Imnovid

/ Neopharm

Treatment must be initiated and monitored under the supervision of physicians experienced in the management of multiple myeloma.
The recommended starting dose of Imnovid 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. T
reatment should be discontinued upon progression of disease.
Instructions for dose interruptions and reductions for pomalidomide related to haematologic adverse reactions are outlined in the doctor’s leaflet.
To initiate a new cycle of pomalidomide, the neutrophil count must be ≥1 x 10^9/l and the platelet count must be ≥ 50 x 10^9/l.
In case of neutropaenia, 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, or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed following discontinuation
from 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%.
For Dexamethasone dose modification instructions please refer to doctor’s leaflet.
Elderly: 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.
Hepatic impairment: 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 ChildPugh 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.
Renal impairment: No dose adjustment of pomalidomide is required for patients with renal impairment. On haemodialysis days, patients should take their pomalidomide dose following haemodialysis.
Paediatric population: There is no relevant use of pomalidomide in children aged 0-17 years for the indication of multiple myeloma.
Method of administration: Oral use. Imnovid hard capsules should be taken orally at the same time each day. The capsules should not be opened, broken or chewed. The capsules should be swallowed whole, preferably with water, with or without food. If the patient forgets to take a dose of pomalidomide on one day, then the patient should take the normal prescribed dose as scheduled on the next day. Patients should not adjust the dose to make up for a missing dose on previous days.
It is recommended to press only on one end of the capsule to remove it from the blister thereby reducing the risk of capsule deformation or breakage.

Imnovid 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.

Pregnancy. Women of childbearing potential, unless all the conditions of the Imnovid Risk Management Program – Pregnancy Prevention Program (RMP-PPP) are met. Male patients unable to follow or comply with the required contraceptive measures. Hypersensitivity to the active substance or to any of the excipients.

Teratogenicity: 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.
See prescribing information for full details.

The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anaemia (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%), anaemia (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 pomalidomide.
See prescribing information for full details.

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 metabolised by CYP1A2 and CYP3A4/5. It is also a substrate for P-glycoprotein.
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% with a 90% confidence interval [91% to 124%] 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% with a 90% confidence interval [98% to 157%] 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%.
Dexamethasone: 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.

Women of childbearing potential / Contraception in males and females:  Women of childbearing potential should use two effective contraception methods for at least 4 weeks before beginning Imnovid therapy, during therapy, during dose interruptions and for 4 weeks following discontinuation of Imnovid therapy unless continuous abstinence from heterosexual sexual contact is the chosen method. If pregnancy occurs in a woman treated with pomalidomide, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking pomalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. Pomalidomide is present in human semen. As a precaution, all male patients taking pomalidomide 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.
Pregnancy: A teratogenic effect of pomalidomide in humans is expected. Pomalidomide is contraindicated during pregnancy and in women of childbearing potential, except when all the conditions for pregnancy prevention have been met.
Breast-feeding: It is not known if pomalidomide is excreted in human milk. Pomalidomide was detected in milk of lactating rats following administration to the mother. Because of the potential for adverse reactions in
nursing infants from pomalidomide, a decision should be made whether to discontinue nursing or to discontinue the medicinal product, taking into account the importance of the medicinal product to the mother.
Fertility: Pomalidomide was found to impact negatively on fertility and be teratogenic in animals. Pomalidomide crossed the lacenta and was detected in foetal blood following administration to pregnant rabbits.

Imnovid doses as high as 50 mg as a single dose in healthy volunteers, and 10 mg as once-daily multiple doses in patients suffering from multiple myeloma have been studied without reported serious adverse events related to overdose. No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialysable. In the event of overdose, supportive care is advised.