Thalomid
Thalidomide · Capsule · Oral
• If THALOMID is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. THALOMID should never be used by females who are pregnant or who could be pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects.
• Pregnancy must be excluded before start of treatment. Prevent pregnancy thereafter by the use of two reliable methods of contraception. ( 5.1 , 8.3 ) THALOMID is only available through a restricted distribution program, the THALOMID REMS ® program ( 5.2 ). VENOUS THROMBOEMBOLISM
• Significant increased risk of deep vein thrombosis (DVT) and pulmonary…
Uses
• THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). ( 1.1 )
• THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. ( 1.2 ) 1.1 Multiple Myeloma THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM) [see Clinical Studies (14.1) ] . 1.2 Erythema Nodosum Leprosum THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence [see Clinical Studies (14.2) ].
Dosage and administration
• MM: 200 mg orally once daily. The recommended dose of dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20 every 28 days. ( 2.2 )
• ENL: 100 to 300 mg/day for an episode of cutaneous ENL. Up to 400 mg/day for severe cutaneous ENL. ( 2.3 ) 2.1 Required Baseline Testing Drug prescribing to females of reproductive potential is contingent upon initial and continued negative results of pregnancy testing [see Warnings and Precautions (5.1 and 5.2) ] . THALOMID must only be administered in compliance with all of the terms outlined in the THALOMID REMS program. THALOMID may only be prescribed by prescribers certified with the THALOMID REMS program and may only be dispensed by pharmacists certified with the THALOMID REMS program. 2.2 Recommended Dosage for Multiple Myeloma The recommended dose of THALOMID in combination with dexamethasone is 200 mg once daily (in 28-day treatment cycles) orally with water, preferably at bedtime and at least 1 hour after the evening meal. The dose of dexamethasone is 40 mg daily administered orally on days 1-4, 9-12, and 17-20 every 28 days. 2.3 Recommended Dosage for Erythema Nodosum Leprosum The recommended dose of THALOMID for an episode of cutaneous ENL is 100 to 300 mg/day once daily orally with water, preferably at bedtime and at least 1 hour after the evening meal. Initiate dosing for patients weighing less than 50 kilograms at the low end of the dose range. Consider dosing in the higher dosage range for patients with a severe cutaneous ENL reaction, or in those who have previously required higher doses to control the reaction (possibly up to 400 mg/day) once daily at bedtime or in divided doses with water, at least 1 hour after meals. Consider concomitant use of corticosteroids in patients with moderate to severe neuritis associated with a severe ENL reaction. Steroid usage can be tapered and discontinued when the neuritis has ameliorated. Continue dosing with THALOMID 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. 2.4 Dosage Modifications for Adverse Reactions Interrupt THALOMID for constipation, somnolence, or peripheral neuropathy. Consider a reduced dose upon resumption of treatment. Consider dose reduction, delay, or discontinuation in patients who develop National Cancer Institute Common Toxicity Criteria (NCI CTC) Grade 3 or 4 adverse reactions and/or based on clinical judgment. Permanently discontinue THALOMID for angioedema, anaphylaxis, Grade 4 rash, skin exfoliation, bullae, or any other severe dermatologic reactions [see Warnings and Precautions (5.12 and 5.16) ] .
Dosage forms and strengths
Capsules:
• 50 mg white, printed with "BMS/50 mg" on the body and a "Do Not Get Pregnant" logo on the cap.
• 100 mg tan, printed with "BMS/100 mg" on the body and a "Do Not Get Pregnant" logo on the cap.
• 150 mg tan body printed with "BMS/150 mg" and blue cap printed with a "Do Not Get Pregnant" logo.
