|Teratogenic effectsThalidomide 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 Thalidomide Celgene Pregnancy Prevention Programme are met. The conditions of the Thalidomide Celgene Pregnancy Prevention Programme must be fulfilled for all male and female patients.
Criteria for women of non-childbearing potentialA 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*.• Premature ovarian failure confirmed by a specialist gynaecologist.• Previous bilateral salpingo-oophorectomy, or hysterectomy.• XY genotype, Turner's syndrome, uterine agenesis.*Amenorrhoea following cancer therapy does not rule out childbearing potential.
CounsellingFor 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, 4 weeks before starting treatment, throughout the entire duration of treatment, and 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 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 • She acknowledges that she understands the hazards and necessary precautions associated with the use of thalidomide.As thalidomide is found in semen, male patients taking thalidomide must meet the following conditions:• Understand the teratogenic risk if engaged in sexual activity with a pregnant woman. • Understand the need for the use of a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential not using effective contraception. The prescriber must ensure that:• The patient complies with the conditions of the Thalidomide Celgene Pregnancy Prevention Programme• The patient confirms that he (she) understand the aforementioned conditions.
ContraceptionWomen of childbearing potential must use one effective method of contraception for 4 weeks before therapy, during therapy, and during 4 weeks after thalidomide therapy and even in case of dose interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred preferably to an appropriately trained healthcare professional for contraceptive advice in order that contraception can be initiated.The following can be considered to be examples of effective methods of contraception:• Subcutaneous hormonal implant• Levonorgestrel-releasing intrauterine system (IUS)• Medroxyprogesterone acetate depot• Tubal sterilisation• Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses• Ovulation inhibitory progesterone-only pills (i.e., desogestrel)Because of the increased risk of venous thromboembolism in patients with multiple myeloma, combined oral contraceptive pills are not recommended (see section 4.5). If a patient is currently using combined oral contraception, she should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception.
Pregnancy testingMedically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.
Prior to starting treatmentA medically supervised pregnancy test should be performed during the consultation, when thalidomide is prescribed or in the 3 days prior to the visit to the prescriber once the patient had been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with thalidomide.
Follow-up and end of treatmentA medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
MenAs thalidomide is found in semen, male patients must use condoms during treatment and for 1 week after dose interruption and/or cessation of treatment if their partner is pregnant or is of childbearing potential not using effective contraception.
Prescribing and dispensing restrictionsFor women of childbearing potential, prescriptions of Thalidomide Celgene should be limited to 4 weeks of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of thalidomide should occur within a maximum of 7 days of the prescription.For all other patients, prescriptions of Thalidomide Celgene should be limited to 12 weeks and continuation of treatment requires a new prescription.
Additional precautionsPatients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.Patients should not donate blood or semen during therapy or for 1 week following discontinuation of thalidomide.
Educational materialsIn order to assist patients in avoiding foetal exposure to thalidomide and to provide additional important safety information, the Marketing Authorisation holder will provide educational material to healthcare professionals. The Thalidomide Celgene Pregnancy Prevention Programme reinforces the warnings about the teratogenicity of thalidomide, provides advice on contraception before therapy is started and provides guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the pregnancy prevention measures as specified in the Thalidomide Celgene Pregnancy Prevention Programme should be given by the physician to women of childbearing potential and, as appropriate, to male patients.
AmenorrheaThe use of thalidomide could be associated with menstrual disorders including amenorrhea. Amenorrhea during thalidomide therapy should be assumed to result from pregnancy, until it is medically confirmed that the patient is not pregnant. A clear mechanism by which thalidomide can induce amenorrhea is not elucidated. The reported events occurred in young (premenopausal) women (median age 36 years) receiving thalidomide for non multiple myeloma indications, had an onset within 6 months of initiating treatment and reversed upon discontinuation of thalidomide. In documented case reports with hormone evaluation, the event of amenorrhoea was associated with decreased estradiol levels and elevated FSH/LH levels. When provided, antiovary antibodies were negative and prolactin level was within the normal range.
Myocardial infarctionMyocardial infarction (MI) has been reported in patients receiving thalidomide, particularly in those with known risk factors. Patients with known risk factors for MI, including prior thrombosis, should be closely monitored and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Venous and arterial thromboembolic eventsPatients treated with thalidomide have an increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (such as myocardial infarction and cerebrovascular event) (see section 4.8). The risk appears to be greatest during the first 5 months of therapy. Thromboprophylaxis and dosing/anticoagulation therapy recommendations are provided in section 4.2.Previous history of thromboembolic events or concomitant administration of erythropoietic agents or other agents such as hormone replacement therapy, may also increase thromboembolic risk in these patients. Therefore, these agents should be used with caution in multiple myeloma patients receiving thalidomide with prednisone and melphalan. Particularly, a haemoglobin concentration above 12g/dl should lead to discontinuation of erythropoietic agents. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia).Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling.
