Pomalid
UkraineTable of Contents
INSTRUCTION FOR MEDICINAL USE OF THE MEDICINAL PRODUCT POMALID (POMALID)
Composition:
Active substance: pomalidomide;
1 capsule contains 2 mg, 3 mg, or 4 mg of pomalidomide;
Excipients: mannitol, pregelatinized starch, sodium croscarmellose, sodium stearyl fumarate, hard gelatin capsule (gelatin, purified water, titanium dioxide (E 171), iron oxide yellow (E 172) (2 mg, 3 mg), FD&C Blue 2, FD&C Red 3 (for 2 mg)).
Pharmaceutical form. Hard capsules.
Main physicochemical properties:
2 mg: size "2" capsules with a dark blue cap and orange body, marked with "NAT" in white ink on the cap and "2mg" in white ink on the body, containing a powder from light yellow to yellow in color.
3 mg: size "2" capsules with a dark blue cap and green body, marked with "NAT" in white ink on the cap and "3mg" in white ink on the body, containing a powder from light yellow to yellow in color.
4 mg: size "2" capsules with a dark blue cap and blue body, marked with "NAT" in white ink on the cap and "4mg" in white ink on the body, containing a powder from light yellow to yellow in color.
Pharmacotherapeutic group. Immunosuppressants. Other immunosuppressants.
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. 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 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 regulator of cullin 1 (Roc1), 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 vitro, in the presence of pomalidomide, 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 multiple myeloma resistant to lenalidomide.
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. After multiple dosing, pomalidomide exhibits 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 from 62 to 138 L at steady state. Pomalidomide distributes into seminal fluid 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, 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 additional 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. However, co-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 effect of a CYP1A2 inhibitor on pomalidomide metabolism, co-administration of fluvoxamine and pomalidomide increased the mean plasma concentration of pomalidomide by 125%, with a 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%. Pomalidomide administration in patients who smoke has a clinically significant effect on plasma concentrations compared to non-smokers, as tobacco is known to induce CYP1A2 isoenzymes.
Based on in vitro data, pomalidomide is neither an inhibitor nor an inducer of cytochrome P-450 isoenzymes and does not inhibit any of the drug transporters studied. Clinically significant drug interactions are not expected when pomalidomide is co-administered with substrates of this metabolic pathway.
Elimination
The mean elimination half-life of pomalidomide is approximately 9.5 hours in healthy subjects and approximately 7.5 hours in patients with multiple myeloma. The mean total clearance of pomalidomide (CL/F) is approximately 7–10 L/hour.
After a single oral dose of [14C]-pomalidomide (2 mg) administered to healthy volunteers, approximately 73% and 15% of the dose is excreted in urine and feces, respectively. Approximately 2% and 8% of the radioactive dose is excreted as unchanged pomalidomide in urine and feces, respectively.
Prior to excretion, pomalidomide undergoes extensive metabolism, with metabolites primarily eliminated 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).
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 conditions 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.
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 administered concomitantly with substrates of these enzymes or transporters. The potential for such drug interactions, including the potential effect of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been clinically evaluated.
Effect of other medicinal products on pomalidomide
Pomalidomide is partially metabolized by CYP1A2 and CYP3A4/5. Pomalidomide is also a substrate of P-glycoprotein (P-gp). Concomitant administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole or the strong CYP3A4/5 inducer carbamazepine did not clinically affect pomalidomide exposure. Concomitant administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole increased the mean exposure to pomalidomide by 107% with a 90% CI [from 91% to 124%] compared to pomalidomide and ketoconazole therapy alone. In a second study evaluating the effect of a CYP1A2 inhibitor on metabolism, fluvoxamine and pomalidomide were co-administered, resulting in an increase in the mean plasma concentration of pomalidomide by 125% with a 90% CI [from 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 at doses of 20 to 40 mg (considered a weak or moderate inducer of several CYP enzymes, including CYP3A) in patients with multiple myeloma did not affect the pharmacokinetics of pomalidomide compared to administration of pomalidomide alone.
The effect of dexamethasone on warfarin 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 known human teratogen associated with severe congenital malformations. Pomalidomide has been shown to be teratogenic in both rats and rabbits when administered during the main period of organogenesis.
