THALOMID Capsule Ref.[27595] Active ingredients: Thalidomide

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.celgeneriskmanagement.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. This risk increases significantly when THALOMID is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving THALOMID in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002).

Ischemic heart disease (11.1%), including myocardial infarction (1.3%), and stroke (cerebrovascular accident, 2.6%) have also occurred in patients with previously untreated MM treated with THALOMID and dexamethasone compared to placebo and dexamethasone (4.7%, 1.7%, and 0.9%, respectively) in one clinical trial [see Adverse Reactions (6.1)].

Consider thromboprophylaxis based on an assessment of individual patients' underlying risk factors. Patients and physicians should be observant for the signs and symptoms of thromboembolism. Advise patients to seek immediate medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling [see Boxed Warning]. Agents that also may increase the risk of thromboembolism should be used with caution in patients receiving THALOMID [see Drug Interactions (7.7)].

5.4 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

5.5 Drowsiness and Somnolence

THALOMID 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 [see Drug Interactions (7.1)]. Advise patients 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. Dose reductions may be required.

5.6 Peripheral Neuropathy

THALOMID is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (≥10%) and potentially severe adverse reaction of treatment with THALOMID that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, peripheral neuropathy following relatively short-term use has been reported. The correlation with cumulative dose is unclear. Symptoms may occur some time after THALOMID 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 THALOMID treatment. However, the inability clinically to differentiate THALOMID neuropathy from the neuropathy often seen in ENL makes it difficult to determine accurately the incidence of THALOMID-related neuropathy in patients with ENL treated with THALOMID.

Patients should be examined at monthly intervals for the first 3 months of THALOMID 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, THALOMID should be discontinued immediately to limit further damage, if clinically appropriate. Usually, treatment with THALOMID 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 THALOMID [see Drug Interactions (7.3)].

5.7 Dizziness and Orthostatic Hypotension

Patients should also be advised that THALOMID 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.

5.8 Neutropenia

Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of THALOMID. 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 THALOMID if clinically appropriate.

5.9 Thrombocytopenia

Thrombocytopenia, including Grade 3 or 4 occurrences, has been reported in association with the clinical use of THALOMID. Monitor blood counts, including platelet counts. Dose reduction, delay, or discontinuation may be required. Monitor for signs and symptoms of bleeding including petechiae, epistaxis, and gastrointestinal bleeding, especially if concomitant medication may increase the risk of bleeding.

5.10 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). A similar trend was observed in a second, unpublished study conducted in patients who were HIV-seropositive. 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.

5.11 Bradycardia

Bradycardia in association with THALOMID 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 THALOMID-treated patients are presently unknown. Monitor patients for bradycardia and syncope. Dose reduction or discontinuation may be required.

Medications known to decrease heart rate should be used with caution in patients receiving THALOMID [see Drug Interactions (7.2)].

5.12 Severe Cutaneous Reactions

Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with THALOMID use. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal. THALOMID interruption or discontinuation should be considered for Grade 2-3 skin rash. Discontinue THALOMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN, or DRESS, and do not resume therapy [see Dosage and Administration (2.4)].

5.13 Seizures

Although not reported from pre-marketing controlled clinical trials, seizures, including grand mal convulsions, have been reported during post-approval use of THALOMID 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 THALOMID has any epileptogenic influence. During therapy with THALOMID, 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.

5.14 Tumor Lysis Syndrome

Monitor patients at risk of tumor lysis syndrome (e.g., patients with high tumor burden prior to treatment) and take appropriate precautions.

5.15 Contraceptive Risks

Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with THALOMID. Because some patients may develop sudden, severe neutropenia and/or thrombocytopenia, use of an intrauterine device (IUD) or implantable contraception in these patients may carry an increased risk for infection or bleeding either at insertion, removal or during use. Treatment with THALOMID, the presence of an underlying malignancy, and/or use of an estrogen-containing contraceptive can each increase the risk of thromboembolism. It is not known if these risks of thromboembolism are additive. However, they should be taken into consideration when choosing contraceptive methods.

5.16 Hypersensitivity

Hypersensitivity, including angioedema and anaphylactic reactions to THALOMID 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 should be discontinued. Do not resume THALOMID treatment after angioedema and anaphylaxis [see Dosage and Administration (2.4)].

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)]

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):

^* 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.

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 ¾ 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.

Table 2. Adverse Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 2 – Safety Population; N=466):

NOS = not otherwise specified.
^* All adverse reactions reported in ≥10% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm.

Table 3. Grade ¾ Adverse Reactions Reported in >2% of Patients in the THALOMID/Dexamethasone Arm (Study 2 – Safety Population; N=466):

NOS = not otherwise specified.
^* All Grade ¾ adverse reactions with >2% of patients in THALOMID/dexamethasone arm and with a higher frequency in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm.

