Thalidomide BMS

/ Neopharm

Thalidomide 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.
To reduce central nervous system effects (e.g. drowsiness, somnolence, sedation) during the day, Thalidomide Celgene is normally taken as a single dose in the evening. Thalidomide Celgene 50mg Hard Capsules should be taken at least one hour after food.
Multiple Myeloma (dosage in adults and adolescents): The required total duration of treatment should be individually determined for each patient depending on tolerability and disease progression.
Patients with Untreated Multiple Myeloma: In combination with Melphalan and Prednisone: The Thalidomide Celgene recommended oral dose is 200 mg per day. A maximum number of 12 cycles of 6 weeks should be used.
In combination with Dexamethasone: The Thalidomide Celgene recommended oral dose is 200 mg per day. For induction, 4 cycles of 4 weeks of thalidomide/dexamethasone is recommended.
For elderly patients of poor performance, tolerability may be improved by starting the patient on 50 mg per day and increasing this dose to 200 mg per day over a 4 week period.
After Failure of Standard Therapies: Dosing should be initiated at 200mg daily orally and increased by 100mg at weekly intervals to a maximum dose of 400mg daily according to tolerance and toxicity.
Depending on tolerance and observed toxicity, lower maintenance doses can be used.
Erythema Nodosum Leprosum (adult dosage): For an episode of cutaneous ENL, dosing should be initiated at 100mg to 300mg/day administered orally once daily preferably at bedtime. Patients weighing less than 50 kilograms should be started at the low end of the dose range. In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, thalidomide dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water. In patients with moderate to severe neuritis (due to leprosy) or other serious complications (e.g. uveitis), corticosteroids and other appropriate therapy may be started concomitantly and tapered/discontinued when neuritis has improved.
Dosing with thalidomide should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks. Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare during tapering, should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every 3-6 months, in decrements of 50mg every 2 to 4 weeks.
Dosage adjustments during treatment: Dosage delay or reduction, dependent upon grade of toxicity, may be necessary. Patients should be monitored for: thromboembolic events; peripheral neuropathy; rash/skin reactions; bradycardia, syncope and somnolence. Dose delay, reduction or discontinuation, dependent upon the NCI CTC grade, may be necessary.
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. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient’s underlying risk factors. If the patient experiences any thromboembolic events during treatment with thalidomide in combination, discontinue treatment and start standard anticoagulation therapy. 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.
For full details see prescribing information.

Multiple Myeloma: For the treatment of multiple myeloma after failure of standard therapies.
In combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma.
In combination with melphalan and prednisone for the treatment of patients with untreated multiple myeloma > or = 65 years or ineligible for high dose chemotherapy.
Erythema Nodosum Leprosum (ENL):  For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Thalidomide is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. Thalidomide Celgene is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

Known hypersensitivity to thalidomide or to any of the excipients. Patients below 12 years of age. Pregnancy and lactation. Women of child bearing potential who are not using, not willing or not able to use adequate contraceptive measures to prevent pregnancy. Women of childbearing potential where there is an alternative treatment of non-inferior efficacy available. Males who are not able or willing to comply with adequate contraceptive measures.

