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Introduction ⬇

VA Class:IM900

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Notification

REMS:

FDA approved a REMS for thalidomide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of thalidomide and consists of the following: elements to assure safe use and implementation system. See the FDA REMS page ([Web]).

Thalidomide, a synthetic glutamic acid derivative, is an immunomodulatory agent with anti-inflammatory, antiangiogenic, and sedative and hypnotic activity; the drug is also a potent teratogen.1,2,112,220

Uses ⬆ ⬇

[Section Outline]

Overview !!navigator!!

Thalidomide is labeled by the US Food and Drug Administration (FDA) for acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) in leprosy patients and for maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence.1 The drug has been designated an orphan drug by FDA for the treatment of ENL and treatment and maintenance of reactional lepromatous leprosy.28 Thalidomide also is used for the treatment of multiple myeloma and is designated an orphan drug by FDA for use in this condition.1,28 Thalidomide also has been designated an orphan drug by FDA for treatment of wasting syndrome associated with human immunodeficiency virus (HIV) infection†;28 prevention and treatment of severe recurrent aphthous stomatitis in severely, terminally immunocompromised patients†;28 prevention and treatment of graft-versus-host disease in patients receiving bone marrow transplantation†;28 treatment of clinical manifestations of mycobacterial infection caused by Mycobacterium tuberculosis and nontuberculous mycobacteria†;28 treatment of Crohn disease†;28 treatment of primary brain tumors†;28 and hereditary hemorrhagic telangiectasia†.28,264 In addition, thalidomide has been used for the treatment of a variety of inflammatory and/or dermatologic disorders,49,59,60,77,93,94,104,110,117,118,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,180,181,182,183,184 treatment of various HIV-associated conditions,12,30,40,41,50,55,56,104,112,140,141,142,143,144,146,147,170 and treatment of various malignancies.29,32,100,161,162,163,168,169,173,174,175 Use of thalidomide may not limit disease progression and/or death.1

Past and Current Therapeutic Perspective

In the late 1950s, thalidomide was marketed in several other countries, including the United Kingdom and Canada, and was available over-the-counter in some countries (e.g., Germany) for use as a sedative and for the treatment of various conditions, including asthma, hypertension, migraine, and common symptoms of early pregnancy (e.g., morning sickness), often in combination with other drugs.2,3,4,5,15,52,53,54 Thalidomide was being used in clinical studies in the US,4,15,16 but did not receive FDA approval at that time principally because of European reports of thalidomide-associated peripheral neuropathy that may be irreversible and unanswered questions about potential adverse effects on fetuses.2,4,5,15,16,52,54,58 Because of thalidomide's prompt sedative effects, lack of hangover, and apparent safety (in regards to overdosage), the drug was considered to be a safe alternative to barbiturates,2,4,5,15,16,52 and its manufacturer at that time promoted it as a nontoxic drug with no adverse effects, and completely safe for administration to pregnant women.16 However, reports of serious adverse effects soon appeared1,2,3,4,5,15,16,52,53,54 and use of thalidomide was linked to an epidemic of severe and often fatal fetal and neonatal malformations (most frequently phocomelia) that affected children in 46 countries.2,3,4,5,15,16,52,53,54 During that time, 17 babies were born in the US with thalidomide-associated phocomelia to mothers who received the drug from overseas sources or received premarketing samples distributed by drug company representatives.52 In 1961, the manufacturer withdrew thalidomide from the world market.2,3,4,5,15,16,53,54

A few years later, there were reports that leprosy patients with inflammatory lesions related to ENL reactions had experienced improvement in these lesions while receiving thalidomide as a sedative.2,4,5,16,52,53,104,112 The discovery of thalidomide's therapeutic efficacy in the treatment of ENL led to investigations that revealed the anti-inflammatory and immunomodulatory effects of the drug and prompted studies evaluating the drug in various autoimmune or inflammatory diseases and various conditions in HIV-infected patients.2,4,5,16,52,53,104,112 In addition, after in vitro and animal studies indicated that thalidomide has anti-angiogenesis activity, investigations were initiated to evaluate use of the drug for a variety of neoplastic diseases.2,112,115 Most information to date regarding use of thalidomide for the treatment of inflammatory or immune disorders or for the treatment of patients with HIV infection or malignancy consists of case reports or data obtained from uncontrolled studies in a limited number of patients.4,20,23,104,112 Well-controlled clinical studies are needed to evaluate the safety and efficacy of thalidomide for the treatment of these various indications.20,23,104,112

Erythema Nodosum Leprosum !!navigator!!

Thalidomide is used for acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) reactions (lepra type 2 reactions) in leprosy patients,1,10,13,34,35,39,44,76,86,89,111,113,114,218,220,232,233,234,235,237,238 and also is used for maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence.1,10 Thalidomide should not be used alone as monotherapy for treatment of ENL reactions complicated by neuritis.1,53,54 In these situations, thalidomide generally is initiated in conjunction with systemic corticosteroid therapy and the corticosteroid is slowly withdrawn if neuritis resolves.1,54

ENL is a recurrent, immunologically mediated syndrome that occurs principally in patients with multibacillary leprosy.3,10,45,82,84,86,111 While ENL reactions have been reported to occur in 10-50% of lepromatous leprosy patients3,10,53,84,86,88,89,111 and 25-30% of borderline lepromatous patients,86,88,89 these reactions are being reported less frequently in patients receiving the currently recommended multidrug antileprosy regimens that include clofazimine than in those who received dapsone monotherapy.88,89,111 ENL usually occurs after initiation of anti-infective therapy for leprosy (generally within the first 2 years of treatment), although occasionally it may occur spontaneously in untreated lepromatous leprosy patients or after treatment is discontinued.10,44,81,82,84,85,86,88 These reactions are considered to be a manifestation of the disease rather than an adverse reaction to antileprosy regimens.84,86,88 Clinical symptoms include cutaneous papules or nodules that are painful or tender, erythematous, and histologically vasculitic;3,10,53,84,89 the papules may pustulate and ulcerate, appear as recurrent crops, and are widely distributed, generally appearing on extensor surfaces of the extremities and on the face.3,10,84 Cutaneous symptoms of ENL may be accompanied by peripheral neuritis (usually of the ulnar nerve), fever, malaise, wasting, uveitis, lymphadenitis orchitis, and glomerulonephritis.3,10,53,84,86,89 Histologically, ENL is an acute vasculitis or panniculitis that is thought to be secondary to immune (i.e., antigen-antibody) complex deposition.10,53,83,89

Depending on the severity of manifestations, ENL reactions generally are treated using analgesics, corticosteroids, and/or thalidomide;76,86,89,111 clofazimine also has anti-inflammatory effects and is beneficial in the treatment of ENL reactions.10,76,86,88 While mild ENL reactions in some patients may be adequately managed with a nonsteroidal anti-inflammatory agent (e.g., aspirin, indomethacin) and bedrest,89,111 moderate to severe ENL reactions generally are treated with corticosteroids and/or thalidomide, and hospitalization may be required.3,10,53,63,64,66,67,69,111,232,233 The antileprosy regimen usually is continued while the ENL reaction is treated.63,65,66,67,69 Corticosteroid therapy (usually prednisolone) generally is effective for the treatment of moderate and severe ENL and usually is necessary when ENL is complicated by neuritis; however, long-term therapy may be required and there is a risk that ENL patients (especially those with chronic ENL) may become steroid dependent.10,76,81,86,89,111

In patients already receiving clofazimine as part of a multidrug antileprosy regimen, a temporary increase in clofazimine dosage may allow a reduction in corticosteroid requirements; clofazimine dosage effective for the treatment of ENL reactions is slightly higher than that usually recommended for the treatment of leprosy.64,66,67,89,111 However, clofazimine is not as effective or as rapidly acting as corticosteroids or thalidomide in the treatment of ENL35,86,89,111 and should not be initiated as the sole agent for the treatment of severe ENL.35,111

Thalidomide is effective for the treatment of moderate to severe ENL reactions,34,35,39,44,45,76,89,111,113,114 and some clinicians suggest that thalidomide may be the drug of choice for the treatment of these reactions, especially severe, recurrent reactions, in part because a prompt response to thalidomide generally is obtained and because of concerns related to long-term use of corticosteroids in leprosy patients.10,86,89,111 However, the risks versus benefits of thalidomide therapy must be considered, especially in females of reproductive age.10,76,89,111 Early diagnosis and treatment of ENL is important since these reactions are associated with considerable morbidity, especially in chronic, recurrent ENL.10,76,89 Therapy for leprosy and leprosy reactional states should be undertaken in consultation with an expert in the treatment of leprosy.10,74 In the US, the National Hansen's Disease (Leprosy) Program at 800-642-2477 should be contacted for further information on the management of leprosy reactional states.74

Information regarding safety and efficacy of thalidomide for the treatment of cutaneous manifestations of moderate to severe ENL is derived from experience with the drug, open-label and controlled studies and case reports involving leprosy patients from many different countries, and a retrospective study of leprosy patients treated in the US by the US Public Health Service (USPHS).1,34,35,38,54,113,114 There is evidence that use of thalidomide in leprosy patients with moderate to severe ENL reactions can result in prompt resolution of the signs and symptoms of ENL.1 In one controlled study in patients with ENL cutaneous lesions who received 7-day regimens of thalidomide (400 mg daily) or placebo, a response (i.e., complete remission of symptoms or advanced remission of about 50% of existing ENL skin lesions) occurred in 66 or 9% of treatment courses in patients receiving thalidomide or placebo, respectively.1,39 In a similar study, a complete response (i.e., the absence of skin lesions) occurred in 75 or 25% of treatment courses in patients receiving thalidomide or aspirin, respectively.1,34,233

In a double-blind, placebo-controlled, randomized, dose-comparison study, 22 male patients with ENL received 6 capsules containing either 100 mg (group A; 12 patients) or 300 mg (group B; 10 patients) of thalidomide for 1 week.238 A 6-week, 4-capsules per day tapering followed in which patients in group A received a 50-mg thalidomide dosage daily in weeks 2 and 3, followed by placebo capsules in weeks 4 through 7, while patients in group B received gradual dosage decreases every 2 weeks.238 Comparable improvement was observed at day 7 in 12 or 7 patients in group A or B, respectively.238 However, slower tapering in group B was associated with less reemergence of ENL through week 7 than patients in group A.238 Most patients developed new lesions soon after discontinuing treatment.238 Some clinicians suggest that slower tapering from a higher initial thalidomide dosage may improve ENL responses, although high recurrence rates after discontinuance indicate that further studies are needed to identify better tapering regimens.238

Safety and efficacy of thalidomide have been evaluated in a prospective, comparative (versus prednisolone) study in 60 patients with moderate to severe ENL.235 Patients were randomized to receive a thalidomide dosage of 300 mg daily for 1 week, which was gradually reduced by 50 mg every 2 weeks (30 patients), or prednisolone 40 mg daily for 2 weeks, which was subsequently tapered by 10 mg every 2 weeks (30 patients).235 Faster clinical response (cutaneous and systemic), fewer relapses, and longer periods of remission were observed in patients receiving thalidomide compared with those receiving prednisolone.235 In addition, adverse effects were more frequently observed in patients receiving prednisolone than in those receiving thalidomide.235

Efficacy of thalidomide for the treatment of chronic ENL reactions has been evaluated in 2 limited crossover studies of hospitalized, corticosteroid-dependent ENL patients who were receiving dapsone and were treated with a 4- to 6-week regimen of thalidomide (300 mg daily) or placebo.1,35 In the first crossover study, the weekly corticosteroid dosage could be reduced in about 89% of patients while thalidomide was administered, but corticosteroid dosage had to be increased when placebo was administered.1,35 In the second crossover study, 100 or 12.5% of patients decreased their weekly dosage of corticosteroids while receiving a 6-week regimen of thalidomide or placebo, respectively.1,35

Information regarding safety and efficacy of thalidomide for the prevention of ENL relapse is limited, and labeling for this use is based on data obtained from a retrospective evaluation of ENL patients treated by the USPHS.1 A subset of these ENL patients receiving thalidomide had repeated relapse of ENL symptoms when thalidomide was discontinued, but remission of symptoms when treatment with the drug was reinitiated.1

Multiple Myeloma !!navigator!!

