Thalidomide Lipomed

4). Posology The recommended dose of thalidomide is 200 mg orally per day. Each coated tablet of Thalidomide Lipomed contains 100 mg of thalidomide, whereas other available thalidomide-containing medicinal products usually contain 50 mg of thalidomide.

This must be taken into account, and the patient must be instructed accordingly. 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 Day 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 (creatinine clearance: < 30 ml/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 have elapsed since missing a dose, the patient can take the dose. If more than 12 hours have 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.

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. fatal sepsis including septic shock)a, viral infections, including herpes zoster and hepatitis B virus reactivationa Neoplasms benign, malignant and unspecified (including cysts and polyps) Common Acute myeloid leukaemiab,c Uncommon Myelodysplastic syndromeb,c Not known Tumour lysis syndromea Blood and lymphatic system disorders Very common Neutropenia, leukopenia, anaemia, lymphopenia, thrombocytopenia Common Febrile neutropeniaa, pancytopeniaa Immune system disorders Not known Allergic reactions (hypersensitivity, angioedema, anaphylactic reaction, urticaria)a 14 System Organ Class Frequency Adverse reaction Endocrine disorders Not known Hypothyroidisma Psychiatric disorders Common Confusional state, depression Nervous system disorders Very common Peripheral neuropathyb, tremor, dizziness, paraesthesia, dysaesthesia, somnolence Common Convulsionsa, abnormal coordination Not known Posterior reversible encephalopathy syndrome (PRES)a,b, worsening of Parkinson’s disease symptomsa Ear and labyrinth disorders Common Hearing impaired or deafnessa Cardiac disorders Common Cardiac failure, bradycardia Uncommon Myocardial infarctiona, atrial fibrillationa, atrioventricular blocka Vascular disorders Common Deep vein thrombosisb Respiratory, thoracic and mediastinal disorders Common Pulmonary embolismb, interstitial lung disease, bronchopneumopathy, dyspnea Not known Pulmonary hypertensiona Gastrointestinal disorders Very common Constipation Common Vomiting, dry mouth Uncommon Intestinal obstructiona Not known Gastrointestinal perforationa, pancreatitisa, gastrointestinal haemorrhagea Hepatobiliary disorders Not known Hepatic disordersa Skin and subcutaneous tissue disorders Common Toxic skin eruption, rash, dry skin Not known Stevens-Johnson syndromea,b, toxic epidermal necrolysisa,b, drug reaction with eosinophilia and systemic symptomsa,b, leukocytoclastic vasculitisa Renal and urinary disorders Common Renal failurea Reproductive system and breast disorders Not known Sexual dysfunctiona, menstrual disorders including amenorrheaa General disorders and administration site conditions Very common Peripheral oedema Common Pyrexia, asthenia, malaise a Identified from post-marketing data.

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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