Brand name: Thalomid
Drug class: Immunomodulatory Agents
ATC class: L04AX02
VA class: IM900
Chemical name: (±)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione
Molecular formula: C₁₃H₁₀N₂O₄
CAS number: 50-35-1

Medically reviewed by Drugs.com on Apr 7, 2023. Written by ASHP.

Introduction

Biologic response modifier; has immunomodulatory, anti-inflammatory, antiangiogenic, and sedative and hypnotic activities.

Uses for Thalidomide

Erythema Nodosum Leprosum

Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL) reactions (lepra type 2 reactions); (designated an orphan drug by FDA for this use).

Suggested by some clinicians as drug of choice for treatment of moderate to severe ENL reactions, especially severe, recurrent reactions.

Maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence.

Designated an orphan drug by FDA for treatment and maintenance of reactional lepromatous leprosy.

Should not be used alone as monotherapy for treatment of ENL reactions complicated by neuritis.

Undertake therapy for leprosy in consultation with an expert.

Multiple Myeloma

Induction therapy (in combination with dexamethasone) in patients with newly diagnosed multiple myeloma (designated an orphan drug by FDA for this use).

Combination therapy with dexamethasone more effective than dexamethasone monotherapy in achieving response and prolonging time to progression in patients with newly diagnosed multiple myeloma. No significant difference in overall survival observed.

Use with bortezomib and dexamethasone^{† [off-label]} may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients (see Multiple Myeloma under Dosage and Administration); however, use of a modified bortezomib-thalidomide-dexamethasone^{† [off-label]} regimen using reduced thalidomide and bortezomib dosages is not fully established because of unclear risk/benefit and/or inadequate experience. Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.

Other Neoplastic Diseases

Has also been used for treatment of melanoma^{† [off-label]}, ovarian cancer^{† [off-label]}, myelodysplastic syndrome (MDS)^{† [off-label]}, advanced pancreatic cancer^†, primary brain tumors^† (designated an orphan drug by FDA for this use), androgen-independent prostate cancer^†, and renal carcinoma^†.

Inflammatory and/or Dermatologic Disorders

Has been used for treatment of a variety of severe, refractory (e.g., unresponsive to other appropriate agents [e.g., corticosteroids]), inflammatory and/or dermatologic disorders (e.g., erosive lichen planus^†, erythema multiforme^†, lupus erythematosus^†, prurigo nodularis^†, actinic prurigo^†, cutaneous Langerhans cell histiocytosis^†, uremic pruritus^†, porphyria cutanea tarda^†, and pyoderma gangrenosum^†). 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.

Has been used to treat dermatologic, mucocutaneous, and arthritic manifestations of Behçet syndrome^†. Some clinicians state that thalidomide and/or anti-tumor necrosis factor (anti-TNF; anti-TNF-α) monoclonal antibodies (e.g., infliximab, adalimumab) may be considered in select patients with Behçet syndrome with mucocutaneous involvement and in those with severe GI involvement (e.g., GI perforation, serious GI bleeding, obstruction).

HIV-associated Aphthous Ulcers

Has been used for treatment of HIV-associated aphthous ulcers^†. However, increases in HIV viral load reported. (See Effects on HIV Viral Load under Cautions.)

May be effective in patients with recurrent ulcers refractory to other therapies (e.g., corticosteroids). Recommended as alternative therapy; not a drug of first choice.

HIV-associated Wasting Syndrome

Has been used for treatment of HIV-associated wasting syndrome^† (designated an orphan drug by FDA for this use). However, increases in HIV viral load reported. (See Effects on HIV Viral Load under Cautions.)

HIV-associated Diarrhea

Has been used for treatment of HIV-associated diarrhea^†. However, increases in HIV viral load reported. (See Effects on HIV Viral Load under Cautions.)

AIDS-related Kaposi Sarcoma

Has been used for treatment of AIDS-related Kaposi sarcoma^† (designated an orphan drug by FDA for this use). However, increases in HIV viral load reported. (See Effects on HIV Viral Load under Cautions.)

Mycobacterium Infections

Has been used as an adjunct to anti-infective agents in treatment of mycobacterial infections^†, including Mycobacterium tuberculosis^† and M. avium complex^† (MAC) infections, in HIV-infected patients. However, increases in HIV viral load reported. (See Effects on HIV Viral Load under Cautions.)

