Thalomid Capsules (Celgene)

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DESCRIPTION

THALOMID® (thalidomide), (alpha)-(N-phthalimido)glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C ₁₃ H ₁₀ N ₂ O ₄ and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.

Chemical Structure of thalidomide

Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25°C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID® (thalidomide) is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.

THALOMID® (thalidomide) is available in 50 mg, 100 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.

CLINICAL PHARMACOLOGY

Mechanism of Action

Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood.

Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-(alpha)) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. ^3-6 For example, administration of thalidomide has been reported to decrease circulating levels of TNF-(alpha) in patients with ENL, ³ however, it has also been shown to increase plasma TNF-(alpha) levels in HIV-seropositive patients. ⁷

Pharmacokinetics and Drug Metabolism

Absorption

The absolute bioavailability of thalidomide from THALOMID® (thalidomide) capsules has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen's disease, the mean time to peak plasma concentrations (T _max ) of THALOMID® (thalidomide) ranged from 2.9 to 5.7 hours indicating that THALOMID® (thalidomide) is slowly absorbed from the gastrointestinal tract. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (C _max ) increased in a less than proportional manner (see Table 1 below). This lack of C _max dose proportionality, coupled with the observed increase in T _max values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of THALOMID® (thalidomide) with a high fat meal causes minor (<10%) changes in the observed AUC and C _max values; however, it causes an increase in T _max to approximately 6 hours.

Distribution

In human blood plasma, the geometric mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and (-)-(S)-thalidomide. ⁸ In a pharmacokinetic study of thalidomide in HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide was detectable in the semen.

Metabolism

At the present time, the exact metabolic route and fate of thalidomide is not known in humans. Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. In a repeat dose study in which THALOMID® (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism.

Elimination

As indicated in Table 1 (above) the mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing. As noted in the metabolism subsection, the precise metabolic fate and route of elimination of thalidomide in humans is not known at this time. Thalidomide itself has a renal clearance of 1.15 mL/minute with less than 0.7% of the dose excreted in the urine as unchanged drug. Following a single dose, urinary levels of thalidomide were undetectable 48 hrs after dosing. Although thalidomide is thought to be hydrolyzed to a number of metabolites, ⁹ only a very small amount (0.02% of the administered dose) of 4-OH-thalidomide was identified in the urine of subjects 12 to 24 hours after dosing.

Pharmacokinetic Data in Special Populations

HIV-seropositive Subjects:    There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single dose administration of THALOMID® (thalidomide) capsules.

Patients with Hansen's Disease:    Analysis of data from a small study in Hansen's patients suggests that these patients, relative to healthy subjects, may have an increased bioavailability of THALOMID® (thalidomide). The increase is reflected both in an increased area under the curve and in increased peak plasma levels. The clinical significance of this increase is unknown.

Patients with Renal Insufficiency:    The pharmacokinetics of thalidomide in patients with renal dysfunction have not been determined.

Patients with Hepatic Disease:    The pharmacokinetics of thalidomide in patients with hepatic impairment have not been determined.

Age:    Analysis of the data from pharmacokinetic studies in healthy volunteers and patients with Hansen's disease ranging in age from 20 to 69 years does not reveal any age-related changes.

Pediatric:    No pharmacokinetic data are available in subjects below the age of 18 years.

Gender:    While a comparative trial of the effects of gender on thalidomide pharmacokinetics has not been conducted, examination of the data for thalidomide does not reveal any significant gender differences in pharmacokinetic parameter values.

Race:    Pharmacokinetic differences due to race have not been studied.

Clinical Studies

The primary data demonstrating the efficacy of thalidomide in the treatment of the cutaneous manifestations of moderate to severe ENL are derived from the published medical literature and from a retrospective study of 102 patients treated by the U.S. Public Health Service.

Two double-blind, randomized, controlled trials reported the dermatologic response to a 7-day course of 100 mg thalidomide (four times daily) or control. Dosage was lower for patients under 50 kg in weight.

Waters ¹² reported the results of two studies, both double-blind, randomized, placebo-controlled, crossover trials in a total of 10 hospitalized, steroid-dependent patients with chronic ENL treated with 100 mg thalidomide or placebo (three times daily). All patients also received dapsone. The primary endpoint was reduction in weekly steroid dosage.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective evaluation of 102 patients treated under the auspices of the U.S. Public Health Service. A subset of patients with ENL controlled on thalidomide demonstrated repeated relapse upon drug withdrawal and remission with reinstitution of therapy.