Thalidomide and Dexamethasone

Thalidomide is used in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma.1,100,161,162,163,198,199,200,201,242 Efficacy of thalidomide in the treatment of newly diagnosed multiple myeloma has been studied in a randomized, multicenter, open label study and a randomized, multicenter, double-blind, placebo-controlled clinical trial.1,255

In the open-label study, patients were randomized to receive thalidomide (200 mg daily; 103 patients) and dexamethasone (40 mg once daily; 104 patients) on days 1-4, 9-12, and 17-20 every 28 days) or dexamethasone alone (40 mg once daily on days 1-4, 9-12, and 17-20 every 28 days).1,242 Each study population group received four 28-day cycles.1,242 Response rates, based on serum or urine paraprotein measurements, were higher in those receiving combination therapy with thalidomide and dexamethasone compared with those receiving dexamethasone alone (52 vs 36%, respectively).1

In the double-blind study, patients were randomized to receive thalidomide (50 mg daily escalated to 100 mg daily on day 15, followed by 200 mg daily beginning on day 1 of cycle 2) and dexamethasone (40 mg daily on days 1-4, 9-12, and 17-20 during cycles 1-4, followed by 40 mg daily on days 1-4) or dexamethasone and placebo; treatment cycles were repeated every 28 days.1,255 Treatment was continued until disease progression.1,255 Time to progression was significantly longer in patients receiving thalidomide and dexamethasone compared with those receiving placebo and dexamethasone (97.7 versus 28.3 weeks; hazard ratio 0.43 [95% CI 0.32-0.58]).1 Overall response rate (according to the Bladé criteria) was also higher in patients receiving thalidomide and dexamethasone compared with those receiving placebo and dexamethasone (63 versus 46%).1 No significant difference was observed between the two treatment groups in overall survival (24 versus 29%; hazard ratio 0.82 [95% CI 0.57-1.16]).1

Use of thalidomide in patients with multiple myeloma is associated with increased risk of thromboembolic events (e.g., deep venous thrombosis, pulmonary embolus).1 Such risk increases substantially when thalidomide is used in combination with standard chemotherapy, including dexamethasone.1 (See Thromboembolic Events under Cautions.)

Thalidomide, Bortezomib, and Dexamethasone

Thalidomide also has been studied in combination with bortezomib and dexamethasone† (bortezomib-thalidomide-dexamethasone) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients in several phase 3, open-label, randomized studies.10013,10014,10015,10027 The GIMEMA and PETHEMA/GEM studies compared bortezomib-thalidomide-dexamethasone with the combination of thalidomide and dexamethasone (thalidomide-dexamethasone),10013,10014 whereas the IFM2013-04 study compared bortezomib-thalidomide-dexamethasone with the combination of bortezomib, cyclophosphamide, and dexamethasone (bortezomib-cyclophosphamide-dexamethasone).10027

In the GIMEMA study in 480 patients with previously untreated multiple myeloma, postinduction complete plus near-complete response rate was 31% in patients receiving bortezomib-thalidomide-dexamethasone compared with 11% in those receiving thalidomide-dexamethasone; improved responses also were observed with bortezomib-thalidomide-dexamethasone following first (52 versus 31%) and second (55 versus 41%) autologous stem cell transplants and subsequent consolidation therapy (62 versus 45%).10013 The median time to best complete or near-complete response was shorter in patients receiving bortezomib-thalidomide-dexamethasone compared with those receiving thalidomide-dexamethasone (9 versus 14 months).10013 At a median follow-up of 36 months, progression-free survival was prolonged in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (hazard ratio 0.63); however, no difference in estimated 3-year overall survival (86 versus 84%, respectively) was observed between the groups.10013 Subgroup analysis based on poor prognostic factors (i.e., older than 60 years of age, advanced disease stage, elevated serum LDH concentration, high infiltration of bone marrow plasma cells, chromosome 13q deletion [del(13q)], t(4;14) translocation with or without chromosome 17p deletion [del(17p)]) suggested that the progression-free survival benefit of bortezomib-thalidomide-dexamethasone was consistent across these subgroups; however, because the proportion of patients with the del(17p) chromosomal abnormality was substantially smaller than the proportion of patients with other high-risk cytogenetic abnormalities, the effect of bortezomib-thalidomide-dexamethasone on progression-free survival in patients with the del(17p) chromosomal abnormality was not evaluated.10013

In the PETHEMA/GEM study in 386 patients with newly diagnosed multiple myeloma, the complete response rate (35 versus 14%) was higher following induction therapy with bortezomib-thalidomide-dexamethasone compared with thalidomide-dexamethasone; improved complete response rates also were maintained following autologous stem cell transplantation (46 versus 24%).10014 Among patients with high-risk cytogenetic features, complete response rate was substantially higher in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (35 versus 0%); complete responses were achieved in 38 or 58% of patients receiving bortezomib-thalidomide-dexamethasone who had t(4;14) or del(17p) chromosomal abnormalities, respectively, compared with 0% of patients receiving thalidomide-dexamethasone who had either chromosomal abnormality.10014 At a median follow-up of 35.2 months, median progression-free survival was prolonged in patients who received bortezomib-thalidomide-dexamethasone compared with those who received thalidomide-dexamethasone (56.2 versus 28.2 months); however, no difference in estimated 4-year overall survival (74 versus 65%, respectively) was observed between the treatment groups.10014

In the IFM2013-04 study in 340 patients with previously untreated multiple myeloma, the overall response rate (92.3 versus 83.4%) and the rate of very good partial response or better (66.3 versus 56.2%) were higher following induction therapy with bortezomib-thalidomide-dexamethasone compared with bortezomib-cyclophosphamide-dexamethasone; however, no significant difference in complete response rate was observed between the treatment groups.10027

Because peripheral neuropathy occurs frequently with thalidomide- and bortezomib-based induction regimens, a modified bortezomib-thalidomide-dexamethasone induction regimen using reduced dosages of thalidomide and bortezomib was compared with bortezomib-dexamethasone in another phase 3 study in 199 patients.10015 In this study, the rate of very good partial response or better following induction therapy was higher with bortezomib-thalidomide-dexamethasone compared with bortezomib-dexamethasone (49 versus 36%); however, postinduction complete response (13 and 12%, respectively) and overall response (88 and 81%, respectively) rates were similar for both treatment groups.10015 At a median follow-up of 32 months, median progression-free survival was similar in patients who received bortezomib-thalidomide-dexamethasone compared with those who received bortezomib-dexamethasone (26 versus 30 months, respectively).10015

Use of thalidomide in combination with bortezomib and dexamethasone also was investigated in an open-label, noncomparative phase 2 study in 98 patients randomized to receive bortezomib-thalidomide-dexamethasone with or without cyclophosphamide.10016,10020 In this study, postinduction rates of overall response and complete plus near-complete response were 100 and 51%, respectively, in patients receiving bortezomib-thalidomide-dexamethasone and 94 and 43%, respectively, in those receiving bortezomib-thalidomide-dexamethasone-cyclophosphamide.10016 At a median follow-up of 64.8 months, median progression-free survival was 56.3 months with bortezomib-thalidomide-dexamethasone and 36.3 months with bortezomib-thalidomide-dexamethasone-cyclophosphamide; the difference was not statistically significant and was largely related to an imbalance between treatment groups in the number of patients receiving subsequent therapy for relapsed disease prior to meeting the specified criteria for disease progression.10020

Use of bortezomib-thalidomide-dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients has improved postinduction response rates and prolonged progression-free survival in several randomized controlled studies;10013,10014,10016,10027 however, the same benefits were not observed in a study evaluating a modified bortezomib-thalidomide-dexamethasone regimen (i.e., reduced thalidomide and bortezomib dosages).10015 Therefore, the role of a modified bortezomib-thalidomide-dexamethasone regimen using reduced dosages of thalidomide and bortezomib10015 is unclear.10033 In addition, in the absence of studies including adequate numbers of patients with the del(17p) chromosomal abnormality, attempts to identify whether these patients might derive clinical benefit (e.g., prolonged progression-free survival) from bortezomib-thalidomide-dexamethasone induction therapy are speculative; additional studies are needed to identify subgroups of patients with high-risk cytogenetic features who might benefit from such therapy.10033 The AHFS Oncology Expert Committee concluded that use of thalidomide in combination with bortezomib and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients may be considered a reasonable choice (accepted; with possible conditions);10033 however, use of a modified bortezomib-thalidomide-dexamethasone regimen using reduced dosages of thalidomide and bortezomib10015 is not fully established because of unclear risk/benefit and/or inadequate experience.10033 (See Thalidomide, Bortezomib, and Dexamethasone under Dosage and Administration.) Factors that should be considered when selecting a combination chemotherapy regimen for use as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients include performance status and preexisting conditions (e.g., peripheral neuropathy).10033

Use of thalidomide in patients with multiple myeloma is associated with increased risk of thromboembolic events (e.g., deep venous thrombosis, pulmonary embolus).1 Such risk increases substantially when thalidomide is used in combination with standard chemotherapy.1 (See Thromboembolic Events under Cautions.)

For further information on the use of combination therapy with thalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients, see Induction Therapy Prior to Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma under Uses: Multiple Myeloma, in Bortezomib 10:00.

Inflammatory and/or Dermatologic Disorders !!navigator!!

Based on the beneficial effects of thalidomide in the treatment of inflammatory dermatoses associated with ENL, the drug has been used for the treatment of a variety of inflammatory and/or dermatologic disorders, including Behcet syndrome†,49,77,93,104,125,126,128,129,130,131,132,133,134,135,136,137,215,218,219,232,237 erosive lichen planus†,104,127,215,219,232 erythema multiforme†,181,182,215,218,219,232,237 lupus erythematosus† (discoid lupus erythematosus, subacute or chronic cutaneous lupus erythematosus, cutaneous manifestations of systemic lupus erythematosus),3,4,53,59,104,110,121,122,123,124,196,215,218,219,220,229,237 prurigo nodularis†,59,60,94,104,117,118,215,219,229,232 actinic prurigo†,104,119,218,219,229,232 cutaneous Langerhans cell histiocytosis†,4,104,183,184,232,237 uremic pruritus†,104,180,215,237 porphyria cutanea tarda†,195,215 and pyoderma gangrenosum†.4,5,53,104,125,126,219,232,237 There is evidence that thalidomide can be beneficial and may result in improvements in the dermatologic and mucocutaneous manifestations of these conditions;59,117,121,122,123,180,195,196,215 however, there is recurrence of lesions and symptoms in many patients when the drug is discontinued and long-term maintenance therapy may be necessary.59,60,124 Most clinicians recommend that thalidomide be used for the treatment of inflammatory and/or dermatologic disorders only in selected patients with severe refractory disease unresponsive to other appropriate agents (e.g., corticosteroids).93,156,186,256

Behcet Syndrome

In patients with Behcet syndrome†,3,4,5,6,49,52,53,77,93,125,126,128,129,130,131,132,134,137 a chronic inflammatory disease of unknown etiology characterized by recurrent orogenital ulceration, skin lesions, and arthritic symptoms that may be complicated by GI, ocular, and neurologic involvement,93,131 thalidomide therapy (100-400 mg daily) has resulted in resolution of dermatologic, mucocutaneous, and arthritic manifestations of the disease.49,77,93,125,126,128,129,130,131,134,137,216,219 However, symptoms and/or lesions generally recur within several weeks after the drug is discontinued.49,77 In a randomized, double-blind, placebo-controlled study in adult males with Behcet syndrome with mucocutaneous lesions (without major organ involvement), a complete response (resolution of orogenital ulcers and follicular lesions) was obtained in 6 or 16% of patients receiving thalidomide in a dosage of 100 or 300 mg daily, respectively; there were no complete responses in those receiving placebo.49 While there are some reports that GI, ophthalmic, and/or neurologic symptoms also may improve during thalidomide therapy,49,128,132,133,136 further study is needed to determine whether thalidomide has any clinically important effect on these manifestations of the disease.49

