THALOMID® (thalidomide) Capsules 50 mg, 100 mg, & 200mg

 

 

                                                            

 

 

DESCRIPTION

 

THALOMID^® (thalidomide), a-(N-phthalimido)glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C₁₃H₁₀N₂O₄ and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.

Chemical Structure of thalidomide         

 

 

                                                           

 

 

 

 

 

 

 

        

        

 

 

                                                                                                                                  Note: · = asymmetric carbon atom                                                     

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-a) 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-a in patients with ENL, ³ however, it has also been shown to increase plasma TNF-a 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.

 

 

 

	Table 1 Pharmacokinetic Parameter Values for THALOMID® (thalidomide) Mean (%CV)
	Population/ Single Dose		AUC0¥ µg·hr/mL			Cmax µg/mL	Tmax (hrs)	Half‑life (hrs)
	Healthy Subjects (n=14)
	50 mg			4.9 (16%)	0.62 (52%)		2.9 (66%)	5.52 (37%)
	200 mg			18.9 (17%)	1.76 (30%)		3.5 (57%)	5.53 (25%)
	400 mg			36.4 (26%)	2.82 (28%)		4.3 (37%)	7.29 (36%)
Patients with Hansen’s Disease  (n=6)
400 mg		46.4 (44.1%)			3.44 (52.6%)		5.7 (27%)	6.86 (17%)

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.

 

*In patients with cutaneous lesions

**Iyer: Complete response or lesions absent

**Sheskin: Complete improvement + “striking” improvement (i.e., >50% improvement)

Waters¹² 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.

Table 3 Double Blind, Controlled Trial of Thalidomide in Patients with ENL: Reduction in Steroid Dosage
Reference	Duration of	No. of Patients	Number Responding
	Treatment		Thalidomide	Placebo
Waters12	4 weeks	9	4/5	0/4
Lep Rev 1971;42:26	6 weeks (crossover)	8	8/8	1/8

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/mm³. 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/mm³ 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 log₁₀ 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- seropositive¹³ 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 are 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 child-bearing 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 care givers 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 the exposed area should be washed 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^Ò (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, pencillins, rifampin, rifabutin, phenytoin, or 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