Graft-versus-host Disease

Has been used for treatment of graft-versus-host disease^† (GVHD) in bone marrow transplant recipients (designated an orphan drug by FDA for this use).

Should not be used for prophylaxis of chronic GVHD.

Also has been used for the treatment of GVHD^† in adult peripheral blood stem cell transplant recipients.

Recurrent Aphthous Stomatitis

Has been used for treatment of severe aphthous oral ulcers^†.

Crohn Disease

Has been used for treatment of refractory Crohn disease^† (designated an orphan drug by FDA for this use).

Rheumatic Diseases

Has been used for treatment of refractory ankylosing spondylitis^† and refractory rheumatoid arthritis^†.

Sarcoidosis

Has been used for treatment of sarcoidosis^†.

Hereditary Hemorrhagic Telangiectasia

Has been used for the treatment of hereditary hemorrhagic telangiectasia^†.

Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin Changes (POEMS) Syndrome

Has been used for the treatment of polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome^†.

Related/similar drugs

Tecvayli, Revlimid, Darzalex, Velcade, Pomalyst, clofazimine, Kyprolis

Thalidomide Dosage and Administration

General

Pretreatment Screening

• Tests to exclude pregnancy must be performed within 10–14 days and again within 24 hours immediately prior to treatment initiation.

• Assess risk factors for thromboembolism.

• Do not initiate therapy in patients with ANC <750/mm³.

Patient Monitoring

• Pregnancy tests weekly during the first month of therapy, then every 2 or 4 weeks in females with irregular or regular menstrual cycles, respectively.

• Bradycardia and syncope periodically.

• Tumor lysis syndrome in patients with a high tumor burden.

• In patients with a history of seizures or other risk factors, closely monitor for clinical changes that could precipitate acute seizure activity.

• Routinely monitor leukocyte and differential counts, especially in those prone to neutropenia (e.g., HIV-infected patients).

Premedication and Prophylaxis

• Manufacturer states to consider thromboprophylaxis based on assessment of patient risk factors.

Thromboprophylaxis in Patients with Multiple Myeloma

• International Myeloma Working Group (IMWG) recommends thromboprophylaxis with aspirin for multiple myeloma patients receiving thalidomide with 1 or no underlying individual and/or myeloma-related risk factors for venous thromboembolism.

• IMWG recommends thromboprophylaxis with a low molecular weight heparin (LMWH) for those with 2 or more individual and/or myeloma-related risk factors.

• IMWG recommends thromboprophylaxis with a LMWH should be considered in thalidomide-treated patients receiving high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors.

• IMWG states that full-dose warfarin (international normalized ratio [INR] 2–3) is an alternative to LMWH; however, there is limited clinical experience with this approach.

• American Society of Clinical Oncology (ASCO) 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 an LMWH, while those at higher risk should receive an LMWH.

Dispensing and Administration Precautions

Handling and Disposal

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.

• Do not extensively handle or open drug capsules; maintain storage in blister packs until ingestion. Avoid contact of capsule content with skin of mucous membranes. If accidental skin or mucous contact with opened capsules or drug powder occurs, wash affected area with soap and water or rinse affected mucosa thoroughly with water.

• When treating patients receiving drug, use precautions (e.g., use of gloves, wash skin exposed to body fluids) to minimize exposure to patient’s body fluids.

REMS

• Distribution of thalidomide is restricted because of known, severe teratogenic effects. (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

• A special restricted distribution program, Thalomid REMS, for thalidomide was approved by FDA. The program requires registration of clinicians, pharmacies, and patients; all must agree to accept specific responsibilities (e.g., mandatory contraceptive measures, pregnancy testing) designed to minimize pregnancy exposures in order to prescribe, dispense, or use thalidomide.

• Thalomid REMS program ensures appropriately timed and properly documented pregnancy testing and counseling of patients before, during, and following thalidomide therapy.

• Prior to initiation of therapy, females must certify that they are not pregnant or not of reproductive potential (i.e., hysterectomy).

• To facilitate pregnancy testing and counseling in accordance with Thalomid REMS program, prescribe and dispense ≤28-day supply of drug. Refills require new prescription and another authorization from Thalomid REMS program; automatic refills not allowed.

