Thalidomide

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

The mechanism of action of THALOMID is not fully understood. Cellular activities of thalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. THALOMID possesses immunomodulatory, anti-inflammatory and antiangiogenic properties. Available data from in vitro studies and clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-α in patients with erythema nodosum leprosum (ENL), however, it has also been shown to increase plasma TNF-α levels in HIV-seropositive patients.

• MM: 200 mg orally once daily. The recommended dose of dexamethasone is 40 mg/day on days 1-4, 9-12, and 17-20 every 28 days. • ENL: 100 to 300 mg/day for an episode of cutaneous ENL. Up to 400 mg/day for severe cutaneous ENL.

• Pregnancy ( Boxed Warning, 4.1, 5.1, 5.2, 8.1, 17 ) • Demonstrated hypersensitivity to the drug or its components Pregnancy THALOMID is contraindicated in females who are pregnant. THALOMID can cause fetal harm when administered to a pregnant female. THALOMID 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 risk to a fetus.

Boxed warning: If THALOMID is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. THALOMID should never be used by females who are pregnant or who could be pregnant while taking the drug. Even a single dose [1 capsule (regardless of strength)] taken by a pregnant woman during her pregnancy can cause severe birth defects. • Pregnancy must be excluded before start of treatment. • Ischemic heart disease (including myocardial infarction) and stroke have been observed in patients treated with THALOMID in combination with dexamethasone. • Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue. • Drowsiness and Somnolence: Instruct patients to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness.

The following clinically significant adverse reactions are described in detail in other labeling sections: • Teratogenicity • Venous and Arterial Thromboembolism • Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone • Drowsiness and Somnolence • Peripheral Neuropathy • Dizziness and Orthostatic Hypotension • Neutropenia • Thrombocytopenia • Increased HIV Viral Load • Bradycardia • Severe Cutaneous Reactions • Seizures • Tumor Lysis Syndrome • Hypersensitivity • MM: The most common adverse reactions (≥20%) are fatigue, hypocalcemia, edema, constipation, neuropathy-sensory, dyspnea, muscle weakness, leukopenia, neutropenia, rash/desquamation, confusion, anorexia, nausea, anxiety/agitation, asthenia, tremor, fever, weight loss, thrombosis/embolism, neuropathy-motor, weight gain, dizziness, and dry skin.

• Use caution if other drugs which have sedative and hypnotic properties, slow cardiac conduction and/or cause peripheral neuropathy must be used. • It is not known whether concomitant use of hormonal contraceptives further increases the risk of thromboembolism with THALOMID. • Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thromboembolism.

Store at 20°C-25°C (68°F-77°F), excursions permitted to 15-30º C (59-86º F). Protect from light.