In a clinical trial, thalidomide has been used in a limited number of young patients (9-34 years of age) with juvenile-onset of severe Behcet syndrome† (manifested by severe abdominal pain; intestinal ulceration, bleeding, perforation, or obstruction; recurrent stomatitis; oral aphthosis; genital ulceration; erythema nodosum in the extremities; ileocolitis; fever).210 All patients, but one, were receiving corticosteroids; severe steroid toxicity, osteoporosis, and/or steroid dependence was reported.210 The initial thalidomide dosage was 2 mg/kg daily; dosage was increased to 3 mg/kg daily or decreased to 0.5-1 mg/kg daily, according to patients' response.210 All patients showed improvement in clinical symptoms and all patients were able to discontinue corticosteroids.210 The end point of the trial was complete remission of the disease without using the drug; however, clinicians failed to withdraw thalidomide from all patients except one.210 Further large-scale clinical trials are needed to determine the appropriate duration of thalidomide therapy.210

Some clinicians state that in patients with Behcet syndrome with mucocutaneous involvement, thalidomide may be considered in select cases based on patient preference.258 Some clinicians also state that in patients with refractory and/or severe GI involvement (e.g., GI perforation, serious GI bleeding, obstruction), anti-tumor necrosis factor (anti-TNF; anti-TNF-α) monoclonal antibodies (e.g., infliximab, adalimumab) and/or thalidomide should be considered based on retrospective data indicating clinical benefit in patients with severe GI involvement refractory to conventional treatment modalities (e.g., azathioprine, corticosteroids).257,258

Other Dermatologic Disorders

Thalidomide has not been effective when used for the treatment of toxic epidermal necrolysis†.97 In a limited placebo-controlled study in adults with toxic epidermal necrolysis, there was no evidence that thalidomide had any beneficial effect on necrolysis, and patients receiving thalidomide had a higher mortality rate than those receiving placebo.97 In another randomized placebo-controlled trial in patients with toxic epidermal necrolysis, therapy with thalidomide was not shown to be effective and was associated with substantially higher mortality than placebo.211 Further randomized, controlled studies are needed to understand the mechanism of toxic epidermal necrolysis and to evaluate treatments of the disease especially in patients receiving high doses of steroids and IV immunoglobulins.211 In addition, there have been several reported cases of patients with malignancies developing toxic epidermal necrolysis while receiving thalidomide (usually with dexamethasone).197,212,214

Uses in HIV-infected Patients !!navigator!!

Thalidomide has been studied for a variety of uses in HIV-infected patients, including treatment of HIV-associated aphthous ulcers†,112,142,143,144,146,147,218,220,221,223 HIV-associated diarrhea†,56,112 HIV-associated wasting syndrome†,11,41,50,112,140,141,224 and Kaposi's sarcoma†.30,140,141,187,218,219,232,237 The drug also has been used as an adjunct to anti-infective agents in the treatment of mycobacterial infections†, including Mycobacterium tuberculosis and M. avium complex (MAC) infections, in HIV-infected patients.40,42,53,218 Although thalidomide may provide some benefits in HIV-infected patients (e.g., promote healing of aphthous ulcers, ameliorate weight loss), further study is needed to evaluate safety and efficacy of thalidomide in HIV-infected patients and to determine whether the drug may increase viral load (i.e., plasma HIV-1 RNA levels) and/or may be associated with an increased incidence of adverse effects in this patient population.5,11,40,41,42,55,58,104

HIV-associated Aphthous Ulcers

Thalidomide (100-300 mg once daily) has been effective for the treatment and prevention of oropharyngeal, esophageal, and anogenital aphthous ulcers in HIV-infected patients†.3,4,5,6,52,53,55,139,142,143,144,145,146,147,221,223,237 The drug has been effective for the treatment of severe recurrent aphthous stomatitis in HIV-infected patients, and also has been effective for the treatment of severe recurrent aphthous stomatitis in immunocompetent patients or patients who are immunocompromised but not HIV-infected† (see Uses: Recurrent Aphthous Stomatitis).138,139,148,149,219 Thalidomide is not considered a drug of first choice for the treatment of aphthous ulcers in HIV-infected patients,55,102,186 but may be effective in patients with recurrent ulcers refractory to other therapies (e.g., corticosteroids).55,142,143,144,147,221

Efficacy of thalidomide for the treatment of oral and esophageal aphthous ulcers in HIV-infected patients has been evaluated in a phase II double-blind, placebo-controlled study through the National Institute of Allergy and Infectious Diseases (NIAID) AIDS Clinical Trials Group (ACTG) (study ACTG 251).12,221,223 HIV-infected patients with oral aphthous ulcers were randomized to receive a 4-week regimen of thalidomide (200 mg once daily) or placebo; if healing of ulcers was not complete after this regimen, an additional 4-week regimen of thalidomide was administered.12 At 4 weeks, a complete response was obtained in 55 or 7% of patients receiving thalidomide or placebo, respectively.12

HIV-associated Wasting Syndrome

Thalidomide has been used for the treatment of wasting syndrome in a limited number of HIV-infected patients†11,41,140,141,224 and also has been used for the treatment of cachexia in other severely immunocompromised patients† (e.g., cancer patients). There is some evidence that thalidomide therapy (50-400 mg daily) may decrease elevated TNF-α plasma concentrations and may promote weight gain in HIV-infected patients.3,11,40,41,42,50,141,224 However, thalidomide may increase plasma TNF-α concentrations in some HIV-infected patients.1,12,186,224 The precise role of TNF-α in the wasting syndrome is unclear and additional study is necessary to evaluate the safety and efficacy of thalidomide in the treatment of HIV-associated wasting syndrome.1,11,41,42,43,112

HIV-associated Diarrhea

Thalidomide has been used with some success in a limited number of patients for the treatment of HIV-associated diarrhea, including microsporidiosis†.56,112 In one group of HIV-infected patients with chronic diarrhea and weight loss caused by Enterocytozoon bieneusi infection that was not responsive to albendazole, use of thalidomide (100 mg daily for 4 weeks) had a beneficial effect (i.e., complete or partial clinical response including increased weight and decreased stool frequency) in 55% of patients.56 Although there is evidence that thalidomide may relieve some symptoms of microsporidian enteritis in some patients, results of an in vitro study indicate that the drug has no direct activity against microsporidia.193

Kaposi Sarcoma

Safety and efficacy of thalidomide for the management of cutaneous Kaposi sarcoma† have been evaluated in a phase II dose-escalating study through the National Cancer Institute (NCI).227 Twenty HIV-infected male patients (29-49 years of age) with biopsy-confirmed Kaposi sarcoma (having at least 5 assessable lesions and objective evidence of tumor progression over 2 months before enrollment), received an initial thalidomide dosage of 200 mg daily; dosage was increased by 200 mg daily every 14 days up to a maximum of 1 g daily (for up to 1 year).227 Dosage reductions or delays in dose escalation were permitted for toxicity.227 To be eligible for the study, patients were required to be either on stable antiretroviral therapy for at least 4 weeks or not receiving such therapy for at least 2 weeks.227 Seventeen patients were assessed for response, using the NIAID ACTG criteria.227 Eight patients achieved partial response (defined as no progressive disease and at least a 4-week persistence of either a 50% decrease in the sum of the cross products of the lesions, a 50% reduction in the total number of lesions, or flattening of 50% or more of the nodular lesions) for an overall major response rate of 47%.227 When all 20 patients were assessed on an intent-to-treat basis, the response rate (partial and complete [defined as the absence of any evident disease for 4 weeks] responses) was 40%.227 Seven of the 20 patients achieved the maximum thalidomide dosage of 1 g daily used for a median of 19.9 weeks.227 Overall, the results suggest that thalidomide has activity against Kaposi sarcoma at dosages that can be tolerated for 6 months or more.227 The severity of adverse effects was graded according to toxicity criteria established by the NCI.227 The principal toxicity that limited dose escalation was drowsiness.227

Preliminary results from a case report and 2 small trials have suggested that Kaposi sarcoma may respond to thalidomide dosages as low as 100 mg daily.227 Further studies are needed to assess the dose-response relationship of thalidomide for this condition.227

Other Neoplastic Diseases !!navigator!!

Because there is evidence that thalidomide is an inhibitor of angiogenesis, the drug is being evaluated for the treatment of a variety of malignancies, including advanced or metastatic breast cancer†,32,173,175 Kaposi sarcoma†30,115,170 (see Kaposi Sarcoma under Uses: Use in HIV-infected Patients), melanoma†,175,232,237 ovarian cancer†, myelodysplastic syndrome (MDS)†,229 advanced pancreatic cancer†,229 primary brain tumors† (recurrent high-grade astrocytomas and mixed gliomas),29,169,174,175,229 androgen-independent prostate cancer†,168,229 and renal carcinoma†.175,229

Cachexia !!navigator!!

Thalidomide also has been used for the treatment of cachexia† in patients with advanced cancer, and there is some evidence that the drug may provide benefits in these patients in terms of improvement in symptoms of insomnia, nausea, appetite, and feelings of well-being.172 (See HIV-associated Wasting Syndrome under Uses.)

Graft-versus-host Disease !!navigator!!

Thalidomide has been used for the treatment of graft-versus-host disease† (GVHD) in adult and pediatric bone marrow transplant recipients,75,101,109,151,152,153,155,218,219,232,237 but has been associated with increased morbidity and mortality when used for prophylaxis of chronic GVHD in adult bone marrow transplant recipients.189

Thalidomide has been used in allogeneic bone marrow transplant recipients for the treatment of chronic or refractory GVHD unresponsive to other therapies (e.g., corticosteroids, azathioprine, tacrolimus, cyclosporine, antithymocyte globulin);75,101,109,151,152,153,155 only limited information is available regarding use of the drug for the treatment of acute GVHD.75 In a study in adult and pediatric patients with chronic or refractory GVHD who received thalidomide therapy (800-1600 mg daily for a median duration of 240 days), a complete response was obtained in 32% and a partial response was obtained in 27%; the overall survival rate was 64%.153 Thalidomide has been effective when used for the treatment of chronic or corticosteroid-dependent GVHD in pediatric patients 0.5-17 years of age†.75,109,151,152,153,155,160

When thalidomide was used for prophylaxis of chronic GVHD in a controlled study of adult allogeneic bone marrow transplant patients who had no evidence of active acute GVHD at study entry, those receiving thalidomide (200 mg twice daily beginning 80 days after transplant) experienced a higher incidence of chronic GVHD and had a substantially higher mortality rate compared with those receiving placebo.186,189 Chronic GVHD occurred in 64 or 38% of patients receiving thalidomide or placebo, respectively;189 overall mortality was about 39 or 8%, and mortality from GVHD was about 21 or 4% in those receiving thalidomide or placebo, respectively.189

Thalidomide also has been used in the treatment of GVHD† in adult peripheral blood stem cell transplant recipients.236,239

Recurrent Aphthous Stomatitis !!navigator!!