• Registering pharmacist must agree to inform all staff pharmacists of dispensing procedures for drug. Before dispensing thalidomide, activate authorization number on every prescription by calling Bristol Myers Squibb Customer Care Center at 1-888-423-5436 and obtaining a confirmation number; write confirmation number on thalidomide prescription. In females of reproductive potential, verify that the prescription was written within 7 days from the date of the last pregnancy test and within 30 days for all other patients. Dispense blister packs containing drug intact (i.e., drug cannot be repackaged).

• For additional details on program requirements, contact Bristol Myers Squibb at 888-423-5436 or visit at [Web].

Administration

Oral Administration

Administer orally with water ≥1 hour after a meal.

Usually administer as a single daily dose, preferably at bedtime (to minimize sedative effects of drug) with water and ≥1 hour after evening meal.

May administer a high daily dosage (e.g., ≤400 mg daily) as a single dose at bedtime or, alternatively, in divided doses with water ≥1 hour after meals.

Prescribe and dispense no more than a 28-day supply at one time.

Dosage

Pediatric Patients

ENL

Oral

Children ≥12 years of age weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).

Children ≥12 years of age weighing ≥50 kg: Initially, 100–300 mg once daily. For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.

Continue therapy until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks). Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.

Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction. Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.

In patients with moderate to severe neuritis associated with severe ENL reactions receiving concomitant corticosteroid therapy, taper corticosteroid dosage and discontinue when neuritis has subsided.

Crohn Disease†

Oral

Children 2–18 years of age weighing <30 kg: 50 mg daily has been used.

Children 2–18 years of age weighing 30–60 kg: 100 mg daily has been used.

Children 2–18 years of age weighing >60 kg: 150 mg daily has been used.

Children 2–18 years of age: 2 mg/kg per day has been used.

Adults

ENL

Oral

Patients weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).

Patients weighing ≥50 kg: Initially, 100–300 mg once daily. For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.

Continue until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks). Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.

Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction. Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.

In patients with moderate to severe neuritis associated with severe ENL reactions receiving concomitant corticosteroid therapy, taper corticosteroid dosage and discontinue when neuritis has subsided.

Multiple Myeloma

Induction Therapy Prior to Stem-cell Transplantation in Newly Diagnosed Multiple Myeloma

Oral

Thalidomide and dexamethasone: Thalidomide 200 mg once daily combined with dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 of a 28-day cycle, with cycles repeated at 28-day intervals.

Thalidomide, bortezomib, and dexamethasone^†: Thalidomide 200 mg daily (after initial dosage escalation during cycle 1 with 100 mg on days 1–14 followed by 200 mg daily thereafter) along with bortezomib 1.3 mg/m² by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment cycles repeated every 21 days for 3 cycles.

Thalidomide, bortezomib, and dexamethasone^†: Thalidomide 200 mg daily (after initial dosage escalation during cycle 1 with 50 mg on days 1–14 followed by 100 mg on days 15–28) along with bortezomib 1.3 mg/m² by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1–4 and 9–12. Treatment cycles repeated every 4 weeks for 6 cycles.

Thalidomide, bortezomib, and dexamethasone^†: Thalidomide 100 mg daily along with bortezomib 1.3 mg/m² by sub-Q or IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) and dexamethasone 40 mg orally on days 1–4 and 9–12. Treatment cycles repeated every 3 weeks for 4 cycles.

Recurrent Aphthous Stomatitis†

Oral

100–300 mg daily for 1–6 weeks has been used. May be necessary to use higher dosages (e.g., 400–600 mg daily). Optimal duration of therapy unknown; may relapse following discontinuance of drug.

100 mg daily for 10 days, followed by 50 mg daily for 10 days, then 25 mg daily for 10 days also has been used.

Crohn Disease†

Oral

50–300 mg daily has been used.

Graft-versus-host Disease†

Oral

800 mg to 1.6 g daily for a median duration of 240 days has been used in a clinical trial.

Dosage Modification for Toxicity

If grade 3 or 4 adverse effects occur, temporarily interrupt therapy, reduce dosage, and/or permanently discontinue thalidomide. If constipation, somnolence, or peripheral neuropathy occurs, temporarily interrupt thalidomide therapy; consider dosage reduction upon resumption of therapy.

