SYNONYM(S):

COMMON TRADE NAME(S): THALOMID(r)

CLASSIFICATION:

miscellaneous, noncytotoxic

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

The mechanism of action of thalidomide is not completely understood. In vitro and in vivo studies indicate that it inhibits the production of tumor necrosis factor-alpha in monocytes. Thalidomide may induce the down-regulation of integrin receptors and other surface adhesion proteins, reduce IgM production, alter CD4/CD8 T-cell ratios as well

as increase the total numbers of CD8 and CD4 T-cells,2 and inhibit angiogenesis. Anti-inflammatory properties have

been suggested through decreasing the production of oxygen-free radicals and other mediators in inflammatory response.1,3 Thalidomide may enhance cell-mediated immunity by directly stimulating cytotoxic T-cells.4,5

PHARMACOKINETICS:

Interpatient variability significant interpatient variability especially in absorption and half-life 6
Oral Absorption high fat meals increase the time to peak concentration but results in < 10% change in AUC or peak plasma concentration 1,6
time to peak plasma concentration 2.5-4.4 h 1,6 (6 h with high fat meal)
Distribution mostly in GI tract, liver, kidneys (less in muscle, brain, adipose tissue); 1 present in ejaculate 7
cross blood brain barrier? yes
volume of distribution 121 L (70-83 L in HIV patients) 1,6
plasma protein binding moderately bound to plasma proteins (55-66%) 1,6
Metabolism exact metabolism not known, possibly by non-enzymatic spontaneous hydrolysis in plasma 1,6
active metabolite(s) none
inactive metabolite(s) phthalic acid
Excretion not well defined
urine 0.7% excreted unchanged 1,6
feces no information found
terminal half life 3-7 h (more variable in HIV patients) 1,6
clearance 170-207 mL/min 6
Gender no information found
Elderly no clinically significant difference
Children no clinically significant difference
Ethnicity no information found

Adapted from reference 1 unless specified otherwise.

USES:

Primary uses: Other uses:
Multiple myeloma 8-19 Graft versus host disease 20-33
Melanoma 34-36
Myelodysplastic syndrome 37,38
Prostate cancer 39
Renal cell carcinoma 36

*Health Canada Therapeutic Products Programme approved indication

SPECIAL PRECAUTIONS:

Contraindicated in women with childbearing potential or sexually mature males unless the patient can comply with the criteria of the System for Thalidomide Education and Prescribing Safety (STEPS) program (see below under Pregnancy).1

Thalidomide is relatively contraindicated in the presence of neutropenia or peripheral neuropathy.

1,40

Carcinogenicity: no information found.

Mutagenicity: Not mutagenic in Ames test or mammalian in vitro mutation test. Thalidomide is not clastogenic in mammalian in vitro or in vivo chromosome tests.1

Fertility: no information found.

Pregnancy: FDA Pregnancy Category X. Thalidomide is teratogenic in humans. Birth defects are believed to occur if embryo is exposed to even a single dose from day 21-56 after conception. Malformations include amelia and phocomelia, polydactyly, syndactyly, facial capillary hemangiomas, hydrocephalus, intestinal, cardiovascular and renal anomalies, and eye, ear, and cranial nerve defects. Other malformations include facial and oculomotor paresthesias, other ocular defects, anal stenoses, vaginal and uterine defects, and heart malformations which are

usually fatal. Mortality at or shortly after birth has been reported to be ~40%.1

Contraception:

Women must use effective contraception for at least 1 month before, during, and 1 month after thalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because patient has been naturally postmenopausal for at least 24 months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from reproductive heterosexual

intercourse is the chosen method.41

Before starting treatment, women of childbearing potential must have a pregnancy test immediately (eg, within 5 days) prior to beginning therapy and regularly (eg, monthly) during therapy. A pregnancy test is required for all women are under the age of 50 years old and who have42:

A pregnancy test should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy does occur during thalidomide therapy, thalidomide must be discontinued immediately.

Men should not have sex without an effective birth control method with a woman who is able to bear children because thalidomide is present in semen.40 A condom must be used every time a man has sex with a female partner.

Avoid drugs that may interact with oral contraceptives (eg, carbamazepine, HIV-protease inhibitors, rifabutin, rifampin) in women taking thalidomide. If these drugs must be used concurrently with thalidomide, use two other reliable methods (other than oral contraceptives).1

Breastfeeding is not recommended due to the potential secretion into breast milk.

