Cedazuridine And Decitabine

1 INDICATIONS AND USAGE INQOVI is indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. INQOVI is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor, indicated for treatment of adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage of INQOVI is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle. ( 2.2 ) Take INQOVI on an empty stomach. ( 2.2 ) 2.1 Important Administration Information Do NOT substitute INQOVI for an intravenous decitabine product within a cycle. Consider administering antiemetics prior to each dose to minimize nausea and vomiting [see Adverse Reactions (6.1) ] . 2.2 Recommended Dosage The recommended dosage of INQOVI is 1 tablet (containing 35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity. A complete or partial response may take longer than 4 cycles. Instruct patients of the following: Take INQOVI at the same time each day. Swallow tablets whole. Do not cut, crush, or chew tablets. Do not consume food 2 hours before and 2 hours after each dose. Take one tablet a day for 5 days in each cycle. If the patient misses a dose within 12 hours of the time it is usually taken, instruct patients to take the missed dose as soon as possible and then to resume the normal daily dosing schedule. Extend the dosing period by one day for every missed dose to complete 5 daily doses for each cycle. Do not take an additional dose if vomiting occurs after INQOVI administration but continue with the next schedule dose. INQOVI is a hazardous drug. Follow applicable special handling and disposal procedures. 1 2.3 Monitoring and Dosage Modifications for Adverse Reactions Hematologic Adverse Reactions Obtain complete blood cell counts prior to initiating INQOVI and before each cycle. Delay the next cycle if absolute neutrophil count (ANC) is less than 1,000/μL and platelets are less than 50,000/μL in the absence of active disease. Monitor complete blood cell counts until ANC is 1,000/μL or greater and platelets are 50,000/μL or greater [see Warnings and Precautions (5.1) ] . If hematologic recovery occurs (ANC at least 1,000/μL and platelets at least 50,000/μL) within 2 weeks of achieving remission, continue INQOVI at the same dose. If hematologic recovery does not occur (ANC at least 1,000/μL and platelets at least 50,000/μL) within 2 weeks of achieving remission, Delay INQOVI for up to 2 additional weeks AND Resume at a reduced dose by administering INQOVI on Days 1 through 4. Consider further dose reductions in the order listed in Table 1 if myelosuppression persists after a dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated. Table 1: Recommended INQOVI Dose Reductions for Myelosuppression Dose Reduction Dosage First 1 tablet orally once daily on Days 1 through 4 Second 1 tablet orally once daily on Days 1 through 3 Third 1 tablet orally once daily on Days 1, 3 and 5 Manage persistent severe neutropenia and febrile neutropenia with supportive treatment [see Warnings and Precautions (5.1) ] . Non-Hematologic Adverse Reactions Delay the next cycle for the following non-hematologic adverse reactions and resume at the same or reduced dose upon resolution: Serum creatinine 2 mg/dL or greater Serum bilirubin 2 times upper limit of normal (ULN) or greater Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2 times ULN or greater Active or uncontrolled infection

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence ≥ 20%) are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taiho Oncology, Inc. at 1-844-878-2446 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia The safety of INQOVI was evaluated in a pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02 [see Clinical Studies (14) ] . Patients were randomized to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 in Cycle 1 and decitabine 20 mg/m 2 intravenously on Days 1 through 5 in Cycle 2, or the reverse sequence, and then INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days 1 through 5 of each 28-day cycle in Cycles 3 and beyond. Patients were allowed to have one prior cycle of decitabine or azacitidine and there was no limit for body weight or surface area. Among the patients who received INQOVI, 61% of patients