If angioedema, anaphylaxis, grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reaction (e.g., grade 4 rash, skin exfoliation, bullae) occurs, permanently discontinue thalidomide. (See Cutaneous Reactions and also Hypersensitivity Reactions under Cautions.)

Prescribing Limits

Pediatric Patients

ENL

Oral

Children ≥12 years of age weighing ≥50 kg: Maximum 400 mg daily.

Adults

ENL

Oral

Patients weighing ≥50 kg: Maximum 400 mg daily.

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage adjustment.

Renal Impairment

Manufacturer makes no specific dosage adjustment.

Experts state dosage modification for renal impairment is not necessary.

No dosage adjustment required in patients undergoing hemodialysis; clinicians should be aware of the risks of thalidomide-associated hyperkalemia in such patients.

Geriatric Patients

Manufacturer makes no specific dosage adjustment.

Cautions for Thalidomide

Contraindications

• Pregnant females. (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Females of reproductive potential and sexually mature males, unless they comply with all special conditions required by manufacturer and Thalomid REMS program.

• Known hypersensitivity (e.g., angioedema, anaphylaxis) to thalidomide or any ingredient in formulation. (See Hypersensitivity Reactions under Cautions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Extremely high risk of severe birth defects (possibly life-threatening) if pregnancy occurs while receiving thalidomide in any amount. (See Boxed Warning.)

Potential risks of birth defects from environmental exposure through cutaneous absorption or inhalation of drug powder by sexually mature females unknown. Birth defects reported only following oral ingestion of thalidomide.

Contraindicated in female patients who are or who may become pregnant.

Females of reproductive potential must use 2 forms of effective contraception ≥4 weeks prior to, throughout, and for ≥4 weeks following completion of therapy. Use a highly effective birth control method (intrauterine device [IUD]; hormonal contraceptives; tubal ligation; vasectomized partner) and effective barrier method (latex or synthetic condom, diaphragm, cervical cap). If either IUD or hormonal contraceptive use contraindicated, may use another highly effective method or 2 simultaneous effective barrier methods.

Efficacy of oral contraceptives may be reduced for up to one month after discontinuation of HIV protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or St. John’s wort; females requiring one or more of these drugs during thalidomide therapy must use 2 other effective methods of contraception or abstain from heterosexual sexual contact.

Thalidomide distributes into semen; risk to fetus from semen of male patients receiving thalidomide unknown. 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. 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.

Patients must not donate blood during and for ≥1 month after therapy because of potential for any thalidomide present in blood to be transfused into a pregnant woman.

Obtain 2 negative pregnancy test reports prior to initiating therapy in females of reproductive potential; tests to exclude pregnancy must be performed within 10–14 days and again within 24 hours immediately prior to treatment initiation. Repeat pregnancy tests weekly during the first month of therapy, then every 2 or 4 weeks in women with irregular or regular menstrual cycles, respectively.

Provide pregnancy testing and counseling if a patient misses a menstrual cycle or has abnormalities in menstrual bleeding. Discontinue drug during evaluation.

If pregnancy occurs, immediately discontinue treatment and apprise of potential fetal hazard. Refer patient to obstetrician-gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to FDA MedWatch Program at 800-FDA-1088 and to manufacturer at 888-423-5436.

Availability of information on emergency contraception at 888-423-4536.

Thromboembolic Events

Increased risk of venous and arterial thromboembolism (e.g., DVT, pulmonary embolism, MI, stroke) in patients with multiple myeloma, especially when used in combination with chemotherapy, including dexamethasone.

Monitor for signs and symptoms of thromboembolism (e.g., shortness of breath, chest pain, arm or leg swelling).

Carefully assess multiple myeloma patients receiving thalidomide for risk factors for thromboembolism; base decisions regarding use of thromboprophylaxis and appropriate thromboprophylaxis regimens (e.g., aspirin, anticoagulant) on patient’s risk.

