THALOMID- thalidomide capsule
Celgene Corporation
WARNING: EMBRYO-FETAL TOXICITY AND VENOUS THROMBOEMBOLISM
EMBRYO-FETAL TOXICITY
If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects.
Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to THALOMID� (thalidomide) as negligible as possible, THALOMID� (thalidomide) is approved for marketing only through a special restricted distribution program: THALOMID REMS� program, approved by the Food and Drug Administration. This program was formerly known as the �System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. � program)".
You can get the information about THALOMID and the THALOMID REMS program on the Internet at www.celgeneriskmanagement.com or by calling the manufacturer�s toll-free number 1-888-423-5436.
VENOUS THROMBOEMBOLISM
The use of THALOMID� (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. 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). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients� underlying risk factors.
1 INDICATIONS AND USAGE
1.1 Multiple Myeloma
THALOMID in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM).
1.2 Erythema Nodosum Leprosum
THALOMID is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).
THALOMID is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis.
THALOMID is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
2 DOSAGE AND ADMINISTRATION
THALOMID� (THALIDOMIDE) MUST ONLY BE ADMINISTERED IN COMPLIANCE WITH ALL OF THE TERMS OUTLINED IN THE THALOMID REMS PROGRAM. THALOMID� (THALIDOMIDE) MAY ONLY BE PRESCRIBED BY PRESCRIBERS CERTIFIED WITH THE THALOMID REMS PROGRAM AND MAY ONLY BE DISPENSED BY PHARMACISTS CERTIFIED WITH THE THALOMID REMS PROGRAM.
Drug prescribing to females of reproductive potential should be contingent upon initial and continued confirmed negative results of pregnancy testing.
? Consider dose reduction, delay, or discontinuation in patients who develop NCI CTC (National Cancer Institute Common Toxicity Criteria) Grade 3 or 4 adverse reactions and/or based on clinical judgment.
2.1 Multiple Myeloma
THALOMID is administered in combination with dexamethasone in 28-day treatment cycles. The dose of THALOMID 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.
2.2 Erythema Nodosum Leprosum
For an episode of cutaneous ENL, THALOMID 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, THALOMID 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 THALOMID. Steroid usage can be tapered and discontinued when the neuritis has ameliorated.
Dosing with THALOMID 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.
3 DOSAGE FORMS AND STRENGTHS
THALOMID 50 mg, 100 mg, 150 mg and 200 mg capsules will be supplied through the THALOMID REMS program
ADVERSE REACTIONS
The following adverse reactions are described in detail in other labeling sections:
Teratogenicity [see Boxed Warning, Warnings and Precautions (5.1, 5.2), and Patient Counseling Information (17)]
Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.3), and Patient Counseling Information (17)]
Drowsiness and Somnolence [see Warnings and Precautions (5.4)]
Peripheral Neuropathy [see Warnings and Precautions (5.5)]
Dizziness and Orthostatic Hypotension [see Warnings and Precautions (5.6)]
Neutropenia [see Warnings and Precautions (5.7)]
Thrombocytopenia [see Warnings and Precautions (5.8)]
Increased HIV Viral Load [see Warnings and Precautions (5.9)]
Bradycardia [see Warnings and Precautions (5.10)]
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis [see Warnings and Precautions (5.11)]
Seizures [see Warnings and Precautions (5.12)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.13)]
Hypersensitivity [see Warnings and Precautions (5.15)]
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.
DESCRIPTION
THALOMID, ?-(N-phthalimido) glutarimide, is an immunomodulatory agent. The empirical formula for thalidomide is C13 H10 N2 O4 and the gram molecular weight is 258.2. The CAS number of thalidomide is 50-35-1.
Thalidomide is an off-white to white, odorless, crystalline powder that is soluble at 25�C in dimethyl sulfoxide and sparingly soluble in water and ethanol. The glutarimide moiety contains a single asymmetric center and, therefore, may exist in either of two optically active forms designated S-(-) or R-(+). THALOMID is an equal mixture of the S-(-) and R-(+) forms and, therefore, has a net optical rotation of zero.
THALOMID is available in 50 mg, 100 mg, 150 mg and 200 mg capsules for oral administration. Active ingredient: thalidomide. Inactive ingredients: pregelatinized starch and magnesium stearate. The 50 mg capsule shell contains gelatin, titanium dioxide, and black ink. The 100 mg capsule shell contains black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black ink. The 150 mg capsule shell contains FD&C blue #2, black iron oxide, yellow iron oxide, titanium dioxide, gelatin, and black and white ink. The 200 mg capsule shell contains FD&C blue #2, titanium dioxide, gelatin, and white ink.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism of action of THALOMID is not fully understood. THALOMID 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-?) 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-? in patients with erythema nodosum leprosum (ENL); however, it has also been shown to increase plasma TNF-? 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.