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 individuals without reproductive potential:
Women or individuals of male sex 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 following 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.
Counseling
Pomalidomide is contraindicated in women of reproductive potential unless all of the following conditions are met:
- The woman understands the expected teratogenic risk to the unborn child.
- The woman understands the necessity of effective contraception for at least 4 weeks before starting treatment, throughout the entire duration of treatment, and for at least 4 weeks after treatment ends.
- Even if a woman of reproductive age has amenorrhea, all recommendations for effective contraception must be followed.
- The woman must be capable of using effective contraceptive methods.
- The woman 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 upon receiving a prescription for pomalidomide.
- The woman understands the necessity and agrees to undergo pregnancy testing at least every 4 weeks, except in cases where tubal sterilization has been confirmed.
- The woman acknowledges that she understands the risks and the necessity of preventive measures associated with pomalidomide use.
The prescribing physician must ensure that women of reproductive age meet the following conditions:
- The patient meets the requirements of the Pregnancy Prevention Programme, including confirmation that she has adequate understanding of the necessity of these measures.
- The patient acknowledges the above conditions.
For male patients receiving pomalidomide, pharmacokinetic data have shown that the drug is present in semen during treatment. As a precautionary measure, and considering special 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 or discontinued. This also applies to men who have undergone vasectomy, who must use a condom if engaging in sexual intercourse with a pregnant woman or a woman of reproductive potential, as semen may still contain pomalidomide even in the absence of 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 recommended to refer the partner to a specialist experienced in teratology for risk assessment and advice.
Contraception
Women of reproductive potential must use at least one effective method of contraception for at least 4 weeks before therapy, during therapy, and for at least 4 weeks after therapy with pomalidomide, even during 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 counseling on 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 progestogen (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 contraceptives is not recommended. If a patient is currently using combined oral contraception, she 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 efficacy of contraceptive steroids may be reduced when administered concomitantly with dexamethasone.
Implants and levonorgestrel-releasing intrauterine systems may increase the risk of infection during insertion and during irregular vaginal bleeding. Prophylactic antibiotic use should be considered in patients with neutropenia.
Copper-releasing intrauterine devices are not recommended due to potential risks of infection during insertion and blood loss during menstruation, which may pose risks to patients with severe neutropenia or marked thrombocytopenia.
Pregnancy testing
According to local practice, women of reproductive potential, as defined above, must undergo physician-monitored pregnancy tests with a minimum sensitivity of 25 mIU/mL. This requirement also applies to women of reproductive potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, prescription, and dispensing of the drug should occur on the same day. Dispensing of pomalidomide to women of reproductive age should occur within 7 days of the prescription.
Prior to starting treatment
A physician-monitored pregnancy test must be performed during the consultation when pomalidomide is prescribed, or within 3 days prior to the visit, provided 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-monitored 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 medication 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 sperm during treatment (including during dose interruptions) and for 7 days after discontinuation of pomalidomide therapy.
Hematological complications
The most commonly observed hematological adverse reactions in patients are neutropenia (grade 3 or 4), followed by anemia and thrombocytopenia, in patients with relapsed/refractory multiple myeloma. Patients should be monitored for hematological adverse reactions, particularly neutropenia. Patients should also be warned to promptly report episodes of fever. Physicians should monitor patients for bleeding, including epistaxis, 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.
Progressive multifocal leukoencephalopathy (PML)
Cases of progressive multifocal leukoencephalopathy, including fatal cases, have been reported with the use of pomalidomide. Cases of PML have been reported from several months to several years after initiation of pomalidomide therapy. Cases have generally occurred in patients who were concurrently receiving dexamethasone or had previously received other immunosuppressive chemotherapy. Physicians should regularly monitor patients and consider PML in the differential diagnosis of patients presenting with new or progressive neurological symptoms, 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.
Evaluation for PML should be based on neurological examination, brain MRI, and analysis of cerebrospinal fluid for JC virus (JCV) DNA by PCR or brain biopsy with JCV testing. A negative JCV PCR does not exclude PML. If an alternative diagnosis cannot be established, further monitoring and evaluation may be necessary.
If PML is suspected, further dosing should be suspended until PML is ruled out. If PML is confirmed, pomalidomide must be permanently discontinued.