• 200 mg blue, printed with "BMS/200 mg" on the body and a "Do not Get Pregnant" logo on the cap. Capsules: 50 mg, 100 mg, 150 mg and 200 mg. ( 3 )
Contraindications
• Pregnancy ( Boxed Warning , 4.1 , 5.1 , 5.2 , 8.1 , 17 )
• Demonstrated hypersensitivity to the drug or its components ( 4.2 , 5.16 , 6.2 ) 4.1 Pregnancy THALOMID is contraindicated in females who are pregnant. THALOMID can cause fetal harm when administered to a pregnant female [see Boxed Warning , Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . THALOMID is a powerful human teratogen, inducing a high frequency of severe and life-threatening birth defects, even after a single dose [see Boxed Warning ] . Mortality at or shortly after birth has been reported in about 40% of infants. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy occurs during THALOMID treatment, the drug should be discontinued immediately. 4.2 Hypersensitivity THALOMID is contraindicated in patients who have demonstrated hypersensitivity to the drug or its components [see Warnings and Precautions (5.16) ].
Warnings and precautions
• Ischemic heart disease (including myocardial infarction) and stroke have been observed in patients treated with THALOMID in combination with dexamethasone. ( 5.3 )
• Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue. ( 5.4 )
• Drowsiness and Somnolence: Instruct patients to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness. ( 5.5 )
• Peripheral Neuropathy: Monitor patients for signs or symptoms of peripheral neuropathy during treatment. Discontinue THALOMID if symptoms of drug-induced peripheral neuropathy occur, if clinically appropriate. ( 5.6 )
• Dizziness and Orthostatic Hypotension: Advise patients to sit upright for a few minutes prior to standing up from a recumbent position. ( 5.7 )
• Neutropenia and Thrombocytopenia: Patients may require dose interruption and/or dose reduction. ( 5.8 , 5.9 )
• Increased HIV Viral Load: Measure viral load during treatment. ( 5.10 )
• Bradycardia: Monitor patients for bradycardia and possible syncope. Dose reduction or discontinuation may be required. ( 5.11 )
• Severe Cutaneous Reactions: Discontinue THALOMID for severe reactions. ( 5.12 )
• Seizures: Monitor patients with a history of seizures or other risk factors for acute seizure activity. ( 5.13 )
• Tumor Lysis Syndrome: Monitor patients at risk (e.g., those with high tumor burden prior to treatment) and take appropriate precautions. ( 5.14 )
• Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue THALOMID for angioedema and anaphylaxis. ( 5.16 ) 5.1 Embryo-Fetal Toxicity THALOMID is a powerful human teratogen that induces a high frequency of severe and life-threatening birth defects, even after a single dose. Mortality at or shortly after birth has been reported in about 40% of infants. When there is no satisfactory alternative treatment, females of reproductive potential may be treated with THALOMID provided adequate precautions are taken to avoid pregnancy. THALOMID is only available through the THALOMID REMS program [see Warnings and Precautions (5.2) ] . Oral ingestion is the only type of maternal THALOMID exposure known to result in drug-associated birth defects. There are no specific data available regarding the reproductive risks of cutaneous absorption or inhalation of THALOMID; however, females of reproductive potential should avoid contact with THALOMID Capsules. THALOMID Capsules should be stored in blister packs until ingestion. If there is contact with non-intact THALOMID capsules or the powder contents, the exposed area should be washed with soap and water. If healthcare providers or other care givers are exposed to body fluids from patients receiving THALOMID, the exposed area should be washed with soap and water. Appropriate precautions should be utilized, such as wearing gloves to prevent the potential cutaneous exposure to THALOMID. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning THALOMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of THALOMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing THALOMID therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations (8.3) ]. Males Thalidomide is present in the semen of patients receiving THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 4 weeks after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm [see Use in Specific Populations (8.3) ] . Blood Donation Patients must not donate blood during treatment with THALOMID and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to THALOMID. 5.2 THALOMID REMS Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1) ], THALOMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the THALOMID REMS program. Required components of the THALOMID REMS program include the following:
• Prescribers must be certified with the THALOMID REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] and males must comply with contraception requirements [see Use in Specific Populations (8.3) ].
• Pharmacies must be certified with the THALOMID REMS program, must only dispense to patients who are authorized to receive THALOMID and comply with REMS requirements. Further information about the THALOMID REMS program is available at www.thalomidrems.com or by telephone at 1-888-423-5436. 5.3 Venous and Arterial Thromboembolism The use of THALOMID in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism.
