Thalomid

Before taking thalidomide,

• tell your doctor and pharmacist if you are allergic to thalidomide or any other medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: antidepressants; barbiturates such as pentobarbital (Nembutal), phenobarbital, and secobarbital (Seconal); chlorpromazine; didanosine (Videx); medications for anxiety, mental illness, or seizures; certain chemotherapy medications for cancer such as cisplatin (Platinol), paclitaxel (Abraxane, Taxol), and vincristine;reserpine (Serpalan); sedatives; sleeping pills; and tranquilizers. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), a low level of white blood cells in your blood, or seizures.
• tell your doctor if you are breast-feeding.
• you should know that thalidomide may make you drowsy. Do not drive a car, operate machinery, or do other activities that require you to be fully alert until you know how this medication affects you.
• ask your doctor about the safe use of alcoholic beverages while you are taking thalidomide. Alcohol can make the side effects from thalidomide worse.
• you should know that thalidomide may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To help avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that thalidomide is present in your blood and body fluids. Anyone who may come into contact with these fluids should wear gloves or wash any exposed areas of skin with soap and water.

Take the missed dose as soon as you remember it. However, if it is less than 12 hours until your next scheduled dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

The following adverse reactions are described in detail in other labeling sections:

• Teratogenicity [see BOX WARNING, WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION]
• Venous and Arterial Thromboembolism [see BOX WARNING, WARNINGS AND PRECAUTIONS, and PATIENT INFORMATION]
• Drowsiness and Somnolence [see WARNINGS AND PRECAUTIONS]
• Peripheral Neuropathy [see WARNINGS AND PRECAUTIONS]
• Dizziness and Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Neutropenia [see WARNINGS AND PRECAUTIONS]
• Thrombocytopenia [see WARNINGS AND PRECAUTIONS]
• Increased HIV Viral Load [see WARNINGS AND PRECAUTIONS]
• Bradycardia [see WARNINGS AND PRECAUTIONS]
• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see WARNINGS AND PRECAUTIONS]
• Seizures [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]

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 thalidomide can be expected to experience adverse reactions.

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

Because thalidomide is present in the semen of patients receiving the drug, males receiving thalidomide must always use a latex or synthetic condom during any sexual contact with females of reproductive potential, even if he has undergone a successful vasectomy.

An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism), ischemic heart disease (including myocardial infarction), and stroke have been reported in patients with multiple myeloma treated with thalidomide [see WARNINGS AND PRECAUTIONS].

Peripheral neuropathy is a very common, potentially severe, adverse reaction of treatment with thalidomide that may result in irreversible damage. Peripheral neuropathy generally occurs following chronic use over a period of months. However, reports following relatively short-term use also exist. Incidence of neuropathy events leading to discontinuation, dose reduction or interruption increases with cumulative dose and duration of therapy. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.

Somnolence, dizziness, and rash are the most commonly observed adverse reactions associated with the use of thalidomide. Adverse event profiles from clinical trials are summarized in the sections that follow.

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 drug 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 Drug Reactions Reported in ≥10% of Patients in the THALOMID/Dexamethasone Arm (Study 1 - Safety Population; N=204)

The safety analysis in Study 2 was conducted on 466 patients who received treatment. Table 2 lists the most common adverse drug reactions (≥ 10%) that were observed. Table 3 lists the most common Grade 3/4 adverse drug 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 events; 37% (86/234) from the THALOMID/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.

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

Table 3: Grade 3/4 Adverse Drug Reactions Reported in >2% of Patients in the THALOMID/Dexamethasone Arm (Study 2 - Safety Population; N=466)

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

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

* 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 3/4 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.

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 Events (AEs) Reported in Celgene-sponsored Controlled Clinical Trials

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 events, similar types of events were grouped into a smaller number of standardized categories using a modified COSTART dictionary/terminology. These categories are used in the listing below. All reported events are included except those already listed in the previous table. Due to the fact that these data were collected from uncontrolled studies, the incidence rate cannot be determined. 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 thalidomide.

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.

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

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.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of THALOMID and are not already included in Clinical Trials Experience [see Clinical Trials Experience]. 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.

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

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, purpura, petechiae.

Special Senses: Diplopia, nystagmus

Read the entire FDA prescribing information for Thalomid (Thalidomide)

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of thalidomide in the elderly.

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For erythema nodosum leprosum:
    • Adults and children 12 years and older—At first, 100 to 300 milligrams (mg) once a day. Your doctor may adjust your dose as needed.
    • Children younger than 12 years—Use and dose must be determined by your doctor.
  • For multiple myeloma:
    • Adults and children 12 years and older—200 milligrams (mg) once a day together with dexamethasone. The dose is repeated every 28 days.
    • Children younger than 12 years—Use and dose must be determined by your doctor.

Tell your healthcare provider about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Thalomid and other medicines may affect each other causing serious side effects.