Twenty U.S. patients between the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg daily. Response rates and safety profiles were similar to that observed in the adult population.

Thirty-two other published studies containing over 1600 patients consistently report generally successful treatment of the cutaneous manifestations of moderate to severe ENL with thalidomide.

INDICATIONS AND USAGE

THALOMID® (thalidomide) is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID® (thalidomide) is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.

THALOMID® (thalidomide) is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

CONTRAINDICATIONS (See BOXED WARNINGS ).

Pregnancy: Category X

Due to its known human teratogenicity, even following a single dose, thalidomide is contraindicated in pregnant women and women capable of becoming pregnant. (See BOXED WARNINGS ). When there is no alternative treatment, women of childbearing potential may be treated with thalidomide provided adequate precautions are taken to avoid pregnancy. Women must commit either to abstain continuously from heterosexual sexual contact or to use two methods of reliable birth control, including at least one highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner's vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with thalidomide, during therapy with thalidomide, and continuing for 4 weeks following discontinuation of thalidomide therapy. If hormonal or IUD contraception is medically contraindicated (see also PRECAUTIONS: Drug Interactions ), two other effective or highly effective methods may be used.

Women of childbearing potential being treated with thalidomide should have a pregnancy test (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning thalidomide therapy and then weekly during the first 4 weeks of thalidomide therapy, then at 4 week intervals in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs during thalidomide treatment, thalidomide must be discontinued immediately. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. The risk to the fetus from the semen of male patients taking thalidomide is unknown.

THALOMID® (thalidomide) is contraindicated in patients who have demonstrated hypersensitivity to the drug and its components.

WARNINGS

(See BOXED WARNINGS ).

Birth defects:

Thalidomide can cause severe birth defects in humans. (See BOXED WARNINGS and CONTRAINDICATIONS ). Patients should be instructed to take thalidomide only as prescribed and not to share their thalidomide with anyone else. Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. The risk to the fetus from the semen of male patients taking thalidomide is unknown.

Drowsiness and Somnolence:

Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.

Peripheral Neuropathy:

Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common, potentially severe, side effect of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, reports following relatively short-term use also exist. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all. Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen's disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide.

Patients should be examined at monthly intervals for the first 3 months of thalidomide therapy to enable the clinician to detect early signs of neuropathy, which include numbness, tingling or pain in the hands and feet. Patients should be evaluated periodically thereafter during treatment. Patients should be regularly counseled, questioned, and evaluated for signs or symptoms of peripheral neuropathy. Consideration should be given to electrophysiological testing, consisting of measurement of sensory nerve action potential (SNAP) amplitudes at baseline and thereafter every 6 months in an effort to detect asymptomatic neuropathy. If symptoms of drug-induced neuropathy develop, thalidomide should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with thalidomide should only be reinitiated if the neuropathy returns to baseline status. Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide.

Thrombotic Events:

Thrombotic events have been reported in patients treated with THALOMID® (thalidomide). Patients with neoplastic and various inflammatory conditions being treated with THALOMID® (thalidomide) may have an increased incidence of pulmonary embolism, deep vein thrombophlebitis, thrombophlebitis, or thrombosis. It is not known if concomitant therapy with other medications, including anticancer agents, are a contributing factor.

Dizziness and Orthostatic Hypotension:

Patients should also be advised that thalidomide may cause dizziness and orthostatic hypotension and that, therefore, they should sit upright for a few minutes prior to standing up from a recumbent position.

Neutropenia:

Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of thalidomide. Treatment should not be initiated with an absolute neutrophil count (ANC) of <750/mm ³ . White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia, such as patients who are HIV-seropositive. If ANC decreases to below 750/mm ³ while on treatment, the patient's medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding thalidomide if clinically appropriate.

Increased HIV Viral Load:

In a randomized, placebo-controlled trial of thalidomide in an HIV-seropositive patient population, plasma HIV RNA levels were found to increase (median change = 0.42 log ₁₀ copies HIV RNA/mL, p = 0.04 compared to placebo). ⁷ A similar trend was observed in a second, unpublished study conducted in patients who were HIV-seropositive. ¹³ The clinical significance of this increase is unknown. Both studies were conducted prior to availability of highly active antiretroviral therapy. Until the clinical significance of this finding is further understood, in HIV-seropositive patients, viral load should be measured after the first and third months of treatment and every 3 months thereafter.