Thalidomide has been effective when used for the treatment of severe oral ulcers in patients with recurrent aphthous stomatitis† (RAS).138,139,148,149,219 The drug has been used effectively for the treatment of RAS in immunocompetent adults and pediatric patients and also has been effective when used in immunocompromised patients, including cancer patients and HIV-infected patients (see HIV-associated Aphthous Ulcers under Uses).138,139,148,149,150 In a placebo-controlled cross-over study in patients with severe RAS, a complete clinical remission was obtained in 48 or 9% of patients receiving thalidomide or placebo, respectively.150 Oral ulcers generally heal within 1-6 weeks after initiation of thalidomide therapy (100-300 mg daily), but higher dosage may be needed in some patients (400-600 mg daily) and ulcers may relapse when the drug is discontinued.148,149,150 In some patients, relapse may be prevented or treated using thalidomide maintenance therapy (50-100 mg daily).148,149,150,222 In one small clinical trial evaluating thalidomide (100 mg daily for 10 days, followed by 50 mg daily for 10 days, and then 25 mg daily for 10 days) compared with prednisone (0.4 mg/kg per day for 15 days followed by 0.2 mg/kg per day for 15 days), thalidomide prolonged the recurrence interval compared with prednisone at 3 months.259

GI Disorders !!navigator!!

Crohn Disease

Thalidomide has been used with some success in a limited number of patients for the treatment of refractory Crohn disease† (e.g., in those with moderately to severely, chronically active or fistulizing disease).4,53,133,136,157,158,159,202,203,204,205,207,208,209,229,230 In patients who did not respond to or were intolerant of usually recommended therapies (e.g., corticosteroids, sulfasalazine, azathioprine, mercaptopurine, methotrexate), thalidomide therapy (50-300 mg daily) resulted in resolution of small bowel ulceration, bleeding, or pain157,158 and improvement related to quality of life or symptoms associated with fistulas.202,203,204,205 In at least one patient with Crohn disease, thalidomide therapy also resulted in resolution of severe, recurrent oral aphthous ulcers.95 Thalidomide has been used in a limited number patients with Crohn disease (i.e., active fistulous disease, luminal disease) who developed infliximab-induced delayed hypersensitivity reactions.231 Complete closure was observed in 2 patients, one with a single perirectal fistula, the other with 5 perianal fistulae at 4 or 12 weeks of thalidomide therapy, respectively.231 Two patients who continued thalidomide for more than 3 months remained in remission at 5 and 7 months.231

Limited data indicate that thalidomide (100 mg daily) may be effective in maintaining response in patients with chronically active and fistulizing refractory Crohn disease whose disease has responded to infliximab (dosage of 5 mg/kg administered as one or more infusions in patients with chronically active disease and 3 or more infusions in those with fistulizing disease).202,206 The median follow-up was 238 days from initiation of thalidomide therapy and 265 days after the last infusion of infliximab.206 Remission rates (full improvement) with thalidomide were 92, 83, or 83% at 3, 6, or 12 months, respectively, after the last dose of infliximab.202,206

Results of a 12-week, open-label study in a limited number of patients (20-77 years of age) with chronic inflammatory bowel disease† (IBD; 5 with Crohn disease, 2 with ulcerative colitis, and 1 with indeterminate colitis) indicate that use of thalidomide can result in clinical response in patients with chronically active Crohn disease who have not responded to prior therapy (e.g., 5-amino-salicylic acid preparations, prednisone, azathioprine).230 Initially, patients were receiving 100 mg of thalidomide daily after which the daily dosage was increased to a maximum of 400 mg according to patients' response or adverse effect profile.230 Patients continued to receive other drugs for IBD during the duration of the trial.230 The Crohn Disease Activity Index (CDAI) decreased from 117 to 48; improvement included decreased stool frequency, erythrocyte sedimentation rate (ESR), and inflammation and histological grades.230 Two months after the trial, stool frequency returned to pretreatment levels indicating that the effect of thalidomide is of short duration.230 Long term studies are needed; minimizing the dosage over an extended period may be a potential solution.230

Thalidomide also has been studied in pediatric patients (2-18 years of age) with active Crohn disease despite other immunosuppressant therapy.260 A total of 56 children and adolescents were randomized to receive thalidomide or placebo for 8 weeks.260 Patients randomized to thalidomide weighing less than 30 kg, 30-60 kg, or greater than 60 kg received daily dosages of 50, 100, or 150 mg, respectively; however, 2 small patients received an individualized dosage of 2 mg/kg per day.260 Disease activity was measured using the Pediatric Crohn Disease Activity Index.260 At 8 weeks, clinical remission rates were significantly improved in patients receiving thalidomide compared with those receiving placebo (46.4 versus 11.5%; risk ratio 4.0; 95% CI, 1.2-12.5).260 The mean duration of clinical remission in patients receiving thalidomide was 181.1 weeks compared with 6.3 weeks in those receiving placebo.260

Other GI Disorder

Thalidomide also has been used with some success in a limited number of patients for the treatment of ulcerative colitis†, but additional study is needed.

Other Uses !!navigator!!

Thalidomide has been used in a limited number of patients for the treatment of refractory ankylosing spondylitis†;98,261 refractory rheumatoid arthritis†;3,4,53,112,178,179 sarcoidosis†;4,99,237,263 hereditary hemorrhagic telangiectasia†;264 or polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome†262 , but additional study and experience are needed.

Because thalidomide is an inhibitor of angiogenesis and there is some evidence that loss of vision in the severe, wet form of macular degeneration may be related to angiogenesis in the blood vessels behind the macula, the drug has been investigated for the treatment of macular degeneration†.3,52,53

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Premedication and Prophylaxis

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Warnings/Precautions !!navigator!!

Warnings

Fetal/Neonatal Morbidity and Mortality

Thalidomide is a known human teratogen and has caused severe, life-threatening birth defects or fetal death when used during pregnancy.1,2,3,4,5,11,12,15,20,21,52,53,54,112 Mortality at or shortly after birth has been reported in approximately 40% of infants.1

The drug can cause teratogenic effects even if only a single dose of the drug (e.g., 50-100 mg; regardless of strength) is taken during pregnancy.1,2,3,4,5,15,52 Since the risks clearly outweigh any possible benefits in women who are or may become pregnant, thalidomide is contraindicated in such women.1 If the drug is inadvertently administered during pregnancy or if a patient becomes pregnant while receiving the drug, the drug should be discontinued immediately and the patient referred to an obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling.1 The patient should be informed that if their clinician is not available, information about emergency contraception (including information regarding clinicians who provide emergency contraceptive services) can be obtained by calling 888-668-2528 or by using other sources (e.g., [Web]).1,24 Any suspected exposure of a fetus to thalidomide should be reported to the FDA MedWatch Program (800-FDA-1088) and also to the manufacturer, Bristol Myers Squibb Corporation (1-888-423-5436).1 Because thalidomide may cause fetal harm and because of the possibility that the drug may be present in blood and be transfused into a woman who is pregnant, patients receiving thalidomide must not donate blood during therapy and for at least 4 weeks following discontinuance of the drug.1

To minimize risk of fetal exposure and help ensure the safe and effective use of thalidomide in the US, patients must be registered in the Thalomid REMS® program before they can receive commercially available drug.1,17,20,22 All female patients of reproductive potential and all sexually mature males receiving thalidomide must use effective contraceptive measures (which may include abstinence) to help ensure that fetal exposure to the drug does not occur.1 Contraceptive measures are indicated even in females with a history of infertility.1 The only females who do not need to observe mandatory contraceptive measures are those who have undergone hysterectomy.1 All female patients of reproductive potential must use 2 reliable forms of contraception simultaneously (unless the patient chooses to remain continuously abstinent from engaging in heterosexual sexual contact) beginning at least 4 weeks prior to initiation of therapy, during therapy (including treatment interruptions), and then for at least 4 weeks following discontinuance of thalidomide therapy.1 At least 1 contraceptive method should be a highly effective method (intrauterine device [IUD], hormonal contraceptives, tubal ligation, vasectomized partner); the other may be an effective barrier method (latex or synthetic condom, diaphragm, cervical cap).1 Sexually mature males receiving thalidomide must completely avoid unprotected sexual contact with women of reproductive potential and must not donate semen while receiving thalidomide and for 4 weeks after discontinuing the drug.1 While receiving thalidomide and for up to 4 weeks after discontinuing the drug, sexually mature males (including those who have successfully undergone vasectomy) must use a latex or synthetic condom each time they have sexual contact with a woman of reproductive potential.1

Therapy with thalidomide, presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism; however, it is not known if these risks are additive.1 Each risk factor for thromboembolism should be taken into consideration when choosing contraceptive methods.1 (See Thromboembolic Events under Cautions.)

Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia during thalidomide therapy, the risk for bleeding or infection may be increased in such patients at insertion, removal, or during use of an IUD or implantable contraception.1 (See Hematologic Effects under Cautions.)

All females of reproductive potential must be tested for pregnancy within 10-14 days and again within 24 hours immediately prior to initiation of thalidomide therapy.1 The prescribing clinician should not provide the patient with a prescription for thalidomide until reports of the pregnancy tests are available indicating that the results are negative.1 Pregnancy tests must then be repeated at regular intervals during thalidomide therapy (i.e., weekly during the first month, then every 2 or 4 weeks in women with irregular or regular menstrual cycles, respectively).1 Pregnancy tests and counseling also should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding.1 The drug should be discontinued during the evaluation period.1

It has been estimated that there were more than 10,000 reported cases of infants born with birth defects related to use of thalidomide in pregnant women in other countries between 1957 (when thalidomide was first introduced in the world market) and 1963 (several years after the drug was removed from the world market).115 Although thalidomide was not commercially available in the US at that time, there were at least 17 reports of infants with thalidomide-associated birth defects being born to women in the US during those years; these women had received the drug from overseas sources or received premarketing samples distributed by drug company representatives.52

A variety of human fetal abnormalities related to thalidomide administration during pregnancy have been documented.1 The most common birth defects reported following fetal exposure to thalidomide are musculoskeletal fetal abnormalities involving the loss of all or part of one or more bones;1,2,3,4,5,15,21 however, fetal deformities may occur in almost any organ of the body15 and defects of internal organs have been reported with some skeletal deformities.4,5 The mortality rate at or shortly after birth in infants born with thalidomide-induced abnormalities has been reported to be about 40%;1,15 most fatalities are related to serious malformations of internal organs.1,15

Skeletal deformities caused by thalidomide include amelia (absence of legs and/or arms)1,5,15 and absence of bones;1,15 phocomelia (short legs and/or arms)1,4,5,15,54 and bone hypoplasia;1,15 hand deformities (e.g., radial club hand);15 thumb aplasia,5,15 hypoplasia,15 triphalangia,5,15 and nonopposability;15 finger aplasia,15 hypoplasia,15 fixed flexion,15 and syndactyly;15 and hip dysplasia5 and dislocation.5,15 Skeletal deformities appear to follow the craniocaudal progression of fetal morphogenesis.15 Most individuals with thalidomide defects of the upper limbs have normal lower limbs, some have defects of all limbs, but those with normal upper limbs and deformed lower limbs are rare.15 When substantial parts of bones are missing, the muscles normally attached to them are hypoplastic, but the degree of muscle hypoplasia does not always correspond to the level of bone loss (e.g., marked hypoplasia of shoulder and upper arm muscles may occur in a patient with a humerus of normal length).15 In general, more pronounced shortness of stature than that associated only with short leg bones occurs,15 resulting from poor growth, spinal osteochondritis, and progressive kyphosis.15 Thalidomide-induced skeletal deformities usually are bilaterally symmetric, similar to malformations reported with other teratogenic drugs.15 However, the extent of symmetry varies with the nature of the defect, both in the number of appreciably asymmetric deformities and in the closeness of the match between left and right.15

