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Thalidomide

Pronunciation

Pronunciation

(tha LI doe mide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Thalomid: 50 mg, 100 mg

Thalomid: 150 mg, 200 mg [contains fd&c blue #2 (indigotine)]

Brand Names: U.S.

  • Thalomid

Pharmacologic Category

  • Angiogenesis Inhibitor
  • Antineoplastic Agent
  • Immunomodulator, Systemic

Pharmacology

Immunomodulatory and antiangiogenic characteristics; immunologic effects may vary based on conditions; may suppress excessive tumor necrosis factor-alpha production in patients with ENL, yet may increase plasma tumor necrosis factor-alpha levels in HIV-positive patients. In multiple myeloma, thalidomide is associated with an increase in natural killer cells and increased levels of interleukin-2 and interferon gamma. Other proposed mechanisms of action include suppression of angiogenesis, prevention of free-radical-mediated DNA damage, increased cell mediated cytotoxic effects, and altered expression of cellular adhesion molecules.

Absorption

Slow, good

Distribution

Vd: 1.1 L/kg

Metabolism

Minimal (unchanged drug is the predominant circulating component)

Excretion

Urine (92%; <4% of the dose as unchanged drug); feces (<2%)

Time to Peak

Plasma: ~2 to 5 hours

Half-Life Elimination

5.5 to 7.3 hours

Protein Binding

55% to 66%

Special Populations Note

Hansen disease:

Based on data from a small study, in relation to healthy subjects, patients with Hansen disease may have increased thalidomide bioavailability, manifested as increased area under the curve and peak plasma levels.

Use: Labeled Indications

US labeling:

Erythema nodosum leprosum: Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum; maintenance treatment for prevention and suppression of cutaneous manifestations of erythema nodosum leprosum recurrence

Limitation of use: Thalidomide is not indicated as monotherapy for erythema nodosum leprosum treatment in the presence of moderate to severe neuritis.

Multiple myeloma: Treatment of newly diagnosed multiple myeloma (in combination with dexamethasone)

Canadian labeling: Multiple myeloma: Treatment of patients ≥65 years of age with previously untreated multiple myeloma (in combination with melphalan and prednisone)

Use: Unlabeled

Treatment of chronic graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation; AIDS-related aphthous stomatitis; Waldenström macroglobulinemia; maintenance therapy of multiple myeloma (following autologous stem cell transplant); salvage therapy for multiple myeloma; systemic light chain amyloidosis

Contraindications

Hypersensitivity to thalidomide or any component of the formulation; pregnancy

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to lenalidomide or pomalidomide; both females at risk of becoming pregnant and male patients who are unable to follow or comply with conditions for use (refer to manufacturer labeling); breast-feeding

Dosing: Adult

Erythema nodosum leprosum, acute cutaneous: Oral: Initial: 100 to 300 mg once daily at bedtime, continue until signs/symptoms subside (usually ~2 weeks), then taper off in 50 mg decrements every 2 to 4 weeks. For severe cases with moderate to severe neuritis, corticosteroids may be initiated with thalidomide (taper off and discontinue corticosteroids when neuritis improves).

Patients weighing <50 kg: Initiate at lower end of the dosing range

Severe cutaneous reaction or patients previously requiring high doses: May be initiated at up to 400 mg once daily at bedtime or in divided doses

Erythema nodosum leprosum, maintenance (prevention/suppression, or with flares during tapering attempts): Oral: Maintain on the minimum dosage necessary to control the reaction; efforts to taper off should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.

Multiple myeloma, newly diagnosed: Oral:

US labeling: 200 mg once daily at bedtime (in combination with dexamethasone)

Canadian labeling: Adults ≥65 years: 200 mg once daily; maximum: 12 six-week cycles (in combination with melphalan and prednisone)

Multiple myeloma (off-label dosing):

In combination with bortezomib and dexamethasone (off-label combination): Induction therapy: 100 mg once daily for the first 14 days, then 200 mg once daily for 3 (21-day) cycles (Cavo, 2010) or 100 mg once daily for up to 8 (21-day) cycles (Kaufman, 2010)

In combination with melphalan and prednisone (off-label combination in US): 200 to 400 mg once daily (Facon, 2007) or 100 mg once daily (Palumbo, 2008)

Multiple myeloma, maintenance (following autologous stem cell transplant; off-label use): Oral: 200 mg once daily starting 3 to 6 months after transplant; continue until disease progression or unacceptable toxicity (Brinker, 2006) or 100 mg once daily starting 42 to 60 days following transplant; increase to 200 mg once daily after 2 weeks if tolerated; continue for up to 12 months (in combination with prednisolone) (Spencer, 2009)

Multiple myeloma, salvage therapy: Initial: 200 mg once daily at bedtime; may increase daily dose by 200 mg every 2 weeks for 6 weeks (if tolerated) to a maximum of 800 mg once daily at bedtime (Singhal, 1999) or 100 mg once daily (in combination with dexamethasone) (Palumbo, 2001) or 200 mg once daily (in combination with bortezomib and dexamethasone) for 1 year (Garderet, 2012) or 400 mg once daily at bedtime (in combination with dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) (Lee, 2003)

AIDS-related aphthous stomatitis (off-label use): Oral: 200 mg once daily at bedtime for up to 8 weeks, if no response, then 200 mg twice daily for 4 weeks (Jacobson, 1997)

Chronic graft-versus-host disease (refractory), treatment (off-label second-line use; optimum dose not determined): Oral: Initial: 100 mg once daily at bedtime, with dose escalation up to 400 mg daily in 3 to 4 divided doses (Wolff, 2010) or Initial: 50 to 100 mg 3 times daily; maximum dose: 600 to 1,200 mg daily (Kulkarni, 2003) or 200 mg 4 times daily (dose adjusted to goal thalidomide concentration of ≥5 mcg/mL 2 hours postdose) (Vogelsang, 1992) or 100 to 300 mg 4 times daily (Parker, 1995)

Systemic light chain amyloidosis (off-label use): Oral: 200 mg once daily (starting dose 50 to 100 mg once daily; titrate at 4-week intervals) in combination with cyclophosphamide and dexamethasone (Wechalekar, 2007)

Waldenström macroglobulinemia (off-label use): Oral: ≤200 mg once daily for up to 52 weeks (in combination with rituximab) (Treon, 2008)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Erythema nodosum leprosum, acute cutaneous: Children ≥12 years: Oral: Refer to adult dosing.

Erythema nodosum leprosum, maintenance (prevention/suppression, or with flares during tapering attempts): Children ≥12 years: Oral: Refer to adult dosing.

Chronic graft-versus-host disease (refractory), treatment (off-label second-line use; limited data): Children ≥3 years: Oral: 3 mg/kg 4 times daily (dose adjusted to goal thalidomide concentration of ≥5 mcg/mL 2 hours postdose) (Vogelsang 1992) or Initial: 3 to 6 mg/kg/day in 2 to 4 divided doses; target dose 12 mg/kg/day; Maximum daily dose: 800 mg (Rovelli, 1998)

Dosing: Renal Impairment

No dosage adjustment necessary for patients with renal impairment and on dialysis (per manufacturer). In a study of 6 patients with end-stage renal disease on dialysis, although clearance was increased by dialysis, a supplemental dose was not needed (Eriksson, 2003).

Multiple myeloma: An evaluation of 29 newly diagnosed myeloma patients with renal failure (serum creatinine ≥2 mg/dL) treated with thalidomide and dexamethasone (some also received cyclophosphamide) found that toxicities and efficacy were similar to patients with normal renal function (Seol, 2010). A study evaluating induction therapy with thalidomide and dexamethasone in 31 newly diagnosed myeloma patients with renal failure (CrCl <50 mL/minute), including 16 patients with severe renal impairment (CrCl <30 mL/minute) and 7 patients on chronic hemodialysis found that toxicities were similar to patients without renal impairment and that thalidomide and dexamethasone could be administered safely (Tosi, 2009).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). However, thalidomide does not appear to undergo significant hepatic metabolism.

Dosing: Adjustment for Toxicity

ANC ≤750/mm3: Withhold treatment if clinically appropriate

Grade 3 or 4 adverse reactions: Consider dose reduction, delay or discontinuation (based on clinical judgment).

Multiple myeloma:

US labeling: Constipation, oversedation, peripheral neuropathy: Temporarily withhold or continue with a reduced dose

Canadian labeling:

ANC <1,500/mm3: Withhold melphalan and prednisone for 1 week; resume melphalan and prednisone after 1 week if ANC >1,500/mm3 or if ANC 1,000 to 1,500/mm3 reduce melphalan dose by 50% or if ANC <1,000/mm3 adjust chemotherapy dose based on clinical status of patient.

Constipation, oversedation: Temporarily withhold thalidomide treatment or continue with a reduced dose

Peripheral neuropathy, Grade 1 (paresthesia, weakness and/or loss of reflexes) without loss of function): Evaluate patient and consider dose reduction with worsening of symptoms; symptom improvement may not follow dose reduction, however.

Peripheral neuropathy, Grade 2 (interferes with function but not with daily activities), Grade 3 (interferes with daily activities), or Grade 4 (disabling neuropathy): Discontinue thalidomide treatment

Thromboembolic events: Withhold therapy and initiate standard anticoagulant treatment; may resume thalidomide therapy at original dose following stabilization of patient and resolution of thromboembolic event; maintain anticoagulant treatment for duration of thalidomide therapy

Off-label dosage adjustment (Richardson, 2012): Peripheral neuropathy:

Grade 1: Reduce dose by 50%

Grade 2: Temporarily interrupt therapy; once resolved to ≤ grade 1, resume therapy with a 50% dosage reduction (if clinically appropriate)

Grade 3 or higher: Discontinue therapy

Extemporaneously Prepared

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). When manipulating capsules, NIOSH recommends double gloving, a protective gown, and preparation in a controlled device; if not prepared in a controlled device, respiratory and eye protection, as well as ventilated engineering controls, are recommended (NIOSH, 2014).

A 20 mg/mL oral suspension may be prepared with capsules and a 1:1 mixture of Ora-Sweet and Ora-Plus. Empty the contents of twelve 100 mg capsules into a glass mortar. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 60 mL; transfer to an amber calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label “shake well,” “protect from light,” and “refrigerate”. Stable for 35 days refrigerated.

Kraft S, Johnson CE, and Tyler RP, "Stability of an Extemporaneously Prepared Thalidomide Suspension," Am J Health Syst Pharm, 2011, 69(1):56-8.22180553

Administration

Oral: Swallow capsules whole with water. Do not open or crush capsules. Avoid extensive handling of capsules; capsules should remain in blister pack until ingestion.

US labeling: Administer orally, preferably at bedtime once daily, at least 1 hour after the evening meal. Doses >400 mg/day may be given in divided doses at least 1 hour after meals.

Canadian labeling: Administer orally as a single dose at the same time each day (preferably at bedtime to decrease somnolence); may be taken without regard to meals.

Missed doses: For missed doses, if <12 hours patient may receive dose; if >12 hours wait until next dose due.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). Wear gloves to prevent cutaneous exposure. If exposed to the powder content from broken capsules or body fluids from patients receiving thalidomide, the exposed area should be washed with soap and water. Although the manufacturer does not recommend opening the capsules, if it is necessary to manipulate the capsules (eg, to prepare an oral suspension), it is recommended to double glove, wear a protective gown, and prepare in a controlled device (NIOSH 2014).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light. Keep in original package.

Drug Interactions

Abatacept: Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Anakinra: Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased risk of serious infection during concomitant use has been reported. Avoid combination

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bisphosphonate Derivatives: Systemic Angiogenesis Inhibitors may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Canakinumab: Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab. Specifically, the risk for serious infections and/or neutropenia may be increased. Avoid combination

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Certolizumab Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

CNS Depressants: May enhance the CNS depressant effect of Thalidomide. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Contraceptives (Estrogens): May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Contraceptives (Progestins): May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dexamethasone (Systemic): May enhance the dermatologic adverse effect of Thalidomide. Dexamethasone (Systemic) may enhance the thrombogenic effect of Thalidomide. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Erythropoiesis-Stimulating Agents: May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Estrogen Derivatives: May enhance the thrombogenic effect of Thalidomide. Monitor therapy

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Metyrosine: CNS Depressants may enhance the sedative effect of Metyrosine. Monitor therapy

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Pamidronate: Thalidomide may enhance the nephrotoxic effect of Pamidronate. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Rilonacept: Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tocilizumab: May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

Tofacitinib: Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Vedolizumab: Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid combination

Zoledronic Acid: Thalidomide may enhance the adverse/toxic effect of Zoledronic Acid. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Edema (57%), thrombosis/embolism (23%; grade 3: 13%, grade 4: 9%), hypotension (16%)

Central nervous system: Fatigue (79%; grade 3: 14%, grade 4: 3%), somnolence (36% to 38%), dizziness (4% to 20%), sensory neuropathy (54%), confusion (28%), anxiety/agitation (9% to 26%), fever (19% to 23%), motor neuropathy (22%), headache (13% to 19%)

Dermatologic: Rash/desquamation (21% to 30%; grade 3: 4%), dry skin (21%), maculopapular rash (4% to 19%), acne (3% to 11%)

Endocrine & metabolic: Hypocalcemia (72%)

Gastrointestinal: Constipation (3% to 55%), nausea (4% to 28%), anorexia (3% to 28%), weight loss (23%), weight gain (22%), diarrhea (4% to 19%), oral moniliasis (4% to 11%)

Hematologic: Leukopenia (17% to 35%), neutropenia (31%), anemia (6% to 13%), lymphadenopathy (6% to 13%)

Hepatic: AST increased (3% to 25%), bilirubin increased (14%)

Neuromuscular & skeletal: Muscle weakness (40%), tremor (4% to 26%), weakness (6% to 22%), myalgia (17%), paresthesia (6% to 16%), arthralgia (13%)

Renal: Hematuria (11%)

Respiratory: Dyspnea (42%)

Miscellaneous: Diaphoresis (13%)

1% to 10%:

Cardiovascular: Peripheral edema (3% to 8%), facial edema (4%)

Central nervous system: Insomnia (9%), nervousness (3% to 9%), malaise (8%), vertigo (8%), pain (3% to 8%)

Dermatologic: Dermatitis (fungal 4% to 9%), pruritus (3% to 8%), nail disorder (3% to 4%)

Endocrine & metabolic: Hyperlipemia (6% to 9%)

Gastrointestinal: Xerostomia (8% to 9%), flatulence (8%), tooth pain (4%)

Genitourinary: Impotence (3% to 8%)

Hepatic: LFTs abnormal (9%)

Neuromuscular & skeletal: Neuropathy (8%), back pain (4% to 6%), neck pain (4%), neck rigidity (4%)

Renal: Albuminuria (3% to 8%)

Respiratory: Pharyngitis (4% to 8%), rhinitis (4%), sinusitis (3% to 8%)

Miscellaneous: Infection (6% to 8%)

Postmarketing and/or case reports (limited to important or life-threatening): Acute renal failure, alkaline phosphatase increased, ALT increased, amenorrhea, angioedema, aphthous stomatitis, arrhythmia, atrial fibrillation, bile duct obstruction, bradycardia, BUN increased, carpal tunnel, cerebral vascular accident, CML, creatinine clearance decreased, creatinine increased, deafness, depression, diplopia, dysesthesia, ECG abnormalities, enuresis, eosinophilia, epistaxis, erythema multiforme, erythema nodosum, erythroleukemia, exfoliative dermatitis, febrile neutropenia, foot drop, galactorrhea, granulocytopenia, gynecomastia, hearing loss, hepatomegaly, Hodgkin's disease, hypercalcemia, hyper-/hypokalemia, hypersensitivity, hypertension, hyper-/hypothyroidism, hypersensitivity, hyperuricemia, hypomagnesemia, hyponatremia, hypoproteinemia, intestinal obstruction, intestinal perforation, interstitial pneumonitis, LDH increased, lethargy, leukocytosis, loss of consciousness, lymphedema, lymphopenia, mental status changes, metrorrhagia, MI, myxedema, nystagmus, oliguria, orthostatic hypotension, pancytopenia, paresthesia, petechiae, peripheral neuritis, photosensitivity, pleural effusion, prothrombin time changes, psychosis, pulmonary embolus, pulmonary hypertension, purpura, Raynaud's syndrome, renal failure, secondary malignancy (AML, MDS, solid tumors), seizure, sepsis, septic shock, sexual dysfunction, sick sinus syndrome, status epilepticus, Stevens-Johnson syndrome, stomach ulcer, stupor, suicide attempt, syncope, tachycardia, thrombocytopenia, toxic epidermal necrolysis, transient ischemic attack, tumor lysis syndrome, urticaria

ALERT: U.S. Boxed Warning

Pregnancy:

If thalidomide is taken during pregnancy, it may cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking thalidomide. Even a single dose (1 capsule [regardless of strength]) taken by a pregnant woman during pregnancy may cause severe birth defects.

Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to thalidomide as negligible as possible, thalidomide is approved for marketing only through a special restricted distribution program: Thalomid REMS program, approved by the Food and Drug Administration (FDA). This program was formerly known as the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. program). Information about Thalomid and the Thalomid REMS program is available at https://www.celgeneriskmanagement.com or by calling the manufacturer's toll-free number 1-888-423-5436.

Thromboembolic events:

The use of thalidomide in multiple myeloma results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In 1 controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared with 4.9% in patients receiving dexamethasone alone (P = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients' underlying risk factors.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: May cause leukopenia and neutropenia; avoid initiating therapy if ANC <750/mm3. Persistent neutropenia may require treatment interruption. Thrombocytopenia (including grades 3 and 4) has been reported; may require dose reduction, treatment delay, or discontinuation. Monitor for signs and symptoms of bleeding (including petechiae, epistaxis, and gastrointestinal bleeding), especially if concomitant medication may increase the risk of bleeding. Monitor CBC with differential and platelets. Anemia has also been observed.

• Bradycardia: May cause bradycardia; use with caution when administering concomitantly with medications that may also decrease heart rate. May require thalidomide dose reduction or discontinuation.

• CNS effects: May cause dizziness, drowsiness, and/or somnolence; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving). Avoid ethanol and concomitant medications that may exacerbate these symptoms; dose reductions may be necessary for excessive drowsiness or somnolence.

• Constipation: Constipation may commonly occur. May require treatment interruption or dosage reduction.

• Dermatologic reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported (may be fatal); withhold therapy and evaluate if skin rash occurs; permanently discontinue if rash is exfoliative, purpuric, bullous or if SJS or TEN is suspected.

• Hepatotoxicity: Abnormal liver function tests have been reported. Hepatotoxicity (including some serious and fatal cases of hepatic injury) has been observed, mostly within the first 2 months of treatment (Thalomid Canadian labeling 2015); most events resolved without intervention after discontinuing thalidomide. Consider monitoring hepatic function periodically during therapy (particularly in patients with preexisting hepatic impairment or with concomitant use of hepatotoxic drugs).

• Hypersensitivity: Hypersensitivity, including erythematous macular rash, possibly associated with fever, tachycardia and hypotension has been reported. May require treatment interruption for severe reactions; discontinue if recurs with rechallenge.

• Orthostatic hypotension: May cause orthostatic hypotension; use with caution in patients who would not tolerate transient hypotensive episodes. When arising from a recumbent position, advise patients to sit upright for a few minutes prior to standing.

• Peripheral neuropathy: Thalidomide is commonly associated with peripheral neuropathy; may be irreversible. Neuropathy generally occurs following chronic use (over months), but may occur with short-term use; onset may be delayed. Use caution with other medications that may also cause peripheral neuropathy. Monitor for signs/symptoms of neuropathy monthly for the first 3 months of therapy and regularly thereafter. Electrophysiological testing may be considered at baseline and every 6 months to detect asymptomatic neuropathy. To limit further damage, immediately discontinue (if clinically appropriate) in patients who develop neuropathy. Reinitiate therapy only if neuropathy returns to baseline; may require dosage reduction or permanent discontinuation.

• Secondary malignancy: Increased incidence of second primary malignancies (SPMs), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), has been observed in previously untreated multiple myeloma patients receiving thalidomide in combination with melphalan, and prednisone. In addition to AML and MDS, solid tumors have been reported with thalidomide maintenance treatment for multiple myeloma (Usmani, 2012). Carefully evaluate patients for SPMs prior to and during treatment and manage as clinically indicated.

• Seizures: Seizures (including grand mal convulsions) have been reported in postmarketing data; monitor closely for clinical changes indicating potential seizure activity in patients with a history of seizures, concurrent therapy with drugs that alter seizure threshold, or conditions that predispose to seizures.

• Thromboembolic events: [US Boxed Warning]: Thalidomide use for the treatment of multiple myeloma is associated with an increased risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE); the risk is increased when used in combination with standard chemotherapy agents, including dexamethasone. In one controlled study, the incidence of VTE was 22.5% in patients receiving thalidomide in combination with dexamethasone, compared to 4.9% for dexamethasone alone. Monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling) and instruct patients to seek prompt medical attention with development of these symptoms. Consider thromboprophylaxis based on risk factors. . Ischemic heart disease, including MI and stroke, also occurred at a higher rate (compared to placebo) in myeloma patients receiving thalidomide plus dexamethasone who had not received prior treatment. Assess individual risk factors for thromboembolism and consider thromboprophylaxis. The American Society of Clinical Oncology guidelines for VTE prophylaxis and treatment recommend thromboprophylaxis for patients receiving thalidomide in combination with chemotherapy and/or dexamethasone; either aspirin or low molecular weight heparin (LMWH) are recommended for lower risk patient and LMWH is recommended for higher risk patients (Lyman, 2013). Anticoagulant prophylaxis should be individualized and selected based on the venous thromboembolism risk of the combination treatment regimen, using the safest and easiest to administer (Palumbo, 2008). The Canadian labeling recommends anticoagulant prophylaxis for at least the first 5 months of thalidomide-based therapy. Monitor for signs/symptoms of thromboembolism and advise patients to seek immediate care if symptoms (shortness of breath, chest pain, arm/leg swelling) develop. Other medications that are also associated with thromboembolism should be used with caution.

• Tumor lysis syndrome: Patients with a high tumor burden may be at risk for tumor lysis syndrome; monitor closely; institute appropriate management for hyperuricemia.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Certain adverse reactions (constipation, fatigue, weakness, nausea, hypokalemia, hyperglycemia, DVT, pulmonary embolism, atrial fibrillation) are more likely in elderly patients.

• HIV-infected patients: Thalidomide is associated with increased viral loads in studies conducted prior to the use of highly active antiretroviral therapy. Monitor viral load after the first and third months of therapy, and every 3 months thereafter.

• Pregnancy: [US Boxed Warning]: Thalidomide may cause severe birth defects or embryo-fetal death if taken during pregnancy. Thalidomide cannot be used in women who are pregnant or may become pregnant during therapy as even a single dose may cause severe birth defects. In order to decrease the risk of fetal exposure, thalidomide is available only through a special restricted distribution program (Thalomid REMS). Use is contraindicated in women who are or may become pregnant. Pregnancy must be excluded prior to therapy initiation with 2 negative pregnancy tests. Women of reproductive potential must avoid pregnancy 4 weeks prior to therapy, during therapy, during therapy interruptions, and for ≥4 weeks after therapy is discontinued; two reliable methods of birth control, or abstinence from heterosexual intercourse, must be used. Males taking thalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of childbearing potential and for up to 28 days following discontinuation of therapy. Males taking thalidomide must not donate sperm. Some forms of contraception may not be appropriate in certain patients. An intrauterine device (IUD) or implantable contraceptive may increase the risk of infection or bleeding; estrogen containing products may increase the risk of thromboembolism.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]). Avoid exposure to nonintact capsules and body fluids of patients receiving thalidomide. If exposure occurs, wash area with soap and water. Wear gloves to prevent cutaneous exposure.

Other warnings/precautions:

• Blood donation: Patients should not donate blood during thalidomide treatment and for 1 month after therapy discontinuation.

• REMS program: Due to the embryo-fetal risk, thalidomide is only available through a restricted program under the Thalomid REMS program. Prescribers and pharmacies must be certified with the program to prescribe or dispense thalidomide. Patients must sign an agreement and comply with the REMS program requirements.

Monitoring Parameters

CBC with differential, platelets; thyroid function tests (TSH at baseline then every 2 to 3 months during thalidomide treatment [Hamnvik 2011]). Hepatic function tests (periodic; particularly with preexisting hepatic dysfunction or concomitant use of drugs associated with hepatotoxicity). In HIV-seropositive patients: viral load after 1 and 3 months, then every 3 months. Pregnancy testing (sensitivity of at least 50 milliunits/mL) is required within 24 hours prior to initiation of therapy, weekly during the first 4 weeks, then every 4 weeks in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Signs of neuropathy monthly for the first 3 months, then periodically during treatment; consider monitoring of sensory nerve application potential amplitudes (at baseline and every 6 months) to detect asymptomatic neuropathy. Monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, arm/leg swelling), tumor lysis syndrome, bradycardia and syncope; monitor for clinical changes indicating potential seizure activity (in patients with a history of seizure).

Pregnancy Risk Factor

X

Pregnancy Considerations

[US Boxed Warning]: Thalidomide may cause severe birth defects or embryo-fetal death if taken during pregnancy. Thalidomide cannot be used in women who are pregnant or may become pregnant during therapy as even a single dose may cause severe birth defects. In order to decrease the risk of fetal exposure, thalidomide is available only through a special restricted distribution program (Thalomid REMS). Reproduction studies in animals and data from pregnant women have shown evidence of fetal abnormalities; use is contraindicated in women who are or may become pregnant. Anomalies observed in humans include amelia, phocomelia, bone defects, ear and eye abnormalities, facial palsy, congenital heart defects, urinary and genital tract malformations; mortality in ~40% of infants at or shortly after birth has also been reported.

Women of reproductive potential must avoid pregnancy 4 weeks prior to therapy, during therapy, during therapy interruptions, and for ≥4 weeks after therapy is discontinued. Two forms of effective contraception or total abstinence from heterosexual intercourse must be used by females who are not infertile or who have not had a hysterectomy. A negative pregnancy test (sensitivity of at least 50 milliunits/mL) 10 to 14 days prior to therapy, within 24 hours prior to beginning therapy, weekly during the first 4 weeks, and every 4 weeks (every 2 weeks for women with irregular menstrual cycles) thereafter is required for women of childbearing potential. Thalidomide must be immediately discontinued for a missed period, abnormal pregnancy test or abnormal menstrual bleeding; refer patient to a reproductive toxicity specialist if pregnancy occurs during treatment.

Females of reproductive potential (including health care workers and caregivers) must also avoid contact with thalidomide capsules.

Thalidomide is also present in the semen of males. Males (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of childbearing potential and for up to 28 days following discontinuation of therapy. Males taking thalidomide must not donate sperm.

The parent or legal guardian for patients between 12 to 18 years of age must agree to ensure compliance with the required guidelines.

If pregnancy occurs during treatment, thalidomide must be immediately discontinued and the patient referred to a reproductive toxicity specialist. Any suspected fetal exposure to thalidomide must be reported to the FDA via the MedWatch program (1-800-FDA-1088) and to Celgene Corporation (1-888-423-5436). In Canada, thalidomide is available only through a restricted-distribution program called RevAid (1-888-738-2431).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, headache, lack of appetite, nausea, edema, dry skin, fatigue, anxiety, tremors, weight gain or loss, or sexual dysfunction. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), angina, coughing up blood, shortness of breath, burning or numbness feeling, severe dizziness, passing out, tachycardia, bradycardia, loss of strength and energy, signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea, or lack of appetite; or feel sluggish), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of a heart attack (angina; pain in arms, back, neck, jaw, or stomach; shortness of breath; cold sweats; severe dizziness; passing out; severe nausea; or vomiting), or signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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