THALIDOMIDE BMS

4). Posology The recommended dose of thalidomide is 200 mg orally per day. A maximum number of 12 cycles of 6 weeks (42 days) should be used. 10 mg/kg daily 2 mg/kg daily * ANC: Absolute Neutrophil Count a Thalidomide dosed once daily at bedtime on Days 1 to 42 of each 42-day cycle.

b Due to the sedative effect associated with thalidomide, administration at bedtime is known to generally improve tolerability. c Melphalan dosed once daily on Days 1 to 4 of each 42-day cycle. d Melphalan dosing: reduce by 50 % for moderate (creatinine clearance: ≥ 30 but < 50 mL/min) or severe (CrCl: < 30mL/min) renal insufficiency e Maximum daily melphalan dose: 24 mg (subjects ≤ 75 years old) or 20 mg (subjects > 75 years old).

f Prednisone dosed once daily on Days 1 to 4 of each 42-day cycle. 8). Dose delay, reduction or discontinuation, dependent upon the NCI CTC (National Cancer Institute Common Toxicity Criteria) grade, may be necessary. If less than 12 hours has elapsed since missing a dose, the patient can take the dose.

If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day. Thromboembolic events Thromboprophylaxis should be administered for at least the first 5 months of treatment especially in patients with additional thrombotic risk factors.

Prophylactic antithrombotic medicinal products, such as low molecular weight heparins or warfarin, should be recommended. 8). If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started.

Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, the thalidomide treatment may be restarted at the original dose dependent upon a benefit-risk assessment.

The patient should continue anticoagulation therapy during the course of thalidomide treatment. Neutropenia White blood cell count and differential should be monitored on an ongoing basis, in accordance with oncology guidelines, especially in patients who may be more prone to neutropenia.

Dose delay, reduction or discontinuation, dependent upon the NCI CTC grade, may be necessary. Thrombocytopenia Platelet counts should be monitored on an ongoing basis, in accordance with oncology guidelines. Dose delay, reduction or discontinuation, dependent upon the NCI CTC grade, may be necessary.

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.

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. g. 8 description of selected adverse reactions † identified from post marketing data ^ Acute myeloid leukaemia and Myelodysplastic syndrome were reported in one clinical study in patients with previously untreated MM receiving the combination of melphalan, prednisone and thalidomide (MPT) Description of selected adverse reactions Blood and lymphatic system disorders Adverse reactions for haematological disorders are provided compared to the comparator arm, as the comparator has a significant effect on these disorders (Table 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 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.

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