Thalidomide
50mg/100mg Capsules

What is Thalidomide?

Thalidomide is a prescription medicine used:

• to treat people who have been newly diagnosed with multiple myeloma (MM), and take along with the medicine dexamethasone.
• to treat people who have moderate to severe new lesions of leprosy. THALIDOMIDE is not used by itself to treat the skin lesions when there is moderate to severe nerve pain.
• to prevent and keep the skin lesions of leprosy from coming back (recurring).

It is not known if Thalidomide is safe and effective in children under 12 years of age.

Who should not take Thalidomide?

Do not take Thalidomide if you are pregnant, plan to become pregnant, or become pregnant during Thalidomide treatment.

Do not take Thalidomide if you are allergic to thalidomide or any of the ingredients in Thalidomide. See the end of this Medication Guide for a complete list of ingredients in Thalidomide.

What should I tell my healthcare provider before taking Thalidomide?

Before you take Thalidomide, tell your healthcare provider if you:

Take Thalidomide exactly as prescribed and follow all the instructions of the Thalidomide

• Before prescribing THALIDOMIDE, your healthcare provider will:
  • explain the THALIDOMIDE to you
  • have you sign the Patient-Physician Agreement Form
• Keep Thalidomide in the blister pack until you take your daily dose.
• Swallow Thalidomide capsules whole with water.
• Thalidomide is taken 1 time each day, at least 1 hour after your evening meal. Bedtime is the preferred time to take Thalidomide.
• Do not open the Thalidomide capsules or handle them any more than needed. If you touch a broken Thalidomide capsule or the medicine in the capsule, wash the area of your body with soap and water.
• If you miss a dose of Thalidomide and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take 2 doses at the same time.
• If you take too much Thalidomide or overdose, call your healthcare provider right away.

Females who can become pregnant:

will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is regular, or every 2 weeks if your menstrual cycle is irregular. If you miss your period or have unusual bleeding, you will need to have a pregnancy test and receive counseling.

must agree to use 2 different forms of effective birth control at the same time every time, for at least 4 weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least 4 weeks after stopping Thalidomide.

Males who take Thalidomide, even those who have had a vasectomy, must agree to use a latex or synthetic condom during sexual contact with a pregnant female or a female who can become pregnant.

What should I avoid while taking Thalidomide?

Females: Do not get pregnant and do not breastfeed while taking Thalidomide.
Males: Do not donate sperm.

Do not share Thalidomide with other people. It may cause birth defects and other serious problems.

Do not donate blood while you take Thalidomide, during breaks (interruptions), and for 4 weeks after stopping Thalidomide. If someone who is pregnant gets your donated blood, her baby may be exposed to Thalidomide and may be born with birth defects.

Thalidomide can cause dizziness and drowsiness. Avoid drinking alcohol, operating machinery, and driving a car when taking Thalidomide Avoid taking other medicines that may cause drowsiness without talking to your healthcare provider first.

What are the possible side effects of Thalidomide?

Thalidomide may cause serious side effects, including:

Drowsiness and sleepiness.

Nerve damage. Nerve damage is common with Thalidomide. If the nerve damage is severe, it may not go away. Stop taking Thalidomide and call your healthcare provider right away if you have any of these early symptoms of nerve damage in your hands, legs, or feet:

• numbness
• tingling
• pain
• burning sensation

Dizziness and decreased blood pressure when changing positions. Thalidomide may cause a decrease in your blood pressure, and you may feel dizzy when you go from a lying down or sitting position to standing up. When changing positions, sit upright for a few minutes before standing to help prevent this.

Decreased white blood cell count. Thalidomide can cause decreased white blood cell counts, including neutrophils. Neutrophils are a type of white blood cell that is important in fighting bacterial infections. Your healthcare provider should check your white blood count before and regularly while you take Thalidomide. If your neutrophils are too low you should not start Thalidomide and if they are low during treatment, your dose of Thalidomide may need to be changed.

Increased HIV virus in the blood. If you are HIV positive, your healthcare provider should check your viral load after one month and three months of treatment, then every 3 months after that.

Slow heartbeat (bradycardia). Tell your healthcare provider if you have a slow heartbeat, fainting, dizziness or shortness of breath. Serious skin reactions. Serious skin reactions can happen with Thalidomide and may cause death. Call your healthcare provider right away if you have any skin reaction while taking Thalidomide.