were exposed for 6 months or longer and 24% were exposed to INQOVI for greater than 1 year. Serious adverse reactions occurred in 68% of patients who received INQOVI. Serious adverse reactions in > 5% of patients included febrile neutropenia (30%), pneumonia (14%), and sepsis (13%). Fatal adverse reactions occurred in 6% of patients. These included sepsis (1%), septic shock (1%), pneumonia (1%), respiratory failure (1%), and one case each of cerebral hemorrhage and sudden death. Permanent discontinuation due to an adverse reaction occurred in 5% of patients who received INQOVI. The most frequent adverse reactions resulting in permanent discontinuation were febrile neutropenia (1%) and pneumonia (1%). Dose interruptions due to an adverse reaction occurred in 41% of patients who received INQOVI. Adverse reactions requiring dosage interruptions in > 5% of patients who received INQOVI included neutropenia (18%), febrile neutropenia (8%), thrombocytopenia (6%), and anemia (5%). Dose reductions due to an adverse reaction occurred in 19% of patients who received INQOVI. Adverse reactions requiring dosage reductions in > 2% of patients who received INQOVI included neutropenia (12%), anemia (3%), and thrombocytopenia (3%). The most common adverse reactions (≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased. Table 2 summarizes the adverse reactions in the pooled safety population. Table 2: Adverse Reactions (≥ 10%) in Patients Who Received INQOVI in Pooled Safety Population Adverse Reactions INQOVI Cycle 1 N=107 Intravenous Decitabine Cycle 1 N=106 INQOVI Includes adverse reactions that occurred during all cycles, including during treatment with 1 cycle of intravenous decitabine. All Cycles N=208 All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) General disorders and administration site conditions Fatigue Includes fatigue, asthenia, and lethargy 29 2 25 0 55 5 Hemorrhage Includes contusion, epistaxis, petechiae, hematuria, conjunctival hemorrhage, mouth hemorrhage, purpura, angina bullosa hemorrhagica, gingival bleeding, hematoma, hemoptysis, eye contusion, hemorrhagic diathesis, increased tendency to bruise, vaginal hemorrhage, abdominal wall hematoma, blood blister, bone contusion, catheter site bruise, ecchymosis, genital hemorrhage, intra-abdominal hematoma, oral mucosa hematoma, periorbital hemorrhage, procedural hemorrhage, pulmonary alveolar hemorrhage, retinal hemorrhage, scleral hemorrhage, thrombotic thrombocytopenic purpura, tongue hemorrhage, and vessel puncture site hemorrhage 24 2 17 0 43 3 Edema Includes edema peripheral, peripheral swelling, swelling face, fluid overload, localized edema, face edema, edema, eye swelling, eyelid edema, fluid retention, periorbital swelling, scrotal edema, scrotal swelling, and swelling 10 0 11 0 30 0.5 Pyrexia 7 0 7 0 19 1 Gastrointestinal disorders Constipation Includes constipation and feces hard 20 0 23 0 44 0 Mucositis Includes oropharyngeal pain, stomatitis, mouth ulceration, proctalgia, oral pain, gingivitis, oral disorder, gingival pain, colitis, glossodynia, mouth swelling, pharyngitis, proctitis, duodenitis, enteritis, gingival discomfort, gingival swelling, lip disorder, lip ulceration, mucosal ulceration, nasal ulcer, noninfective gingivitis, oral mucosal blistering, oral mucosal erythema, pharyngeal erythema, pharyngeal ulceration, tongue ulceration, and vulvitis 18 1 24 2 41 4 Nausea 25 0 16 0 40 0.5 Diarrhea Includes diarrhea and feces soft 16 0 11 0 37 1 Transaminase increased Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, liver function test increased, and transaminases increased 12 1 3 0 21 3 Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal pain lower, epigastric discomfort, and abdominal discomfort 9 0 7 0 19 1 Vomiting 5 0 5 0 15 0 Musculoskeletal and connective tissue disorders Myalgia Includes myalgia, pain in extremity, muscle spasms, pain, musculoskeletal pain, non-cardiac chest pain, muscular weakness, musculoskeletal chest pain, flank pain, musculoskeletal stiffness, muscle strain, and musculoskeletal discomfort 9 2 16 1 42 3 Arthralgia Includes arthralgia, back pain, neck pain, joint stiffness, pain in jaw, joint swelling, bursitis, joint range