The next most common group of abnormalities reported following fetal exposure to thalidomide are craniofacial and orofacial fetal abnormalities involving the ear, eye, and nerve supplies to the face, external ocular muscles, and lacrimal glands;15,21 these deformities tend to occur in a variety of combinations and permutations.15 External ear deformities tend to be bilateral and symmetric,15 and include anotia,1,15 microtia or micropinna,1,15 and small or absent auditory canals.1,5,15 Individuals with anotia and a blind or absent external auditory canal (meatus) are profoundly deaf in the affected ear.15 Facial palsy may occur1,15 (usually unilaterally rather than bilaterally) and almost always is associated with anotia or microtia on the same side.15 Abnormalities of ocular structures occur frequently,2,5,15 including anophthalmos,1,15 microphthalmos1,15 coloboma of the iris and retina,15 and conjunctival dermoid cyst.15 Microphthalmos and coloboma often occur together, and are predominantly bilateral.15 Restricted ocular movements may occur;15 ocular movement defects are nearly always associated with otic defects, often associated with facial weakness, and tend to be bilateral.15 Tear-saliva syndrome (crocodile tears) has been reported, in which tears are secreted in association with eating (rather than saliva) but may not be secreted in association with crying.15 This syndrome results from incorrect neural connections (probably in the brain stem), is bilateral or unilateral, and usually is associated with otic abnormalities and ocular movement defects.15 Less common orofacial defects that have reported include cleft palate,15 high arched palate,15 bifid uvula,15 palatal palsy,15 cleft lip,15 choanal atresia,15 and mandibular and dental abnormalities.15

Other fetal deformities that have been associated with thalidomide exposure during pregnancy include congenital heart defects and other cardiovascular malformations (e.g., patent ductus arteriosus, ventricular and/or atrial septal defects, pulmonary stenosis);1,5,15,21 renal and urinary tract malformations (e.g., defects of the kidney, ureter, and bladder);15,21 genital malformations (e.g., hypospadias, vaginal atresia, fallopian tube interruption, bicornate uterus, hypoplasia of the scrotum or labia, and undescended, small, or absent testis);1,15,21 GI tract malformations (e.g., duodenal atresia, duodenal stenosis, pyloric stenosis, anorectal stenosis, imperforate anus with fistula, anteriorly placed anus); gallbladder aplasia;5,15 and respiratory tract malformations.5

Most teratogenic effects appear to have occurred as the result of exposure to thalidomide early in pregnancy, and there is some evidence that a distinct window of embryonic sensitivity to thalidomide's teratogenic effects exists (i.e., from about 34-50 days after the beginning of the last menstrual period).1,4,5,15 Some malformations appear to be associated with particular periods of embryonic exposure, including aplasia of the ear or stenosis of the rectum which appear to be associated with exposure to thalidomide at 34-38 or 49-50 days, respectively, after the beginning of the last menstrual period.5,15 However, incorrect reporting of the dates of last menstrual periods and/or thalidomide administration dates as well as atypical menstrual cycle duration may have resulted in considerable inaccuracy in these data.5 It has been suggested that limb defects may be secondary to an inhibition of blood vessel growth in the developing fetal limb bud,4 and studies of thalidomide's effects in fetal animal tissues have suggested that neural as well as limb development effects occur.4 The risk of potentially severe birth defects occurring following fetal thalidomide exposure later in pregnancy is unknown, but may be substantial.1 Animal studies to characterize the effects of thalidomide on late stage pregnancy have not been conducted.1 While numerous mechanisms for thalidomide-induced fetal abnormality and mortality have been proposed, some have been refuted and others have not been adequately studied;4,46 additional study is required to elucidate how thalidomide causes teratogenic effects in fetuses.1,4,46

The only type of thalidomide exposure known to have resulted in drug-associated birth defects was related to oral administration of the drug.1 Currently no specific data are available regarding cutaneous absorption or inhalation of thalidomide in women of childbearing potential and whether such exposures may result in any birth defect.1 Patients should be instructed not to handle extensively or open thalidomide capsules and to maintain capsules stored in blister packs until ingestion.1 If there has been contact with a non-intact thalidomide capsule or the powder contents, the exposed area should be washed with soap and water.1 Thalidomide has been shown to be present in the serum and semen of patients receiving thalidomide.1 If healthcare providers or other care givers are exposed to body fluids from patients receiving thalidomide, appropriate precautions should be taken (e.g., wearing gloves to prevent the potential cutaneous exposure to thalidomide, washing the exposed area with soap and water).1

Thromboembolic Events

Use of thalidomide in patients with multiple myeloma is associated with increased risk of arterial or venous thromboembolic events (e.g., deep-vein thrombosis, pulmonary embolism).1 Such risk increases substantially when thalidomide is used in combination with standard chemotherapy, including dexamethasone.1 In a controlled clinical trial, an increased incidence of venous thromboembolic events was observed in patients receiving thalidomide in combination with dexamethasone compared with those receiving dexamethasone alone (22.5 versus 4.9%).1 Ischemic heart disease, including myocardial infarction and stroke also has been reported in patients with previously untreated multiple myeloma receiving thalidomide and dexamethasone.1

Therapy with thalidomide, presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism; however, it is not known if these risks of thromboembolism are additive.1 Each risk factor for thromboembolism should be taken into consideration when choosing contraceptive methods.1

Patients and clinicians are advised to watch for signs and symptoms of thromboembolism.1 Patients should be instructed to notify a clinician if they develop shortness of breath, chest pain, and/or arm or leg swelling.1

The manufacturer and some experts state that decisions regarding use of thromboprophylaxis and selection of an appropriate thromboprophylaxis regimen (e.g., aspirin, anticoagulant) should be based on careful assessment of the patient's risk factors for thromboembolism.253,254 The International Myeloma Working Group (IMWG) currently recommends thromboprophylaxis with aspirin for multiple myeloma patients receiving thalidomide who have one or no underlying individual and/or myeloma-related risk factors for venous thromboembolism and thromboprophylaxis with a low molecular weight heparin (LMWH) for those with 2 or more individual and/or myeloma-related risk factors.253 The IMWG also recommends that thromboprophylaxis with a LMWH be considered in thalidomide-treated patients receiving high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors.253 The IMWG states that although full-dose warfarin (international normalized ratio [INR] 2-3) is an alternative to LMWHs, there is limited clinical experience with this approach.253 The American Society of Clinical Oncology (ASCO) currently recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving thalidomide in conjunction with dexamethasone or antineoplastic agents, and states that those at lower risk for thromboembolism may receive either aspirin or a LMWH, while those at higher risk should receive a low molecular weight heparin.254

Deep-vein thrombosis and pulmonary embolism also have been reported in patients with ENL.240

Other Warnings and Precautions

Treatment-related Mortality

Increased mortality has been reported in clinical trials in patients with multiple myeloma receiving pembrolizumab in combination with a thalidomide analogue and dexamethasone.1 The manufacturer of thalidomide states that an anti-programmed death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) antibody should not be used in combination with a thalidomide analogue and dexamethasone in patients with multiple myeloma outside of a controlled clinical trial.1 FDA recommends that ongoing clinical trials evaluating an anti-PD-1 or anti-PD-L1 agent in combination with an immunomodulatory agent (e.g., thalidomide) be evaluated for permanent discontinuance or protocol amendments.265

Drowsiness and Somnolence

Patients should be warned that thalidomide frequently causes drowsiness and somnolence, and may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).1 Patients also should be warned not to take any other drugs that may cause drowsiness without consulting their clinician.1 Patients should be advised that thalidomide may potentiate the drowsiness caused by alcohol.1 (See CNS Agents under Drug Interactions.)

Peripheral Neuropathy

Thalidomide may cause potentially severe nerve damage (i.e., polyneuritis or peripheral neuropathy) that may be irreversible.1,3,4,5,20,41,53,54,57,59,60,61,62,232 The incidence of peripheral neuropathy in patients receiving thalidomide has been reported to range from less than 1% to more than 70%.4,6,61,112 Incidence data regarding this adverse effect has been difficult to obtain, in part because the drug often is used in patients with diseases that may be associated with neuropathy (e.g., leprosy patients with erythema nodosum leprosum [ENL], patients with HIV infection) and it may be difficult to differentiate the neuropathologic symptoms and changes caused by the underlying disease from those caused by the drug.1,5,6,61,62,89,112

Despite long-term experience with use of thalidomide in leprosy patients with ENL, there have been few reports of thalidomide-associated peripheral neuropathy in these patients;1 in some studies, less than 1% of patients receiving the drug for treatment of ENL experienced peripheral neuropathy.4,59,60,62 It has been suggested that this may not be an accurate reflection of the incidence of this adverse effect in these patients since peripheral neuritis was not recognized as a potential adverse effect of thalidomide in early studies of the drug,86,112 in part because ENL patients frequently have neuropathy in association with their disease and may not have reported such effects while receiving the drug.76,81,82,89 Therefore, preexisting neuropathy in ENL patients may complicate recognition of thalidomide-associated peripheral neuropathy.5,89,112 In addition, such symptoms may be difficult to monitor since ENL neuritis may improve during thalidomide therapy, but relapse after therapy with the drug is discontinued.35

In controlled studies in HIV-infected patients, neuropathy occurred in 7-8% of those receiving thalidomide.41 In one limited study in HIV-infected patients receiving thalidomide 400 mg daily for 3 months, 7% of patients experienced neuropathy symptoms requiring discontinuance of the drug.41 In other limited studies, 4% of HIV infected patients receiving 200-300 mg of thalidomide for 14-21 days experienced severe symptoms of neuropathy.58 It has been suggested that HIV-infected patients may be particularly susceptible to the development of thalidomide-associated polyneuritis.5 However, since axonal degeneration with clinical and electrophysiologic symptoms resembling those of thalidomide-associated polyneuropathies may occur in HIV-infected patients and other forms of polyneuropathy (including demyelinating and polyradiculopathy) also are reported in such patients, it may be difficult to differentiate neuropathologic changes caused by the underlying disease from those caused by thalidomide.5

In a retrospective study of patients receiving thalidomide for a variety of dermatologic conditions, thalidomide-associated peripheral neuropathy occurred in 21-50% of patients and was most frequent in women and geriatric patients.61 Limited data indicate that peripheral neuropathy occurs in up to 75% of patients receiving thalidomide for the treatment of prurigo nodularis†.4,59,60,61,62

Thalidomide-associated peripheral neuropathy generally has been reported with chronic use of the drug over a period of months,53,60 but also has been reported with relatively short-term use of the drug.58,61,62 The correlation between peripheral neuropathy and the cumulative thalidomide dose is unclear;1,4,5,59,60,61,62 symptoms have been reported to begin after a cumulative dose of 40-50 g in some patients,4,60,61,139 but also have occurred with no apparent relationship to cumulative dose.49,59,61 There have been some cases when symptoms of thalidomide-associated peripheral neuropathy were not apparent until after the drug was discontinued.1

Polyneuropathic symptoms may improve in some patients when thalidomide is discontinued, but symptoms may resolve slowly or not at all after discontinuance of the drug.4,5,41,59,60,61,62 In a study of patients with thalidomide-induced peripheral neuropathy who were followed for 4-6 years after discontinuing the drug, 25% experienced full recovery, 25% had some improvement of symptoms, and 50% had no improvement in signs and symptoms of neuropathy.116

Clinical symptoms of thalidomide-induced neuropathy include predominantly symmetric painful paresthesia of the hands and feet, often accompanied by sensory loss in lower limbs.4,59,60,61,62 Muscle weakness and cramps, signs of pyramidal tract involvement, and carpal tunnel syndrome have been reported often.4,59,60,61,62 An unpleasant pedal symptom, described as “tightness around the feet,” was reported in 8-47% of patients in some studies.4,59 In early reports, thalidomide-associated peripheral neuropathies were characterized mostly by sensory symptoms, including hypoesthesia and hyperesthesia, hyperalgesia, impaired temperature sensitivity,4,5 and impaired vegetative (i.e., autonomic) nervous functions.5 These symptoms occasionally were accompanied by mild proximal muscle weakness,4,5,61,62 or evidence of pyramidal tract damage,4 but motor disturbances appeared to occur rarely.5 Muscle weakness rapidly improved after discontinuance of the drug, but sensory deficits were slow to improve, and occasionally worsened even while the patient was not receiving thalidomide.4 Because there was no substantial correlation between the severity of the condition and the total dose of the drug, and because discontinuance of thalidomide did not result in improvement in many cases, initially it could not be established that such neurologic disturbances were actually caused by thalidomide.5 Subsequently, the association between thalidomide and peripheral neuropathies was established in clinical studies of patients with discoid lupus erythematosus, prurigo nodularis, and aphthous stomatitis; in these studies, the neurologic status of patients was assessed before and after initiation of thalidomide therapy.5