Certain medicines can affect the way that birth control pills, injections, patches, or implants work. You could become pregnant.

Especially tell your healthcare provider if you also take:

• a pain medicine
• antihistamines
• a medicine for psychosis
• a medicine for anxiety
• a medicine for your heart
• a medicine for depression
• famotidine (Pepcid, Duexis)
• cimetidine (Tagamet)
• lithium (lithobid)
• bortezomib (Velcade)
• amiodarone (Cordarone, Pacerone)
• cisplatin
• paclitaxel (Abraxane)
• vincristine
• disulfiram (Antabuse)
• metronidazole (Flagyl, Metrocream, Metrolotion, Metrogel, Helidac, Noritate, Plera)
• a penicillin antibiotic
• an anti-HIV medicine
• phenytoin (Fosphenytoin, Cerebyx, Dilantin-125, Extended Phenytoin Sodium, Prompt Phenytoin Sodium, Phenytek, Dilantin, Phenytoin Sodium)
• carbamazepine (Carbatrol, Equetro, Tegretol, Tegretol-XR, Teril, Epitol)
• rifampin (Rifater, Rifamate, Rimactane, Rifadin)
• the herbal supplement St. John’s Wort (Hypericum perforatum)
• modafinil (Nuvigil, Provigil)
• griseofulvin (Grifulvin V, Gris-Peg)

Ask your healthcare provider if you are not sure if your medicine is one of these.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist.

General

ENL

• In patients with moderate to severe neuritis associated with severe ENL reactions receiving concomitant corticosteroid therapy, taper corticosteroid dosage and discontinue when neuritis has subsided.1

Administration

Restricted Distribution

Distribution of thalidomide is restricted because of known, severe teratogenic effects.1 9 54 185 186 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

A special restricted distribution program, called STEPS, for thalidomide was approved by FDA.1 9 54 185 186 The program requires registration of clinicians, pharmacies, and patients; all must agree to accept specific responsibilities (e.g., mandatory contraceptive measures, pregnancy testing) designed to minimize pregnancy exposures in order to prescribe, dispense, or use thalidomide.1 9 22

STEPS program ensures appropriately timed and properly documented pregnancy testing and counseling of patients before, during, and following thalidomide therapy.1 9 17 22

Prior to initiation of therapy, females must certify that they are not pregnant or not of childbearing potential (i.e., hysterectomy, postmenopausal [no menses for ≥24 consecutive months]).1 22

To facilitate pregnancy testing and counseling in accordance with STEPS program, prescribe and dispense ≤28-day supply of drug.9 1 Refills require new prescription and another authorization from STEPS program; automatic refills not allowed.1 9 22

Registering pharmacist must agree to inform all staff pharmacists of dispensing procedures for drug.1 9 22 Before dispensing thalidomide, activate authorization number on every prescription by calling Celgene Customer Care Center at 1-888-423-5436 and obtaining a confirmation number; write confirmation number on thalidomide prescription.1 Verify that each prescription was written within ≤7 days.1 9 Dispense blister packs containing drug intact (i.e., drug cannot be repackaged).1

Oral Administration

Administer orally with water ≥1 hour after a meal.1

Usually administer as a single daily dose, preferably at bedtime (to minimize sedative effects of drug) with water and ≥1 hour after evening meal.1 9

May administer a high daily dosage (e.g., ≤400 mg daily) as a single dose at bedtime or, alternatively, in divided doses with water ≥1 hour after meals.1

Dosage

Pediatric Patients

Children ≥12 years of age weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).1

Children ≥12 years of age weighing ≥50 kg: Initially, 100–300 mg once daily.1 For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.1

Continue therapy until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks).1 Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.1

Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction.1 Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.1

Adults

Patients weighing <50 kg: Initially, administer at lower end of dosage range (e.g., 100 mg daily).1

Patients weighing ≥50 kg: Initially, 100–300 mg once daily.1 For treatment of severe cutaneous reactions or in patients who previously required high dosages to control a reaction, may initiate at ≤400 mg once daily at bedtime or in divided doses.1

Continue until signs and symptoms of active ENL reaction have subsided (usually ≥2 weeks).1 Gradually taper daily dosage in 50-mg decrements every 2–4 weeks until drug withdrawn or recurrence of ENL occurs.1

Maintenance therapy in patients who have recurrence of ENL during tapering and those who have a documented history of recurrences: Institute minimum dosage as required to control ENL reaction.1 Attempt gradual decrease (i.e., 50-mg decrements every 2–4 weeks) and withdrawal every 3–6 months.1

Induction therapy: 200 mg once daily combined with dexamethasone 40 mg daily on days 1–4, 9–12, and 17–20 of a 28-day cycle, with cycles repeated at 28-day intervals.1