of motion decreased, and joint injury 9 1 13 1 40 3 Respiratory, thoracic, and mediastinal disorders Dyspnea Includes dyspnea, dyspnea exertional, hypoxia, wheezing, chronic obstructive pulmonary disease, and tachypnoea 17 3 9 3 38 6 Cough Includes cough and productive cough 7 0 8 0 28 0 Blood & lymphatic system disorders Febrile neutropenia 10 10 13 13 33 32 Skin and subcutaneous tissue disorders Rash Includes maculo-papular rash, rash, erythema, skin lesion, folliculitis, dermatitis, dermatitis acneiform, eczema, erythema multiforme, rash erythematous, seborrheic keratosis, skin ulcer, dermatitis allergic, dermatitis contact, eczema nummular, genital erythema, rash papular, rash pruritic, rash pustular, seborrheic dermatitis, skin exfoliation, skin irritation, stasis dermatitis, and ulcerative keratitis 12 1 11 1 33 0.5 Nervous system disorders Dizziness Includes dizziness, vertigo, postural dizziness, and positional vertigo 16 1 11 0 33 2 Headache Includes headache, sinus pain, and sinus headache 22 0 13 0 30 0 Neuropathy Includes hypoesthesia, paresthesia, neuropathy peripheral, gait disturbance, peripheral sensory neuropathy, ataxia, balance disorder, brachial plexopathy, carpal tunnel syndrome, and radicular pain 4 0 8 0 13 0 Metabolism and nutritional disorders Decreased appetite 10 1 6 0 24 2 Infections and infestations Upper respiratory tract infection Includes upper respiratory tract infection, nasopharyngitis, sinusitis, and viral upper respiratory tract infection 6 0 3 0 23 1 Pneumonia Includes pneumonia, pneumonitis, atypical pneumonia, and lung infection 7 7 7 5 21 15 Sepsis Includes sepsis, bacteremia, septic shock, endocarditis, pseudomonal bacteremia, and staphylococcal bacteremia 6 6 2 1 14 11 Cellulitis Includes cellulitis, catheter site cellulitis, and infected bite 4 1 3 2 12 5 Investigations Renal impairment Includes blood creatinine increased, acute kidney injury, blood urea increased, blood creatine increased, and renal failure 9 0 8 1 18 0 Weight decreased 5 0 3 0 10 1 Injury, poisoning, and procedural complications Fall 4 0 1 0 12 1 Psychiatric disorders Insomnia 6 0 2 0 12 0.5 Vascular disorders Hypotension Includes hypotension, blood pressure decreased, and cardiogenic shock 4 0 6 1 11 2 Cardiac Disorders Arrhythmia Includes sinus tachycardia, atrial fibrillation, bradycardia, tachycardia, atrial flutter, sinus bradycardia, and conduction disorder 3 0 2 0 11 1 Clinically relevant adverse reactions in < 10% of patients who received INQOVI included: Acute febrile neutrophilic dermatosis (Sweet’s syndrome) (1%) Tumor lysis syndrome (0.5%) Table 3: Select Laboratory Abnormalities (> 20%) Worsening from Baseline in Patients Who Received INQOVI in Pooled Safety Population Lab Abnormality Includes any lab abnormalities that worsened by one or more grades. Grade 3-4 includes any lab abnormalities that worsened to Grade 3 or Grade 4. INQOVI Cycle 1 The denominator used to calculate the rate varied from 103 to 107 for INQOVI Cycle 1, from 102 to 106 for Intravenous Decitabine Cycle and from 203 to 208 for INQOVI All Cycles based on the number of patients with a baseline value and at least one post-treatment value. Intravenous Decitabine Cycle 1 INQOVI All Cycles All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hematology Leukocytes decreased 79 65 77 59 87 81 Platelet count decreased 79 65 77 67 82 76 Neutrophil count decreased 70 65 62 59 73 71 Hemoglobin decreased 58 41 59 36 71 55 Chemistry Glucose increased 19 0 11 0 54 7 Albumin decreased 22 1 20 0 45 2 Alkaline phosphatase increased 22 1 12 0 42 0.5 Glucose decreased 14 0 17 0 40 1 Alanine aminotransferase increased 13 1 7 0 37 2 Sodium decreased 9 2 8 0 30 4 Calcium decreased 16 0 12 0 30 2 Aspartate aminotransferase increased 6 1 2 0 30 2 Creatinine increased 7 0 8 0 29 0.5 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of intravenous decitabine. 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: Differentiation syndrome Respiratory, Thoracic and Mediastinal Disorders: Interstitial lung disease Cardiac Disorders: Cardiomyopathy