Seizures. Tell your healthcare provider right away if you have a seizure while taking Thalidomide.

Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and sometimes death. Your healthcare provider may do blood tests to check you for TLS.

Birth control. Certain birth control methods may pose a higher risk of serious side effects and should not be used in some females. These risks include severe decreased white blood cell count, low platelet counts, and blood clots. Use of an intrauterine device (IUD) or implantable birth control may also increase your risk of infection or bleeding during insertion, removal or during use of the device.

Allergic reaction. Allergic reactions can happen with Thalidomide and may be severe. Call your healthcare provider or get medical help right away if you have any of these symptoms of allergic reaction:

• a red, itchy rash
• fever
• fast heartbeat
• feel dizzy or faint

The most common side effects of THALIDOMIDE for treatment of multiple myeloma include:

• tiredness
• decreased calcium levels
• swelling of the hands and feet
• constipation
• numbness or tingling
• low blood counts
• skin rash or peeling
• confusion
• decreased appetite
• nausea
• anxiety
• decreased energy or strength
• tremor
• fever
• weight loss
• muscle twitching and cramping
• weight gain
• dizziness
• dry skin

The most common side effects THALIDOMIDE for treatment of leprosy include:

• sleepiness
• rash
• headache
• dizziness
• impotence
• decreased energy or strength
• not feeling well
• pain

These are not all the possible side effects of Thalidomide.

Call your doctor for medical advice about side effects. You may report side effects to FDA.

How should I store Thalidomide?

• Store Thalidomide at room temperature between, 68°F to 77°F (20° C to 25° C) with excursions permitted to 59°F to 86°F (15°C to 30°C).
• Protect from light.
• Return any unused Thalidomide to Celgene or your healthcare provider.

Keep Thalidomide and all medicines out of the reach of children.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Thalidomide for conditions for which it was not prescribed. Do not give THALIDOMIDE to other people, even if they have the same symptoms you have. It may harm them and may cause birth defects.

This Medication Guide provides a summary of the most important information about Thalidomide. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Thalidomide that is written for health professionals.

What are the ingredients in Thalidomide?

Active ingredient: thalidomide capsule
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.

Thalidomide
50mg/100mg Capsules

INDICATIONS AND USAGE

Thalidomide in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM).

Thalidomide is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).

Thalidomide is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.

Thalidomide is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.

DOSAGE AND ADMINISTRATION

Thalidomide MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE Thalidomide REMS PROGRAM. Thalidomide (THALIDOMIDE) MAY ONLY BE PRESCRIBED BY PRESCRIBERS CERTIFIED WITH THE Thalidomide REMS PROGRAM AND MAY ONLY BE DISPENSED BY PHARMACISTS CERTIFIED WITH THE Thalidomide REMS PROGRAM.

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

Thalidomide is administered in combination with dexamethasone in 28-day treatment cycles. The dose of Thalidomide is 200 mg administered orally once daily 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.

Patients who develop adverse reactions such as constipation, somnolence, or peripheral neuropathy may benefit by either temporarily discontinuing the drug or continuing at a lower dose. With the abatement of these adverse reactions, the drug may be started at a lower dose or at the previous dose based on clinical judgment.

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

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

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

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

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

DOSAGE FORMS AND STRENGTHS

Thalidomide 50 mg, 100 mg, 150 mg and 200 mg capsules will be supplied through the Thalidomide REMS program.

Thalidomide is available in the following capsule strengths:

• 50 mg capsules [white opaque], imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.
• 100 mg capsules [tan], imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.
• 150 mg capsules [tan and blue], imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo
• 200 mg capsule [blue], imprinted “Celgene/200 mg” with a “Do not Get Pregnant” logo.

CONTRAINDICATIONS

[see Boxed Warning]

Thalidomide can cause fetal harm when administered to a pregnant female. Thalidomide is contraindicated in females who are pregnant. Thalidomide is a powerful human teratogen, inducing 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.  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 hazard to the fetus. If pregnancy occurs during thalidomide treatment, the drug should be discontinued immediately.

Thalidomide is contraindicated in patients who have demonstrated hypersensitivity to the drug and its components.