Side effects
The following clinically significant adverse reactions are described in detail in other labeling sections:
• Teratogenicity [see Boxed Warning , Warnings and Precautions (5.1 , 5.2) , and Patient Counseling Information (17) ]
• Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.3) , and Patient Counseling Information (17) ]
• Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions (5.4) ]
• Drowsiness and Somnolence [see Warnings and Precautions (5.5) ]
• Peripheral Neuropathy [see Warnings and Precautions (5.6) ]
• Dizziness and Orthostatic Hypotension [see Warnings and Precautions (5.7) ]
• Neutropenia [see Warnings and Precautions (5.8) ]
• Thrombocytopenia [see Warnings and Precautions (5.9) ]
• Increased HIV Viral Load [see Warnings and Precautions (5.10) ]
• Bradycardia [see Warnings and Precautions (5.11) ]
• Severe Cutaneous Reactions [see Warnings and Precautions (5.12) ]
• Seizures [see Warnings and Precautions (5.13) ]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.14) ]
• Hypersensitivity [see Warnings and Precautions (5.16) ]
• MM: The most common adverse reactions (≥ 20%) are fatigue, hypocalcemia, edema, constipation, neuropathy-sensory, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin. ( 6.1 )
• ENL: The most common adverse reactions (≥ 10%) are somnolence, rash, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS or embryo-fetal exposure: contact Bristol Myers Squibb at 1-800-721-5072 or 1-888-423-5436, respectively, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most patients taking THALOMID can be expected to experience adverse reactions. Adverse Reactions in Multiple Myeloma Controlled Clinical Trials The safety analyses were conducted in two controlled clinical studies (Study 1 and Study 2). The safety analysis in Study 1 was conducted on 204 patients who received treatment. Table 1 lists the most common adverse reactions (≥ 10%). The most frequently reported adverse reactions were fatigue, hypocalcemia, edema, constipation, sensory neuropathy, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin. Twenty-three percent of patients (47/204) discontinued due to adverse reactions; 30% (31/102) from the THALOMID/dexamethasone arm and 16% (16/102) from the dexamethasone alone arm. Table 1: Adverse Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 1 - Safety Population; N=204) Body System Adverse Reaction Thal + Dex* (N=102) Dex Alone* (N=102) All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) * Treatment-emergent adverse reactions reported in ≥10% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in the THALOMID/dexamethasone arm compared to the dexamethasone alone arm. Metabolic/Laboratory 97 (95) 33 (32) 96 (94) 30 (29) Hypocalcemia 73 (72) 11 (11) 60 (59) 5 (5) Neurology 92 (90) 30 (29) 76 (74) 18 (18) Neuropathy-sensory 55 (54) 4 (4) 28 (28) 1 (1) Confusion 29 (28) 9 (9) 12 (12) 3 (3) Anxiety/agitation 26 (26) 1 (1) 14 (14) 3 (3) Tremor 26 (26) 1 (1) 6 (6) 0 (0) Neuropathy-motor 22 (22) 8 (8) 16 (16) 5 (5) Dizziness/ lightheadedness 20 (20) 1 (1) 14 (14) 0 (0) Depressed level of consciousness 16 (16) 3 (3) 3 (3) 3 (3) Constitutional Symptoms 91 (89) 19 (19) 84 (82) 16 (16) Fatigue 81 (79) 17 (17) 72 (71) 13 (13) Fever 24 (24) 1 (1) 20 (20) 3 (3) Weight loss 23 (23) 1 (1) 21 (21) 2 (2) Weight gain 22 (22) 1 (1) 13 (13) 0 (0) Blood/Bone Marrow 88 (86) 29 (29) 96 (94) 19 (19) Leukocytes (decreased) 36 (35) 6 (6) 30 (29) 3 (3) Neutrophils (decreased) 32 (31) 10 (10) 24 (24) 10 (10) Gastrointestinal 83 (81) 22 (22) 70 (69) 8 (8) Constipation 56 (55) 8 (8) 29 (28) 1 (1) Anorexia 29 (28) 4 (4) 25 (24) 2 (2) Nausea 29 (28) 5 (5) 23 (22) 1 (1) Mouth dryness 12 (12) 1 (1) 6 (6) 0 (0) Cardiovascular 70 (69) 37 (36) 60 (59) 21 (21) Edema 58 (56) 6 (6) 47 (46) 4 (4) Thrombosis/embolism 23 (22) 21 (21) 5 (5) 5 (5) Pain 64 (63) 10 (10) 66 (65) 15 (15) Myalgia 17 (17) 0 (0) 14 (14) 1 (1) Arthralgia 13 (13) 0 (0) 10 (10) 