasone (Pom + Dex).
Teratogenicity
Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen causing severe congenital birth defects. Pomalidomide has been shown to be teratogenic when administered during the period of major organogenesis in both rats and rabbits. If pomalidomide is used during pregnancy, teratogenic effects on humans are expected.
Neutropenia and thrombocytopenia
In patients receiving combination therapy with pomalidomide (Pom + Btz + Dex), neutropenia was observed in 54.0% of patients (of which 47.1% were Grade 3 or 4). Neutropenia led to interruption of pomalidomide therapy in 0.7% of all patients and was mostly non-serious.
Febrile neutropenia was reported in 3.2% (Pom + Btz + Dex) and 6.7% (Pom + Dex) of patients, considered serious in 1.8% (Pom + Btz + Dex) and 4.0% (Pom + Dex) of patients.
In patients receiving combination pomalidomide therapy, thrombocytopenia occurred in 27.0% (Pom + Dex) and 36.7% (Pom + Btz + Dex) of patients. Grade 3 or 4 thrombocytopenia occurred in 28.1% (Pom + Btz + Dex) and 20.7% (Pom + Dex) of patients, leading to discontinuation of pomalidomide therapy in 0.7% (Pom + Btz + Dex and Pom + Dex) of patients and considered serious in 0.7% (Pom + Btz + Dex) and 1.7% (Pom + Dex) of patients.
Neutropenia and thrombocytopenia occurred more frequently during the first two cycles of pomalidomide treatment in combination with bortezomib and dexamethasone or with dexamethasone (see sections "Special precautions for use" and "Dosage and administration").
Infection
Infection was the most common non-hematological toxic effect.
In patients receiving combination pomalidomide therapy, infection occurred in 83.1% (Pom + Btz + Dex) and 55.0% (Pom + Dex) of patients (of which 34.9% (Pom + Btz + Dex) and 24.0% (Pom + Dex) were Grade 3 or 4).
Upper respiratory tract infections and pneumonia were the most common infectious manifestations. Fatal infections (Grade 5) occurred in 4.0% (Pom + Btz + Dex) and 2.7% (Pom + Dex) of patients. Infections led to discontinuation of pomalidomide therapy in 3.6% (Pom + Btz + Dex) and 2.0% (Pom + Dex) of patients.
Thromboembolic complications
Prophylaxis with acetylsalicylic acid (and other anticoagulants for patients at high risk) was mandatory for all patients in clinical trials. Anticoagulant therapy is recommended (if not contraindicated).
Venous thromboembolic complications occurred in 12.2% (Pom + Btz + Dex) and 3.3% (Pom + Dex) of patients (of which 5.8% (Pom + Btz + Dex) and 1.3% (Pom + Dex) were Grade 3 or 4). Venous thromboembolic complications were recorded as serious adverse reactions in 4.7% (Pom + Btz + Dex) and 1.7% (Pom + Dex) of patients. No fatal reactions were recorded. Venous thromboembolic complications were associated with discontinuation of pomalidomide therapy in up to 2.2% (Pom + Btz + Dex) of patients.
Peripheral neuropathy
- Pomalidomide in combination with bortezomib and dexamethasone
Patients with pre-existing peripheral neuropathy ≥ Grade 2 with pain lasting ≥14 days prior to randomization were excluded from clinical trials. Peripheral neuropathy was observed in 55.4% of patients (of which 10.8% were Grade 3; 0.7% Grade 4). Time-adjusted incidence rates were comparable across treatment groups. Approximately 30% of patients who developed peripheral neuropathy had a history of neuropathy at study entry. Peripheral neuropathy led to discontinuation of bortezomib in approximately 14.4% of patients, pomalidomide in 1.8%, and dexamethasone in 1.8% of patients in the Pom + Btz + Dex group, and in 8.9% of patients in the Btz + Dex group.
- Pomalidomide in combination with dexamethasone
Patients with pre-existing peripheral neuropathy ≥ Grade 2 were excluded from clinical trials. Peripheral neuropathy was observed in 12.3% of patients (of which 1.0% were Grade 3 or 4). No serious peripheral neuropathy reactions were recorded, and therapy was interrupted due to peripheral neuropathy in 0.3% of patients.
Bleeding
Hemorrhagic disorders have been reported following pomalidomide administration, particularly in patients with risk factors such as concomitant use of drugs increasing bleeding risk. Hemorrhagic complications included epistaxis, intracranial hemorrhage, and gastrointestinal bleeding.
Hypersensitivity reactions and severe skin reactions
Angioedema, anaphylactic reactions, and severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported following pomalidomide administration. Patients with a history of severe skin reactions associated with lenalidomide or thalidomide should not receive pomalidomide therapy.
Pediatric population
Adverse reactions reported in children (aged 4 to 18 years) with recurrent or progressive brain tumors were consistent with the known safety profile of pomalidomide in adult patients (see section "Pharmacological properties").
Reporting suspected adverse reactions
Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and 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
No special storage conditions required. Keep out of reach and sight of children.
Packaging
High-density polyethylene (HDPE) bottles with child-resistant polypropylene caps. Each bottle contains 21 capsules, with 1 bottle per cardboard box.
Blister packs containing 7 capsules; 3 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer
Sandoz España, S.L.
Manufacturer's address and place of business
C/ Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.