WARNINGS AND PRECAUTIONS

Thalidomide 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 thalidomide provided adequate precautions are taken to avoid pregnancy. Thalidomide is only available through the Thalidomide REMS program (formerly known as the “S.T.E.P.S.® program”).

Oral ingestion is the only type of maternal thalidomide 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 thalidomide; however, females of reproductive potential should avoid contact with Thalidomide (thalidomide) Capsules.  Thalidomide Capsules should be stored in blister packs until ingestion. If there is contact with non-intact thalidomide capsules or the powder contents, the exposed area should be washed with soap and water.

If healthcare providers or other care givers are exposed to body fluids from patients receiving Thalidomide (thalidomide) 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 Thalidomide.

Females of Reproductive Potential
Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning Thalidomide 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 Thalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Thalidomide 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 Thalidomide therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles.

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

Blood Donation
Patients must not donate blood during treatment with Thalidomide and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Thalidomide.

Because of the embryo-fetal risk, Thalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Thalidomide REMS program (formerly known as the “S.T.E.P.S.®” program).

Required components of the Thalidomide REMS program include the following:

• Prescribers must be certified with the Thalidomide REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Prescriber 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 and males must comply with contraception requirements.
• Pharmacies must be certified with the Thalidomide REMS program, must only dispense to patients who are authorized to receive Thalidomide and comply with REMS requirements.

The use of Thalidomide in patients with MM results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolus. This risk increases significantly when thalidomide 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 thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). 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. Patients should seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.

Thalidomide frequently causes drowsiness and somnolence. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. 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.

Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (=10%) and potentially severe adverse reaction of treatment with thalidomide 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 thalidomide treatment has been stopped and may resolve slowly or not at all.

Few reports of neuropathy have arisen in the treatment of ENL despite long-term thalidomide treatment. However, the inability clinically to differentiate thalidomide neuropathy from the neuropathy often seen in Hansen’s disease makes it difficult to determine accurately the incidence of thalidomide-related neuropathy in ENL patients treated with thalidomide.

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

Medications known to be associated with neuropathy should be used with caution in patients receiving thalidomide.

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

Decreased white blood cell counts, including neutropenia, have been reported in association with the clinical use of thalidomide. Treatment should not be initiated with an absolute neutrophil count (ANC) of <750/mm3. White blood cell count and differential should be monitored on an ongoing basis, especially in patients who may be more prone to neutropenia, such as patients who are HIV-seropositive. If ANC decreases to below 750/mm3 while on treatment, the patient’s medication regimen should be re-evaluated and, if the neutropenia persists, consideration should be given to withholding thalidomide if clinically appropriate.

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.

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

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

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

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

Some contraceptive methods may pose a higher risk of adverse effects or may be medically contraindicated in some patients treated with Thalidomide. 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 Thalidomide, 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.

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

ADVERSE REACTIONS

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

• Teratogenicity
• Venous Thromboembolism
• Drowsiness and Somnolence
• Peripheral Neuropathy
• Dizziness and Orthostatic Hypotension
• Neutropenia
• Increased HIV Viral Load
• Bradycardia
• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
• Seizures
• Tumor Lysis Syndrome
• Hypersensitivity

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.

Teratogenicity:
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.

Venous thromboembolism:
An increased risk of venous thromboembolism (such as deep vein thrombosis and pulmonary embolism) has been reported in patients with multiple myeloma treated with thalidomide.

Peripheral neuropathy:
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.

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 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 Thalidomide/dexamethasone arm and 16% (16/102) from 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 drug reactions (= 10%) that were observed. Table3 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 Thalidomide/dexamethasone were constipation, peripheral edema, tremor, asthenia, dizziness and fatigue. Adverse reactions with a frequency at least 2-fold higher in the Thalidomide/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 Thalidomide/dexamethasone arm and 15% (35/232) from the placebo/dexamethasone arm.

Less Common Adverse Drug Reactions in Multiple Myeloma Controlled Clinical Trials

In Study 2, Thalidomide 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 Thalidomide/dexamethasone arm and with a =1% difference in proportion of patients between the Thalidomide/dexamethasone arm compared to the placebo/dexamethasone arm. All grade 3/4 and serious adverse reactions reported >2 patients in Thalidomide/dexamethasone arm and with a percentage higher in the Thalidomide/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 Thalidomide-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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Muscular Skeletal: Myalgia, myasthenia.