2 (2) Pulmonary 52 (51) 19 (19) 51 (50) 20 (20) Dyspnea 43 (42) 13 (13) 32 (31) 15 (15) Dermatology/Skin 48 (47) 5 (5) 35 (34) 2 (2) Rash/desquamation 31 (30) 4 (4) 18 (18) 2 (2) Dry skin 21 (21) 0 (0) 11 (11) 0 (0) Hepatic 47 (46) 7 (7) 45 (44) 4 (4) Bilirubin 14 (14) 2 (2) 10 (10) 2 (2) Musculoskeletal 42 (41) 9 (9) 41 (40) 14 (14) Muscle weakness 41 (40) 6 (6) 38 (37) 13 (13) The safety analysis in Study 2 was conducted on 466 patients who received treatment. Table 2 lists the most common adverse reactions (≥10%) that were observed. Table 3 lists the most common Grade 3/4 adverse reactions (occurring at >2%) that were observed. The adverse reactions most often reported by patients treated with THALOMID/dexamethasone were constipation, peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with a frequency at least 2-fold higher in the THALOMID/dexamethasone group than in the placebo/dexamethasone group include constipation, tremor, deep vein thrombosis and peripheral sensory neuropathy. Twenty-six percent of patients (121/466) discontinued due to adverse reactions; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.
Drug interactions
• Use caution if other drugs which have sedative and hypnotic properties, slow cardiac conduction and/or cause peripheral neuropathy must be used. ( 7.1 , 7.2 , 7.3 )
• It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID. ( 5.15 , 7.4 )
• Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thromboembolism. ( 7.7 ) 7.1 Opioids, Antihistamines, Antipsychotics, Anti-anxiety Agents, or Other CNS Depressants (Including Alcohol) The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with THALOMID may cause an additive sedative effect and should be avoided. 7.2 Drugs which Cause Bradycardia The use of drugs which slow cardiac conduction concomitantly with THALOMID may cause an additive bradycardic effect and should be used with caution. Cardiovascular medications which may cause bradycardia include calcium channel blockers, beta blockers, alpha/beta-adrenergic blockers, and digoxin. Non-cardiac drugs that may cause bradycardia include H2 blockers (e.g., famotidine, cimetidine), lithium, tricyclic antidepressants and neuromuscular blockers (succinylcholine). In 16 healthy men, the pharmacokinetic profile of a single 0.5 mg digoxin dose was similar with and without the coadministration of THALOMID 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of THALOMID. The safety of long-term concomitant use of THALOMID and digoxin has not been evaluated. 7.3 Drugs which Cause Peripheral Neuropathy The use of drugs which cause peripheral neuropathy (e.g., bortezomib, amiodarone, cisplatin, docetaxel, paclitaxel, vincristine, disulfiram, phenytoin, metronidazole, alcohol) can cause an additive effect and should be used with caution. 7.4 Hormonal Contraceptives Hormonal contraceptives increase the risk of thromboembolism. It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID. 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 mcg of ethinyl estradiol were studied. The results were similar with and without coadministration of THALOMID 200 mg/day to steady-state levels. 7.5 Warfarin In 13 healthy men, the pharmacokinetic profile and international normalized ratio (INR) of prothrombin time for warfarin, following a single oral dose of 25 mg, were similar with and without the coadministration of THALOMID 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide. 7.6 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 up to one month after discontinuation of these concomitant therapies. Therefore, females requiring treatment with one or more of these drugs must use two OTHER effective or highly effective methods of contraception while taking THALOMID. 7.7 Concomitant Therapies that may Increase the Risk of Thromboembolism Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving THALOMID with dexamethasone [see Warnings and Precautions (5.3) ].