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 in combination with dexamethasone. Patients with known risk factors for thromboembolism, including prior thrombosis, should be closely monitored. Measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia). Patients and physicians should be vigilant for signs and symptoms of thromboembolism. Patients should seek medical 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 agents that may increase the risk of thromboembolic complications should be used with caution.
Thyroid disorders
Cases of hypothyroidism have been reported. Comorbid conditions affecting thyroid function should be assessed before starting treatment. Monitoring of thyroid function is recommended before and during pomalidomide therapy.
Peripheral neuropathy
Patients with peripheral neuropathy ≥ grade 2 were excluded from pomalidomide clinical trials. Caution should be exercised when considering pomalidomide therapy in such patients.
Severe cardiac dysfunction
Patients with significant cardiac dysfunction (NYHA class III or IV heart failure; myocardial infarction within 12 months of study initiation; unstable or poorly controlled angina) were excluded from pomalidomide clinical trials. Adverse cardiac events, including congestive heart failure, pulmonary edema, and atrial fibrillation, have been reported, primarily in patients with pre-existing cardiac disease or cardiac risk factors. Appropriate caution should be exercised when prescribing pomalidomide to such patients, including periodic monitoring for signs or symptoms of cardiovascular disease.
Tumor lysis syndrome
Patients at highest risk for tumor lysis syndrome are those with high tumor burden prior to starting treatment. Such patients should be closely monitored and appropriate preventive measures taken when risk arises.
Secondary primary malignancies
Secondary primary malignancies, such as non-melanoma skin cancer, have been reported in patients receiving pomalidomide. Physicians should carefully monitor patients before and during treatment using standard oncological screening for secondary 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 following pomalidomide administration. 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 cases of exfoliative or bullous rash or suspected Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS. Reinitiation of therapy after resolution of the reaction is not recommended. Patients with a history of serious allergic reactions to thalidomide or lenalidomide were excluded from clinical trials. Such patients are at high risk of hypersensitivity reactions and must not take pomalidomide. Discontinuation of the drug should be considered in cases of grade 2–3 rash. Pomalidomide therapy must be permanently discontinued in cases of angioedema.
Dizziness and confusion
Dizziness and confusion have been reported following pomalidomide administration. Patients should avoid situations where dizziness or confusion could be problematic and should not use other medications that may cause dizziness or confusion without consulting their physician.
Interstitial lung disease (ILD)
Cases of ILD and ILD-related events, including pneumonia, have been reported following pomalidomide administration. Patients with acute onset or unexplained worsening of pulmonary symptoms should undergo careful evaluation to exclude ILD. Pomalidomide therapy should be suspended during investigation of these symptoms, and appropriate treatment initiated if ILD is confirmed. Pomalidomide therapy may be resumed only after careful benefit-risk assessment.
Hepatic disorders
Marked elevations 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 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, necessitating discontinuation of pomalidomide therapy. HBV status should be determined before starting pomalidomide therapy. Patients with positive HIV infection should be referred to a physician experienced in hepatitis B management. Caution should be exercised when treating patients previously exposed to HBV, including those 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, including fatal cases, have been reported with the use of pomalidomide. Cases of PML have been reported from several months to several years after initiation of pomalidomide therapy. Cases have generally occurred in patients who were concurrently receiving dexamethasone or had previously received other immunosuppressive chemotherapy. Physicians should regularly monitor patients and consider PML in the differential diagnosis of patients presenting with new or progressive neurological symptoms, 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.
Evaluation for PML should be based on neurological examination, brain MRI, and analysis of cerebrospinal fluid 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, further monitoring and evaluation may be necessary.
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 referred to a physician 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 experienced in teratology for fetal risk assessment and counseling. Pomalidomide penetrates into human semen. As a precautionary measure, all male patients receiving pomalidomide must use condoms throughout the entire treatment period, during dose interruptions, and for 7 days after treatment discontinuation, if their 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 pregnancy prevention are fulfilled.
Breastfeeding
There are no data confirming the passage of the drug into human breast milk. Pomalidomide has been detected in the milk of lactating rats after administration. Due to the potential risk of adverse reactions in breastfed infants, a decision must be made whether to discontinue breastfeeding or discontinue pomalidomide therapy, taking into account the benefit of breastfeeding for the infant and the benefit of therapy for the woman.