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

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

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

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

The following adverse reactions have been identified during post approval use of Thalidomide.  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.

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

Digestive System: Intestinal perforation, gastrointestinal perforations, intestinal obstruction.

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

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

Skin and Appendages: Erythema multiforme, toxic epidermal necrolysis.

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

Respiratory System: Pleural effusion.

Reproductive System and Breast Disorders: amenorrhea, sexual dysfunction.

Immune System Disorders: Hypersensitivity, angioedema/urticaria.

Ear and Labyrinthine Disorders: Hearing impairment/deafness.

Renal and Urinary Disorders: Renal failure.

Other Adverse Events in the Published Literature or Reported from Other Sources
The following additional events have been identified either in the published literature or from spontaneous reports from other sources: acute renal failure, amenorrhea, aphthous stomatitis, bile duct obstruction, carpal tunnel, chronic myelogenous leukemia, diplopia, dysesthesia, dyspnea, enuresis, erythema nodosum, erythroleukemia, foot drop, galactorrhea, gynecomastia, hangover effect, hypomagnesemia, hypothyroidism, lymphedema, lymphopenia, metrorrhagia, migraine, myxedema, nodular sclerosing Hodgkin’s disease, nystagmus, oliguria, pancytopenia, petechiae, purpura, Raynaud’s syndrome, stomach ulcer, suicide attempt, interstitial lung disease and severe infections (e.g., fatal sepsis including septic shock).

DRUG INTERACTIONS

Thalidomide is not a substrate for cytochrome P450 (CYP450) isoenzymes and does not inhibit or induce human CYP450 enzymes in vitro.  Therefore, pharmacokinetic drug-drug interactions are not anticipated when thalidomide is coadministered with drugs that are substrates, inhibitors or inducers of cytochrome P450.

The use of opioids, antihistamines, antipsychotics, anti-anxiety agents, or other CNS depressants concomitantly with Thalidomide may cause an additive sedative effect and should be avoided.

The use of drugs which slow cardiac conduction concomitantly with Thalidomide 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 thalidomide 200 mg/day at steady state levels. The single dose of digoxin had no effect on the pharmacokinetic profile of thalidomide.  The safety of long-term concomitant use of Thalidomide and digoxin has not been evaluated.

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.

Hormonal contraceptives increase the risk of thromboembolism. It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with Thalidomide.

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

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 thalidomide 200 mg/day at steady-state levels. The single dose of warfarin had no effect on the pharmacokinetic profile of thalidomide.

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 thalidomide.

USE IN SPECIFIC POPULATIONS

[see Boxed Warnings and Contraindications (4.1)]

Risk Summary
Thalidomide can cause embryofetal harm when administered to a pregnant female and is contraindicated during pregnancy.

Thalidomide 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 hazard 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 Thalidomide to the FDA.

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 µg/mL).

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

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 Thalidomide 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.

Thalidomide can cause fetal harm when administered during pregnancy. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking Thalidomide, during dose interruptions and for at least 4 weeks after completing therapy.

Females
Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two 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 one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with Thalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Thalidomide 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.

Females of reproductive potential must have 2 negative pregnancy tests before initiating Thalidomide. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Thalidomide. 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. Thalidomide treatment must be discontinued during this evaluation.

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

No clinical studies were conducted with Thalidomide 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.

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

DRUG ABUSE AND DEPENDENCE

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

OVERDOSAGE

Overdosages of up to 14.4 g have been reported in the literature.  No fatalities have been reported and all overdosed patients recovered without sequelae. There is no specific antidote for a thalidomide 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

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

Chemical Structure of Thalidomide

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-(+). Thalidomide is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.

Thalidomide 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.

CLINICAL PHARMACOLOGY

The mechanism of action of Thalidomide is not fully understood. Thalidomide possesses immunomodulatory, antiinflammatory 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-a) 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-a in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-a 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.