Use in specific populations
• Lactation: Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to THALOMID during pregnancy as well as female partners of male patients who are exposed to THALOMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1) ] , human and animal data (see Data ) , THALOMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning , Contraindications (4.1) , and Warnings and Precautions (5.1) ] . THALOMID is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Even a single dose taken by a pregnant woman can cause birth defects. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also the REMS Call Center at 1-888-423-5436. Thalidomide crossed the placenta after administration to pregnant hamsters (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal Data A pre- and postnatal reproductive toxicity study was conducted in pregnant female rabbits. Compound-related increased abortion incidences and elevated fetotoxicity were observed at the lowest oral dose level of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA) and all higher dose levels. Neonatal mortality was elevated at oral dose levels to the lactating female rabbits ≥150 mg/kg/day (approximately 7.5-fold the maximum human dose based upon BSA). No delay in postnatal development, including learning and memory functions, were noted at the oral dose level to the lactating female rabbits of 150 mg/kg/day (average thalidomide concentrations in milk ranged from 22 to 36 mcg per mL). In a study conducted in pregnant rabbits, thalidomide levels in fetal plasma were approximately 11% to 73% of the maternal C max . In a study conducted with 14 C-thalidomide (150 mg/kg orally) in pregnant hamsters, radioactivity was detected in the embryo, and the relative concentrations of radioactivity in the embryo and maternal plasma were about the same at 4, 12 and 24 hours after dosing. Based on the radioactivity data, thalidomide crossed the placental barrier, and the fetal levels of drug-related material were approximately similar to those of maternal levels. 8.2 Lactation Risk Summary There is no information regarding the presence of thalidomide in human milk, the effects of THALOMID on the breastfed child, or the effects of THALOMID on milk production. Thalidomide is excreted in the milk of lactating rabbits (see Data ) . Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from THALOMID, advise women not to breastfeed during treatment with THALOMID. Data Animal Data In lactating female rabbits at an oral dose of 150 mg/kg/day, the average thalidomide concentrations in milk ranged from 22 to 36 mcg per mL. In the study of lactating female rabbits, high concentrations of thalidomide (7741 – 71425 ng per mL) were noted in milk during four weeks of pre-weaning period. Milk concentrations were 1.16 - 2.11, 1.05 – 2.43, and 0.64 – 3.63 times that of plasma at 30, 150 and 500 mg/kg thalidomide doses, respectively; thalidomide, as a lipophilic compound, distributed into milk, with concentrations attained similar to or slightly higher than those of systemic concentrations. 8.3 Females and Males of Reproductive Potential Pregnancy Testing THALOMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1) ] . Verify the pregnancy status of females of reproductive potential prior to initiating THALOMID therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking THALOMID, during dose interruptions and for at least 4 weeks after completing therapy. Females of reproductive potential must have 2 negative pregnancy tests before initiating THALOMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing THALOMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks.
Pregnancy
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to THALOMID during pregnancy as well as female partners of male patients who are exposed to THALOMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and to the REMS Call Center at 1-888-423-5436. Risk Summary Based on the mechanism of action [see Clinical Pharmacology (12.1) ] , human and animal data (see Data ) , THALOMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [see Boxed Warning , Contraindications (4.1) , and Warnings and Precautions (5.1) ] . THALOMID is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Even a single dose taken by a pregnant woman can cause birth defects. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to THALOMID to the FDA via the MedWatch program at 1-800-FDA-1088 and also the REMS Call Center at 1-888-423-5436. Thalidomide crossed the placenta after administration to pregnant hamsters (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Data Animal Data A pre- and postnatal reproductive toxicity study was conducted in pregnant female rabbits. Compound-related increased abortion incidences and elevated fetotoxicity were observed at the lowest oral dose level of 30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA) and all higher dose levels. Neonatal mortality was elevated at oral dose levels to the lactating female rabbits ≥150 mg/kg/day (approximately 7.5-fold the maximum human dose based upon BSA). No delay in postnatal development, including learning and memory functions, were noted at the oral dose level to the lactating female rabbits of 150 mg/kg/day (average thalidomide concentrations in milk ranged from 22 to 36 mcg per mL). In a study conducted in pregnant rabbits, thalidomide levels in fetal plasma were approximately 11% to 73% of the maternal C max . In a study conducted with 14 C-thalidomide (150 mg/kg orally) in pregnant hamsters, radioactivity was detected in the embryo, and the relative concentrations of radioactivity in the embryo and maternal plasma were about the same at 4, 12 and 24 hours after dosing. Based on the radioactivity data, thalidomide crossed the placental barrier, and the fetal levels of drug-related material were approximately similar to those of maternal levels.
