Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
thalidomide
Thalidomide is an immunomodulatory agent with anti-inflammatory activity. The drug also has anti-angiogenic, sedative and hypnotic effects. The mechanisms of action of the immunomodulatory and anti-inflammatory effects of thalidomide are complex and have not been fully determined, but thalidomide appears to reduce TNF-α production, modulate integrins, alter T-cell ratios or T cell-derived cytokines and modulate interleukin production.
Thalidomide is a nonpolar compound and it appears to be distributed throughout the body. Crosses the placenta and found in semen.
Cross blood brain barrier? | yes |
PPB | 55 - 66 % |
The exact metabolic fate of thalidomide in human is unknown. Hepatic metabolism of thalidomide is limited. The principal metabolic pathway of thalidomide appears to be non-enzymatic spontaneous hydrolysis. Does not appear to be a substrate, inhibitor or inducer of CYP 450. Thalidomide does not induce or inhibit its own metabolism.
Active metabolites | No |
Inactive metabolites | Yes (most likely) |
Urine | 92% of the dose (mainly as hydrolytic metabolites), 0.7% as unchanged drug |
Half-life | 5 - 7 hours |
- 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
Other Uses:
- 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.
ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
---|---|---|---|---|---|
Cardiovascular | Arrhythmia (rare) | E | |||
Arterial thromboembolism (rare) | E | ||||
Cardiotoxicity (rare) | L | ||||
Hypotension (<10%) | I | ||||
Venous thromboembolism (10%) | E | ||||
Dermatological | Rash (<10%) (may be severe) | E | |||
Gastrointestinal | Abdominal pain (<10%) | E | |||
Constipation (23%) | E | ||||
Diarrhea (<10%) | E | ||||
Dry mouth (<10%) | E | ||||
GI obstruction / perforation (rare) | E | ||||
Nausea, vomiting (<10%) | E | ||||
General | Edema (<10%) | E | |||
Fatigue (<10%) | E | ||||
Hematological | Myelosuppression ± infection, bleeding (44%) (severe) | E | |||
Hepatobiliary | Hepatic failure (rare) | D | |||
↑ LFTs (rare, may be severe) | E | ||||
Pancreatitis (rare) | E | ||||
Hypersensitivity | Hypersensitivity (rare) | I | |||
Infection | Infection (<10%) (may be severe, including opportunistic) | E | |||
Metabolic / Endocrine | Abnormal electrolyte(s) (K - < 10%) | E | |||
Musculoskeletal | Musculoskeletal pain (<10%) | E | |||
Neoplastic | Leukemia (secondary) , MDS (rare; up to 4% with MPT after 3 years) | L | |||
Nervous System | Confusion (>10%) | E | |||
Depression (<10%) | E | ||||
Dizziness (12%) | I | ||||
Neuropathy (19%) (peripheral and autonomic) | E D | ||||
Seizure (rare) | E | ||||
Somnolence (23%) | E | ||||
Tremor (11%) | E | ||||
Renal | Renal failure (<10%) | D | |||
Respiratory | Cough, dyspnea (<10%) | E | |||
Pneumonitis (<10%) | E |
* "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.
Refer to protocol by which patient is being treated. Prophylactic anticoagulants should be used, especially in patients with other risk factors and for at least the first five months of treatment. Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
Patients ≤ 75 years: 200 mg PO daily
Patients > 75 years: 100 mg PO daily
Refer to the MPT regimen monograph for details when given with melphalan and prednisone.