Fertility
Pomalidomide has been shown to have negative effects on fertility and teratogenic effects in animals. Pomalidomide 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 effect on the ability to drive or operate machinery. Cases of fatigue, decreased level of consciousness, confusion, and dizziness have been reported after pomalidomide administration. 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 supervised by physicians experienced in the management 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 initial 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 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 until toxicity occurs.
Table 1
Recommended dosing schedule 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 neutrophil count must be > 1 x 10⁹/L and the platelet count must be > 50 x 10⁹/L.
Guidelines for dose interruption or reduction to manage adverse reactions related to pomalidomide are provided in Table 2, and dose levels are specified in Table 3.
Table 2
Dose modification guidelines for pomalidomide
| Toxicity |
Dose adjustment |
| 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. |
| ANC** 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. |
| ANC** returns to ≥ 50 x 109/L |
Resume pomalidomide treatment at a dose one level lower than the previous dose. |
| Rash Grade 2–3 rash |
Consider dose modification or discontinuation of pomalidomide. |
| Grade 4 rash or blistering (including angioedema, exfoliative or bullous rashes, 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 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 |
Pomalidomide oral dose |
| Initial dose |
4 mg |
| Dose level-1 |
3 mg |
| Dose level-2 |
2 mg |
| Dose level-3 |
1 mg |
Dose modification guidelines in this table apply to pomalidomide in combination with bortezomib and dexamethasone, and to pomalidomide in combination with dexamethasone.
If adverse reactions occur after dose reduction to 1 mg, the drug should be discontinued.
Strong CYP1A2 inhibitors
When strong CYP1A2 inhibitors such as ciprofloxacin, enoxacin, and fluvoxamine are coadministered 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 product information 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 product information for the medicinal product.
Table 4
Dexamethasone dose modification guidelines
| Toxicity |
Dose adjustment |
| Mild to moderate dyspepsia (Grade 1–2) |
Maintain dose and treat with H2-histamine receptor blockers or analogs. Reduce dose by one level if symptoms persist. |
| Severe dyspepsia (Grade ≥ 3) |
Temporarily discontinue the medicinal product until symptoms are controlled. Add H2-histamine receptor blockers or analogs to therapy and resume treatment at a dose one level lower than the previous dose. |
| Edema > Grade 3 |
If necessary, add diuretics to therapy and reduce the medicinal product dose by one level from the previous dose. |
| Disorientation and mood changes ≥ Grade 2 |
Interrupt treatment with the medicinal product until symptoms are resolved. Resume treatment at a dose one level lower than the previous dose. |
| Muscle weakness ≥ Grade 2 |
Interrupt treatment with the medicinal product until muscle weakness symptoms improve to ≤ Grade 1. Resume treatment at a dose one level lower than the previous dose. |
| Hyperglycemia ≥ Grade 3 |
Reduce the medicinal product dose by one level. If needed, add insulin or oral hypoglycemic agents to therapy. |
| Acute pancreatitis |
Discontinue dexamethasone from the treatment regimen. |
| Other dexamethasone-related adverse reactions ≥ Grade 3 |
Discontinue dexamethasone therapy until manifestations of adverse reactions resolve 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 a 28-day cycle.
The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15, and 22 of each 28-day treatment cycle.
Treatment with pomalidomide in combination with dexamethasone should continue until disease progression or the occurrence of toxic effects.
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 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 in accordance with the current product information for medical use.
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 |
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 for 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, the initial dose of dexamethasone is:
- Doses in cycles 1 to 8: 10 mg once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.
- For cycle 9 and subsequent cycles: 10 mg once daily on days 1, 2, 8, and 9 of each 21-day cycle.
Pomalidomide in combination with dexamethasone
Dose adjustment for pomalidomide is not required.
For patients >75 years, 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. No initial dose adjustment of pomalidomide is required for patients with hepatic impairment as defined by Child-Pugh criteria. However, patients with hepatic impairment should be monitored more closely for the occurrence of adverse reactions, and dose reductions or 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 taken after hemodialysis.
Method of administration
Oral administration.