Physiologically, thalidomide polyneuropathy is characterized by axonal degeneration without demyelinization (i.e., a “dying back process”).4,5,60,62 Electrophysiologic alteration principally is characterized by a decreased sensory action potential amplitude on medial nerves of the arm, and peroneal and sural (medial cutaneous) nerves of the leg, with relative conservation of conduction velocities;4,59,60,61,62 however, decreased sensory and motor conduction velocities have been observed.5,60 Also, increased somatosensory latency of activation after sural nerve stimulation may occur in the absence of clinical abnormalities in patients receiving thalidomide.4,5 Because electrophysiologic alterations may occur before the onset of subjective symptoms, the reported incidence of neuropathy in thalidomide studies is higher if neurophysiologic tests, rather than clinical symptoms, are used for diagnosis.5

Patients should be instructed to immediately report initial symptoms (e.g., numbness, tingling, pain or a burning sensation in the hands and feet) of peripheral neuropathy to their prescribing clinician.1 To ensure that early signs of neuropathy are detected, patients should be examined, counseled, and questioned regularly during thalidomide therapy (i.e., monthly for the first 3 months of thalidomide treatment, and periodically thereafter).1,4

Early detection and differential diagnosis of thalidomide-induced neuritis may be difficult in leprosy patients with ENL and in HIV-infected patients because neuritis associated with these diseases may be similar to that caused by thalidomide.1,5,34,61,62,89,112

To assist in detection of asymptomatic neuropathy, the manufacturer states that consideration should be given to using electrophysiologic testing, consisting of sensory nerve action potential (SNAP) amplitude measurement at baseline and every 6 months thereafter.1 If manifestations of peripheral neuropathy develop, thalidomide should be discontinued immediately (if clinically appropriate) to minimize further damage.1 Usually, treatment with thalidomide should be resumed only if manifestations of neuropathy return to baseline.1

Drugs known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide.1 (See Drugs Associated with Peripheral Neuropathy under Drug Interactions.)

Dizziness and Orthostatic Hypotension

Because thalidomide may cause dizziness and orthostatic hypotension,1,53,54 patients receiving the drug should be instructed to sit upright for a few minutes before standing up from a reclining position.1

Hematologic Effects

Because decreased leukocyte counts, including neutropenia,1,34,53,54 have been reported in patients receiving thalidomide, the drug should not be initiated in patients with absolute neutrophil counts (ANC) less than 750/mm3.1 Leukocyte counts and differentials should be routinely monitored, especially in patients who are prone to neutropenia (e.g., HIV-infected patients).1 If the ANC decreases to less than 750/mm3 while the patient is receiving thalidomide, the patient's drug regimen should be reevaluated and consideration given to withholding thalidomide if clinically appropriate.1,20

Because grade 3 or 4 thrombocytopenia has been reported, CBCs, including platelets, should be monitored.1 If hematologic toxicity occurs, dosage interruption, dosage reduction, or discontinuance of therapy may be required.1 Patients, particularly those receiving concomitant medications that may increase the risk of bleeding, should be monitored for signs and symptoms of bleeding (e.g., petechiae, epistaxis, GI bleed).1

Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia during thalidomide therapy, the risk for bleeding or infection may be increased in such patients at insertion, removal, or during use of an intrauterine device (IUD) or implantable contraception.1

Effects on HIV Viral Load

Increased HIV viral load (i.e., increased plasma HIV-1 RNA levels)1,12,53,54 has been reported in some HIV-infected patients receiving thalidomide. In one controlled study in HIV-infected patients, median plasma HIV-1 RNA levels increased by 0.42 log10 copies/mL in patients receiving thalidomide compared with a 0.05 log10-copies/mL increase in those receiving placebo.1,12 A similar trend of increased HIV load was reported in another study in HIV-infected patients.1 However, the clinical importance of these effects is unknown since the patients involved were not receiving the potent antiretroviral agent combination regimens currently recommended for HIV-infected patients.1,12,54

Plasma HIV-1 RNA levels should be measured after the first and third months of thalidomide treatment and every 3 months thereafter.1

Bradycardia

Bradycardia, sometimes requiring medical intervention, has been reported in patients receiving thalidomide; however, the underlying etiology and clinical significance of this finding is unknown.1

Patients should be monitored for bradycardia and syncope.1 If bradycardia occurs, dosage reduction or discontinuance of therapy may be required.1 Concomitant medications that lower heart rate should be used with caution.1

Cutaneous Reactions

Severe cases of cutaneous reactions (i.e., Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported.1 DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.1 These reactions can be fatal.1 For grade 2 or 3 skin rash, temporary interruption or discontinuance of thalidomide should be considered.1 If grade 4 rash, exfoliative or bullous rash, or other severe cutaneous reactions (SJS, TEN, or DRESS) occur, thalidomide should be permanently discontinued.1

Seizures

Seizures, including tonic-clonic (grand mal) seizures, have been reported during postmarketing experience with thalidomide. Because the reports of seizures in patients receiving thalidomide were submitted voluntarily from a population of unknown size, their frequency cannot be estimated.1 Most of the patients in whom seizures were reported had disorders that may have predisposed them to seizure activity, and it currently is not known whether thalidomide has any epileptogenic activity.1

Patients with a history of seizures or other risk factors for the development of seizures should be monitored closely for clinical changes that could precipitate acute seizure activity.1

Tumor Lysis Syndrome

Tumor lysis syndrome has been reported during postmarketing experience with thalidomide.1 Patients at risk of tumor lysis syndrome (e.g., high tumor burden at baseline) should be monitored for tumor lysis syndrome, and appropriate precautions should be instituted.1

Hypersensitivity Reactions

Thalidomide is contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation.1 The drug should be discontinued if signs and symptoms of hypersensitivity (e.g., erythematous macular rash associated with fever, tachycardia, hypotension) occur and are severe; if thalidomide therapy is resumed and the reaction recurs, thalidomide should be permanently discontinued.1 Thalidomide therapy should not be resumed if angioedema or anaphylaxis occurs.1 Because hypersensitivity reactions characterized by cutaneous and/or febrile manifestations have been reported in HIV-infected patients receiving thalidomide and because rechallenge with the drug resulted in accelerated hypersensitivity (including hypotension) in some of these patients,58 some clinicians recommend that if thalidomide rechallenge is unavoidable in an HIV-infected patient (e.g., to elucidate a drug reaction in a patient receiving a complex drug regimen), the patient should be hospitalized when the drug is administered and for at least 24 hours following the rechallenge.58

Hypersensitivity reactions characterized by cutaneous and/or febrile symptoms have been reported in HIV-infected patients receiving thalidomide.58 In some of these HIV-infected patients, rechallenge with thalidomide resulted in accelerated hypersensitivity, including hypotension.58 Therefore, some clinicians state that if thalidomide rechallenge in an HIV-infected patient is unavoidable (e.g., to elucidate a drug reaction in a patient receiving a complex drug regimen), the patient should be hospitalized when the drug is administered and for at least 24 hours following the rechallenge.58

Specific Populations

Pregnancy

Thalidomide is a human teratogen and is contraindicated for use during pregnancy.1 (See REMS under Dosage and Administration and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Females or Males of Reproductive Potential

Results of animal studies suggest that thalidomide may impair male fertility.1

Pregnancy must be excluded prior to treatment initiation and throughout therapy.1,22 Pregnancy must be prevented for ≥4 weeks prior to and during therapy and for 4 weeks after completion of therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

It is not known whether thalidomide is distributed into human milk.1 Because many drugs are distributed into milk, and because of the potential for serious thalidomide-related adverse effects in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.1

Pediatric Use

Although safety and efficacy of thalidomide in pediatric patients younger than 12 years of age have not been established,1 the drug has been used in a limited number of children 6 months to 12 years of age†.75,77,119,149,151,159,210 When thalidomide was used for the treatment of graft-versus-host disease in a limited number of bone marrow transplant recipients 1.5-17 years of age†, adverse effects of the drug included somnolence (which required discontinuance of the drug in at least one child), constipation, and a syndrome of rash, eosinophilia, and pancreatitis (which resolved after the drug was discontinued).75

When thalidomide was used for the treatment of Crohn disease in a limited number of children and adolescents 2-18 years of age†, the most frequent severe adverse effect was peripheral neuropathy.260

Geriatric Use

In clinical trials evaluating thalidomide in combination with dexamethasone, 52% of patients were 65 years of age or older and 15% were 75 years of age or older.1 Atrial fibrillation, constipation, fatigue, nausea, hypokalemia, thromboembolism, hyperglycemia, and asthenia occurred at a higher incidence compared with younger adults.1

Hepatic Impairment

Thalidomide has not been studied in patients with hepatic impairment.1

Renal Impairment

Renal impairment is not expected to affect systemic exposure of thalidomide since less than 3.5% of the dose is excreted in urine as unchanged drug.1

When dialysis was performed 10-15 hours after administration of thalidomide, no significant difference in pharmacokinetics of thalidomide was observed on non-dialysis or dialysis days.245

Common Adverse Effects !!navigator!!

Adverse effects reported in at least 20% of patients with multiple myeloma receiving thalidomide include fatigue, hypocalcemia, edema, constipation, sensory or motor neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thromboembolism, weight gain, dizziness, and dry skin.1

Adverse effects reported in at least 10% of patients with erythema nodosum leprosum (ENL) receiving thalidomide include somnolence, rash, and headache.1

Drug Interactions ⬆ ⬇

[Section Outline]

In vitro, thalidomide does not inhibit or induce cytochrome P-450 (CYP) isoenzymes at clinically relevant concentrations.1 Thalidomide is not a substrate of CYP isoenzymes.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes !!navigator!!

Drug interactions with thalidomide unlikely.1

Hormonal Contraceptives and Drugs that Interfere with Hormonal Contraceptives !!navigator!!

Concomitant administration of thalidomide and oral contraceptives containing ethinyl estradiol and norethindrone does not appear to affect the pharmacokinetics of the hormones.1,78,79 In 2 studies in healthy women 21-45 years of age who received a 3-week regimen of thalidomide (200 mg of thalidomide daily) followed by a single oral dose of an estrogen-progestin combination oral contraceptive (70 mcg of ethinyl estradiol and 2 mg of norethindrone), the pharmacokinetics of both ethinyl estradiol and norethindrone were the same as those obtained in these women when the contraceptive was administered without thalidomide.78,79

While it is unlikely that thalidomide would affect efficacy of oral contraceptives since the drug does not appear to affect the pharmacokinetics of the hormones,79,186 other drugs that the patient may be receiving, including HIV protease inhibitors, griseofulvin, rifampin, rifabutin, phenytoin, carbamazepine, or herbal supplements such as St. John's wort, may reduce efficacy of oral contraceptives up to 1 month after discontinuance of these agents.1,25,26 Because it is mandatory that females of reproductive potential receiving thalidomide use effective contraceptive measures for at least 4 weeks prior to, throughout, and for at least 4 weeks after completion of thalidomide therapy, females of reproductive potential receiving thalidomide concomitantly with any other drug that can reduce efficacy of oral contraceptives must use 2 other effective methods of contraception or abstain from heterosexual sexual contact.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

The risk of thromboembolism may be increased in patients receiving estrogen-containing therapy; therefore, estrogen-containing therapy should be used with caution in patients with multiple myeloma receiving thalidomide in combination with dexamethasone.1

CNS Agents !!navigator!!