SIDE EFFECTS:

ORGAN SITE SIDE EFFECT ONSET
Dose-limiting side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
blood/bone marrow febrile neutropenia anemia (5-12%, severe < 4%) 8,43 E D
leukopenia (5-25%) 8,43 E D
thrombocytopenia (severe < 4%) 8 E D
cardiovascular (arrhythmia) sinus bradycardia (rare) 44 I E
cardiovascular (general) edema (may be symptomatic) (4-22%) (dose- related) 8,19,43 D
coagulation venous thrombosis (up to 27% when used with other chemotherapy), 45-48 arterial thrombosis (rare) 45 D
constitutional symptoms weakness or fatigue (mild-moderate) (8- 48%) 8,19,43 I
dermatology/skin cutaneous ulcers (rare) E 49
rash < 50% of body (16-26%), 8,10 > 50% of body (rare) 19 E D
toxic epidermal necrolysis (Steven-Johnson syndrome) (rare) E 43,50,51 D 43,50,51
endocrine gynecomasty (rare) E 52
hypothyroidism (rare) E 12,53 D 12,53
gastrointestinal emetogenic potential : low-moderate
constipation (4-59%) 8,10,19,43 E
nausea (11-23%) 8 I
hepatic hepatitis (rare) 54 I E
hyperlipidemia (5-9%) 43 E D
metabolic/laboratory tumor lysis syndrome (rare) 55 I
neurology ataxia (mild) (16-22%) 8 E
dizziness (mild) (4-28%) 8,43 I E
insomnia with withdrawal L 56
mood alterations or depression (mild) (16-22%) 8 E D
neuropathy - sensory (numbness, tingling) (8- 28%) 8,10,43 E
somnolence (5-43%) 8,43 I
tremors (mild) (10-22%) 8 E
pain mild-moderate headache (10-14%) 8,43 E
sexual/reproductive function amenorrhea (transient) (rare) E 57-59 D 57-59
teratogenicity (common) 1,6 E 1 D 1

Somnolence and fatigue usually improves with continued use or dose reduction.8 Thalidomide is best started at bedtime to minimize somnolence as its effects usually wear off by morning. For example, it can be started at 200mg

at bedtime and titrated up by adding equally to the bedtime and a morning dose, ie, the bedtime dose remains 200mg higher than the morning dose.60

Peripheral neuropathy occurs due to axonal degeneration without demyelination and affects mainly the lower limbs. It can be quite painful60 and is characterized by a stocking-glove distribution and begins in the feet with paresthesias, progresses to the hands with a burning sensation and muscle cramps. Motor disability does not

usually occur although may present late in the course of neuropathy and is generally reversible. The risk and severity of sensory neuropathy may depend on the cumulative dose, particularly when it exceeds 20 g.61

Thalidomide should be discontinued when neuropathy is present in early stages as sensory effects may not be reversible if thalidomide is continued with ongoing symptoms. Thalidomide should be restarted only if the neuropathy returns to baseline levels.1

Amenorrhea, usually transient, has rarely been reported.57-59,62 Average onset is about 14 months and persists for the duration of therapy. Menses resumed 2-3 months after stopping thalidomide. Serum follicle-stimulating hormone (FSH) levels were in the post-menopausal range and returned to normal when thalidomide was stopped.

There was no change in serum luteinizing hormone (LH) or prolactin levels.57

INTERACTIONS:

No known drug interactions. See also Contraception under SPECIAL PRECAUTIONS for drugs that can affect contraception.

SUPPLY AND STORAGE:

Capsules: hard, gelatin, white 50 mg capsules. Store at room temperature.43

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy.

Adults:

Oral:

BCCA usual dose noted in bold, italics

start at 200 mg PO once daily, then increase to the maximum tolerated dose (usual dose range 50-800 mg/day), preferably one hour after meals

Capsule can be opened for patients who have difficulty in swallowing.1 Dose may be given as once daily or divided as follows63:

Total dose (mg) Schedule

50 50 mg once daily

100 50 mg twice daily

150 50 mg three times daily

200 50 mg four times daily

Above 200 mg dose, divide into four doses throughout the day

Dosage in myelosuppression: no information found Dosage in renal failure: no adjustment required Dosage in hepatic failure: no adjustment required Dosage in dialysis no information found

Children:

Oral: No information found. Not generally recommended for use in children.

REFERENCES:

  1. Thalidomide. USP DI. Volume 1. Drug information for the health care professional. 20th ed. Englewood, Colorado: Micromedex, Inc.; 2002.

  2. McHugh SM, Rifkin IR, Deighton J, et al. The immunosuppressive drug thalidomide induces T helper cell type 2 (Th2) and concomitantly inhibits Th1 cytokine production in mitogen- and antigen-stimulated human peripheral blood mononuclear cell cultures. Clinical and Experimental Immunology 1995; 99(2):160-7.