Pomalidomide hard capsules should be taken orally at the same time each day. The capsules must not be opened, crushed, 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 taken on previous days.
Children
There is no data on the use of pomalidomide in children under 18 years of age for the indication multiple myeloma.
Overdose
Administration of pomalidomide at single doses up to 50 mg in healthy volunteers and multiple daily doses of 10 mg in patients with multiple myeloma has been studied, without identification of serious adverse reactions related to overdose. Studies have shown that pomalidomide is removed by hemodialysis.
In case of overdose, supportive therapy is recommended.
Adverse Reactions
- Pomalidomide in combination with bortezomib and dexamethasone
The most frequently reported 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 grade 3 or 4 adverse reactions were hematologic and lymphatic system disorders: neutropenia (41.7%), thrombocytopenia (27.3%), and anemia (14.0%). The most common serious adverse reaction reported 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 embolic events in 3.3%. The most commonly 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 events (1.7%).
Adverse reactions generally occur during the first 2 treatment cycles with pomalidomide.
List of adverse reactions in tabular form
- Pomalidomide in combination with bortezomib and dexamethasone
In the randomized trial CC-4047-MM-007, 278 patients received pomalidomide, bortezomib, and dexamethasone (Pom+Btz+Dex arm) (see section "Dosage and administration").
Adverse reactions observed in patients receiving pomalidomide in combination with bortezomib and dexamethasone are listed in Table 7 by System Organ Class (SOC), frequency of all adverse reactions, and frequency of grade 3 and 4 adverse reactions.
The frequency of adverse reactions for the combination therapy Pom + Btz + Dex (any grade) is defined according to current standards: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100).
Table 7
All adverse reactions (ARs) reported in the MM-007 clinical trial for 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 Elevated ALT, weight decreased |
Common Weight decreased Uncommon Elevated ALT |
| 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 once daily on days 1 to 21 of each 28-day cycle in combination with low-dose dexamethasone administered weekly.
Adverse reactions observed in patients receiving pomalidomide in combination with dexamethasone are listed below in Table 8 by System Organ Class (SOC), frequency of all adverse reactions, and for adverse reactions of grade 3 or 4.
The frequency of adverse reactions is as observed in the group of patients who received pomalidomide and dexamethasone in 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 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 |
Grade 3–4 common adverse reactions/Frequency |
| Infections and infestations |
Very common Pneumonia (bacterial, viral and fungal infections, including opportunistic infections) Common Neutropenic sepsis, bronchopneumonia, bronchitis, respiratory tract infections, upper respiratory tract infections, nasopharyngitis, herpes zoster |
Common Neutropenic sepsis, pneumonia (bacterial, viral and fungal infections, including opportunistic infections), bronchopneumonia, respiratory tract infections, upper respiratory tract infections Uncommon Bronchitis, herpes zoster |
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Uncommon Basal cell carcinoma, squamous cell carcinoma of the skin |
Uncommon Basal cell carcinoma, squamous cell carcinoma of the skin |
| Blood and lymphatic system disorders |
Very common Neutropenia, thrombocytopenia, leukopenia, anemia Common Febrile neutropenia |
Very common Neutropenia, thrombocytopenia, anemia Common Febrile neutropenia, leukopenia |
| Metabolism and nutrition disorders |
Very common Decreased appetite Common Hyperkalemia, hyponatremia |
Common Hyperkalemia, hyponatremia Uncommon Decreased appetite |
| Psychiatric disorders |
Common Confusional state |
Common Confusional state |
| Nervous system disorders |
Common Decreased level of consciousness, peripheral sensory neuropathy, dizziness, tremor |
Common Decreased level of consciousness Uncommon Peripheral sensory neuropathy, dizziness, tremor |
| Ear and labyrinth disorders |
Common Dizziness |
Common Dizziness |
| Vascular disorders |
Common Deep vein thrombosis |
Uncommon Deep vein thrombosis |
| Respiratory, thoracic and mediastinal disorders |
Very common Dyspnea, cough Common Pulmonary embolism |
Common Dyspnea Uncommon Pulmonary embolism, cough |
| Gastrointestinal disorders |
Very common Diarrhea, nausea, constipation Common Vomiting, gastrointestinal hemorrhage |