Absorption
Absorption of Thalidomide is slow after oral administration. The maximum plasma concentrations are reached approximately 2-5 hours after administration. The absolute bioavailability of thalidomide from thalidomide capsules has not yet been characterized in human subjects due to its poor aqueous solubility. Based on the 14C-radiolabel thalidomide study in human, greater than 90% of the total radioactivity is recovered in urine suggesting good oral absorption. While the extent of absorption (as measured by area under the curve [AUC]) is proportional to dose in healthy subjects, the observed peak concentration (Cmax) increased in a less than proportional manner (see Table 5 below). This lack of Cmax dose proportionality, coupled with the observed increase in Tmax values, suggests that the poor solubility of thalidomide in aqueous media may be hindering the rate of absorption.

Coadministration of Thalidomide (thalidomide) with a high-fat meal causes minor (<10%) changes in the observed AUC and Cmax values; however, it causes an increase in Tmax to approximately 6 hours.

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

Metabolism
In a 14C-radiolabel ADME study in humans, unchanged drug is the predominant circulating component. Thalidomide is not a substrate of the cytochrome P450 system.   At therapeutic concentrations, thalidomide is not an inhibitor or inducer of human cytochrome P450 enzymes in vitro.  Pharmacokinetic drug-drug interactions with substrates, inhibitors or inducers of CYP450 are not anticipated.

Elimination
The mean elimination half-life of thalidomide in plasma following single oral doses between 50 mg and 400 mg was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide, the total mean recovery was 93.6% of the administered dose by Day 8. The majority of the radioactive dose was excreted within 48 hours following dose administration. In humans, 14C-thalidomide is primarily excreted in urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while fecal excretion is minor (<2% of the dose).  Unchanged thalidomide is not eliminated by the kidney to a notable degree (<3.5% of the dose).

Effects of Weight
There is a linear relationship between body weight and estimated thalidomide clearance.  In MM patients with body weight from 47-133 kg, thalidomide clearance ranged from approximately 6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10 kg body weight increase.

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

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

Pharmacokinetic differences due to race have not been studied.

Pharmacokinetic Data in Special Populations
HIV-seropositive Subjects: There is no apparent significant difference in measured pharmacokinetic parameter values between healthy human subjects and HIV-seropositive subjects following single-dose administration of Thalidomide Capsules.

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

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

NONCLINICAL TOXICOLOGY

Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).

Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.

Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25-fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels =30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).

CLINICAL STUDIES

The efficacy and safety of Thalidomide 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 Thalidomide plus dexamethasone (N = 103) versus dexamethasone alone (N=104). The Thalidomide 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 Thalidomide plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235). In the Thalidomide/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 Thalidomide 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=Thalidomide/dexamethasone

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.

REFERENCES

1. OSHA Hazardous Drugs. OSHA [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html].

HOW SUPPLIED/STORAGE AND HANDLING

 (THIS PRODUCT IS ONLY SUPPLIED TO PHARMACIES CERTIFIED IN THE Thalidomide REMS PROGRAM

50 mg capsules [white opaque], imprinted “Celgene/50 mg” with a “Do Not Get Pregnant” logo.
Individual blister packs of 1 capsule.
Individual blister packs of 28 capsules.
Boxes of 280 containing 10 prescription packs of 28 capsules each.

100 mg capsules [tan], imprinted “Celgene/100 mg” with a “Do Not Get Pregnant” logo.
Individual blister packs of 28 capsules.
Boxes of 140 containing 5 prescription packs of 28 capsules each.

150 mg capsules [tan and blue], imprinted “Celgene/150 mg” with a “Do Not Get Pregnant” logo.
Individual blister packs of 28 capsules.
Boxes of 112 containing 4 prescription packs of 28 capsules.

200 mg capsules [blue], imprinted “Celgene/200 mg” with a “Do Not Get Pregnant” logo.
Individual blister packs of 28 capsules.
Boxes of 84 containing 3 prescription packs of 28 capsules each.

This drug must not be repackaged.

Store at 20°C- 25°C (68°F -77°F); excursions permitted to 15-30° C (59-86° F). [See USP Controlled Room Temperature]. Protect from light.

Care should be exercised in handling of Thalidomide. Thalidomide capsules should not be opened or crushed. If powder from Thalidomide contacts the skin, wash the skin immediately and thoroughly with soap and water. If Thalidomide 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 published1.

Rx only and only able to be prescribed and dispensed under the terms of the Thalidomide REMS Restricted Distribution Program.