Pomalidomide

WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM WARNING: EMBRYO-FETAL TOXICITY and VENOUS AND ARTERIAL THROMBOEMBOLISM Embryo-Fetal Toxicity • Pomalidomideis contraindicated in pregnancy. Pomalidomide is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting pomalidomide treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping pomalidomide treatment [see Contraindications (4), Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3) ]. Pomalidomide is only available through a restricted distribution program called PS-Pomalidomide REMS [see Warnings and Precautions (5.2) ] . Information about PS-Pomalidomide REMS is available at www.PS-PomalidomideREMS.com or by calling the REMS Call Center at 1-888-423-5436. Venous and Arterial Thromboembolism • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with pomalidomide. Prophylactic antithrombotic measures were employed in clinical trials. Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors [see Warnings and Precautions (5.3) ]. See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • Pomalidomide is contraindicated in pregnancy. Pomalidomide is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects ( 4 , 5.1 , 8.1 ). • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of 2 reliable methods of contraception ( 5.1 , 8.3 ). Pomalidomide is available only through a restricted program called PS-Pomalidomide REMS ( 5.2 ). VENOUS AND ARTERIAL THROMBOEMBOLISM • Deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke occur in patients with multiple myeloma treated with pomalidomide. Antithrombotic prophylaxis is recommended ( 5.3 ).

5 WARNINGS AND PRECAUTIONS • Increased Mortality: Observed in patients with MM when pembrolizumab was added to dexamethasone and a thalidomide analogue ( 5.4 ). • Hematologic Toxicity: Neutropenia was the most frequently reported Grade 3/4 adverse event. Monitor patients for hematologic toxicities, especially neutropenia ( 5.5 ). • Hepatotoxicity: Hepatic failure including fatalities; monitor liver function tests monthly ( 5.6 ). • Severe Cutaneous Reactions: Discontinue pomalidomide for severe reactions ( 5.7 ). • Tumor Lysis Syndrome (TLS): Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions ( 5.11 ). • Hypersensitivity: Monitor patients for potential hypersensitivity. Discontinue pomalidomide for angioedema and anaphylaxis ( 5.12 ). 5.1 Embryo-Fetal Toxicity Pomalidomide is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations ( 8.1)]. Pomalidomide is only available through the PS-Pomalidomide REMS program [see Warnings and Precautions ( 5.2 )]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4weeksbefore beginning pomalidomide 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 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of pomalidomide therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10 to 14 days and the second test within 24 hours prior to prescribing pomalidomide therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles, or every 2 weeks in females with irregular menstrual cycles [see Use in Specific Populations ( 8.3)]. Males Pomalidomide 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 pomalidomide and for up to 4 weeks after discontinuing pomalidomide, even if they have undergone a successful vasectomy. Male patients taking pomalidomide must not donate sperm [see Use in Specific Populations ( 8.3)]. Blood Donation Patients must not donate blood during treatment with pomalidomide and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to pomalidomide. 5.2 PS-Pomalidomide REMS Because of the embryo-fetal risk [see Warnings and Precautions (5.1) ] , pomalidomide is available only through a restricted program under a Risk Evaluationand Mitigation Strategy (REMS), “PS-Pomalidomide REMS”. Required componentsof PS-Pomalidomide REMS include the following: • Prescribers must be certified with PS-Pomalidomide REMS by enrolling and complying with the REMS requirements. • Patients must signaPatient-Physician Agreement Form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ] and males must comply with contraception requirements [see Use in Specific Populations (8.3) ]. • Pharmacies mustbe certified with PS-Pomalidomide REMS , must only dispense to patients who are authorized to receive pomalidomide and comply with REMS requirements. Further information about PS-Pomalidomide REMS is availableat www.PS-PomalidomideREMS.com or by telephone at 1-888-423-5436. 