PRECAUTIONS

General:

The only type of thalidomide exposure known to result in drug-associated birth defects is as a result of direct oral ingestion of thalidomide. Currently no specific data are available regarding the cutaneous absorption or inhalation of thalidomide in women of childbearing potential and whether these exposures may result in any birth defects. Patients should be instructed to not extensively handle or open THALOMID® (thalidomide) Capsules and to maintain storage of capsules in blister packs until ingestion. If there is contact with non-intact thalidomide capsules or the powder contents, the exposed area should be washed with soap and water.

Thalidomide has been shown to be present in the serum and semen of patients receiving thalidomide. If healthcare providers or other caregivers are exposed to body fluids from patients receiving THALOMID® (thalidomide), appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to THALOMID® (thalidomide) or washing the exposed area with soap and water.

Hypersensitivity:

Hypersensitivity to THALOMID® (thalidomide) has been reported. Signs and symptoms have included the occurrence of erythematous macular rash, possibly associated with fever, tachycardia, and hypotension, and if severe, may necessitate interruption of therapy. If the reaction recurs when dosing is resumed, THALOMID® (thalidomide) should be discontinued.

Bradycardia:

Bradycardia in association with thalidomide use has been reported. Cases of bradycardia have been reported, some required medical interventions. The clinical significance and underlying etiology of the bradycardia noted in some thalidomide-treated patients are presently unknown.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis:

Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have been reported. THALOMID® (thalidomide) should be discontinued if a skin rash occurs and only resumed following appropriate clinical evaluation. If the rash is exfoliative, purpuric, or bullous or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of THALOMID® (thalidomide) should not be resumed.

Seizures:

Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of THALOMID® (thalidomide) in clinical practice. Because these events are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Most patients had disorders that may have predisposed them to seizure activity, and it is not currently known whether thalidomide has any epileptogenic influence. During therapy with thalidomide, patients with a history of seizures or with other risk factors for the development of seizures should be monitored closely for clinical changes that could precipitate acute seizure activity.

Information for Patients (See BOXED WARNINGS ) .

Patients should be instructed about the potential teratogenicity of thalidomide and the precautions that must be taken to preclude fetal exposure as per the S.T.E.P.S. ® program and boxed warnings in this package insert. Patients should be instructed to take thalidomide only as prescribed in compliance with all of the provisions of the S.T.E.P.S. ® Restricted Distribution Program.

Patients should be instructed to not extensively handle or open THALOMID® (thalidomide) Capsules and to maintain storage of capsules in blister packs until ingestion.

Patients should be instructed not to share medication with anyone else.

Patients should be instructed that thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Patients should be advised as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex machinery. Patients should be instructed that thalidomide may potentiate the somnolence caused by alcohol.

Patients should be instructed that thalidomide can cause peripheral neuropathies that may be initially signaled by numbness, tingling, or pain or a burning sensation in the feet or hands. Patients should be instructed to report such occurrences to their prescriber immediately.

Patients should also be instructed that thalidomide may cause dizziness and orthostatic hypotension and that, therefore, they should sit upright for a few minutes prior to standing up from a recumbent position.

Patients should be instructed that they are not permitted to donate blood while taking thalidomide. In addition, male patients should be instructed that they are not permitted to donate sperm while taking thalidomide.

Laboratory Tests

Pregnancy Testing:    (See BOXED WARNINGS ). Women of childbearing potential should have a pregnancy test performed (sensitivity of at least 50 mIU/mL). The test should be performed within the 24 hours prior to beginning thalidomide therapy and then weekly during the first 4 weeks of use, then at 4 week intervals in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in menstrual bleeding.

Neutropenia:    (See WARNINGS ) .

Increased HIV Viral Load:    (See WARNINGS ).

Drug Interactions

Thalidomide has been reported to enhance the sedative activity of barbiturates, alcohol, chlorpromazine, and reserpine.

Peripheral Neuropathy:    Medications known to be associated with peripheral neuropathy should be used with caution in patients receiving thalidomide.

Oral Contraceptives:    In 10 healthy women, the pharmacokinetic profiles of norethindrone and ethinyl estradiol following administration of a single dose containing 1.0 mg of norethindrone acetate and 75 µg of ethinyl estradiol were studied. The results were similar with and without coadministration of thalidomide 200 mg/day to steady-state levels.

