Pomalidomide Zentiva · 4.1 Therapeutic indications · 1

HOS-100772 · has-adverse-reaction-information · PDF-Seite 14

Summary of the safety profile Pomalidomide in combination with bortezomib and dexamethasone The most commonly reported blood and lymphatic system disorders were neutropenia (54.0%), thrombocytopenia (39.9%) and anaemia (32.0%). Other most frequently reported adverse reactions included peripheral sensory neuropathy (48.2%), fatigue (38.8%), diarrhoea (38.1%), constipation (38.1%), and oedema peripheral (36.3%). The most commonly reported Grade 3 or 4 adverse reactions were blood and lymphatic system disorders including neutropenia (47.1%), thrombocytopenia (28.1%) and anaemia (15.1%). The most commonly reported serious adverse reaction was pneumonia (12.2%). Other serious adverse reactions reported 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 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. Tabulated list of adverse reactions The adverse reactions observed in patients treated with pomalidomide in combination with bortezomib and dexamethasone, pomalidomide in combination with dexamethasone and from post-marketing surveillance are listed in table 7 by system organ class (SOC) and frequency for all adverse

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HOS-100768 · has-contraindication-information · PDF-Seite 7

• Pregnancy. • Women of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see sections 4.4 and 4.6). • Male patients unable to follow or comply with the required contraceptive measures (see section 4.4). • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

HOS-100767 · has-indication-information · PDF-Seite 3

Pomalidomide Zentiva in combination with bortezomib and dexamethasone is indicated in the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide. Pomalidomide Zentiva 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.

HOS-100770 · has-interaction-information · PDF-Seite 12

Effect of pomalidomide on other medicinal products Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic 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 interactions, including the potential impact of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been evaluated clinically (see section 4.4 Teratogenicity). 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 12 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.

HOS-100771 · has-pregnancy-information · PDF-Seite 13

Women of childbearing potential / Contraception in males and females Women of childbearing potential should use effective method of contraception. 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 (see sections 4.3 and 4.4). 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 (see sections 4.3 and 4.4). Breast-feeding It is unknown whether 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 breastfed infants from pomalidomide, a decision must be made whether to discontinue breast-feeding or to discontinue the medicinal product, taking into account the benefit of breast- feeding for the child and the benefit of the therapy for the woman. Fertility Pomalidomide was found to impact negatively on fertility and be teratogenic in animals. Pomalidomide crossed the placenta and was detected in foetal blood following administration to pregnant rabbits (see section 5.3).

HOS-100769 · has-warning-information · PDF-Seite 7

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 section 5.3). The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential. Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered of non-childbearing potential if she meets at least one of the following criteria: • Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential) • Premature ovarian failure confirmed by a specialist gynaecologist • Previous bilateral salpingo-oophorectomy, or hysterectomy 7 • XY genotype, Turner syndrome, uterine agenesis. Counselling For women of childbearing potential, pomalidomide is contraindicated unless all of the following are met: • She understands the expected teratogenic risk to the unborn child • She understands the need for effective contraception, without interruption, at least 4 weeks before starting treatment, throughout the entire duration of treatment, and at least 4 weeks after the end of treatment • Even if a woman of childbearing potential has amenorrhoea she must follow all the advice on effective contraception • She should be capable of complying with effective contraceptive measures • She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy • She understands the need to commence the treatment as soon as pomalidomide is dispensed following a negative pregnancy test • She understands the need and accepts to undergo pregnancy testing at least every 4 weeks except in case of confirmed tubal sterilisation • She acknowledges that she understands the hazards and necessary precautions associated with the use of pomalidomide. The prescriber must ensure that for women of childbearing potential: • The patient complies with the conditions of the Pregnancy Pre

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