  3. De Vita V. Cancer Principles and Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 366-367.

  4. Haslett PA, Corral LG, Albert M, et al. Thalidomide costimulates primary human T lymphocytes, preferentially inducing proliferation, cytokine production, and cytotoxic responses in the CD8+ subset. Journal of Experimental Medicine 1998; 187(11):1885-92.

  5. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001; 98(1):210-6.

  6. McEvoy GK editor. AHFS 2002 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2002.

  7. Teo SK, Harden JL, Burke AB, et al. Thalidomide is distributed into human semen after oral dosing. drug metabolism & Disposition 2001; 29(10):1355-7.

  8. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341(21):1565-1571.

  9. Barlogie B, Desikan R, Eddlemon P, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001; 98(2):492-4.

  10. Hus M, Dmoszynska A, Soroka-Wojtaszko M, et al. Thalidomide treatment of resistant or relapsed multiple myeloma patients. Haematologica. 2001; 86(4):404-8.

  11. Moehler TM, Neben K, Benner A, et al. Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy. Blood. 2001; 98(13):3846-8.

  12. Palumbo A, Giaccone L, Bertola A, et al. Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma. Haematologica. 2001; 86(4):399-403.

  13. Rajkumar SV, Dispenzieri A, Fonseca R, et al. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001; 15(8):1274-6.

  14. Zomas A, Anagnostopoulos N, Dimopoulos MA. Successful treatment of multiple myeloma relapsing after high-dose therapy and autologous transplantation with thalidomide as a single agent. Bone Marrow Transplantation 2000; 25(12):1319-20.

  15. Juliusson G, Celsing F, Turesson I, et al. Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. British Journal of Haematology 2000; 109(1):89-96.

  16. Kneller A, Raanani P, Hardan I, et al. Therapy with thalidomide in refractory multiple myeloma patients - the revival of an old drug. British Journal of Haematology 2000; 108(2):391-3.

  17. Myers B, Grimley C, Dolan G. Thalidomide and low-dose dexamethasone in myeloma treatment. British Journal of Haematology 2001; 114(1):245.

  18. Blade J, Esteve J, Rosinol L, et al. Thalidomide in refractory and relapsing multiple myeloma. Seminars in Oncology 2001; 28(6):588-92.

  19. Tosi P, Ronconi S, Zamagni E, et al. Salvage therapy with thalidomide in multiple myeloma patients relapsing after autologous peripheral blood stem cell transplantation. Haematologica. 2001; 86(4):409-13.

  20. Heney D, Bailey CC, Lewis IJ. Thalidomide in the treatment of graft-versus-host disease. Biomedicine and Pharmacotherapy 1990; 44(4):199-204.

  21. Heney D, Norfolk DR, Wheeldon J, et al. Thalidomide treatment for chronic graft-versus-host disease. British Journal of Haematology 1991; 78(1):23-7.

  22. Lim SH, McWhannell A, Vora AJ, et al. Successful treatment with thalidomide of acute graft-versus-host disease after bone- marrow transplantation. Lancet. 1988; 1(8577):117.

  23. Parker PM, Chao N, Nademanee A, et al. Thalidomide as salvage therapy for chronic graft-versus-host disease. Blood. 1995; 86(9):3604-9.

  24. Rovelli A, Arrigo C, Nesi F, et al. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplantation 1998; 21(6):577-81.

  25. Sastry PS, Powles RL. Thalidomide for chronic GVHD. Bone Marrow Transplantation. 1998; 22(9):933-4.

  26. van de Poel MH, Pasman PC, Schouten HC. The use of thalidomide in chronic refractory graft versus host disease. Netherlands Journal of Medicine 2001; 59(2):45-9.

  27. Vogelsang GB, Hess AD, Gordon G, et al. Treatment and prevention of acute graft-versus-host disease with thalidomide in a rat model. Transplantation. 1986; 41(5):644-7.

  28. Vogelsang GB, Hess AD, Santos GW. Thalidomide for treatment of graft-versus-host disease. Bone Marrow Transplantation 1988; 3(5):393-8.

  29. Vogelsang GB, Santos GW, Colvin OM, et al. Thalidomide for graft-versus-host disease. Lancet. 1988; 1(8589):827.

  30. Vogelsang GB, Farmer ER, Hess AD, et al. Thalidomide for the treatment of chronic graft-versus-host disease. New England Journal of Medicine 1992; 326(16):1055-8.

  31. Browne PV, Weisdorf DJ, DeFor T, et al. Response to thalidomide therapy in refractory chronic graft-versus-host disease. Bone Marrow Transplantation 2000; 26(8):865-9.