Teratogenic effects: Thalidomide is a known human teratogen and should not, under any circumstances, be administered during pregnancy, or to women of childbearing potential, unless they are using at least two effective means of contraception. A single dose taken by pregnant women can cause birth defects. Major human foetal abnormalities related to thalidomide administration during pregnancy are: amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, external ear abnormalities (including anotia, micro pinna, small or absent external auditory canals), facial palsy, eye abnormalities (anopthalmos, micropthalmos) and congenital heart defects. Alimentary tract, urinary tract and genital malformations have also been documented. Mortality at or shortly after birth has been reported at or about 40%.
Thalidomide has been found in the semen of men taking the medicine; therefore, male patients with female partners of childbearing potential must use adequate contraceptive methods. Contraception must be used 4 weeks before, during thalidomide treatment, during dose interruptions and for 4 weeks after stopping thalidomide treatment.
If a female patient, or female partner of a male patient, misses or is suspected to have missed her period or there is any abnormality in menstrual bleeding, or suspects she is pregnant then a pregnancy test and counselling should be performed.
If pregnancy occurs in a female patient, or female partner of a male patient, during thalidomide treatment, thalidomide should be discontinued immediately by the female patient. The female patient or pregnant partner should be referred to an obstetrician or gynaecologist experienced in reproductive toxicity for further evaluation and counselling.
Patients (or their legal guardians where appropriate) should give individual, written, fully informed consent for the use of thalidomide. Fully informed consent implies good understanding of the probability and the magnitude of harms that thalidomide can cause, the need to avoid pregnancy (and an understanding of appropriate choices for contraception, where needed), the limitations of thalidomide’s treatment efficacy (including the potential for treatment failure) and the existence of alternative therapies. Appropriate counselling and information should be provided to the patient’s sexual partner. Patients should be counselled monthly regarding risks of thalidomide and precautions to be taken when using thalidomide.
Patients should be instructed to take thalidomide only as prescribed and not to share thalidomide with anyone else.
Procedure for prescribing Thalidomide BMS 50mg Hard Capsules:
Because of the potential for severe teratogenicity, Neopharm Ltd. will only supply Thalidomide BMS according to the Risk Management Program / Pregnancy Prevention Program approved by the Israeli MoH.
Criteria for a female 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
• Previous bilateral salpingo-oophorectomy, or hysterectomy
• XY genotype, Turner syndrome, uterine agenesis
• Premature ovarian failure confirmed by a specialist gynaecologist
*Amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential.
Pregnancy testing:
Medically 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. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. For women of childbearing potential, dispensing of thalidomide should occur within a maximum of 3 days from the date of a negative pregnancy test.
Prior to starting treatment
A medically supervised pregnancy test should be performed when thalidomide is prescribed. The test should occur either at the time of consultation, or in the 3 days prior to the visit to the prescriber and at a point where the patient has been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with thalidomide. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.
Follow-up and end of treatment
A medically supervised pregnancy test should be repeated every 4 weeks, during dose interruptions and 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. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.
In female patients in whom the time of the next menstrual bleeding can reasonably be determined (i.e. who are having regular cycles), thalidomide should be initiated on day 2 or 3 of the menstrual cycle.
It is strongly recommended that pregnancy testing be carried out weekly in the first month of treatment, then monthly in women with regular menstrual cycles or fortnightly in women with irregular menstrual cycles.
Females Patients of childbearing potential:
Women of childbearing potential must use at least one highly effective AND one additional effective barrier method of contraception for at least 4 weeks before start of treatment, during treatment, and until at least 4 weeks after thalidomide treatment and even in case of dose interruptions unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis.
The following can be considered to be examples of highly effective methods of contraception:
• Intrauterine device (IUD)
• Levonorgestrel-releasing intrauterine system (IUS)
• Medroxyprogesterone acetate depot
• Tubal ligation
• Sexual intercourse with a vasectomized male partner only; vasectomy must be confirmed by two negative semen analyses
• Ovulation inhibitory progesterone-only pills (ie, desogestrel)
The following can be considered to be examples of additional effective barrier methods of contraception:
• Condom
• Diaphragm
• Cervical cap
Because of the increased risk of venous thromboembolism in patients with multiple myeloma, combined oral contraceptive pills are not recommended.
Male patients:
Thalidomide is present in semen, therefore males receiving thalidomide must always use a latex or polyurethane condom when engaging in sexual activity with women of childbearing potential. Condom use is required during thalidomide treatment, during dose interruptions and continue for 4 weeks after cessation of thalidomide treatment. If a male patient is allergic to latex or polyurethane, sexual abstinence is recommended.
Drowsiness, somnolence and sedation: Thalidomide frequently causes drowsiness, somnolence and sedation. reduction may be required. Thalidomide may potentiate the drowsiness caused by alcohol. As with any sedative medication, the potential for impaired consciousness may increase the risk for aspiration of food, vomitus and oral secretions.
Peripheral neuropathy: Peripheral neuropathy is a very common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months, however, reports following relatively short-term use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy.
Symptoms may occur sometime after thalidomide treatment has been stopped and may resolve slowly or not at all. If thalidomide is contemplated for long-term use, baseline and 6-monthly sensory nerve action potential (SNAP) data should be collected. Where such monitoring is not feasible, regular clinical assessment is required.
Neuritis in ENL patients: Thalidomide is known to cause neuritis which may be irreversible. The medicine potentially aggravates existing neuritis and should therefore not be used in such patients unless the clinical benefits outweigh the risks.
Thrombogenicity: Use of thalidomide in patients with malignant neoplastic disease, including multiple myeloma, has been associated with an increased risk of deep vein thrombosis (DVT) and pulmonary embolus (PE).
This risk increases significantly when thalidomide is used in combination with
standard chemotherapeutic agents including melphalan, prednisone or dexamethasone.
Myocardial Infarction: Myocardial 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).
Syncope and bradycardia: Patients receiving thalidomide should be monitored for syncope and bradycardia and dose reduction or discontinuation may be required.
Haematological disorders: Neutropenia or Thrombocytopenia: Neutropenia or thrombocytopenia, including Grade 3 or 4 occurrences for both events, has been reported in association with the clinical use of thalidomide in combination with melphalan and prednisone. For thalidomide in combination with other medicines and as monotherapy, treatment should be initiated with caution in patients with neutropenia.
Patients should be monitored and dose reduction, delay or discontinuation may be required
Infections: Reactivation of hepatitis B virus (HBV) has been reported in patients receiving thalidomide in combination with corticosteroids who have previously been infected with HBV. Some of these cases progressed to acute hepatic failure, and resulted in discontinuation of thalidomide. Caution should be exercised when thalidomide in combination with corticosteroids is used in patients previously infected with HBV.
These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.
Allergic Reactions and Serious Skin reactions: Angioedema, anaphylaxis and serious dermatological reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported.
Progressive Multifocal Leukoencephalopathy: Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with Thalidomide in combination with immunosuppressive therapy including dexamethasone. PML was reported several months to several years after starting the treatment with thalidomide.
Tumour lysis syndrome: Patients with high tumour burden prior to treatment are at risk of tumour lysis syndrome. These patients should be monitored closely and appropriate precautions taken.
Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndromes (MDS): AML and MDS were observed in one clinical trial in patients with previously untreated MM receiving the combination of melphalan, prednisone, and thalidomide (MPT).
Pulmonary hypertension: Cases of pulmonary hypertension, some fatal, have been reported following treatment with thalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during thalidomide therapy.
Other warnings: Thyroid activity should be monitored during ongoing treatment with thalidomide as cases of hypothyroidism have been reported.
See prescribing information for full details.