Important Non-Thalidomide Drug Interactions

Drugs That Interfere with Hormonal Contraceptives:    Concomitant use of HIV-protease inhibitors, griseofulvin, modafinil, penicillins, rifampin, rifabutin, phenytoin, carbamazepine, or certain herbal supplements such as St. John's Wort with hormonal contraceptive agents may reduce the effectiveness of the contraception and up to one month after discontinuation of these concomitant therapies. Therefore, women requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception or abstain from heterosexual sexual contact while taking thalidomide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity tests have not been conducted using thalidomide. Thalidomide gave no evidence of mutagenic effects when assayed in in vitro bacterial ( Salmonella typhimurium and Escherichia coli; Ames mutagenicity test), in vitro mammalian (AS52 Chinese hamster ovary cells; AS52/XPRT mammalian cell forward gene mutation assay) and in vivo mammalian (CD-1 mice; in vivo micronucleus test) test systems.

Animal studies to characterize the effects of thalidomide on fertility have not been conducted.

Pregnancy

Pregnancy Category X    (See BOXED WARNING and CONTRAINDICATIONS ).

Because of the known human teratogenicity of thalidomide, thalidomide is contraindicated in women who are or may become pregnant and who are not using the two required types of birth control or who are not continually abstaining from heterosexual sexual contact. If thalidomide is taken during pregnancy, it can cause severe birth defects or death to an unborn baby. Thalidomide should never be used by women who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (50 mg, 100 mg, or a 200 mg)] taken by a pregnant woman can cause birth defects. If pregnancy does occur during treatment, the drug should be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to THALOMID® (thalidomide) must be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation.

Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential. The risk to the fetus from the semen of male patients taking thalidomide is unknown.

Animal studies to characterize the effects of thalidomide on late-stage pregnancy have not been conducted.

Use in Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

Geriatric Use

No systematic studies in geriatric patients have been conducted. Thalidomide has been used in clinical trials in patients up to 90 years of age. Adverse events in patients over the age of 65 years did not appear to differ in kind from those reported for younger individuals.

ADVERSE REACTIONS

The most serious toxicity associated with thalidomide is its documented human teratogenicity. (See BOXED WARNINGS and CONTRAINDICATIONS ). The risk of severe birth defects, primarily phocomelia or death to the fetus, is extremely high during the critical period of pregnancy. The critical period is estimated, depending on the source of information, to range from 35 to 50 days after the last menstrual period. The risk of other potentially severe birth defects outside this critical period is unknown, but may be significant. Based on present knowledge, thalidomide must not be used at any time during pregnancy.

Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex condom during any sexual contact with women of childbearing potential.

Thalidomide is associated with drowsiness/somnolence, peripheral neuropathy, dizziness/orthostatic hypotension, neutropenia, and HIV viral load increase. (See WARNINGS ).

Hypersensitivity to THALOMID® (thalidomide) and bradycardia in patients treated with thalidomide have been reported. (See PRECAUTIONS ) .

Somnolence, dizziness, and rash are the most commonly observed adverse events associated with the use of thalidomide. Thalidomide has been studied in controlled and uncontrolled clinical trials in patients with ENL and in people who are HIV-seropositive. In addition, thalidomide has been administered investigationally for more than 20 years in numerous indications. Adverse event profiles from these uses are summarized in the sections that follow.

Other Adverse Events

Due to the nature of the longitudinal data that form the basis of this product's safety evaluation, no determination has been made of the causal relationship between the reported adverse events listed below and thalidomide. These lists are of various adverse events noted by investigators in patients to whom they had administered thalidomide under various conditions. The use of thalidomide may not limit disease progression and/or death.

Incidence in Controlled Clinical Trials

Table 4 lists treatment-emergent signs and symptoms that occurred in THALOMID® (thalidomide)-treated patients in controlled clinical trials in ENL. Doses ranged from 50 to 300 mg/day. All adverse events were mild to moderate in severity, and none resulted in discontinuation. Table 4 also lists treatment-emergent adverse events that occurred in at least three of the THALOMID® (thalidomide)-treated HIV-seropositive patients who participated in an 8-week, placebo-controlled clinical trial. Events that were more frequent in the placebo-treated group are not included. (See WARNINGS , PRECAUTIONS , and Drug Interactions ).