Cole CH, Rogers PC, Pritchard S, et al. Thalidomide in the management of chronic graft-versus-host disease in children following bone marrow transplantation. Bone Marrow Transplantation 1994; 14(6):937-42. Saurat JH, Camenzind M, Helg C, et al. Thalidomide for graft-versus-host disease after bone marrow transplantation. Lancet. 1988; 1(8581):359. Hwu WJ, Krown SE, Panageas KS, et al. Temozolomide plus thalidomide in patients with advanced melanoma: results of a dose-finding trial. Journal of Clinical Oncology 2002; 20(11):2610-5. Kudva GC, Collins BT, II DFR. Thalidomide for Malignant Melanoma. N Engl J Med 2001; 345(16):1214-1215. Eisen T, Boshoff C, Mak I, et al. Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. British Journal of Cancer 2000; 82(4):812-7. Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98(4):958-65. Kyrtsonis MC, Kokoris SI, Kontopidou FN, et al. Development of a myeloproliferative disorder in a patient with monoclonal gammopathy of undetermined significance secreting immunoglobulin of the M class and treated with thalidomide and anti-CD20 monoclonal antibody. Blood 2001; 97(8):2527-8. Figg WD, Dahut W, Duray P, et al. A randomized phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clinical Cancer Research 2001; 7(7):1888-93. Celgene. Thalidomide Product monograph. January 2003. Celgene. Thalidomide STEPS (System for Thalidomide Education and Prescribing Safety). Important information about avoiding fetal exposure to thalidomide for prescribers and patients. 1999. Celgene Coporation. Thalidomide request form. Warren, New Jersey; 8 March 2002. Celgene. Thalidomide Product monograph. 1999. Kaur A, Yu SS, Lee AJ, et al. Thalidomide-induced sinus bradycardia. Annals of Pharmacotherapy 2003; 37(7/8):1040-3. Osman K, Comenzo R, Rajkumar SV. Deep venous thrombosis and thalidomide therapy for multiple myeloma. New England Journal of Medicine 2001; 344(25):1951-2. Zangari M, Anaissie E, Barlogie B, et al. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001; 98(5):1614-5. Camba L, Peccatori J, Pescarollo A, et al. Thalidomide and thrombosis in patients with multiple myeloma. Haematologica 2001; 86(10):1108-9. Urbauer E, Kaufmann H, Nosslinger T, et al. Thromboembolic events during treatment with thalidomide. Blood. 2002; 99(11):4247-8. Schlossberg H, Klumpp T, Sabol P, et al. Severe cutaneous ulceration following treatment with thalidomide for GVHD. Bone Marrow Transplantation 2001; 27(2):229-30. Rajkumar SV, Gertz MA, Witzig TE. Life-Threatening Toxic Epidermal Necrolysis with Thalidomide Therapy for Myeloma. N Engl J Med 2000; 343(13):972-973. Horowitz SB, Stirling AL. Thalidomide-induced toxic epidermal necrolysis. Pharmacotherapy 1999; 19(10):1177-80. Pulik M, Genet P, Lionnet F, et al. Thalidomide-associated gynecomasty in a patient with multiple myeloma. American Journal of Hematology. 2002; 70(3):265. Badros AZ, Siegel E, Bodenner D, et al. Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. American Journal of Medicine 2002; 112(5):412-3. Fowler R, Imrie K. Thalidomide-associated hepatitis: a case report. Am J Hematol 2001; 66:300-302. Cany L, Fitoussi O, Boiron JM, et al. Tumor lysis syndrome at the beginning of thalidomide therapy for multiple myeloma. Journal of Clinical Oncology 2002; 20(8):2212. Fox MR, Harris A. Intractable insomnia after cessation of treatment with thalidomide. Gastroenterology 2001; 120(6):1567-8. Frances C, El Khoury S, Gompel A, et al. Transient secondary amenorrhea in women treated by thalidomide. European Journal of Dermatology 2002; 12(1):63-5. Passeron T, Lacour JP, Murr D, et al. Thalidomide-induced amenorrhoea: two cases. British Journal of Dermatology 2001; 144(6):1292-3. Gutierrez-Rodriguez O, Starusta-Bacal P, Gutierrez-Montes O. Treatment of refractory rheumatoid arthritis--the thalidomide experience. Journal of Rheumatology 1989; 16(2):158-63. Joseph Connors MD. Personal communication. BC Cancer Agency Lymphoma Tumour Group; April 2004. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology 2004; 62(12):2291-2293. Ordi J, Cortes F, Martinez N, et al. Thalidomide induces amenorrhea in patients with lupus disease. Arthritis and Rheumatism 1998; 41(12):2273-5. B.C. Cancer Agency Lymphoma Group. BCCA protocol summary for therapy of multiple myeloma using thalidomide (LYTHALID). Vancouver, British Columbia: BC Cancer Agency; 1 February 2004.