International Myeloma Working Group (IMWG) recommends aspirin for thalidomide-treated multiple myeloma patients with ≤1 individual and/or myeloma-related risk factor and a low molecular weight heparin (LMWH) for those with ≥2 such risk factors. IMWG also recommends that thromboprophylaxis with an LMWH be considered in patients receiving thalidomide with high-dose dexamethasone, doxorubicin, or multiple antineoplastic agents, independent of additional risk factors. IMWG states full-dose warfarin (INR 2–3) is an alternative to LMWHs, but clinical experience is limited.

ASCO recommends pharmacologic thromboprophylaxis for multiple myeloma patients receiving thalidomide with dexamethasone or antineoplastic agents. Those at lower risk for thromboembolism may receive aspirin or an LMWH; those at higher risk should receive an LMWH.

DVT and pulmonary embolism also reported in patients with ENL.

Other Warnings and Precautions

Treatment-related Mortality

Increased mortality reported in patients with multiple myeloma receiving pembrolizumab in combination with a thalidomide analogue and dexamethasone.

Patients with multiple myeloma should not receive an anti-programmed death receptor-1 (anti-PD-1) or anti-programmed-death ligand-1 (anti-PD-L1) in combination with a thalidomide analogue and dexamethasone outside of a clinical trial.

Drowsiness and Somnolence

Drowsiness and somnolence reported in patients in patients receiving thalidomide.

Advise patients to avoid situations where mental alertness or physical coordination is required.

Avoid other medications that may cause drowsiness. (See CNS Agents under Drug Interactions.)

Peripheral Neuropathy

Potentially severe and irreversible nerve damage (i.e., polyneuritis or peripheral neuropathy); generally reported with chronic use, but has occurred with relatively short-term use and after discontinuance of therapy.

Correlation with cumulative thalidomide dose unclear.

Differentiation of neuropathologic symptoms caused by thalidomide and changes caused by underlying disease (i.e., ENL, HIV infection) may be difficult.

Evaluate patients for signs and symptoms of peripheral neuropathy (e.g., numbness, tingling, pain or a burning sensation in the hands and feet), and counsel and question patients regularly during therapy (i.e., monthly for first 3 months of thalidomide treatment, and periodically thereafter).

Consider using electrophysiologic testing, consisting of sensory nerve action potential (SNAP) amplitude measurement at baseline and every 6 months thereafter to detect asymptomatic neuropathy.

If manifestations of peripheral neuropathy develop, discontinue therapy immediately (if clinically appropriate) to minimize further damage. Usually, resume treatment only if manifestations of neuropathy return to baseline.

Use concomitantly with drugs known to be associated with peripheral neuropathy with caution. (See Specific Drugs under Interactions.)

Dizziness and Orthostatic Hypotension

Possible orthostatic hypotension and dizziness. (See Advice to Patients.)

Hematologic Effects

Decreased leukocyte counts, including neutropenia, reported. Do not initiate therapy in patients with ANC <750/mm³. Routinely monitor leukocyte and differential counts, especially in those prone to neutropenia (e.g., HIV-infected patients). If ANC decreases to <750/mm³, reevaluate drug regimen. If neutropenia persists, consider withholding drug if clinically appropriate.

Grade 3 or 4 thrombocytopenia reported. Monitor CBCs, including platelets, and interrupt therapy, reduce dosage, or discontinue therapy if thrombocytopenia occurs.

Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia during thalidomide therapy, 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.

Effects on HIV Viral Load

Increases in HIV viral load (i.e., plasma HIV-1 RNA concentrations) reported.

Measure plasma HIV-1 RNA concentrations in HIV-seropositive patients after first and third months of treatment and every 3 months thereafter.

Bradycardia

Bradycardia, possibly requiring medical intervention, reported; clinical importance and underlying etiology unknown.

Monitor for bradycardia and syncope. If bradycardia occurs, reduce dosage or discontinue therapy. Use concomitant medications that lower heart rate with caution.

Cutaneous Reactions

Severe, and potentially fatal, cases of cutaneous reactions (Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], and drug reaction with eosinophilia and systemic symptoms [DRESS]) reported.

If grade 2 or 3 skin rash occurs, consider withholding or discontinuing thalidomide. If grade 4 rash, exfoliative or bullous rash, or other severe cutaneous reactions (SJS, TEN, or DRESS) occur, permanently discontinue drug. (See Advice to Patients.)