Other Adverse Events Observed in ENL Patients

Thalidomide in doses up to 400 mg/day has been administered investigationally in the United States over a 19-year period in 1465 patients with ENL. The published literature describes the treatment of an additional 1678 patients. To provide a meaningful estimate of the proportion of the individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using a modified COSTART dictionary/terminology. These categories are used in the listing below. All reported events are included except those already listed in the previous table. Due to the fact that these data were collected from uncontrolled studies, the incidence rate cannot be determined. As mentioned previously, no causal relationship between thalidomide and these events can be conclusively determined at this time. These are reports of all adverse events noted by investigators in patients to whom they had administered thalidomide.

Body as a Whole:    Abdomen enlarged, fever, photosensitivity, upper extremity pain.

Cardiovascular System:    Bradycardia, hypertension, hypotension, peripheral vascular disorder, tachycardia, vasodilation.

Digestive System:    Anorexia, appetite increase/weight gain, dry mouth, dyspepsia, enlarged liver, eructation, flatulence, increased liver function tests, intestinal obstruction, vomiting.

Hemic and Lymphatic:    ESR decrease, eosinophilia, granulocytopenia, hypochromic anemia, leukemia, leukocytosis, leukopenia, MCV elevated, RBC abnormal, spleen palpable, thrombocytopenia.

Metabolic and Endocrine:    ADH inappropriate, amyloidosis, bilirubinemia, BUN increased, creatinine increased, cyanosis, diabetes, edema, electrolyte abnormalities, hyperglycemia, hyperkalemia, hyperuricemia, hypocalcemia, hypoproteinemia, LDH increased, phosphorus decreased, SGPT increased.

Muscular Skeletal:    Arthritis, bone tenderness, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, periosteal disorder.

Nervous System:    Abnormal thinking, agitation, amnesia, anxiety, causalgia, circumoral paresthesia, confusion, depression, euphoria, hyperesthesia, insomnia, nervousness, neuralgia, neuritis, neuropathy, paresthesia, peripheral neuritis, psychosis.

Respiratory System:    Cough, emphysema, epistaxis, pulmonary embolus, rales, upper respiratory infection, voice alteration.

Skin and Appendages:    Acne, alopecia, dry skin, eczematous rash, exfoliative dermatitis, ichthyosis, perifollicular thickening, skin necrosis, seborrhea, sweating, urticaria, vesiculobullous rash.

Special Senses:    Amblyopia, deafness, dry eye, eye pain, tinnitus.

Urogenital:    Decreased creatinine clearance, hematuria, orchitis, proteinuria, pyuria, urinary frequency.

Other Adverse Events Observed in HIV-seropositive Patients

In addition to controlled clinical trials, THALOMID® (thalidomide) has been used in uncontrolled studies in 145 patients. Less frequent adverse events that have been reported in these HIV-seropositive patients treated with THALOMID® (thalidomide) were grouped into a smaller number of standardized categories using modified COSTART dictionary/terminology and these categories are used in the listing below. Adverse events that have already been included in the tables and narrative above, or that are too general to be informative, are not listed.

Body as a Whole:    Ascites, AIDS, allergic reaction, cellulitis, chest pain, chills and fever, cyst, decreased CD4 count, facial edema, flu syndrome, hernia, thyroid hormone level altered, moniliasis, photosensitivity reaction, sarcoma, sepsis, viral infection.

Cardiovascular System:    Angina pectoris, arrhythmia, atrial fibrillation, bradycardia, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, heart arrest, heart failure, hypertension, hypotension, murmur, myocardial infarct, palpitation, pericarditis, peripheral vascular disorder, postural hypotension, syncope, tachycardia, thrombophlebitis, thrombosis.

Digestive System:    Cholangitis, cholestatic jaundice, colitis, dyspepsia, dysphagia, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gum disorder, hepatitis, pancreatitis, parotid gland enlargement, periodontitis, stomatitis, tongue discoloration, tooth disorder.

Hemic and Lymphatic:    Aplastic anemia, macrocytic anemia, megaloblastic anemia, microcytic anemia.

Metabolic and Endocrine:    Avitaminosis, bilirubinemia, dehydration, hypercholesteremia, hypoglycemia, increased alkaline phosphatase, increased lipase, increased serum creatinine, peripheral edema.

Muscular Skeletal:    Myalgia, myasthenia.

