Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Celgene Europe B.V., Winthontlaan 6 N, 3526 KV Utrecht, Netherlands
Thalidomide Celgene 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 Celgene is prescribed and dispensed according to the Thalidomide Celgene Pregnancy Prevention Programme (see section 4.4).
Treatment must be initiated and monitored under the supervision of physicians with expertise in managing immunomodulatory or chemotherapeutic agents and a full understanding of the risks of thalidomide therapy and monitoring requirements (see section 4.4).
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.
Table 1. Starting doses for thalidomide in combination with melphalan and prednisone:
| Age (years) | ANC* (/µL) | Platelet Count (/µL) | Thalidomidea,b | Melphalanc,d,e | Prednisonef | |
|---|---|---|---|---|---|---|
| ≤75 | ≥1,500 | AND | ≥100,000 | 200 mg daily | 0.25 mg/kg daily | 2 mg/kg daily |
| ≤75 | <1,500 but ≥1,000 | OR | <100,000 but ≥50,000 | 200 mg daily | 0.125 mg/kg daily | 2 mg/kg daily |
| >75 | ≥1,500 | AND | ≥100,000 | 100 mg daily | 0.20 mg/kg daily | 2 mg/kg daily |
| >75 | <1,500 but ≥1,000 | OR | <100,000 but ≥50,000 | 100 mg daily | 0.10 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.
Patients should be monitored for: thromboembolic events, peripheral neuropathy, severe skin reactions, bradycardia, syncope, somnolence, neutropenia and thrombocytopenia (see sections 4.4 and 4.8). 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.
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. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient’s underlying risk factors (see sections 4.4, 4.5 and 4.8).
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.
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.
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.
Dose modifications due to peripheral neuropathy are described in Table 2.
Table 2. Recommended dose modifications for thalidomide-related neuropathy in first line treatment of multiple myeloma:
| Severity of neuropathy | Modification of dose and regimen |
|---|---|
| Grade 1 (paraesthesia, weakness and/or loss of reflexes) with no loss of function | Continue to monitor the patient with clinical examination. Consider reducing dose if symptoms worsen. However, dose reduction is not necessarily followed by improvement of symptoms. |
| Grade 2 (interfering with function but not with activities of daily living) | Reduce dose or interrupt treatment and continue to monitor the patient with clinical and neurological examination. If no improvement or continued worsening of the neuropathy, discontinue treatment. If the neuropathy resolves to Grade 1 or better, the treatment may be restarted, if the benefit/risk is favourable. |
| Grade 3 (interfering with activities of daily living) | Discontinue treatment |
| Grade 4 (neuropathy which is disabling) | Discontinue treatment |
Thalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Thalidomide 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 for these reactions.
No specific dose adjustments are recommended for the elderly ≤75 years of age. For patients >75 years of age, the thalidomide recommended starting dose is 100 mg per day. The initial dose of melphalan is reduced for elderly >75 years of age considering baseline bone marrow reserve and renal function. The melphalan recommended starting dose is 0.1 to 0.2 mg/kg daily according to bone marrow reserve along with a further 50% dose reduction for moderate (creatinine clearance: ≥30 but <50 mL/minute) or severe (CrCl: <30 mL/minute) renal insufficiency. The maximum daily melphalan dose is 20 mg in patients >75 years of age (see Table 1).
Thalidomide Celgene has not formally been studied in patients with impaired renal or hepatic function. No specific dose recommendations for these patient populations are available. Patients with severe organ impairment should be carefully monitored for adverse reactions.
There is no relevant use of Thalidomide Celgene in the paediatric population in the indication of multiple myeloma.
Thalidomide Celgene should be taken as a single dose at bedtime, to reduce the impact of somnolence.
Capsules should not be opened or crushed (see section 6.6).
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.
Eighteen cases of overdose have been reported in the literature concerning doses up to 14.4 grams. In thirteen of these cases, patients took thalidomide alone; amounts ranged from 350 mg to 4000 mg. These patients either exhibited no symptoms or exhibited symptoms of drowsiness, irritability, “sickness,” and/or headache. In one 2-year-old child who took 700 mg, there was an abnormal plantar response in addition to drowsiness and irritability. No fatalities have been reported and all overdose patients recovered without sequelae. There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.
5 years.
This medicinal product does not require any special storage conditions.
PVC/PCTFE/aluminium blister containing 14 capsules.
Pack sizes: 28 capsules (two blisters) in a wallet card.
Capsules should not be opened or crushed. If powder from thalidomide makes contact with the skin, the skin should be washed immediately and thoroughly with soap and water. If thalidomide makes contact with the mucous membranes, they should be thoroughly flushed with water.
All unused capsules should be returned to the pharmacist at the end of treatment.
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