Thalidomide has been reported to enhance the sedative effects of some drugs, including opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants, and may potentiate the somnolence caused by alcohol.1

Drugs Associated with Bradycardia !!navigator!!

The risk of bradycardia may be increased in patients receiving thalidomide concomitantly with drugs known to cause bradycardia (e.g., calcium-channel blocking agents, α- or β-adrenergic blocking agents, digoxin, histamine H2-receptor antagonists, lithium, tricyclic antidepressants, neuromuscular blocking agents).1

Drugs Associated with Peripheral Neuropathy !!navigator!!

Because of the potential for additive effects, drugs known to be associated with peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) should be used with caution in patients receiving thalidomide.1

Drugs Associated with an Increased Risk of Thromboembolism !!navigator!!

The risk of thrombosis may be increased in multiple myeloma patients receiving thalidomide and dexamethasone concomitantly with erythropoietic stimulating agents, estrogen-containing therapies, or other agents that increase the risk of thrombosis.1

Digoxin !!navigator!!

In 16 healthy men, the pharmacokinetic profile of a single 0.5-mg dose of digoxin was similar with and without coadministration of thalidomide 200 mg/day at steady state levels.1 A single dose of digoxin also had no effect on the pharmacokinetic profile of thalidomide.1 The safety of long-term concomitant use of thalidomide and digoxin has not been evaluated.1

Warfarin !!navigator!!

Following coadministration of a single 25-mg dose of warfarin and thalidomide 200 mg daily at steady-state, the pharmacokinetic profile of warfarin, international normalized ratio (INR), and prothrombin time were similar to those observed without coadministration of thalidomide.1 A single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide.1

Other Information ⬆ ⬇

[Section Outline]

Description

Thalidomide has immunomodulatory, anti-inflammatory, and antiangiogenic activities.1,2,3,4,7,12,53,90,112,164,167,232,237 The drug also has sedative and hypnotic effects.4,112 Thalidomide is structurally similar to, but pharmacologically different from, glutethimide.1,3,4,5,112 Thalidomide contains a phthalimide ring and a glutarimide ring;1,4 the glutarimide ring is similar to that contained in glutethimide and may be responsible for the sedative and hypnotic effects of thalidomide.4 Because the glutarimide ring has a single asymmetric carbon (chiral center), thalidomide may exist as either an optically active levorotatory or dextrorotatory enantiomer.1,4,90,106,112 The enantiomers rapidly interconvert in vivo and in vitro;4,90,106,108,112 it is unknown whether the enantiomers have distinct pharmacologic properties.4,106 Thalidomide is commercially available as a 1:1 racemic mixture of the 2 enantiomers with a net optical rotation of zero.1,4,112

The mechanism(s) of action of the immunomodulatory and anti-inflammatory effects of thalidomide are complex and have not been fully determined.2,3,5,6,12,14,41,42,43,53,112,230 Cellular activities of thalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex.1 Data from in vitro models suggest the effects of thalidomide appear to result in part from modulation of tumor necrosis factor alpha (TNF-α) levels,1,3,7,13,14,40,41,42,44,53,90,112,230,232,237 costimulatory or adjuvant effect on T-cells resulting in increased T-cell proliferation and increased production of interleukin-2 and interferon-γ,90,190,191,194,237,246 and/or modulation of leukocyte migration and chemotaxis.1,2,6,14,44,112,248 Other anti-inflammatory and immunomodulatory effects of the drug may include suppression of macrophage involvement of prostaglandin synthesis and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells.1,244

The immunomodulatory and anti-inflammatory effects of thalidomide differ from those of other immunosuppressive agents, including corticosteroids, cyclosporin (e.g., cyclosporine) or macrolide (e.g., tacrolimus) immunosuppressants, pentoxifylline, immunosuppressive purine analogs (e.g. azathioprine) and purine metabolism inhibitors (e.g., mycophenolic acid),2 and also differ from those of nonsteroidal anti-inflammatory agents.2 Thalidomide does not appear to interfere with important host antimicrobial mechanisms; the drug has no substantial inhibitory effect on lymphocyte proliferation, does not impair delayed-type hypersensitivity reactions, and does not impair granuloma formation.2,40,190,191

Thalidomide has no direct antibacterial activity against Mycobacterium leprae .2 In addition, results of an in vitro study using Enterocytozoon bieneusi , Encephalitozoon intestinalis , and E. cuniculi indicate that thalidomide has no direct activity against microsporidia.193

Immunomodulatory Effects !!navigator!!

Use of thalidomide in the management of multiple myeloma, erythema nodosum leprosum (ENL], and various inflammatory and/or dermatologic disorders is based on the drug's immunomodulatory effects.2,112 Thalidomide's immunomodulatory effects may result from modulation of TNF-α levels,1,3,7,13,14,40,41,42,44,53,112,232,233 costimulatory or adjuvant effect on T-cells resulting in increased T-cell proliferation and increased production of interleukin-2 and interferon-γ,90,190,191,194,244 and/or modulation of leukocyte extravascular migration mechanisms.1,2,6,14,44,112 However, in vitro studies and preliminary clinical studies indicate that the immunomodulatory effects of thalidomide vary considerably under different conditions,1,2,41,42,43,90 and some evidence indicates that effects of the drug may be species specific.6

Treatment of thalidomide in patients with multiple myeloma is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell derived cytokines associated with cytotoxic activity).1 In patients with multiple myeloma, thalidomide inhibits TNF-α expression by bone marrow stromal cells, resulting in inhibition of growth of multiple myeloma cells.243,248,249 Thalidomide enhances T cell activation, releasing cytokines IL-2 and interferon-γ.1,248 These cytokines activate natural killer cells causing lysis of multiple myeloma cells.1,243,248

The difficulty in characterizing thalidomide's mechanism of action has been attributed in part to numerous in vivo metabolites that result from the combination of optical enantiomerism, hydrolysis, and hydroxylation of the drug.5,6 In studies of enantiomerically stable thalidomide analogs (with an α-methyl group attached to the chiral carbon), levorotatory analogs demonstrated more immunomodulatory, sedative, and teratogenic activity, and more inhibition of TNF-α release, than dextrorotatory analogs.2 Although apparent enantiomer-specific effects of thalidomide have been reported from in vitro and in vivo studies, data from such studies are limited by rapid racemization and the pharmacokinetics of the drug in the system being studied, and should be interpreted with caution.2,90 Spontaneous hydrolysis of thalidomide yields products that do not appear to have immunomodulatory activity;2,92 the extent of hepatic metabolism of the drug appears to be limited,1,2 and some experts state that insufficient evidence exists to support speculation that formation of active metabolites is required for thalidomide's effects.2

The immunomodulatory effects of thalidomide may be related to suppression of excessive TNF-α production;1,3,7,13,14,40,41,44,45,53,112,232 however, there also is some evidence that thalidomide is capable of enhancing TNF-α synthesis.1,12,90,186 The drug selectively inhibits the production of TNF-α by cultured human monocytes (possibly by inhibiting production and/or enhancing the degradation of TNF-α messenger RNA) without influencing either general protein synthesis or the expression of other monocyte-derived cytokines (e.g., IL-1, IL-6, GM-CSF).6,7,8,11,40,112 Administration of thalidomide has been reported to decrease circulating TNF-α levels in patients with erythema nodosum leprosum (ENL).1,6,8,44,112

Wasting syndrome and the associated systemic symptoms (e.g., anorexia, fever) also may be mediated by excessive TNF-α production,8,11,40,41 and there is limited evidence that thalidomide may reduce plasma TNF-α concentrations and ameliorate wasting in patients with HIV infection and/or tuberculosis.11,40,41,42 However, the role of TNF-α in HIV infection is unclear because evidence of TNF-α production in patients with HIV infection is inconsistent and includes reports of undetected, increased, or unchanged production of the cytokine.12,14,41,42,43,47 Also, serum and plasma TNF-α levels fluctuate because of the cytokine's short half-life, and may not accurately reflect the actual extent of TNF-α production and/or the degree of TNF-α-related toxicities.42 Such discrepancies in apparent TNF-α levels may result from the different assays used,41,43 or from defects in the methods used to determine in vitro and in vivo cytokine production.41 In addition, cytokines may be produced and act locally in tissue, and it is possible that circulating levels of TNF-α do not reflect tissue activity.41,112

The effect of thalidomide on TNF-α levels, HIV replication, and HIV disease manifestations such as wasting is unclear.1,8,11,12,41,42,43 In one limited controlled study of patients with wasting syndrome associated with HIV-1 infection (with or without tuberculosis), those receiving thalidomide experienced a substantially greater weight gain than those receiving placebo;42 however, only the patients with HIV and tuberculosis experienced decreased plasma TNF-α and decreased plasma HIV-1 RNA levels while receiving thalidomide, and these patients experienced a higher mean weight gain than those with HIV infection alone.42 Data from some studies in patients with HIV infection indicate that thalidomide inhibited TNF-α activation of latent HIV-1 in monocytes and reduced replication of the virus;8,11 however, some evidence indicates that thalidomide increases plasma TNF-α and soluble TNF-α type II receptor levels in patients with HIV infection, and may increase HIV replication.1,12 In a placebo-controlled study in HIV-infected patients, thalidomide therapy (200 mg daily for 4 weeks) apparently had no inhibitory effect on HIV replication and no effect on plasma TNF-α levels, but did increase plasma levels of soluble IL-2 receptor, soluble CD8 antigen, and IL-12.194 In addition, in vitro studies using purified T-cells from these patients indicated that exposure to thalidomide resulted in a costimulatory effect resulting in increased production of IL-2 and interferon-γ.194

There is evidence that thalidomide induces down-modulation of selected cell surface adhesion molecules involved in leukocyte migration,1,2,6,14,45 and the drug's immunomodulatory mechanism of action may result in part from modulation of cellular interactions involving direct physical contact (i.e., adhesion and detachment) of leukocytes with endothelial cells.2 Limited data indicate that thalidomide may modulate TNF-α induction of endothelial cell adhesion molecules; this effect may interfere with leukocyte adhesion to endothelium, and prevent the initiation of leukocytic extravasation into inflammatory foci.2 Also, once adhesion of leukocytes to vascular endothelium occurs, thalidomide may interfere with their detachment, and impede transmigration of leukocytes into extravascular tissue.2 Although thalidomide may up- or down-modulate different adhesion receptors, and its effects on various types of leukocytes is variable,2,14 treatment with thalidomide induces a prompt reduction in the number of neutrophils and CD4+ T-cells in the lesions of patients with ENL.14,44 Leukocyte infiltration and cytokine (especially TNF-α) responses are present in focal inflammatory lesions characterized by post-capillary vasculitis (e.g., ENL lesions and mucocutaneous aphthae),2 and these immunopathologic conditions are those most clearly responsive to thalidomide.2 Such antivasculitic effects also may be enhanced by thalidomide's modulation of TNF-α synthesis or release.2 However, the exact mechanism of action for the drug's clinical immunomodulatory activity is unclear,1,2,3,5,6,12,14 and further study is required to elucidate the drug's mechanism of action.2,5,6,14

Effects on Angiogenesis !!navigator!!

Thalidomide inhibits angiogenesis,2,3,12,164,167 and it has been suggested that the teratogenic effects of thalidomide on fetal limbs may be related to inhibition of blood vessel growth in the developing fetal limb bud.3,12,112,164,167 Thalidomide's anti-angiogenic effects have been demonstrated in several animal angiogenesis models;112,164,167 however, there is evidence that the drug's anti-angiogenic effects may be species specific and possibly may be related to a species-specific metabolite and/or metabolic activation.112,164,167 Thalidomide reduced the area of vascularization in a rabbit corneal model of induced neovascularization.112,164 The drug also inhibited angiogenesis in a rat aorta model and in human aortic endothelial cells when human or rabbit microsomes were present, but not when rat microsomes were present.112,167

The mechanism of thalidomide's anti-angiogenic effects is unknown.164 It has been suggested that inhibition of cytokine synthesis (especially that of TNF-α) may contribute to thalidomide's anti-angiogenic effect;2,112,164 however, there is some evidence from animal models that thalidomide's effect on angiogenesis is independent of the drug's effect on TNF-α and possibly may result from a direct inhibitory effect on some component of angiogenesis.112

Sedative and Hypnotic Effects !!navigator!!