Nervous System:    Abnormal gait, ataxia, decreased libido, decreased reflexes, dementia, dysesthesia, dyskinesia, emotional lability, hostility, hypalgesia, hyperkinesia, incoordination, meningitis, neurologic disorder, tremor, vertigo.

Respiratory System:    Apnea, bronchitis, lung disorder, lung edema, pneumonia (including Pneumocystis carinii pneumonia), rhinitis.

Skin and Appendages:    Angioedema, benign skin neoplasm, eczema, herpes simplex, incomplete Stevens-Johnson syndrome, nail disorder, pruritus, psoriasis, skin discoloration, skin disorder.

Special Senses:    Conjunctivitis, eye disorder, lacrimation disorder, retinitis, taste perversion.

Other Adverse Events Observed in Post-Marketing Use

Cardiovascular System:    Cardiac arrhythmias including atrial fibrillation, bradycardia, tachycardia, sick sinus syndrome and EKG abnormalities.

Digestive System:    Intestinal perforation.

Metabolic and Endocrine:    Electrolyte imbalance, including hypercalcemia or hypocalcemia, hyperkalemia and hypokalemia, hyponatremia, hypothyroidism, and increased alkaline phosphatase, tumor lysis syndrome.

Nervous System:    Changes in mental status or mood including depression and suicide attempts, disturbances in consciousness including lethargy, syncope, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepicus.

Skin and Appendages:    Erythema multiforme.

Hemic and Lymphatic:    Decreased white blood cell counts including neutropenia and febrile neutropenia, changes in prothrombin time.

Respiratory System:    Pleural effusion.

Other Adverse Events in the Published Literature or Reported from Other Sources

The following additional events have been identified either in the published literature or from spontaneous reports from other sources: acute renal failure, amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin's disease, nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud's syndrome, stomach ulcer, and suicide attempt.

DRUG ABUSE AND DEPENDENCE

Physical and psychological dependence has not been reported in patients taking thalidomide. However, as with other tranquilizers/hypnotics, thalidomide too has been reported to create in patients habituation to its soporific effects.

OVERDOSAGE

There have been three cases of overdose reported, all attempted suicides. There have been no reported fatalities in doses of up to 14.4 grams, and all patients recovered without reported sequelae.

DOSAGE AND ADMINISTRATION

THALOMID® (thalidomide) MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE S.T.E.P.S. ® PROGRAM. THALOMID® (thalidomide) MAY ONLY BE PRESCRIBED BY PRESCRIBERS REGISTERED WITH THE S.T.E.P.S. ® PROGRAM AND MAY ONLY BE DISPENSED BY PHARMACISTS REGISTERED WITH THE S.T.E.P.S. ® PROGRAM.

Drug prescribing to women of childbearing potential should be contingent upon initial and continued confirmed negative results of pregnancy testing.

For an episode of cutaneous ENL, THALOMID® (thalidomide) dosing should be initiated at 100 to 300 mg/day, administered once daily with water, preferably at bedtime and at least 1 hour after the evening meal. Patients weighing less than 50 kilograms should be started at the low end of the dose range.

In patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction, THALOMID® (thalidomide) dosing may be initiated at higher doses up to 400 mg/day once daily at bedtime or in divided doses with water, at least 1 hour after meals.

In patients with moderate to severe neuritis associated with a severe ENL reaction, corticosteroids may be started concomitantly with THALOMID® (thalidomide). Steroid usage can be tapered and discontinued when the neuritis has ameliorated.

Dosing with THALOMID® (thalidomide) should usually continue until signs and symptoms of active reaction have subsided, usually a period of at least 2 weeks. Patients may then be tapered off medication in 50 mg decrements every 2 to 4 weeks.

Patients who have a documented history of requiring prolonged maintenance treatment to prevent the recurrence of cutaneous ENL or who flare during tapering, should be maintained on the minimum dose necessary to control the reaction. Tapering off medication should be attempted every 3 to 6 months, in decrements of 50 mg every 2 to 4 weeks.

HOW SUPPLIED

(THIS PRODUCT IS ONLY SUPPLIED TO PHARMACISTS REGISTERED WITH THE S.T.E.P.S. ® PROGRAM - See BOXED WARNINGS ).

THALOMID® (thalidomide) Capsules are supplied in the following dosages:

50 mg capsules [white opaque], imprinted "Celgene / 50 mg" with a "Do Not Get Pregnant" logo.