Dose levels (thalidomide):
Dose level |
Age ≤ 75 years |
Age > 75 years |
0 |
200 mg daily |
100 mg daily |
-1 |
100 mg daily |
50 mg daily |
-2 |
50 mg daily |
50 mg every other day |
-3 |
50 mg every other day |
Discontinue |
Toxicity |
Thalidomide Dose and Action |
Melphalan/Prednisone Dose and Action (if applicable) |
ANC < 1.5 (x 109/L) |
No change |
Refer to the MPT regimen, dosage with toxicity section. |
Grade 3 or 4 thromboembolism |
Hold, ensure adequately anticoagulated. Maintain dose level unless occurred despite adequate anticoagulation; if so, discontinue |
No change
|
Grade 3 neurotoxicity |
Hold until resolves to ≤ grade 1, then decrease by 1 dose level |
No change |
Grade 4 neurotoxicity |
Discontinue |
Discontinue |
Grade 3 rash or mild hypersensitivity |
Hold until rash resolves to ≤ grade 1, then decrease by 1 dose level |
No change |
Grade 4 rash or severe hypersensitivity |
Discontinue |
Discontinue |
Grade 3 or 4 constipation |
Initiate bowel regimen and hold until resolves to ≤ grade 2, then decrease by 1 dose level |
No change |
Over sedation |
Consider short drug holiday or ↓ dose; may restart at the same or lower dose when recovered |
No change |
Severe syncope/bradycardia |
Consider ↓ dose or discontinue |
No change |
Other grade 3 toxicity |
If thalidomide-related, hold until resolves to ≤ grade 2 then decrease by 1 dose level |
No change |
Other grade 4 toxicity |
Discontinue |
Not specifically studied in patients with hepatic impairment.
Not specifically studied in patients with renal impairment. Monitor patients with severe renal impairment as metabolites are eliminated via urine. Some data suggested that no dose modification is needed in renal impairment (including patients on dialysis); however monitor closely as there have been reports of fatal hyperkalemia in renally impaired patients.
For patients older than 75, the recommended starting dose is 100 mg/day. The frequency of serious adverse effects, such as atrial fibrillation, back pain and fall, including fatal reactions was higher in patients over 75 compared to younger patients.
Not recommended for use in patients under 19 years of age.
- Oral self-administration; taken on a specified schedule (usually once daily) once daily preferably with a glass of water, with or without food at about the same time each day.
- Swallow capsules whole; they should not be broken, chewed, or opened.
- Thalidomide should be administered at bedtime to minimize adverse effects such as dizziness and somnolence.
- Avoid use of alcohol since this may potentiate sedation.
- Do not extensively handle the capsules. Females who may become or plan to become pregnant can handle thalidomide if they are using latex gloves.
- Remove capsule from the original packaging only at administration time. Do not put the capsule on the counter or dish/container before taking it; give the capsule directly from the packaging and place into the mouth.
- If a dose is missed, take it if it is within 12 hours from the missed dose, otherwise skip this and give the next dose as scheduled. Do not double the dose to make up for the forgotten one.
- Drug available by outpatient prescription in pharmacy registered with the RevAid® program. Please call 1-888-RevAid-1 or log onto www.RevAid.ca (see section G)
- 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.
AGENT | EFFECT | MECHANISM | MANAGEMENT |
---|---|---|---|
Neurotoxins (i.e. lithium, vincristine, cisplatin, bortezomib) | ↑ neuropathy | Additive effects | Caution |
Sedatives (i.e. barbiturates, alcohol, chlorpromazine) | Enhance CNS sedation | Additive | Caution |
Beta-blockers, anticholinesterase agents | ↑ risk of bradycardia | Additive effects | Caution |
Hormonal therapy (contraception/HRT), erythropoietic agents, corticosteroids | ↑ risk of thromboembolic events | Additive | Caution; monitor carefully; consider prophylaxis with anticoagulants |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Monitor Type | Monitor Frequency |
---|---|
CBC |
Baseline and monthly |
RevAid requirements regarding pregnancy tests for women of childbearing potential |
Before starting and as indicated per RevAid |
Neurological exams |
Baseline and monthly for the first 3 months, and periodically thereafter; consider using electrophysiologic testing at baseline and every 6 months. |
Liver function tests |
Baseline and periodic, especially in patients with pre-existing liver disorder or with concurrent use of potentially hepatotoxic medications |
EKG |
as clinically indicated (bradycardia, AV block) |
Hepatitis serology |
If hepatitis or reactivation suspected |
Clinical assessments of bleeding, rash, constipation, CNS effects (including neuropathy, seizures, somnolence), arterial and venous thromboembolism, syncope/bradycardia, infections, hepatitis |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Monitor Type | Monitor Frequency |
---|---|
Renal function tests | Baseline and regular |
Seizures |
as clinically indicated, especially in at risk patients |
HIV viral load (in HIV-seropositive patients) | After the first and third months of treatment, and then every 3 months |
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.
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.