5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep venous thrombosis and pulmonary embolism) and arterial thromboembolic events (myocardial infarction and stroke) have been observed in patients treated with pomalidomide. In Trial 2, where anticoagulant therapies were mandated, thromboembolic events occurred in 8.0% of patients treated with pomalidomide and low dose-dexamethasone (Low-dose Dex), and 3.3% of patients treated with high-dose dexamethasone. Venous thromboembolic events (VTE) occurred in 4.7% of patients treated with pomalidomide and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Arterial thromboembolic events include terms for arterial thromboembolic events, ischemic cerebrovascular conditions, and ischemic heart disease. Arterial thromboembolic events occurred in 3.0% of patients treated with pomalidomide and Low-dose Dex, and 1.3% of patients treated with high-dose dexamethasone. Patients with known risk factors, including prior thrombosis, may be at greater risk, and actions should be taken to try to minimize all modifiable factors (e.g., hyperlipidemia, hypertension, smoking). Thromboprophylaxis is recommended, and the choice of regimen should be based on assessment of the patient's underlying risk factors. 5.4 Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or PD-L1 blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials. 5.5 Hematologic Toxicity Multiple Myeloma In trials 1 and 2 in patients who received pomalidomide + Low-dose Dex, neutropenia was the most frequently reported Grade 3 or 4 adverse reaction, followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 51% of patients in both trials. The rate of Grade 3 or 4 neutropenia was 46%. The rate of febrile neutropenia was 8%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.4) ]. 5.6 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with pomalidomide. Elevated levels of alanine aminotransferase and bilirubin have also been observed in patients treated with pomalidomide. Monitor liver function tests monthly. Stop pomalidomide upon elevation of liver enzymes and evaluate. After return to baseline values, treatment at a lower dose may be considered. 5.7 Severe Cutaneous Reactions Severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These reactions can be fatal. Consider pomalidomide interruption or discontinuation for Grade 2 or 3 skin rash. Permanently discontinue pomalidomide for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS [see Dosage and Administration (2.5) ]. 5.8 Dizziness and Confusional State In trials 1 and 2 in patients who received pomalidomide + Low-dose Dex, 14% of patients experienced dizziness and 7% of patients experienced a confusional state; 1% of patients experienced Grade 3 or 4 dizziness, and 3% of patients experienced Grade 3 or 4 confusional state. Instruct patients to avoid situations where dizziness or confusional state may be a problem and not to take other medications that may cause dizziness or confusional state without adequate medical advice. 5.9 Neuropathy In trials 1 and 2 in patients who received pomalidomide + Low-dose Dex, 18% of patients experienced neuropathy, with approximately 12% of the patients experiencing peripheral neuropathy. Two percent of patients experienced Grade 3 neuropathy in trial 2. There were no cases of Grade 4 neuropathy adverse reactions reported in either trial. 5.10 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving pomalidomide as an investigational therapy outside of MM. 5.11 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) may occur in patients treated with pomalidomide. Patients at risk for TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.12 Hypersensitivity Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to pomalidomide have been reported. Permanently discontinue pomalidomide for angioedema or anaphylaxis [see Dosage and Administration (2.5) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other labeling sections: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1, 5.2) ] • Venous and Arterial Thromboembolism [see Warnings and Precautions ( 5.3 )] • Increased Mortality in Patients with Multiple Myeloma When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone [see Warnings and Precautions ( 5.4 )] • Hematologic Toxicity [see Warnings and Precautions ( 5.5 )] • Hepatotoxicity [see Warnings and Precautions ( 5.6 )] • Severe Cutaneous Reactions [see Warnings and Precautions ( 5.7 )] • Dizziness and Confusional State [see Warnings and Precautions ( 