Thalidomide BMS (previously Thalidomide Celgene) · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-094846 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile Most patients taking thalidomide can be expected to experience adverse reactions. The most commonly observed adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone are: neutropenia, leukopenia, constipation, somnolence, paraesthesia, peripheral neuropathy, anaemia, lymphopenia, thrombocytopenia, dizziness, dysaesthesia, tremor and peripheral oedema. In addition to the adverse reactions outlined above, thalidomide in combination with dexamethasone in other clinical studies led to the very common adverse reaction of fatigue; common adverse reactions of transient ischaemic event, syncope, vertigo, hypotension, mood altered, anxiety, blurred vision, nausea and dyspepsia; and uncommon adverse reactions of cerebrovascular accident, diverticular perforation, peritonitis, orthostatic hypotension and bronchitis. The most clinically important adverse reactions associated with the use of thalidomide in combination with melphalan and prednisone or dexamethasone include: deep vein thrombosis and pulmonary embolism, peripheral neuropathy, severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms, syncope, bradycardia, and dizziness (see sections 4.2, 4.4 and 4.5). Tabulated list of adverse reactions Table 3 contains only the adverse reactions for which a causal relationship with medicinal product treatment could reasonably be established observed in the pivotal study and from post-marketing experience. Frequencies given are based on the observations during a pivotal comparative clinical study investigating the effect of thalidomide in combination with melphalan and prednisone in previously untreated multiple myeloma patients. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 3: Adverse drug reactions (ADRs) reported in pivotal clinical study with thalidomide in combination with melphalan and prednisone and from post marketing use System Organ Class Frequency Adverse reaction Common Pneumonia Infections and infestations Severe infections

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HOS-094842 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to thalidomide or to any of the excipients listed in section 6.1. • Women who are pregnant (see section 4.6). • 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).

HOS-094841 · has-indication-information · PDF-Seite 2

Thalidomide BMS in combination with melphalan and prednisone is indicated as first line treatment of patients with untreated multiple myeloma, aged ≥ 65 years or ineligible for high dose chemotherapy. Thalidomide BMS is prescribed and dispensed according to the Thalidomide BMS Pregnancy Prevention Programme (see section 4.4).

HOS-094844 · has-interaction-information · PDF-Seite 10

Thalidomide is a poor substrate for cytochrome P450 isoenzymes and therefore clinically important interactions with medicinal products that are inhibitors and/or inducers of this enzyme system are unlikely. Non-enzymatic hydrolysis of thalidomide, being the primary clearance mechanism, suggests that the potential for drug-drug interactions with thalidomide is low. Increase of sedative effects of other medicinal products Thalidomide has sedative properties, thus may enhance the sedation induced by anxiolytics, hypnotics, antipsychotics, H1 antihistamines, opiate derivatives, barbiturates and alcohol. Caution should be used when thalidomide is given in combination with medicinal products that cause drowsiness. Bradycardic effect Due to thalidomide’s potential to induce bradycardia, caution should be exercised with medicinal products having the same pharmacodynamic effect such as active substances known to induce torsade de pointes, beta blockers or anticholinesterase agents. Medicinal products known to cause peripheral neuropathy Medicinal products known to be associated with peripheral neuropathy (e.g. vincristine and bortezomib) should be used with caution in patients receiving thalidomide. Hormonal contraceptives Thalidomide does not interact with hormonal contraceptives. In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl oestradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 0.75 mg of ethinyl oestradiol were studied. The results were similar with and without co-administration of thalidomide 200 mg/day to steady-state levels. However, combined hormonal contraceptives are not recommended due to the increased risk of venous thromboembolic disease. 10 Warfarin Multiple dose administration of 200 mg thalidomide q.d. for 4 days had no effect on the international normalized ratio (INR) in healthy volunteers. However, due to the increased risk of thrombosis in cancer patients, and a potentially accelerated metabolism of warfarin with corticosteroids, close monitoring of INR values is advised during thalidomide-prednisone combination treatment as well as during the first weeks after ending these treatments. Digoxin Thalidomide does not interact with digoxin. In 18 healthy male volunteers, multiple dose administration of 200 mg thalidomide had no apparent effect on the single dose pharmacokinetics of digoxin. In addition, sin

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HOS-094845 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential/Contraception in males and females Women of childbearing potential must use one effective method of contraception for at least 4 weeks before start of treatment, during treatment including during dose interruptions, and until at least 4 weeks after thalidomide treatment (see section 4.4). If pregnancy occurs in a woman treated with thalidomide, treatment must be stopped immediately and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. As thalidomide is found in semen, as a precaution all male patients must use condoms during treatment, during dose interruption and for at least 7 days following discontinuation of treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential who is not using effective contraception. This applies even if the man has had a vasectomy. If pregnancy occurs in a partner of a male patient taking thalidomide, the female partner should be referred to a physician specialised or experienced in teratology for evaluation and advice. Pregnancy Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the Pregnancy Prevention Programme are met (see section 4.3) Thalidomide is a powerful human teratogen, inducing a high frequency (about 30 %) of severe and live-threatening birth defects such as: ectromelia (amelia, phocomelia, hemimelia) of the upper and/or lower extremities, microtia with abnormality of the external acoustic meatus (blind or absent), middle and internal ear lesions (less frequent), ocular lesions (anophthalmia, microphthalmia), congenital heart disease, renal abnormalities. Other less frequent abnormalities have also been described. Breast-feeding It is unknown whether thalidomide is excreted in human breast milk. Animal studies have shown excretion of thalidomide in breast milk. Therefore breast-feeding should be discontinued during treatment with thalidomide. Fertility A study in rabbits demonstrated no effect on fertility indices in males or females although testicular degeneration was observed in males. 11

HOS-094843 · has-warning-information · PDF-Seite 4

Teratogenic effects Thalidomide is a powerful human teratogen, inducing a high frequency of severe and life- threatening birth defects. Thalidomide must never be used by women who are pregnant or by women who could become pregnant unless all the conditions of the Pregnancy Prevention Programme are met. The conditions of the Pregnancy Prevention Programme must be fulfilled for all male and female patients. Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered to have childbearing potential unless 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. • XY genotype, Turner’s syndrome, uterine agenesis. 4 Counselling For women of childbearing potential, thalidomide is contraindicated unless all of the following conditions are met: • She understands the 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 amenorrhea 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 her doctor if there is a risk of pregnancy • She understands the need to commence the treatment as soon as thalidomide is dispensed following a negative pregnancy test • She understands the need and accepts to undergo pregnancy testing 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 thalidomide. As thalidomide is found in semen, as a precaution all male patients taking thalidomide must meet the following conditions: • He understands the teratogenic risk if engaged in sexual activity with a pregnant woman or a woman of childbearing potential. •

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