Individual blister packs of 28 capsules (NDC 59572-205-14).

Boxes of 280 containing 10 prescription packs of 28 capsules each (NDC 59572-205-94).

100 mg capsules [tan], imprinted "Celgene / 100 mg" with a "Do Not Get Pregnant" logo.

Individual blister packs of 28 capsules (NDC 59572-210-15).

Boxes of 140 containing 5 prescription packs of 28 capsules each (NDC 59572-210-95).

200 mg capsules [blue], imprinted "Celgene / 200 mg" with a "Do Not Get Pregnant" logo.

Individual blister packs of 28 capsules (NDC 59572-220-16).

Boxes of 84 containing 3 prescription packs of 28 capsules each (NDC 59572-220-96).

STORAGE AND DISPENSING

PHARMACISTS NOTE:

BEFORE DISPENSING THALOMID® (thalidomide), YOU MUST ACTIVATE THE AUTHORIZATION NUMBER ON EVERY PRESCRIPTION BY CALLING THE CELGENE CUSTOMER CARE CENTER AT 1-888-4-CELGENE (1-888-423-5436) AND OBTAINING A CONFIRMATION NUMBER. YOU MUST ALSO WRITE THE CONFIRMATION NUMBER ON THE PRESCRIPTION. YOU SHOULD ACCEPT A PRESCRIPTION ONLY IF IT HAS BEEN ISSUED WITHIN THE PREVIOUS 7 DAYS (TELEPHONE PRESCRIPTIONS ARE NOT PERMITTED); DISPENSE NO MORE THAN A 4-WEEK (28-DAY) SUPPLY. A NEW PRESCRIPTION IS REQUIRED FOR FURTHER DISPENSING. DISPENSE BLISTER PACKS INTACT (CAPSULES CANNOT BE REPACKAGED); DISPENSE SUBSEQUENT PRESCRIPTIONS ONLY IF FEWER THAN 7 DAYS OF THERAPY REMAIN ON THE PREVIOUS PRESCRIPTION; AND EDUCATE ALL STAFF PHARMACISTS ABOUT THE DISPENSING PROCEDURE FOR THALOMID® (thalidomide).

This drug must not be repackaged.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature].

Protect from light.

Rx only and only able to be prescribed and dispensed under the terms of the S.T.E.P.S. ® Restricted Distribution Program

Manufactured for Celgene Corporation

86 Morris Avenue

Summit, New Jersey 07901

1-(888) 423-5436

Important Information and Warnings for All Patients Taking THALOMID® (thalidomide)

REFERENCES

1. Manson JM. 1986. Teratogenicity. Cassarett and Doull's Toxicology: The Basic Science of Poisons. Third Edition. Pages 195-220. New York: MacMillan Publishing Co.
   
2. Smithels RW and Newman CG. 1992. J. Med. Genet. 29(10):716-723.
   
3. Sampaio EP, Kaplan G, Miranda A, et al. 1993. J. Infect. Dis. 168(2):408-414.
   
4. Sarno EN, Grau GE, Vieira LM, et al. 1991. Clin. Exp. Immunol. 84:103-108.
   
5. Sampaio EP, Moreira AL, Sarno EN, et al. 1992. J. Exp. Med. 175:1729-1737.
   
6. Nogueira AC, Neubert R, Helge H, et al. 1994. Life Sciences. 55(2):77-92.
   
7. Jacobson JM, Greenspan JS, Spritzler J, et al. 1997. New Eng. J. Med. 336(21):1487-1493
   
8. Eriksson T, Björkman S, Roth B, et al. 1998. Chirality. 10(3): 223-228.
   
9. Schumaker H, Smith RL, and Williams RT. 1965. Br. J. Pharmacol. 25:324-337.
   
10. Iyer CGS, Languillon J, Ramanujam K, et al. 1971. Bull. WHO. 45:719-732.
    
11. Sheskin J and Convit J. 1969. Intl. J. Leprosy. 37:135-146.
    
12. Waters MFR. 1971. Lepr. Rev. 42:26-42.
    
13. Unpublished data, on file at Celgene.

S.T.E.P.S. ® is a registered trademark of Celgene Corporation.

U.S. Pat. Nos. 6,045,501 & 6,315,720.

THALPI.009 02/05 CG

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