thalidomide

thalidomide

COMMON TRADE NAME(S):   Thalomid®

• In combination with melphalan and prednisone for treating previously untreated multiple myeloma in patients 65 years and older.

Thalidomide is only available through a controlled distribution program- RevAid®. For more information, please call 1-888-revaid1 (1-888-738-2431) or visit www.revaid.ca

• In combination with dexamethasone for newly diagnosed multiple myeloma for patients who are candidates for stem cell transplant
• Maintenance therapy post stem cell transplant
• Relapsed refractory myeloma

Emetogenic Potential:  

Extravasation Potential:   Not applicable

Thalidomide is usually used in combination with melphalan and prednisone. Adverse effects noted below (unless indicated) are from controlled clinical trials of combination, where the incidence in the thalidomide combination arm was considered higher and clinically relevant (in general incidence ≥10% higher or severe event incidence ≥ 2%). Life-threatening adverse events reported from post-marketing surveillance are also indicated.

* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for thalidomide include myelosuppression ± infection, bleeding, constipation, somnolence, peripheral neuropathy, dizziness, tremor, abdominal pain, confusion, cough, dyspnea and depression.

The sedative properties of thalidomide are believed to be due to activation of the thalamic and hypothalamic sleep centres and are dose-related, and are additive with other sedatives. Administering thalidomide at bedtime minimizes daytime somnolence, but patients should still be cautioned to avoid situations in which drowsiness could be hazardous. It may be necessary to adjust concomitant sedative medications.

The mechanism by which thalidomide-associated edema occurs is unknown, but is mild and short-lived. Dose modification is usually not necessary.

The most common rash described in association with thalidomide use is a pruritic, erythematous, macular rash over the trunk, back and proximal extremities, which does not appear to be dose-related, and occurs 10 to 14 days after starting therapy. The rash usually resolves within 24 hours after discontinuation. Serious dermatological reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have rarely been reported in association with thalidomide therapy; patients should not be re-challenged. Hypersensitivity reactions (i.e. rash, fever, tachycardia, hypotension, etc) have also been reported.

Cases of viral reactivation have been reported, including hepatitis B and C virus (HBV, HCV) infections and may result in acute hepatic failure, including fatal events. Use with caution in patients previously infected with HBV or HCV.

Thalidomide-associated peripheral and autonomic neuropathies are not dose-related and are associated with axonal degeneration without demyelination. Baseline evaluation and monitoring should be considered in patients at risk. Neuropathy may be irreversible if thalidomide is not discontinued early, or may develop after treatment is discontinued.

Dizziness and hypotension may be related to the central sedative action of thalidomide. Administering thalidomide at bedtime may minimize symptoms due to decrease in blood pressure, but patients should still be cautioned to sit upright for several minutes before standing up from a recumbent position.

Bradycardia and AV block have been reported.

Venous and arterial thromboembolism are increased especially in combination with chemotherapy and/or steroids, or in high risk patients (age≥ 65 years, male patients, hyperlipidemia, hypertension, diabetes, obesity, renal disease and tobacco use); patients should be closely monitored and prophylaxis considered, especially for the first 5 months of treatment.

Severe bleeding (especially when used with other drugs that may increase the risk of bleeding) or infection have been reported in patients using thalidomide with melphalan and prednisone. Increased viral loads have been reported when thalidomide is used in HIV seropositive patients.

Thalidomide was withdrawn from the worldwide market in 1961 because of its teratogenic and neurotoxic effects. Severe congenital malformation or fetal deaths are associated with maternal thalidomide usage. Thalidomide is detected in sperm and seminal fluid. Both male and female patients must adhere to the requirements of the RevAid program. (Refer to section G.)

Hepatotoxicity has been reported and may be fatal. The pattern may be hepatocellular or cholestatic, usually occurred within the first 2 months of therapy and resolved spontaneously without treatment after discontinuing thalidomide.

• Patients with peripheral neuropathy, or with known hypersensitivity to thalidomide, lenalidomide, or pomalidomide.
• Women who are pregnant.
• Breastfeeding women.
• Patients unable to follow or comply with the required contraceptive measures (see below section regarding the RevAid® program).
   