Reduce dosage or temporarily discontinue if adverse effects such as constipation, oversedation, or peripheral neuropathy occur.1 Once adverse effects subside, reinitiate at lower or previous dosage, based on clinical judgment.1

100–300 mg daily for 1–6 weeks has been used.9 148 149 150 May be necessary to use higher dosages (e.g., 400–600 mg daily).9 148 149 150 Optimal duration of therapy unknown; may relapse following discontinuance of drug.9 148 149

Maintenance therapy to prevent or treat relapse: 50–100 mg daily.9 148 149

50–300 mg daily has been used.157 158 159 202 203 204 205 207 208

800 mg to 1.6 g daily for a median duration of 240 days has been used in a clinical trial.153

Prescribing Limits

Pediatric Patients

Children ≥12 years of age weighing ≥50 kg: Maximum 400 mg daily.1

Adults

Patients weighing ≥50 kg: Maximum 400 mg daily.1

Special Populations

No dosage adjustment required in patients undergoing hemodialysis.1 245

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Because thalidomide is a known human teratogen and can cause severe, life-threatening birth defects if administered during pregnancy, commercially available thalidomide must be obtained through a restricted distribution program, the System for Thalidomide Education and Prescribing Safety (STEPS), designed to help ensure that fetal exposure to the drug does not occur. See Restricted Distribution Program under Dosage and Administration.

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 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. 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 Cmax. 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.

Lactation

Risk Summary

There is no information regarding the presence of thalidomide in human milk, the effects of Thalomid on the breastfed infant, 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 breastfed infants 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.

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 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)].

Pediatric Use

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

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.

Renal Impairment

No clinical studies were conducted with Thalomid in patients with mild, moderate or severe renal function. Renal impairment is not expected to influence drug exposure since <3.5% of the dose is excreted in the urine as unchanged drug.

In a study of 6 patients with end-stage renal disease, thalidomide (200 mg/day) was administered on a non-dialysis day and on a dialysis day and blood samples for pharmacokinetics were collected at least 10 hours following the dose. Comparison of concentration-time profiles on a non-dialysis day and during dialysis showed that the mean total clearance increased by a 2.5-fold during hemodialysis. Because the dialysis was performed 10 hours following administration of the dose, the drug-concentration time curves were not statistically significantly different for days patients were on and off of dialysis. In addition, there were no major differences in thalidomide PK between patients with end-stage renal disease and healthy volunteers. Thus, no dosage adjustment is needed for patients with renal impairment or patients on dialysis.

Hepatic Impairment

No clinical studies have been conducted in patients with hepatic impairment.

Multiple Myeloma (MM)

The efficacy and safety of Thalomid in patients with multiple myeloma were evaluated in two randomized, multi-center studies (Study 1 and Study 2).  Study 1 was an open-label study which randomized 207 symptomatic patients with newly diagnosed MM to Thalomid plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The Thalomid dose was 200 mg daily and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and 17-20 every 28-days. Each group was treated for four 28-day cycles.

Study 2 randomized 470 newly diagnosed patients with MM to Thalomid plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the Thalomid/dexamethasone arm, a starting dose of thalidomide 50 mg was escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both treatment groups took 40 mg of dexamethasone once daily given on days 1-4, 9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle. Treatment continued as tolerated until disease progression.

Baseline demographics for both studies are presented in Table 6 and disease characteristics for the study population are summarized in Tables 7 (Study 1) and 8 (Study 2).

In Study 1, response rate was the primary endpoint. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm (52% vs. 36%). The primary efficacy endpoint in Study 2 was time to progression (TTP), defined as the time from randomization to the first documentation of disease progression, based on the myeloma response criteria. A preplanned interim analysis for Study 2 demonstrated that the combination of Thalomid plus dexamethasone was superior to placebo plus dexamethasone with respect to TTP (Table 9).

The Kaplan-Meier plot of the time to progression by treatment group is presented in Figure 1.

Figure 1: Kaplan-Meier Plot of Time to Disease Progression

KEY: Placebo/Dex=placebo/dexamethasone; Thal/Dex=Thalomid/dexamethasone

Erythema Nodosum Leprosum (ENL)

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

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

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

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

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

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

Never use Thalomid if you are pregnant. Even one dose of Thalomid can cause severe, life-threatening birth defects or death of a baby if the mother or the father is taking this medicine at the time of conception or during pregnancy.

Use birth control to prevent pregnancy, whether you are a man or a woman. For women: Use two forms of birth control beginning 4 weeks before you start taking Thalomid and ending 4 weeks after you stop taking it. For men: Use a condom to prevent pregnancy during your treatment, and for up to 4 weeks after your treatment ends.

Thalomid may cause blood clots. Stop using this medicine and call your doctor at once if you have symptoms such as sudden numbness, severe headache, problems with vision or speech, chest pain, shortness of breath, or swelling in your arm or leg.