5.8 )] • Neuropathy [see Warnings and Precautions ( 5.9)] • Risk of Second Primary Malignancies [see Warnings and Precautions ( 5.10 )] • Tumor Lysis Syndrome [see Warnings and Precautions ( 5.11 )] • Hypersensitivity [see Warnings and Precautions (5.12) ] • MM: Most common adverse reactions (≥30%) included fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Multiple Myeloma (MM) In Trial 1, data were evaluated from 219 patients (safety population) who received treatment with pomalidomide + Low-dose Dex (112 patients) or pomalidomide alone (107 patients). Median number of treatment cycles was 5. Sixty-seven percent of patients in the study had a dose interruption of either drug due to adverse reactions. Forty-two percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to adverse reactions was 11%. In Trial 2, data were evaluated from 450 patients (safety population) who received treatment with pomalidomide + Low-dose Dex (300 patients) or High-dose Dexamethasone (High-dose Dex) (150 patients). The median number of treatment cycles for the pomalidomide + Low-dose Dex arm was 5. In the pomalidomide + Low-dose Dex arm, 67% of patients had a dose interruption of pomalidomide, the median time to the first dose interruption of pomalidomide was 4.1 weeks. Twenty-seven percent of patients had a dose reduction of pomalidomide, the median time to the first dose reduction of pomalidomide was 4.5 weeks. Eight percent of patients discontinued pomalidomide due to adverse reactions. Tables 3 and 4 summarize the adverse reactions reported in Trials 1 and 2, respectively. Table 3: Adverse Reactions in Any Pomalidomide Treatment Arm in Trial 1* *Regardless of attribution of relatedness to pomalidomide. a Pomalidomide alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. b Serious adverse reactions were reported in at least 2 patients in any pomalidomide treatment arm. Data cutoff: 01 March 2013 Table 4: Adverse Reactions in Trial 2 a Percentage did not meet the criteria to be considered as an adverse reaction for pomalidomide for that category of event (i.e., all adverse events or Grade 3 or 4 adverse events). b Serious adverse reactions were reported in at least 3 patients in the POM + Low-dose Dex arm, AND at least 1% higher than the High-dose-Dex arm percentage. Data cutoff: 01 March 2013 Other Adverse Reactions Other adverse reactions of pomalidomide in patients with MM, not described above, and considered important: Cardiac Disorders: Myocardial infarction, Atrial fibrillation, Angina pectoris, Cardiac failure congestive Ear and Labyrinth Disorders: Vertigo Gastrointestinal disorders: Abdominal pain General Disorders and Administration Site Conditions: General physical health deterioration, Non-cardiac chest pain, Multi-organ failure Hepatobiliary Disorders: Hyperbilirubinemia Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis, Bacteremia, Pneumonia respiratory syncytial viral, Cellulitis, Urosepsis, Septic shock, Clostridium difficile colitis, Pneumonia streptococcal, Lobar pneumonia, Viral infection, Lung infection Investigations: Alanine aminotransferase increased, Hemoglobin decreased Injury, poisoning and procedural complications: Fall, Compression fracture, Spinal compression fracture Metabolism and nutritional disorders: Hyperkalemia, Failure to thrive Nervous system disorders: Depressed level of consciousness, Syncope Psychiatric disorders: Mental status change Renal and urinary disorders: Urinary retention, Hyponatremia Reproductive system and breast disorders: Pelvic pain Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease, Pulmonary embolism, Respiratory failure, Bronchospasm Vascular disorders: Hypotension table3 table4 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of pomalidomide. 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 System Disorders: Pancytopenia Endocrine Disorders: Hypothyroidism, hyperthyroidism Gastrointestinal Disorders: Gastrointestinal hemorrhage Hepatobiliary Disorders: Hepatic failure (including fatal cases), elevated liver enzymes Immune system Disorders: Allergic reactions (e.g., angioedema, anaphylaxis, urticaria), solid organ transplant rejection Infections and Infestations: Hepatitis B virus reactivation, Herpes zoster, progressive multifocal leukoencephalopathy (PML) Neoplasms benign, malignant and unspecified (incl cysts and polyps): Tumor lysis syndrome, basal cell carcinoma, and squamous cell carcinoma of the skin Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)