Nearly all patients can be expected to experience adverse reactions. The most
commonly observed adverse reactions associated with the use of thalidomide in
combination with dexamethasone or melphalan and prednisone are: deep vein
thrombosis, constipation, peripheral oedema, tremor, dizziness, fatigue, somnolence, peripheral neuropathy, neutropenia, lymphopenia, leukopenia, anaemia, thrombocytopenia, paraesthesia and dysaesthesia.
See prescribing information for full details.

Thalidomide is a poor substrate for cytochrome P450 isoenzymes and therefore clinically important interactions with medicinal products metabolized by this enzyme system are unlikely. Non-enzymatic hydrolysis suggests that the potential for drug-drug interactions with thalidomide is low.
Increase of sedative effects of other drugs: 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.
Medications known to cause peripheral neuropathy: Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide. (e.g. zalcitabine, vincristine, didanosine and bortezomib).
Cytotoxic drugs: An increased risk for thrombosis and thrombo-embolic events has been reported in association with the use of thalidomide in combination with cytotoxic drugs e.g. doxorubicin and melphalan.
Oral contraceptives: Thalidomide does not interact with oral contraceptives. However, combined hormonal contraceptives are not recommended due to the increased risk of venous thrombo-embolic disease. Therefore, effective contraceptive measures to avoid pregnancy must be taken.
Concomitant therapies that may increase the risk of thromboembolism:
Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as oestrogen-containing therapies, should be used with caution in multiple myeloma.
Warfarin: Thalidomide does not interact with warfarin.
Digoxin: Thalidomide does not interact with digoxin.
Important non-thalidomide drug interactions – drugs that interfere with hormonal contraceptives:Concomitant use of glucocorticoids (including dexamethasone and prednisone), HIVprotease inhibitors, griseofulvin, rifampin, rifabutin, phenytoin, or carbamazepine with hormonal contraceptive agents, may reduce the effectiveness of the contraception. Therefore, women of childbearing potential requiring treatment with one or more of these medicines must use two other effective methods of contraception or abstain from heterosexual contact while taking thalidomide.
See prescribing information for full details.

Pregnancy: (Category X) Thalidomide is a known human teratogen and should not, under any circumstances, be administered during pregnancy, or to women of child-bearing potential, unless they are using two effective means of contraception. A single dose taken by pregnant women can cause birth defects. Thalidomide has been found in the semen of men taking the drug; therefore male patients with female partners of child bearing potential must use adequate contraceptive methods. Contraception must continue for 4 weeks after stopping thalidomide treatment. If a female patient, or female partner of a male patient misses, or is suspected to have missed her period or there is any abnormality in menstrual bleeding, or suspects she is pregnant then a pregnancy test and counselling should be performed. If pregnancy occurs in a patient during thalidomide treatment, thalidomide should be discontinued immediately. The patient or pregnant partner should be referred to an obstetrician or gynaecologist experienced in reproductive toxicity for further evaluation and counselling. See prescribing information for full details.
Lactation: It is not known whether thalidomide is excreted in human milk. Thalidomide has been detected in the milk of lactating rabbits given thalidomide by oral gavage, at concentrations up to 3.6 times maternal plasma levels. Women who are taking thalidomide should not breast feed; and for 4 weeks from discontinuation of treatment with thalidomide.

Eighteen cases of overdose have been reported in the literature concerning doses up to 14.4 g. 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.