Thalidomide has CNS depressant effects and causes sedation.4,112,232 The drug has a prompt sedative effect, and does not cause a hangover.4,232 The glutarimide ring contained in thalidomide appears to be responsible for the sedative and hypnotic effects of the drug; the ring is structurally similar to ring moieties contained in some other sedative and hypnotic drugs (e.g., glutethimide).4 Thalidomide may activate a sleep center in the forebrain, a mechanism of action unlike that of barbiturates.4 Thalidomide has little acute CNS toxicity, and does not cause incoordination or respiratory depression even at large doses.2,4,15 While thalidomide initially was investigated for use as a sedative and hypnotic in the late 1950s,2,3,4,5,15,52,53,54 the drug is no longer promoted for use as a sedative and hypnotic because of its teratogenic risk.2,3,4,5,15,16,53,54 (See Uses: Overview.)

Pharmacokinetics !!navigator!!

The pharmacokinetics of thalidomide have been studied in healthy adults,1,78,79,107 adults with leprosy,1 adults with human immunodeficiency virus (HIV) infection,1,51,176 and geriatric men with prostate cancer.96 While there is some evidence that bioavailability of oral thalidomide (i.e., peak plasma concentrations, area under the plasma concentration-time curve [AUC]) may be greater in leprosy patients than in healthy individuals,1 results of a single-dose study indicate that the pharmacokinetics of thalidomide in HIV-infected individuals are similar to those in healthy individuals.1 Age-related changes in the pharmacokinetics of thalidomide have not been observed in healthy individuals,1 leprosy patients 20-69 years of age,1 or prostate cancer patients 55-80 years of age.96 The pharmacokinetics of thalidomide have not been studied to date in individuals younger than 18 years of age.1 While limited data indicate that the pharmacokinetics of thalidomide are similar in males and females, specific comparative studies have not been performed to determine whether there are any gender- or race-related differences in the pharmacokinetics of the drug.1 The pharmacokinetics of thalidomide in patients with renal (except those with end-stage renal disease) or hepatic impairment have not been determined.1

Based on studies in healthy adults78,107 and HIV-infected patients,176 the pharmacokinetics of thalidomide can best be described by a single-compartment model with first-order absorption and elimination.78,107,112,176 Results of studies in healthy adults indicate that accumulation of thalidomide does not occur, and pharmacokinetic parameters are similar following single or multiple doses of the drug.1,78,79

Absorption

The absolute bioavailability of thalidomide administered as the commercially available racemic mixture of the drug has not been determined to date, in part because racemic thalidomide has poor aqueous solubility.1,2,232 The limited aqueous solubility of racemic thalidomide does not appear to be due to a lipophilic structure, since the drug has a relative distribution between lipid and aqueous phases of about 2:1.2 However, the 4 carboxyl groups of the racemic form of the drug appear to interact through hydrogen bonding to result in relative aqueous insolubility.2 In contrast, the pure levorotatory or dextrorotatory enantiomers of thalidomide are 3-5 times more soluble than the racemic drug and are more readily absorbed.2,106,108

Following oral administration of racemic thalidomide, the drug is slowly absorbed from the GI tract,1,5,51,96,107 and some interindividual variation in absorption has been reported.1,186 The relative bioavailability of thalidomide capsules compared with an oral polyethylene glycol (PEG) solution of the drug is 90%.1 When thalidomide is administered in increasing doses in healthy individuals, the extent of absorption (as measured by the AUC) increases proportionally with increasing dose; however, peak plasma concentrations of the drug increase in a less than proportional manner and the time to peak plasma concentrations is delayed, indicating that thalidomide's poor aqueous solubility affects the rate of oral absorption.1

Mean peak plasma concentrations of thalidomide generally are attained 2.5-5 hours after an oral dose.1,5,51,78,107,112,176 In a study in healthy men 21-43 years of age who received a single 200-mg dose of thalidomide given as tablets (not commercially available in the US), mean peak plasma concentrations of 1.15 mcg/mL were attained at a mean of 4.4 hours.107,112 In healthy women 21-45 years of age who received a single 200-mg dose of thalidomide given as 50- or 100-mg capsules (100-mg capsules not commercially available in the US), mean peak plasma concentrations of 2.3-3.2 mcg/mL were attained within about 6 hours.78,79 In healthy adults who received a single 50-, 200-, or 400-mg oral dose of thalidomide as 50-mg capsules, mean peak plasma concentrations of 0.62, 1.76, or 2.82 mcg/mL, respectively, were attained at 2.9, 3.5, or 4.3 hours, respectively, after the dose.1

In adults with leprosy who received a single 400-mg oral dose of thalidomide as 50-mg capsules, peak plasma concentrations of 3.44 mcg/mL were attained 5.7 hours after the dose.1

In adults with HIV infection (without active opportunistic infections or concomitant disease that potentially could alter drug absorption) who received a single 100- or 300-mg dose of thalidomide as capsules, mean peak plasma concentrations of the drug were 1.2 or 3.5 mcg/mL, respectively, and were attained at a mean of 3.4 hours after either dose.51 In another study in asymptomatic HIV-infected adults who received single 100- or 200-mg doses of the drug, peak plasma concentrations averaged 1.2 or 1.9 mcg/mL, respectively, and were attained at 2.5 or 3.3 hours, respectively.176

In men 55-80 years of age with prostate cancer who received a single 200- or 800-mg oral dose of thalidomide as 50-mg capsules, median peak plasma concentrations were 1.97 or 4.42 mcg/mL, respectively, and were attained at a median of 3.32 or 4.42 hours, respectively, after the dose.96 When these patients received multiple doses of thalidomide, mean peak plasma concentrations at steady state were 1.8 mcg/mL in those receiving 200 mg once daily and 7.57 mcg/mL in those receiving 800 mg daily.96

Distribution

Information on distribution of thalidomide in humans is not available.186 Although pharmacologic and adverse effects of thalidomide appear to be organ specific, such effects do not correspond well with pharmacokinetic distribution data obtained in animals.2 While results of some animal studies indicate that high concentrations of thalidomide are found in the GI tract, liver, and kidneys, and lower concentrations are found in muscle, brain, and adipose tissue,5 other distribution studies in animals have failed to detect substantial accumulation of the drug in any particular organ.2 When radiolabeled thalidomide was administered to animals in one study, there was an even distribution of radioactivity, except for slight enhancement of radioactivity in kidneys, liver, biliary tissue, white (but not grey) matter of the CNS, and peripheral nerve trunks.2 In rabbits, thalidomide concentrations in CSF are about 50% of concurrent plasma concentrations of the drug.2 Thalidomide is present in semen; in at least one study, the drug was detectable in the semen of HIV-infected men receiving thalidomide 100 mg daily.1

Thalidomide crosses the placenta in humans and in animals.1,2,5 Malformations of human fetuses exposed to thalidomide during the first trimester of pregnancy exhibit striking organ specificity.2,15 Fetal skeletal deformities involving the loss of part or all of one or more bones are most common,1,2,3,4,5,15,21 but fetal deformities may occur in almost any organ of the body15 and defects of internal organs accompany some skeletal deformities (e.g., amelia, phocomelia).4,5 Seemingly isolated neurodevelopmental regions (e.g., the eyes, ears, and possibly some brain stem neurons innervating facial muscles) are affected in cases of thalidomide embryopathy, but other neurodevelopmental defects rarely occur, and the skin and the lymphatic organs are notably not affected by fetal exposure to thalidomide.2,15 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

The apparent volume of distribution of thalidomide has been reported to be 69.9-82.7 L in HIV-infected adults.176

Results of an in vitro study indicate that the dextrorotatory and levorotatory enantiomers of thalidomide are 55 and 66%, respectively, bound to plasma proteins.1,108

Elimination

The mean elimination half-life of thalidomide following a single 200-mg oral dose ranges from 3-6.7 hours,78,79,96 and the elimination half-life appears to be similar following multiple doses of the drug.1,78,96 In a study in healthy adults who received a single 50- to 400-mg oral dose of the drug, the mean elimination half-life of thalidomide was 5.5-7.3 hours, respectively.1 The mean elimination half-life of thalidomide was 4.6-6.5 hours in HIV-infected adults who received a single 100- to 300-mg dose.51,176

Numerous metabolites may be formed as a result of optical enantiomerism and hydrolysis and hydroxylation of the drug.2,5,6,105,106,108,232 Commercially available thalidomide is a 1:1 racemic mixture of the dextrorotatory and levorotatory enantiomers of the drug,4,112 and chiral inversion and spontaneous hydrolysis of the enantiomers occurs in vivo or in vitro.4,105,106,107,108 The half-life for racemization of an enantiomer in whole blood is about 2.25 hours.2,5,6 In vivo, chiral inversion appears to occur principally in the circulation and in albumin-rich extravascular sites.108 Chiral inversion and hydrolysis of thalidomide apparently occur by several different mechanisms.108

Hepatic metabolism of thalidomide is limited,1,4 and only the parent compound appears to be metabolized by cytochrome P-450 (CYP) isoenzymes.4

The principal metabolic pathway of thalidomide appears to be nonenzymatic spontaneous hydrolysis.1,2,4,6,108,112,232,245 All 4 amide bonds in thalidomide are susceptible to hydrolytic cleavage and, under physiologic conditions, ring opening occurs first in the phthalimide moiety.2,4 Spontaneous hydrolysis to form more than 10 metabolites occurs rapidly in vitro, with a mean half-life (dependent on incubation temperature and pH) of 2-5 hours for both optical isomers.2,6 There is evidence that thalidomide metabolites formed by spontaneous hydrolysis in vitro have no immunomodulatory activity;2,92 however, further study is required to characterize the pharmacologic activity, if any, of metabolites formed in vivo.2,5

Hydroxylation can occur at 4 sites in thalidomide (i.e., 2 sites in each of the phthalimide and glutarimide moieties).2 Metabolism and some pharmacologic effects of thalidomide may be species specific.2,46 Hydroxylated metabolites have been identified in species sensitive to the teratogenic effects of thalidomide (e.g., rabbit),2,6 and there is evidence that rat (a species not sensitive to teratogenic effects of the drug) microsomes are not able to produce a metabolite that is toxic to lymphocytes in other species.6,46 Intermediary forms (i.e., arene oxides or epoxides) proposed to be responsible for the teratogenic effects of the drug have not been demonstrated, hydroxylated metabolites resulting from epoxide activation have not been confirmed in human samples, and in vitro human microsomal preparations do not appear to catalyze the formation of hydroxylated metabolites.2

Following administration of a radiolabeled dose of thalidomide, 91.9% of the dose is excreted in urine, mainly as hydrolytic metabolites;1 some of the drug may be eliminated in the bile.232 Although total body clearance of the drug is about 170-207 mL/minute,4,5 unmetabolized thalidomide has a renal clearance of 1.15-1.38 mL/minute1,5 and less than 3.5% of the drug is excreted in urine as unchanged drug.1,5

Advice to Patients

Additional Information

Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Because thalidomide is a known human teratogen and can cause severe, life-threatening birth defects if administered during pregnancy, distribution of thalidomide is restricted.1 (See REMS under Dosage and Administration.)

Thalidomide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Thalomid®

Bristol Myers Squibb

100 mg

Thalomid®

Bristol Myers Squibb

150 mg

Thalomid®

Bristol Myers Squibb

200 mg

Thalomid®

Bristol Myers Squibb

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions April 7, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References ⬆

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