Common Diarrhea, vomiting, constipation Uncommon Nausea, gastrointestinal hemorrhage |
| Hepatobiliary 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 serious adverse reactions occurring during the post-marketing period with pomalidomide therapy
| System organ class/Precferred term |
All adverse reactions/frequency |
Grade 3-4 adverse reactions/frequency |
| Infections and infections |
Frequency unknown Hepatitis B reactivation |
Frequency unknown Hepatitis B reactivation |
| Blood and lymphatic system disorders |
Common Pancytopenia |
Common Pancytopenia |
| Immune system disorders |
Common Angioedema, urticaria Frequency unknown Anaphylactic reaction Rejection of solid organ transplant |
Uncommon Angioedema, urticaria Frequency unknown Anaphylactic reaction |
| Endocrine disorders |
Uncommon Hypothyroidism |
|
| Metabolism and nutrition disorders |
Common Hyperuricemia Uncommon Tumor lysis syndrome |
Common Hyperuricemia Uncommon Tumor lysis syndrome |
| Nervous system disorders |
Common Intracranial hemorrhage Uncommon Stroke |
Uncommon Stroke, intracranial hemorrhage |
| Cardiac disorders |
Common Heart failure, atrial fibrillation, myocardial infarction |
Common Heart failure, atrial fibrillation Uncommon Myocardial infarction |
| Respiratory, thoracic and mediastinal disorders |
Common Nosebleed, URI |
Uncommon Nosebleed, URI |
| Hepatobiliary disorders |
Uncommon Hepatitis |
|
| Skin and subcutaneous tissue disorders |
Frequency unknown Drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, Stevens-Johnson syndrome |
Frequency unknown Drug reaction with eosinophilia and systemic symptoms, toxic epidermal necrolysis, Stevens-Johnson syndrome |
| Investigations |
Common Increased blood uric acid level |
Uncommon Increased blood uric acid level |
Description of selected adverse reactions
Teratogenicity
Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen causing severe birth defects. Pomalidomide has been shown to be teratogenic in both rats and rabbits when administered during the main period of organogenesis. If pomalidomide is used during pregnancy, teratogenic effects on humans are expected.
Neutropenia and thrombocytopenia
In patients receiving pomalidomide combination therapy in clinical trials, neutropenia was observed in 46.8% of patients (of which 41.7% were grade 3 or 4). Neutropenia did not lead to treatment interruption in any patient and was mostly non-serious.
Febrile neutropenia was reported in 3.2–6.7% of patients, considered serious in 1.8–4.0% of patients.
In patients receiving pomalidomide combination therapy during clinical trials, 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 treatment interruption in 0.7% of patients and considered serious in 0.4–1.7% of patients.
Neutropenia and thrombocytopenia occurred more frequently during the first two cycles of pomalidomide treatment (see sections "Special precautions for use" and "Method of administration and dosage").
Infection
Infection was the most common non-hematological toxic effect.
In patients receiving pomalidomide combination therapy during clinical trials, infections 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 events. 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 trials. Anticoagulant therapy is recommended (if not contraindicated).
In patients receiving pomalidomide combination therapy during clinical trials, venous thromboembolic complications occurred in 3.3–11.5% of patients (of which 1.3–5.4% were grade 3 or 4). Venous thromboembolic complications were recorded as serious adverse reactions in 1.7–4.3% of patients, with no fatal 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 trials. Peripheral neuropathy was observed in 55.4% of patients (of which 10.8% were grade 3; 0.7% grade 4). Duration-adjusted incidence rates were comparable across treatment groups. Approximately 30% of patients who developed peripheral neuropathy had a history of neuropathy at study initiation. 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 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 reported, and treatment discontinuation due to peripheral neuropathy occurred 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 medications 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 rashes related to lenalidomide or thalidomide should not receive pomalidomide therapy.
Reporting suspected adverse reactions.
Reporting of adverse reactions after drug registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 30 °C. Keep out of reach of children.
Packaging.
21 capsules in a bottle, 1 bottle in a cardboard box; or 7 capsules in a blister, 3 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Natco Pharma Limited.
Manufacturer's address and location of operations.
Pharma Division, Kothur, Rangareddy, Telangana 509228, India.