Pomalidomide

1 INDICATIONS AND USAGE Pomalidomide capsules are a thalidomide analogue indicated, for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy ( 1.1 ). with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART) or in patients with KS who are HIV- negative. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) ( 1.2 ). 1.1 Multiple Myeloma Pomalidomide capsules , in combination with dexamethasone, is indicated for adult patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy. 1.2 Kaposi Sarcoma Pomalidomide capsules are indicated for the treatment of: Adult patients with AIDS-related Kaposi sarcoma (KS) after failure of highly active antiretroviral therapy (HAART). Kaposi sarcoma (KS) in adult patients who are HIV-negative. This indication is approved under accelerated approval based on overall response rate [see Clinical Studies ( 14.2 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION MM: 4 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression ( 2.2 ). Refer to section 14.1 for dexamethasone dosing ( 14.1 ) KS: 5 mg per day taken orally on Days 1 through 21 of repeated 28-day cycles until disease progression or unacceptable toxicity ( 2.3 ) Modify the dosage for certain patients with renal impairment ( 2.7 , 8.6 ) or hepatic impairment ( 2.8 , 8.7 ) 2.1 Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating pomalidomide capsules [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1, 8.3 ) ]. 2.2 Recommended Dosage for Multiple Myeloma The recommended dosage for pomalidomide capsules is 4 mg once daily orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression. Give pomalidomide capsules in combination with dexamethasone [ see Clinical Studies ( 14.1 ) ]. 2.3 Recommended Dosage for Kaposi Sarcoma The recommended dosage of pomalidomide capsules is 5 mg once daily taken orally with or without food on Days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. Continue HAART as HIV treatment in patients with AIDS-related Kaposi sarcoma (KS) [see Clinical Studies ( 14.2 )] . 2.4 Dosage Modifications for Hematologic Adverse Reactions Multiple Myeloma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules in patients with multiple myeloma (MM) when the neutrophil count is at least 500 per mcL and the platelet count is at least 50,000 per mcL. Dosage modification for pomalidomide capsules for hematologic adverse reactions in patients with MM are summarized in Table 1. Table 1: Dosage Modifications for Pomalidomide for Hematologic in MM Adverse Reaction Severity Dose Modification Neutropenia [see Warnings and Precautions (5.5)] ANC less than 500 per mcL or febrile neutropenia (fever greater than or equal to 38.5°C and ANC less than 1,000 per mcL) Withhold pomalidomide capsules until ANC is greater than or equal to 500 per mcL; follow CBC weekly. Resume pomalidomide capsules dose at 1 mg less than the previous dose.* For each subsequent drop of ANC less than 500 per mcL Withhold pomalidomide capsules until ANC is greater than or equal to 500 mcL. Resume pomalidomide capsules dose at 1 mg less than the previous dose.* Thrombocytopenia [see Warnings and Precautions (5.5)] Platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per mcL; follow CBC weekly. Resume pomalidomide capsules dose at 1 mg less than the previous dose* For each subsequent drop of platelets less than 25,000 per mcL Withhold pomalidomide capsules until platelets are greater than or equal to 50,000 per cmL. Resume pomalidomide capsules at 1 mg less than previous dose* *Permanently discontinue pomalidomide capsules if unable to tolerate 1mg once daily. ANC= absolute neutrophil count Kaposi Sarcoma: Dosage Modifications for Hematologic Adverse Reactions Initiate a new cycle of pomalidomide capsules in patients with KS when the neutrophil count is at least 1000 per mcL and the platelet count is at least 75,000 per mcL. Dose modifications for pomalidomide capsules for hematologic adverse reactions in patients with KS are summarized in Table 2. Table 2: Dosage Modifications for Pomalidomide for Hematologic Adverse Reactions in KS Adverse Reaction Severity Dosage Modification Neutropenia [ see Warnings and Precautions ( 5.5 )] Day 1 of cycle Withhold pomalidomide capsules until ANC is greater than or equal to 1,000 per mcL. Resume pomalidomide capsules at the same dose. During cycle Continue pomalidomide capsules at the current dose. ANC less than 500 per mcL Febrile Neutropenia [ see Warnings and Precautions ( 5.5 ) ] ANC less than 1,000 per mcL and single temperature greater than or eq…