Peripheral neuropathyPeripheral neuropathy is a very common, potentially severe, adverse reaction to treatment with thalidomide that may result in irreversible damage (see section 4.8). In a phase 3 study, the median time to first neuropathy event was 42.3 weeks.If the patient experiences peripheral neuropathy, follow the dose and schedule modification instruction provided in section 4.2.Careful monitoring of patients for symptoms of neuropathy is recommended. Symptoms include paraesthesia, dysaesthesia, discomfort, abnormal co-ordination or weakness.It is recommended that clinical and neurological examinations are performed in patients prior to starting thalidomide therapy, and that routine monitoring is carried out regularly during treatment. Medicinal products known to be associated with neuropathy should be used with caution in patients receiving thalidomide (see section 4.5).Thalidomide may also potentially aggravate existing neuropathy and should therefore not be used in patients with clinical signs or symptoms of peripheral neuropathy unless the clinical benefits outweigh the risks.
Syncope, bradycardia and atrioventricular blockPatients should be monitored for syncope, bradycardia and atrioventricular block; dose reduction or discontinuation may be required.
Neutropenia The incidence of neutropenia grade 3 or 4 reported as adverse reactions was higher in multiple myeloma patients receiving MPT (Melphalan, Prednisone, Thalidomide) than in those receiving MP (Melphalan, Prednisone): 42.7% versus 29.5% respectively (study IFM 99-06). Adverse reactions from post-marketing experience such as febrile neutropenia and pancytopenia were reported with thalidomide. Patients should be monitored and dose delay, reduction or discontinuation may be required (see section 4.2).
ThrombocytopeniaThrombocytopenia, including grade 3 or 4 adverse reactions, has been reported in multiple myeloma patients receiving MPT. Patients should be monitored and dose delay, reduction or discontinuation may be required (see section 4.2). Patients and physicians are advised to be observant for signs and symptoms of bleeding including petechiae, epistaxis and gastrointestinal haemorrhage, especially in case of concomitant medication susceptible to induce bleeding (see section 4.8).
Hepatic disordersHepatic disorders, mainly abnormal liver test results, were reported. No specific pattern was identified between hepatocellular and cholestatic abnormalities, with some cases having a mixed presentation. The majority of the reactions occurred within the first 2 months of therapy and resolved spontaneously without treatment after thalidomide discontinuation. Patients should be monitored for liver function, particularly in case of pre-existing liver disorder or concomitant use of medication susceptible to induce liver dysfunction (see section 4.8).
Skin reactionsIf at anytime the patient experiences a toxic skin reaction e.g. Stevens-Johnson Syndrome, the treatment should be discontinued permanently.
SomnolenceThalidomide frequently causes somnolence. Patients should be instructed to avoid situations where somnolence may be a problem and to seek medical advice before taking other medicinal products known to cause somnolence. Patients should be monitored and dose reduction may be required.Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks (see section 4.7).
Tumour lysis syndromeThe patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Severe infectionsPatients should be monitored for severe infections including sepsis and septic shock.
Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)A statistically significant increase of AML and MDS has been observed in an ongoing clinical study in patients with previously untreated MM receiving the combination of melphalan, prednisone, and thalidomide (MPT). The risk increases over time and was about 2% after two years and about 4% after three years. An increased incidence of second primary malignancies (SPM) has also been observed in patients with newly diagnosed MM receiving lenalidomide. Among invasive SPMs, cases ofMDS/AML were observed in patients receiving lenalidomide in combination with melphalan or immediately following high dose melphalan and autologous stem cell transplantation. The benefit achieved with thalidomide and the risk of AML and MDS must be taken into account before initiating treatment with thalidomide in combination with melphalan and prednisone. Physicians should carefully evaluate patients before and during treatment using standard cancer screening and institute treatment as indicated.
Patients with renal or hepatic impairmentStudies conducted in healthy subjects and patients with multiple myeloma suggest that Thalidomide is not influenced to any significant extent by renal or hepatic function (see section 5.2). However, this has not formally been studied in patients with impaired renal or hepatic function; therefore patients with severe renal or hepatic impairment should be carefully monitored for any adverse effects.
Allergic reactions Cases of allergic reactions/angioedema have been reported. Thalidomide should be discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation. If angioedema occurs, use of thalidomide should not be resumed.