Pediatric use
8.4 Pediatric Use Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
Geriatric use
8.5 Geriatric Use One hundred and seventy-six (52%) of 336 patients treated with THALOMID in combination with dexamethasone were ≥65 of age while 50 (15%) were ≥75. Patients ≥65 years of age on Study 2 had higher incidences of atrial fibrillation, constipation, fatigue, nausea, hypokalemia, deep venous thrombosis, hyperglycemia, pulmonary embolism, and asthenia compared to patients <65.
Overdosage
There is no specific antidote for a THALOMID overdose. In the event of an overdose, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.
Description
11 DESCRIPTION THALOMID, α-(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 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 is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero. THALOMID is available in 50 mg, 100 mg, 150 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 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink. Chemical Structure
Mechanism of action
12.1 Mechanism of Action The mechanism of action of THALOMID is not fully understood. Cellular activities of thalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. THALOMID possesses immunomodulatory, anti-inflammatory and antiangiogenic properties. Available data from in vitro studies and 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-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients. Other anti-inflammatory and immunomodulatory properties of thalidomide may include suppression of macrophage involvement in prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12 production by peripheral blood mononuclear cells. Thalidomide treatment of multiple myeloma patients is accompanied by an increase in the number of circulating natural killer cells, and an increase in plasma levels of interleukin-2 and interferon-gamma (T cell-derived cytokines associated with cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human umbilical artery explant model in vitro . The cellular processes of angiogenesis inhibited by thalidomide may include the proliferation of endothelial cells.
How supplied
(THIS PRODUCT IS ONLY SUPPLIED TO PHARMACIES CERTIFIED IN THE THALOMID REMS PROGRAM - See BOXED WARNING ) 16.1 How Supplied 50 mg capsules [white opaque], imprinted "BMS/50 mg" with a "Do Not Get Pregnant" logo. Individual blister packs of 1 capsule (NDC 59572-205-17). Individual blister packs of 28 capsules (NDC 59572-205-14). 100 mg capsules [tan], imprinted "BMS/100 mg" with a "Do Not Get Pregnant" logo. Individual blister packs of 28 capsules (NDC 59572-210-15). 150 mg capsules [tan and blue], imprinted "BMS/150 mg" with a "Do Not Get Pregnant" logo. Individual blister packs of 28 capsules (NDC 59572-215-13). 200 mg capsules [blue], imprinted "BMS/200 mg" with a "Do Not Get Pregnant" logo. Individual blister packs of 28 capsules (NDC 59572-220-16). 16.2 Storage This drug must not be repackaged. Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30º C (59-86º F). [See USP Controlled Room Temperature]. Protect from light. 16.3 Handling and Disposal Care should be exercised in handling of THALOMID. THALOMID capsules should not be opened or crushed. If powder from THALOMID contacts the skin, wash the skin immediately and thoroughly with soap and water. If THALOMID contacts the mucous membranes, flush thoroughly with water. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published 1 . Rx only and only able to be prescribed and dispensed under the terms of the THALOMID REMS Restricted Distribution Program.
Storage
16.2 Storage This drug must not be repackaged. Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30º C (59-86º F). [See USP Controlled Room Temperature]. Protect from light.
Patient information
Advise the patient to read the FDA-approved Patient Labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that THALOMID is contraindicated in pregnancy and can cause serious birth defects or death to a developing baby [see Boxed Warning , Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ].
• Advise females of reproductive potential that they must avoid pregnancy while taking THALOMID and for at least 4 weeks after completing therapy.
• Initiate THALOMID treatment in females of reproductive potential only following a negative pregnancy test.