12.3 Pharmacokinetics The pharmacokinetics of decitabine and cedazuridine following administration of INQOVI at the recommended dosage in patients with MDS and CMML are shown in Table 4 . The geometric mean ratio (GMR) of decitabine area under the curve (AUC) following the first dose of INQOVI compared to that of intravenous decitabine on Day 1 was 60% (90% confidence intervals (CI): 55, 65) in patients with MDS and CMML [see Dosage and Administration (2.1) ]. The GMR of decitabine AUC following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine on Day 5 was 106% (90% CI: 98, 114) and the GMR of the 5-day cumulative decitabine AUC following 5 consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106). An approximately dose-proportional increase in peak concentrations (C max ) and AUC over the dosing interval was observed for decitabine following administration of oral decitabine at 20 mg to 40 mg once daily (0.6 to 1.1 times the recommended dose) in combination with 100 mg oral cedazuridine, and for cedazuridine following administration of oral cedazuridine at 40 to 100 mg once daily (0.4 to 1.0 times the recommended dose) in combination with 20 mg oral decitabine. Table 4: Pharmacokinetics of the Components of INQOVI Mean (%CV) Parameter Decitabine Cedazuridine C max = maximum plasma concentration; AUC 0-24h =area under the plasma concentration-time curve from time zero to 24 hours; CV=coefficient of variation; SD=standard deviation; T max = Time to maximum concentration; V/F=apparent volume of distribution; CL/F=apparent clearance General Information With the recommended dosage of INQOVI for 5 consecutive days: 5-day cumulative AUC, ng.hr/mL 851 (50%) -- Day 1 AUC, ng·hr/mL 103 (55%) 2950 (49%) Steady state AUC, ng·hr/mL 178 (53%) 3291 (45%) Time to steady state, days 2 2 Accumulation ratio based on AUC 1.7 (42%) 1.1 (63%) C max , ng/mL 145 (55%) 371 (52%) Absorption Bioavailability Cedazuridine increases oral decitabine exposure 20% (23%) T max , hours Median (range) 1 (0.3 to 3.0) 3 (1.5 to 6.1) Distribution V/F at steady state, L 417 (54%) 296 (51%) Fraction unbound, in vitro 96% (4%) to 94% (2%) between 17 ng/mL to 342 ng/mL 66% (6%) to 62% (2%) between 1000 ng/mL and 50000 ng/mL Elimination Half-life at steady state Mean (SD) , hours 1.5 (27%) 6.7 (19%) CL/F at steady state, L/hours 197 (53%) 30.3 (46%) Metabolism Primary Pathways Primarily by cytidine deaminase (CDA) and by physicochemical degradation Conversion to epimer by physicochemical degradation Excretion Healthy subjects Total (% unchanged) -- 46% (21%) in urine and 51% (27%) in feces Specific Populations Age (32 to 90 years), sex, and mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN or AST > ULN) did not have an effect on the pharmacokinetics of decitabine or cedazuridine after dosing with INQOVI. Decitabine exposure (AUC) increased with decreasing body surface area or body weight, and cedazuridine exposure increased with decreasing CLcr; however, body surface area (1.3 to 2.9 m 2 ), body weight (41 to 158 kg), and mild to moderate renal impairment (CLcr 30 to 89 mL/min based on Cockcroft Gault) did not have a clinically meaningful effect on the pharmacokinetics of decitabine and cedazuridine after dosing with INQOVI. The effects of moderate (total bilirubin > 1.5 to 3 × ULN and any AST) and severe hepatic impairment (total bilirubin > 3 × ULN and any AST) or severe renal impairment (CLcr 15 to <30 mL/min) and ESRD (CLcr <15 mL/min) on the pharmacokinetics of decitabine and cedazuridine are unknown. Drug Interaction Studies Clinical Studies Decitabine had no clinically meaningful effect on the pharmacokinetics of cedazuridine. Cedazuridine increased the exposure of decitabine. The coadministration of INQOVI with proton pump inhibitors had no clinically meaningful effect on exposure to decitabine or cedazuridine. In vitro Studies CYP Enzymes: Cedazuridine is not a substrate of cytochrome P450 (CYP) enzymes. Cedazuridine does not induce CYP1A, CYP2B6, CYP2C9, or CYP3A or inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A. Transporter Systems: Cedazuridine is not a substrate of P-glycoprotein (P-gp), MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OAPT1B3, OATP2B1, OCT1, or OCT2, and does not inhibit P-gp, BCRP, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.