• Patients should be warned of the risk of drowsiness, dizziness or orthostatic hypotension. Caution in patients using sedatives or alcohol.
• May increase viral load if used in patients with HIV.
• Use with caution and monitor closely in patients with previous viral infections such as HBV and HCV.
• Use with caution in patients with risk factors for VTE or ATE, or using thrombogenic agents. Oral contraceptives should be avoided due to the increased risk of VTE.
• Use with caution in combination with corticosteroids in myeloma due to the risk of thromboembolism - consider prophylactic anticoagulation.
• Use with caution in patients with risk factors for peripheral neuropathy, taking neurotoxic drugs, or taking drugs that may cause severe skin reactions.
   

Pregnancy and Lactation:

Although in vitro or animal studies suggested thalidomide to be non-mutagenic, non-genotoxic and non-carcinogenic, it is associated with secondary malignancies; fertility may be affected.  Thalidomide is excreted into milk in animals; breastfeeding is contraindicated.  It is a known human teratogen, is fetotoxic, an abortifacient, and can cause severe, life-threatening birth defects or fetal death if taken during pregnancy, especially 34-50 days after the beginning of the last menstrual period. The drug can cause teratogenic effects even if only a single dose of the drug is taken during pregnancy. Thalidomide is contraindicated in pregnant women and in females of childbearing potential and in males who do not comply with the contraception conditions of the RevAid® program. 

Male patients:

• Must be capable of understanding and complying with the patient registration, education, and safety requirements of the RevAid®,
• Mandatory contraceptive measures for men (condoms should be used even with vasectomized males).
• Should not donate semen while taking thalidomide and for 4 weeks after treatment cessation.
• Must inform their female sexual partners of child-bearing potential that he is taking thalidomide, of the potential risk of birth defects, stillbirths, and spontaneous abortions, and that a condom must be used during any sexual contact.
• If a pregnancy occurs in a partner of a male patient taking thalidomide, the female partner should be referred to a physician specialized in teratology for evaluation and advice. 

Females of childbearing potential (all women except those who had hysterectomy or bilateral oophorectomy):

• Must be capable of understanding and complying with the patient registration, education, and safety requirements of the RevAid® program,
• Undergo regular pregnancy testing
• Use two simultaneous contraception methods (must be started at least one month prior to starting treatment, continued during dose interruptions, during treatment and for at least 1 month following the cessation of thalidomide).
• It is not recommended for patients to use hormonal contraceptives due to the increased risk of thromboembolism. 
• If pregnancy occurs during treatment, thalidomide must be discontinued and patient referred to a gynecologist/obstetrician for evaluation and counselling.

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Exceptional Access Program (EAP Website)

• thalidomide - Multiple myeloma in patients ≥65 years of age in combination with melphalan and prednisone, with specific criteria

Clark T, Edom N, Larson J et al. Thalomid ® (thalidomide) capsules: A review of the first 18 months of spontaneous post-marketing adverse event surveillance, including off-label prescribing. Drug Safety 2001;24(2):87-117.

Eriksson T, Hoglund P, Turesson I, et al. Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis. Journal of Pharmacy and Pharmacology 2003;55:1701-6.

Harris E, Behrens J, Samson D, et al. Use of thalidomide in patients with myeloma and renal failure may be associated with unexplained hyperkalaemia. British Journal of Haematology 2003;122:159–67.

McEvoy GK, editor. AHFS Drug Information 2013. Bethesda: American Society of Health-System Pharmacists, p. 3468-59.

Product Monograph: Thalomid ® (thalidomide). Celgene, November 2016.

Prescribing Information: Thalomid® (thalidomide). Celgene (US), Feb 2013.

Singhal S, Metha J, Desikan R et al. Antitumor activity of thalidomide in refractory multiple myeloma. NEJM 1999;341(21):1565-71.

Tosi P, Zamagni E, Cellini C, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004;73:98–103.

June 2019 Updated emetic risk category.