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception, including at least 1 highly effective form, simultaneously during THALOMID therapy, during therapy interruption and for 4 weeks after she has completely finished taking THALOMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner's vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
• Instruct patient to immediately stop taking THALOMID and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
• Advise patient that if her healthcare provider is not available, she should call the REMS Call Center at 1-888-423-5436 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ].
• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID and for up to 4 weeks after discontinuing THALOMID, even if they have undergone a successful vasectomy.
• Advise male patients taking THALOMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ].
• All patients must be instructed to not donate blood while taking THALOMID and for 4 weeks following discontinuation of THALOMID [see Warnings and Precautions (5.1) ]. THALOMID REMS Program Because of the risk of embryo-fetal toxicity, THALOMID is only available through a restricted program called the THALOMID REMS program [see Warnings and Precautions (5.2) ].
• Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive THALOMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.3) ] .
• THALOMID is available only from pharmacies that are certified in THALOMID REMS program. Provide patients with the telephone number and website for information on how to obtain the product. Pregnancy Exposure Registry Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to THALOMID during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436 [see Use in Specific Populations (8.1) ] . Venous and Arterial Thromboembolism Inform patients of the potential risk of developing venous thromboembolism (such as DVT and PE), ischemic heart disease (including myocardial infarction), and stroke, and discuss the need for appropriate prophylactic treatment [see Boxed Warning and Warnings and Precautions (5.3) ] . Drowsiness and Somnolence Inform patients of the risk of drowsiness and somnolence with the drug and to avoid situations where drowsiness or somnolence may be a problem and not to take other medications that may cause drowsiness or somnolence without adequate medical advice [see Warnings and Precautions (5.5) ] . Peripheral Neuropathy Inform patients of the risk of peripheral neuropathy and report the signs and symptoms associated with this event to their health care provider for further evaluation [see Warnings and Precautions (5.6) ] . Dizziness and Orthostatic Hypotension Inform patients of the risk of dizziness and orthostatic hypotension with the drug. Inform patients to sit upright for a few minutes prior to standing [see Warnings and Precautions (5.7) ]. Neutropenia Inform patients on the risk of developing neutropenia and the need to monitor their white blood cell count [see Warnings and Precautions (5.8) ]. Thrombocytopenia Inform patients of the risk of developing thrombocytopenia and the need to monitor their platelet count [see Warnings and Precautions (5.9) ] . Increased HIV Viral Load Inform HIV seropositive patients of the risk of increased viral load and the need to monitor viral load [see Warnings and Precautions (5.10) ]. Bradycardia Inform patients of the risk of bradycardia and report signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.11) ]. Severe Cutaneous Reactions Inform patients of the potential risk for severe skin reactions such as SJS, TEN and DRESS and report any signs and symptoms associated with these events to their healthcare provider for evaluation [see Warnings and Precautions (5.12) ]. Seizures Inform patients of the risk of seizures and report any seizure while taking THALOMID [see Warnings and Precautions (5.13) ]. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.14) ]. Contraceptive Risks Inform patients that some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID [see Warnings and Precautions (5.15) , Drug Interactions (7.4 , 7.7) ].
Label text from the FDA structured product label by Celgene Corporation (revised Mar 24, 2023). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Thalidomide in 4 products
Thalomid NDC products (4)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 59572-205 | Thalidomide 50 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-210 | Thalidomide 100 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-215 | Thalidomide 150 mg/1 Capsule | Celgene Corporation | NDA |
| 59572-220 | Thalidomide 200 mg/1 Capsule | Celgene Corporation | NDA |
Frequently asked questions
What is Thalomid used for?
• THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). ( 1.1 ) • THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID is…
What are the side effects of Thalomid?
The following clinically significant adverse reactions are described in detail in other labeling sections: • Teratogenicity [see Boxed Warning , Warnings and Precautions (5.1 , 5.2) , and Patient Counseling Information (17) ] • Venous and Arterial Thromboembolism [see Boxed Warning , Warnings and Precautions (5.3) , and Patient Counseling Information (17) ] • Increased Mortality in Patients with… See the full label for the complete list.
Who makes Thalomid?
Thalomid is listed by 1 labeler in the FDA NDC directory, including Celgene Corporation.