Seizures

Seizures, including tonic-clonic (grand mal) seizures, reported, usually in patients with predisposing risk factors. Epileptogenic activity of thalidomide unknown.

Monitor patients with a history of seizures or other risk factors closely for clinical changes that could precipitate acute seizure activity.

Tumor Lysis Syndrome

Tumor lysis syndrome reported during postmarketing experience.

Monitor patients at risk of tumor lysis syndrome (e.g., high tumor burden at baseline), and institute appropriate precautions.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., erythematous macular rash associated with fever, tachycardia, hypotension) reported. Discontinue if signs and symptoms of hypersensitivity are severe. If therapy resumed and reaction recurs, permanently discontinue. Do not resume drug if angioedema or anaphylaxis occurs.

Specific Populations

Pregnancy

Contraindicated for use during pregnancy. (See REMS under Dosage and Administration and also see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Males or Reproductive Potential

May impair male fertility.

Lactation

Not known whether thalidomide is distributed into milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <12 years of age.

For information on risks associated with thalidomide in patients 12–18 years of age, see Boxed Warning.

Geriatric Use

Higher incidence of adverse effects (i.e., atrial fibrillation, constipation, fatigue, nausea, hypokalemia, thromboembolism, hyperglycemia, and asthenia) in patients ≥65 years of age.

Hepatic Impairment

Not studied in patients with hepatic impairment.

Renal Impairment

Exposure to thalidomide is not anticipated to be affected by renal impairment.

Common Adverse Effects

Multiple myeloma (≥20%): 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, thrombosis/embolism, weight gain, dizziness, dry skin.

ENL (≥10%): Somnolence, rash, headache.

Drug Interactions

Limited hepatic metabolism; does not inhibit or induce CYP isoenzymes in vitro. Not a substrate of CYP isoenzymes.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drug interactions unlikely.

CNS Agents

May enhance sedative effects of some drugs and somnolence caused by alcohol.

Drugs Associated with Bradycardia

Increased risk of bradycardia.

Drugs Associated with Peripheral Neuropathy

May potentiate peripheral neuropathy; use with caution.

Hormonal Contraceptives and Drugs that Interfere with Hormonal Contraceptives

Increased risk of thromboembolism in patients receiving estrogen-containing therapy; use estrogen-containing therapy with caution in patients with multiple myeloma receiving thalidomide in combination with dexamethasone.

Efficacy of oral contraceptives may be reduced for up to one month after discontinuation of HIV protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or St. John’s wort; females requiring one or more of these drugs during thalidomide therapy must use 2 other effective methods of contraception or abstain from heterosexual sexual contact.

Drugs Associated with an Increased Risk of Thromboembolism

Increased risk of thrombosis.

Specific Drugs

Thalidomide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not determined; racemic drug has poor aqueous solubility.

Slowly absorbed from GI tract; mean peak plasma concentrations generally attained 2–5 hours after oral dose.

Food

Food decreases rate but not does not substantially affect extent of absorption.

Special Populations

Pharmacokinetics similar in HIV-infected patients and in healthy individuals.

Pharmacokinetics not established in pediatric and adolescent patients (<18 years of age).

Bioavailability may be greater in patients with leprosy than in healthy individuals.

Distribution

Extent

Distributes into semen. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Crosses placenta in humans and animals, resulting in fetal malformations. (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Plasma Protein Binding

55 and 66% for R- and S-enantiomers, respectively.

Elimination

Metabolism

Principally, rapid nonenzymatic spontaneous hydrolysis in plasma. Insufficient evidence exists that formation of active metabolites required for thalidomide’s effects.

Hepatic metabolism limited.

Elimination Route

Predominantly renally excreted in urine as hydrolytic metabolites.

Half-life

Averages approximately 5–7 hours in healthy individuals.

Special Populations

In patients with severe renal impairment, accumulation of drug does not occur. Mean total clearance increased 2.5-fold in patients undergoing hemodialysis. (See Special Populations under Dosage and Administration.)

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C); protect from light.

Actions

• In patients with ENL, activates T cells and modulates production of cytokines TNF-α, interleukin-2 (IL-2), interleukin-12 (IL-12), and interferon-γ by T cells.

• Induces direct cytotoxic and immunomodulatory effects following ubiquitination and degradation of substrate proteins.

