Adult patients with relapsed and refractory multiple myeloma
Mechanism of action
Pomalidomide has direct anti-myeloma tumoricidal activity, immunomodulatory activities and inhibits stromal cell support for multiple myeloma tumor cell growth. Specifically, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. Additionally, pomalidomide inhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergizes with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumor cell apoptosis. Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells.
Pomalidomide in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.
RRMM: reimbursed in Belgium: paper Chapter IV 7100000
Administration and dosage
The recommended starting dose of pomalidomide is 4 mg once daily taken orally 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. Dosing is continued or modified based upon clinical and laboratory findings. Treatment should be discontinued upon progression of disease.
No dose adjustment is required for pomalidomide. For patients >75 years of age, the starting dose of
dexamethasone is 20 mg once daily on Days 1, 8, 15 and 22 of each 28-day treatment cycle.
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.
In case of neutropenia, the physician should consider the use of growth factors.
For other Grade 3 or 4 adverse reactions judged to be related to pomalidomide, stop treatment and restart treatment at 1 mg less than the previous dose when an adverse reaction has resolved to ≤ Grade 2 at the physician’s discretion.
If adverse reactions occur after dose reductions to 1 mg, then the medicinal product should be discontinued.
Pomalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Pomalidomide must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, and should not be resumed following discontinuation for these reactions.
If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide, reduce the dose of pomalidomide by 50%.
Patients with serum total bilirubin > 2.0 mg/dL were excluded from clinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide. No adjustment of the starting dose of pomalidomide is required for patients with hepatic impairment as defined by the Child- Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed.
No dose adjustment of pomalidomide is required for patients with renal impairment. On hemodialysis
days, patients should take their pomalidomide dose following hemodialysis.
Effect of Pomalidomide on other medicinal products
Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic drug-drug interactions due to P450 isoenzyme inhibition or induction or transporter inhibition when co-administered with substrates of these enzymes or transporters. The potential for such drug-drug interactions, including the potential impact of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been evaluated clinically.
Effect of other medicinal products on Pomalidomide
Pomalidomide is partly metabolized by CYP1A2 and CYP3A4/5. It is also a substrate for P-glyco-protein. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide in the presence of ketoconazole, increased mean exposure to pomalidomide by 107% compared to pomalidomide plus ketoconazole. In a second study to evaluate the contribution of
a CYP1A2 inhibitor alone to metabolism changes, co-administration of fluvoxamine alone with
pomalidomide increased mean exposure to pomalidomide by 125% compared to pomalidomide alone. If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co administered with pomalidomide, reduce the dose of pomalidomide by 50%.
Co-administration of multiple doses of up to 4 mg pomalidomide with 20 mg to 40 mg dexamethasone (a weak to moderate inducer of several CYP enzymes including CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.
The effect of dexamethasone on warfarin is unknown. Close monitoring of warfarin concentration is
advised during treatment.
Adverse events of special interest
Summary of the safety profile
The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); in general disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) and oedema peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheral neuropathy adverse reactions were reported in 12.3% of patients and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3% of patients. The most commonly reported Grade 3 or 4 adverse reactions were in the blood and lymphatic system disorders including neutropenia (41.7%), anemia (27%) and thrombocytopenia (20.7%); in infections and infestations including pneumonia (9%); and in general disorders and administration site conditions including fatigue (4.7%), pyrexia (3%) and oedema peripheral (1.3%). The most commonly reported serious adverse reaction was pneumonia (9.3%). Other serious adverse reactions reported included febrile neutropenia (4.0%), neutropenia (2.0%), thrombocytopenia (1.7%) and VTE adverse reactions (1.7 %).
Adverse reactions tended to occur more frequently within the first 2 cycles of treatment with
Management of adverse events
Patients receiving pomalidomide in combination with dexamethasone have developed venous
thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and cerebrovascular accident). Patients with known risk factors for thromboembolism – including prior thrombosis – should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidemia). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Anti-coagulation therapy (unless contraindicated) is recommended, (such as acetylsalicylic acid, warfarin, heparin or clopidogrel), especially in patients with additional thrombotic risk factors. A decision to take prophylactic measures should be made after a careful assessment of the individual patient’s underlying risk factors. In clinical studies, patients received prophylactic acetylsalicylic acid or alternative anti-thrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic events including thromboembolism. Therefore, erythropoietic agents, as well as other agents that may increase the risk of thromboembolic events, should be used with caution.
Initial work-up before start of treatment
Pomalidomide must not be taken during pregnancy, since a teratogenic effect is expected. Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats and rabbits when administered during the period of major organogenesis.
The conditions of the Pregnancy Prevention Program must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.
Prior to starting treatment
A medically supervised pregnancy test should be performed during the consultation, when pomalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with pomalidomide.
Follow-up and end of treatment
A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment, except in the case of confirmed tubal sterilization. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
Pomalidomide is present in human semen during treatment. As a precaution, and taking into account special populations with potentially prolonged elimination time such as renal impairment, all male patients taking pomalidomide, including those who have had a vasectomy, should use condoms throughout treatment duration, during dose interruption and for 7 days after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception.
Male patients should not donate semen or sperm during treatment (including during dose interruptions) and for 7 days following discontinuation of pomalidomide.
Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood, semen or sperm during treatment (including during dose interruptions) and for 7 days following discontinuation of pomalidomide.
Reference: SmPC Imnovid® (pomalidomide) latest update 30/08/2017
Celgene Approval Number: BE-HEMA180006
For the full SmPC visit: