Thalidomide

Trade Names:Thalomid- Capsules 50 mg- Capsules 100 mg- Capsules 200 mg

Pharmacology

Possesses immunomodulatory, anti-inflammatory, and antiangiogenic properties; mechanism of action not fully understood.

Pharmacokinetics

Absorption

T _max is 2.9 to 5.7 h. Coadministration with a high-fat meal causes minor (less than 10%) changes in AUC and C _max ; however, it causes an increase in T _max to approximately 6 h.

Metabolism

Not hepatically metabolized to any large extent but appears to undergo nonenzymatic hydrolysis in plasma to multiple metabolites.

Elimination

Half-life is 5 to 7 h. Renal Cl of 1.15 mL/min with less than 0.7% of the dose excreted in urine as unchanged drug.

Duration

Urinary levels were undetectable 48 h after dosing.

Indications and Usage

Acute treatment of cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL); maintenance therapy for prevention and suppression of cutaneous manifestations of ENL recurrence; treatment of newly diagnosed multiple myeloma in combination with dexamethasone.

Unlabeled Uses

Graft versus host disease after bone marrow transplantation; refractory multiple myeloma; primary brain tumors; appetite stimulant for cachexia in advanced cancer; aphthous ulcers; prostate cancer (in combination with docetaxel).

Contraindications

Pregnancy; women capable of becoming pregnant; hypersensitivity to any component of the product.

Dosage and Administration

PO Initial dose 100 to 300 mg per day, preferably 1 h after the evening meal. Give 400 mg per day at bedtime or in divided doses at least 1 h after meals to patients with severe cutaneous ENL reaction or to those who have previously required higher doses to control reaction.

Continue dosing until signs and symptoms have subsided, usually for at least 2 wk. Taper in 50 mg decrements every 2 to 4 wk. In patients requiring prolonged maintenance treatment to prevent recurrence or who flare during tapering, decrease medication every 3 to 6 mo in decrements of 50 mg every 2 to 4 wk.

PO 200 mg once daily, preferably at bedtime and at least 1 h after the evening meal. Dexamethasone 40 mg is administered on days 1 to 4, 9 to 12, and 17 to 20 every 28 days.

General Advice

• This product is only supplied to pharmacists registered with the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program.
• Take each dose with a full glass of water at least 1 h after meals. For single daily doses, take at bedtime at least 1 h after the evening meal.

Storage/Stability

Store capsules at 59° to 86°F. Protect from light.

Drug Interactions

The sedative effect of these drugs may be enhanced.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions are treatment-emergent signs and symptoms occurring in thalidomide-treated ENL and multiple myeloma patients. Percentages are listed for adverse reactions occurring in controlled clinical trials. Adverse reactions that do not contain percentages were collected from uncontrolled studies in ENL-treated patients, and the incidence rate cannot be determined. Adverse reactions listed as occurring during treatment of ENL involved thalidomide monotherapy while treatment of multiple myeloma involved coadministration of thalidomide plus dexamethasone.

Cardiovascular

Angina pectoris; arrhythmia; atrial fibrillation; bradycardia; cerebral ischemia; cerebrovascular accident; CHF; deep thrombophlebitis; heart arrest; heart failure; hypertension; hypotension; MI; murmur; orthostatic hypotension; palpitation; pericarditis; peripheral vascular disorder; tachycardia; thrombophlebitis; thrombosis; vasodilation; ECG abnormalities, sick sinus syndrome, syncope (postmarketing).

Thrombosis/embolism (22%); hypotension (16%); hypertension (11%).

CNS

Somnolence (38%); headache (12%); asthenia, malaise, vertigo (8%); dizziness, tremor (4%); abnormal gait; abnormal thinking; agitation; amnesia; anxiety; ataxia; causalgia; circumoral paresthesia; confusion; decreased libido; decreased reflexes; dementia; depression; dizziness; drowsiness; dysesthesia; dyskinesia; emotional lability; euphoria; hostility; hypalgesia; hyperesthesia; hyperkinesias; incoordination; insomnia; meningitis; nervousness; neuralgia; neuritis; neurologic disorder; neuropathy; paresthesia; peripheral neuritis; peripheral neuropathy; psychosis; tremor; disturbances in consciousness (including lethargy), hangover effect, loss of consciousness or stupor, mental status or mood changes (including depression and suicide attempts), migraine, seizures (including tonic-clonic seizures and status epilepticus) (postmarketing).

Fatigue (79%); sensory neuropathy (54%); confusion (28%); anxiety/agitation, tremor (26%); depression, insomnia, motor neuropathy (22%); dizziness/light-headedness (20%).

Dermatologic

Rash (21%); pruritus (8%); fungal dermatitis, maculopapular rash, nail disorder (4%); acne; alopecia; angioedema; benign skin neoplasm; dry skin; eczema; eczematous rash; exfoliative dermatitis; herpes simplex; ichthyosis; incomplete Stevens-Johnson syndrome; perifollicular thickening; psoriasis; seborrhea; skin discoloration; skin disorder; skin necrosis; sweating; urticaria; vesiculobullous rash; erythema multiforme, erythema nodosum, petechiae, purpura (postmarketing).

Rash/desquamation (30%); dry skin (21%).

EENT

Pharyngitis, rhinitis (4%); amblyopia; conjunctivitis; deafness; dry eyes; eye pain; lacrimation disorder; retinitis; taste perversion; tinnitus; diplopia, nystagmus (postmarketing).

GI

Abdominal pain, constipation, diarrhea, nausea, oral moniliasis, toothache (4%); anorexia; cholangitis; cholestatic jaundice; colitis; dry mouth; dyspepsia; dysphagia; enlarged abdomen; esophagitis; flatulence; gastroenteritis; GI disorder; GI hemorrhage; gum disorder; increased appetite; pancreatitis; parotid gland enlargement; periodontitis; stomatitis; tongue discoloration; tooth disorder; aphthous stomatitis, stomach ulcer (postmarketing).

Constipation (55%); anorexia, nausea (28%); diarrhea, vomiting (12%); dyspepsia (8%).

Genitourinary

Impotence (8%); acute renal failure; albuminuria; decreased CrCl; hematuria; orchitis; proteinuria; pyuria; urinary frequency; amenorrhea, enuresis, galactorrhea, gynecomastia, metrorrhagia, oliguria (postmarketing).

Creatinine increased (35%).

Hematologic

Abnormal RBC; aplastic anemia; decreased erythrocyte sedimentation rate; elevated mean cell volume; eosinophilia; granulocytopenia; hypochromic anemia; leukemia; leukocytosis; leukopenia; macrocytic anemia; megaloblastic anemia; microcytic anemia; myelogenous leukemia; neutropenia; thrombocytopenia; chronic myelogenous leukemia, erythroleukemia, pancytopenia, PT changes, WBC decrease (including neutropenia and febrile neutropenia) (postmarketing).

Decreased hemoglobin (78%); decreased leukocytes (35%); decreased neutrophils (31%); decreased platelets (24%).

Hepatic

Abnormal LFTs; enlarged liver; hepatitis; increased AST; bile duct obstruction (postmarketing).

Increased alkaline phosphatase (26%); increased AST (24%); increased bilirubin (14%).

Metabolic

Peripheral edema (4%); abnormal electrolytes; amyloidosis; avitaminosis; bilirubinemia; cyanosis; decreased phosphate; dehydration; diabetes; edema; facial edema; hyperlipidemia; inappropriate antidiuretic hormone; hypercholesteremia; hyperglycemia; hyperkalemia; hyperuricemia; hypocalcemia; hypoglycemia; hypomagnesemia; hypoproteinemia; increased alkaline phosphatase; increased BUN; increased LDH; increased lipase; increased serum creatinine; peripheral edema; hyponatremia, hypothyroidism, myxedema (postmarketing).

Hyperglycemia (72%); edema (57%); hypocalcemia (43%); hypokalemia, weight gain, weight loss (22%); hyperkalemia (19%).

Musculoskeletal

Back pain, neck pain, neck rigidity (4%); arthritis; bone tenderness; hypertonia; joint disorder; leg cramps; myalgia; myasthenia; periosteal disorder.

Muscle weakness (40%); bone pain (30%); myalgia (17%); arthralgia (13%).

Respiratory

Sinusitis (4%); apnea; bronchitis; cough; emphysema; epistaxis; lung disorder; lung edema; pulmonary embolus; pneumonia (including Pneumocystis carinii pneumonia); rales; rhinitis; upper respiratory tract infection; voice alteration; dyspnea, pleural effusion (postmarketing).

Dyspnea (42%); cough (15%).

Miscellaneous

Pain (8%); accidental injury, chills, facial edema (4%); AIDS; allergic reactions; altered thyroid hormone level; ascites; cellulitis; chest pain; cyst; decreased CD4 count; flu syndrome; hernia; HIV viral load increase; hypersensitivity; infection; lymphadenopathy; moniliasis; palpable spleen; photosensitivity; sarcoma; sepsis; teratogenicity; upper extremity pain; viral infection; carpal tunnel, dysesthesia, foot drop, lymphadenopathy, lymphopenia, nodular sclerosing Hodgkin disease (postmarketing).

Fever, pain (24%); infection (22%).

Precautions

Pregnancy

Category X. If pregnancy occurs, discontinue treatment immediately.

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 12 yr of age not established.

Hypersensitivity

Has been reported; signs and symptoms may include erythematous macular rash, possibly associated with fever, hypotension, and tachycardia.

Photosensitivity

May occur; avoid exposure to sunlight or ultraviolet light.

Females

Contraindicated in women of childbearing potential unless alternative therapies are inappropriate and patient meets the following conditions (ie, unable to become pregnant while on thalidomide): understands and can carry out instructions; is capable of complying with mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey described in the S.T.E.P.S. program; received both oral and written warning of hazards of taking thalidomide during pregnancy and of exposing fetus to drug; received oral and written warnings of risk of possible contraception failure and need to use 2 reliable forms of contraception simultaneously, unless continuous abstinence from reproductive heterosexual intercourse is chosen (sexually mature women who have not undergone hysterectomy or who have not been postmenopausal for at least 24 consecutive mo [who have had menses at some time in the preceding 24 consecutive mo] are considered to be of childbearing potential); acknowledges in writing understanding of these warnings and of need for using 2 reliable methods of contraception for 1 mo prior to starting thalidomide therapy, during therapy, and for 1 mo after stopping thalidomide; has had negative pregnancy test with sensitivity of 50 milliunits/mL or greater within 24 h of starting therapy; parent or legal guardian reads this material and agrees to ensure compliance with previous instructions for patients between 12 and 18 yr of age.

Males

Contraindicated in sexually mature males unless the following conditions are met: understands and can carry out instructions; is capable of complying with mandatory contraceptive measures appropriate for men, patient registration, and patient survey as described in S.T.E.P.S. program; received both oral and written warnings of risk of possible contraception failure and of need for barrier contraception (latex condom) in women of childbearing potential (even if he has undergone vasectomy); acknowledges in writing understanding of these warnings and the need for barrier contraception; parent or legal guardian reads this material and agrees to ensure compliance with the previous instructions for patients between 12 and 18 yr of age.

Dermatology

Serious and life-threatening dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur.

Drug abuse and dependence

Physical and psychological dependence not reported in patients taking thalidomide.

HIV patients

Plasma HIV RNA levels were found to increase.

Neutropenia

Decreased WBC, including neutropenia, has been reported. Treatment should not be initiated with an absolute neutrophil count (ANC) of less than 750/mm ³ . Monitor WBC and differential on an ongoing basis.

Peripheral neuritis

May cause permanent nerve damage. Not indicated as monotherapy for ENL treatment in presence of moderate to severe neuritis. Use drugs associated with peripheral neuropathy with caution.

Prescribers/Dispensers

May only be prescribed and dispensed by prescribers in the S.T.E.P.S. program.

Patient Information

• Carefully instruct patient about the potential teratogenicity of thalidomide and the precautions (eg, pregnancy tests, use of effective contraception in women, condom use in men) that must be taken to prevent fetal exposure according to the S.T.E.P.S. program and Boxed warnings.
• Caution patient that under no circumstances should this drug be shared with anyone and that even a single dose taken by a pregnant woman could cause severe birth defects.
• Advise patient not to donate blood while taking thalidomide. Advise men not to donate sperm while taking thalidomide.
• Instruct patient to take exactly as prescribed and not to change the dose or stop taking unless advised by health care provider.
• Instruct patient not to extensively handle or open thalidomide capsules and to maintain storage of capsules in blister packs until time to take dose. Advise patient that if there is accidental contact with a nonintact thalidomide capsule or the powder contents to wash the exposed area with soap and water.
• Advise patient to take each dose with a full glass of water at least 1 h after meals. Advise patient taking single daily dose to try to take at bedtime, at least 1 h after the evening meal.
• Advise patient that if medication needs to be discontinued, it will be slowly withdrawn over a period of several wk unless safety concerns (eg, rash) require a more rapid withdrawal.
• Caution patient that drug may cause drowsiness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise patient that medication can cause dizziness and orthostatic hypotension and to sit upright for a few min before standing up from a lying position.
• Instruct patient to stop using and immediately notify health care provider if numbness, tingling, or pain in the hands or feet; chest pain; shortness of breath; or arm or leg swelling occur.
• Advise patient that medication may cause photosensitivity (sensitivity to sunlight) and to avoid unnecessary exposure to sunlight or tanning lamps, and to use sunscreens and wear protective clothing to avoid photosensitivity reactions.
• Caution patient to avoid alcohol and other CNS depressants while taking this medication.

Copyright © 2009 Wolters Kluwer Health.