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 Pomalidomide REMS program [ see Warnings and Precautions ( 5.2 ) ]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before 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 Pomalidomide REMS Program Because of the embryo-fetal risk [ see Warnings and Precautions ( 5.1 ) ], pomalidomide is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the “ Pomalidomide REMS ” program. Required components of the Pomalidomide REMS program include the following: Prescribers must be certified with the Pomalidomide REMS program by enrolling and complying with the REMS requirements. Patients must sign a Patient-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 must be certified with the Pomalidomide REMS program, must only dispense to patients who are authorized to receive pomalidomide and comply with REMS requirements. For information about the Pomalidomide REMS program, please contact Apotex Corp. at 1-800-706-5575. 5.3 Venous and Arterial Thromboembolism Venous thromboembolic events (deep ve…

4 CONTRAINDICATIONS Pregnancy ( 4 .1) Hypersensitivity (4.2) 4.1 Pregnancy Pomalidomide is contraindicated in females who are pregnant. Pomalidomide can cause fetal harm when administered to a pregnant female [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 ) ]. Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. 4.2 Hypersensitivity Pomalidomide is contraindicated in patients who have demonstrated severe hypersensitivity (e.g., angioedema, anaphylaxis) to pomalidomide or any of the excipients [see Warnings and Precautions (5.7), Description (11)].

7 DRUG INTERACTIONS Strong CYP1A2 Inhibitors: Avoid concomitant use of strong CYP1A2 inhibitors. If concomitant use of a strong CYP1A2 inhibitor is unavoidable, reduce pomalidomide dose to 2 mg ( 2.6 , 7.1 , 12.3 ). 7.1 Drugs That Affect Pomalidomide Plasma Concentrations CYP1A2 inhibitors : In healthy subjects, co-administration of fluvoxamine, a strong CYP1A2 inhibitor, increased C max and AUC of pomalidomide by 24% and 125% respectively [ see Clinical Pharmacology ( 12.3 ) ]. Increased pomalidomide exposure may increase the risk of exposure related toxicities. Avoid co-administration of strong CYP1A2 inhibitors (e.g. ciprofloxacin and fluvoxamine). If co-administration is unavoidable, reduce the pomalidomide dose [ see Dosage and Administration ( 2.6 ) ].

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to pomalidomide during pregnancy as well as female partners of male patients who are exposed to pomalidomide. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to pomalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Apotex Corp. at 1-800-706-5575. Risk Summary Based on the mechanism of action [ see Clinical Pharmacology ( 12.1 ) ] and findings from animal studies, pomalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy [ see Contraindications ( 4 ), and Warnings and Precautions ( 5.1 ) ]. Pomalidomide is a thalidomide analogue. 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. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. Pomalidomide crossed the placenta after administration to pregnant rabbits [ see Data ]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to pomalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Apotex Corp. at 1-800-706-5575. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryo-fetal developmental studies when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg/kg/day. Malformations or absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central, and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg/day. Other embryo-fetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg/kg/day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg/kg/day. Additional malformations observed at 250 mg/kg/day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased averag…

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 ). KS: Most common adverse reactions including laboratory abnormalities (≥30%) are decreased absolute neutrophil count or white blood cells, elevated creatinine or glucose, rash, constipation, fatigue, decreased hemoglobin, platelets, phosphate, albumin, or calcium, increased ALT, nausea, and diarrhea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp at 1-800-706-5575 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* All Adverse Reactions ≥10% in Either Arm Grade 3 or 4 ≥5% in Either Arm Body System Adverse Reaction Pomalidomide a (N=107) Pomalidomide + Low-dose Dex (N=112) Pomalidomide (N=107) Pomalidomide + Low-dose Dex (N=112) Number (%) of patients with at least one adverse reaction 107 (100) 112 (100) 98 (92) 102 (91) Blood and lymphatic system disorders Neutropenia b 57 (53) 55 (49) 51 (48) 46 (41) Anemia b 41 (38) 47 (42) 25 (23) 24 (21) Thrombocytopenia b 28 (26) 26 (23) 24 (22) 21 (19) Leukopenia 14 (13) 22 (20) 7 (7) 11 (10) Febrile neutropenia b <10% <10% 6 (6) 3 (3) Lymphopenia 4 (4) 17 (15) 2 (2) 8 (7) General disorders and administration site conditions Fatigue and asthenia b 62 (58) 70 (63) 13 (12) 19 (17) Edema peripheral 27 (25) 19 (17) 0 (0.0) 0 …