Less Common Adverse Reactions in Multiple Myeloma Controlled Clinical Trials

In Study 2, THALOMID in combination with dexamethasone in patients with multiple myeloma, the following adverse reactions not described above were reported¹:

Gastrointestinal disorders: Vomiting NOS, dry mouth, peritonitis, diverticular perforation

Nervous system disorders: Somnolence, hypoesthesia, polyneuropathy NOS, transient ischemic attack

Respiratory, thoracic, and mediastinal disorders: Bronchitis NOS

Psychiatric disorders: Mood alteration NOS

Vascular disorders: Hypotension NOS, orthostatic hypotension

Cardiac disorders: Bradycardia NOS

Eye disorders: Blurred vision

¹ All adverse reactions with ≥3% of patients in THALOMID/dexamethasone arm and with a ≥1% difference in proportion of patients between the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm. All grade ¾ and serious adverse reactions reported >2 patients in THALOMID/dexamethasone arm and with a percentage higher in the THALOMID/dexamethasone arm compared to the placebo/dexamethasone arm have been considered for possible inclusion. In any cases medical judgment has been applied for consideration of causality assessment.

Adverse Reactions in Erythema Nodosum Leprosum (ENL) Clinical Trials

Table 4 lists treatment-emergent signs and symptoms that occurred in THALOMID-treated patients in clinical trials in ENL. The most common adverse reactions (≥10%) reported in patients with ENL were somnolence, rash, headache. Doses ranged from 50 to 300 mg/day. All adverse reactions were mild to moderate in severity, and none resulted in discontinuation.

Table 4. Summary of Adverse Reactions (ARs) Reported in Celgene-sponsored Controlled Clinical Trials:

Other Adverse Reactions Observed in ENL Patients

THALOMID 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 reactions, 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. No causal relationship between THALOMID 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 THALOMID.

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

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.

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 Reactions Observed in HIV-seropositive Patients

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

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

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.

Metabolic and Endocrine: Avitaminosis, bilirubinemia, dehydration, hypercholesterolemia, 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.

The following additional adverse reactions have been identified during post approval use of THALOMID and are not already included in Clinical Trials Experience [see Adverse Reactions (6.1)]. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic: Decreased white blood cell counts including febrile neutropenia, changes in prothrombin time, pancytopenia, chronic myelogenous leukemia, nodular sclerosing Hodgkin’s disease, erythroleukemia, lymphedema, lymphopenia.

Body as a Whole: Hangover effect

Cardiovascular System: Sick sinus syndrome, EKG abnormalities, pulmonary hypertension.

Digestive System: Intestinal perforation, gastrointestinal perforations, bile duct obstruction, stomach ulcer, aphthous, stomatitis.

Ear and Labyrinthine Disorders: Hearing impairment.

Immune System Disorders: Hypersensitivity including anaphylaxis, solid organ transplant rejection.

Infections and infestations: Severe infections (e.g., fatal sepsis including septic shock), viral infections (including varicella zoster virus, cytomegalovirus, and hepatitis B virus reactivation) and progressive multifocal leukoencephalopathy (PML).

Metabolic and Endocrine: Electrolyte imbalance including hypercalcemia, hyponatremia and hypomagnesemia, hypothyroidism, increased alkaline phosphatase, tumor lysis syndrome, myxedema.

Nervous System: Changes in mental status or mood including suicide attempts, disturbances in consciousness including lethargy, loss of consciousness or stupor, seizures including grand mal convulsions and status epilepticus, Parkinson’s disease, stroke, carpal tunnel, Raynaud’s syndrome, migraine, foot drop.

Renal and Urinary Disorders: Renal failure, acute renal failure, oliguria, enuresis.

Reproductive System and Breast Disorders: amenorrhea, sexual dysfunction, galactorrhea, gynecomastia, metrorrhagia.

Respiratory System: Pleural effusion, interstitial lung disease.

Skin and Appendages: Erythema multiforme, erythema nodosum, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), purpura, petechiae.

Special Senses: Diplopia, nystagmus

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)].

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 Celgene Corporation 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 to Celgene Corporation 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 ¹⁴C-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.

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.

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 testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. THALOMID treatment must be discontinued during this evaluation.

Contraception

Females

Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with THALOMID, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of THALOMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed.

Males

Thalidomide is present in the semen of males who take THALOMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking THALOMID, during dose interruptions and for up to 28 days after discontinuing THALOMID, even if they have undergone a successful vasectomy. Male patients taking THALOMID must not donate sperm.

Infertility

Based on findings in animals, male fertility may be compromised by treatment with THALOMID [see Nonclinical Toxicology (13.1)].

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

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.

Physical and psychological dependence has not been reported in patients taking THALOMID; however, as with other tranquilizers/hypnotics, thalidomide has been reported to result in habituation to its soporific effects.