• Induces down-modulation of selected cell surface adhesion molecules involved in leukocyte migration, resulting in decreased dermal infiltrations of leukocytes (e.g., neutrophils) in ENL lesions.

• In multiple myeloma patients, inhibits TNF-α expression by bone marrow stromal cells, resulting in inhibition of growth of multiple myeloma cells. Enhances T cell activation, releasing cytokines IL-2 and interferon-γ. These cytokines activate natural killer cells causing lysis of multiple myeloma cells.

• Impairs angiogenesis in bone marrow by decreasing fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) production.

• Decreases production of selected cell surface adhesion molecules involved in binding multiple myeloma cells to bone marrow stromal cells.

• Suppresses production of prostaglandins by macrophages.

• Modulates interleukin-10 (IL-10) and IL-12 production by peripheral blood mononuclear cells and T cells.

• Inhibits angiogenesis; teratogenic effects may be related to such effects.

Advice to Patients

• Importance of comprehensive counseling on benefits and risks (e.g., severe, potentially life-threatening birth defects) of drug. (See Boxed Warning.)

• Importance of taking thalidomide only as prescribed, and in compliance with requirements of Thalomid REMS program. (See REMS under Dosage and Administration.)

• Importance of informing patients of Pregnancy Exposure Registry for females exposed to thalidomide during pregnancy.

• Importance of warning females of reproductive potential not to take drug if pregnant, breast-feeding, or able to get pregnant (e.g., not using required methods of birth control).

• Necessity of advising females of reproductive potential to avoid pregnancy by using mandatory contraceptive measures, unless abstinence from heterosexual contact is practiced. (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of immediately discontinuing therapy if pregnancy suspected.

• Importance of females of reproductive potential informing clinicians of pregnancy, suspected pregnancy, missed menstrual period, unusual menstrual bleeding, or cessation of using contraceptive measures.

• Importance of informing patient how to obtain information about emergency contraception (including information regarding clinicians who provide emergency contraceptive services). (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of informing sexually mature male patients (including those who have undergone a vasectomy) of necessity of using a latex or synthetic condom when engaging in sexual contact with a female of reproductive potential or a pregnant female. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Importance of male patients informing clinician of unprotected heterosexual sexual contact during therapy and first 4 weeks after drug discontinuance. Importance of male patients informing clinician of suspected pregnancy of their sexual partner.

• Importance of avoiding extensive handling or opening of drug capsules. Importance of maintaining storage of drug capsules in blister packs until ingestion.

• Importance of not donating blood or semen while receiving drug.

• Importance of swallowing capsules intact and not breaking, chewing, or opening capsules.

• Importance of keeping thalidomide out of reach of children and from females of reproductive potential, unless part of Thalomid REMS program.

• Importance of advising patients of risk of dizziness and orthostatic hypotension. Importance of sitting upright for a few minutes before standing up from reclining position.

• Risk of drowsiness and somnolence; importance of avoiding situations where such drowsiness could create a problem. Risk of impaired ability to perform tasks that require mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Importance of warning patients not to take any other drugs or alcohol that may cause drowsiness without consulting their clinician. (See Specific Drugs under Interactions.)

• Importance of immediately reporting initial symptoms (e.g., numbness, tingling, pain or a burning sensation in hands and feet) of peripheral neuropathy to clinician.

• Importance of contacting clinician if symptoms of thromboembolism (e.g., shortness of breath, chest pain, arm or leg swelling) develop.

• Risk of neutropenia and thrombocytopenia. Importance of regular monitoring of blood cell counts during thalidomide therapy.

• Risk of increased HIV viral load in HIV-seropositive patients and need for monitoring.

• Importance of informing clinician if symptoms of bradycardia occur.

• Importance of advising patients to seek medical care for signs and symptoms of severe skin reactions such as SJS, TEN, or DRESS.

• Importance of informing clinicians of any seizures.

• Importance of informing patients that some forms of contraception are contraindicated or increase the risk of adverse events in patients treated with thalidomide.

• Importance of advising patients to seek medical care for signs and symptoms of hypersensitivity.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription or OTC drugs and herbal supplements, as well as concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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. (See REMS under Dosage and Administration.)

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