DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dosage of INQOVI is tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days through of each 28-day cycle. (2.2)Take INQOVI on an empty stomach. (2.2). The recommended dosage of INQOVI is tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days through 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 cycle.Consider administering antiemetics prior to each dose to minimize nausea and vomiting [see Adverse Reactions (6.1)]. Take INQOVI on an empty stomach at least hours before or hours after eating.When INQOVI is given in combination with venetoclax, advise patients to take INQOVI hours before or hours after venetoclax. Refer to the venetoclax Prescribing Information for recommended dosage and administration.. When INQOVI is given in combination with venetoclax, advise patients to take INQOVI hours before or hours after venetoclax. Refer to the venetoclax Prescribing Information for recommended dosage and administration.. 2.2 Recommended Dosage. INQOVI Monotherapy for MDS or CMMLThe recommended dosage of INQOVI is tablet (containing 35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of each 28-day cycle for minimum of cycles until disease progression or unacceptable toxicity. complete or partial response may take longer than cycles.INQOVI in Combination with Venetoclax for AMLThe recommended dosage of INQOVI in combination with venetoclax is tablet (containing 35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of each 28-day cycle until disease progression or unacceptable toxicity. Match Day of INQOVI dosing with Day of venetoclax dosing for each 28-day cycle.. 2.3Administration. Instruct patients of the following:Take INQOVI at approximately the same time each day.Swallow tablets whole. Do not cut, crush, or chew tablets.Take one tablet day for days in each cycle. If the patient misses 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 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 hazardous drug. Follow applicable special handling and disposal procedures.1 Take INQOVI at approximately the same time each day.. Swallow tablets whole. Do not cut, crush, or chew tablets.. Take one tablet day for days in each cycle. If the patient misses 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 daily doses for each cycle.. Do not take an additional dose if vomiting occurs after INQOVI administration but continue with the next schedule dose.. 2.4 Monitoring and Dosage Modifications for Adverse Reactions. INQOVI Monotherapy for MDS or CMMLHematologic Adverse ReactionsObtain 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/uL and platelets are less than 50,000/uL in the absence of active disease. Monitor complete blood cell counts until ANC is 1,000/uL or greater and platelets are 50,000/uL or greater [see Warnings and Precautions (5.1)].If hematologic recovery occurs (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, continue INQOVI at the same dose.If hematologic recovery does not occur (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, Delay INQOVI for up to additional weeks ANDResume at reduced dose by administering INQOVI on Days through 4. Consider further dose reductions in the order listed in Table if myelosuppression persists after dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated. Table 1: Recommended INQOVI Dose Reductions for Myelosuppression (Monotherapy for MDS or CMML)Dose ReductionDosageFirst1 tablet orally once daily on Days through 4Second1 tablet orally once daily on Days through 3Third1 tablet orally once daily on Days 1, and 5Manage persistent severe neutropenia and febrile neutropenia with supportive treatment [see Warnings and Precautions (5.1)]. Non-Hematologic Adverse ReactionsDelay the next cycle for the following non-hematologic adverse reactions and resume at the same or reduced dose upon resolution: Serum creatinine mg/dL or greaterSerum bilirubin times upper limit of normal (ULN) or greaterAspartate aminotransferase (AST) or alanine aminotransferase (ALT) times ULN or greaterActive or uncontrolled infection INQOVI in Combination with Venetoclax for AMLMonitor blood cell counts frequently through resolution of cytopenias. Dose modification and interruptions for cytopenias are dependent on remission status. For Cycle 1, bone marrow assessment for response may be performed as early as Day 22. In the absence of bone marrow remission (bone marrow blasts 5%), do not delay INQOVI in combination with venetoclax.Hematologic Adverse ReactionsObtain complete blood cell counts prior to initiating INQOVI and before each cycle. Monitor complete blood cell counts until neutrophils and platelet counts have recovered to Grade or [see Warnings and Precautions (5.1)].If hematologic recovery occurs (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, continue INQOVI at the same dose.If hematologic recovery does not occur (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, delay INQOVI for up to additional weeks and consider reducing the number of days of INQOVI per cycle according to Table 2.Table 2: Recommended INQOVI Dose Reductions for Adverse Reactions (Combination with Venetoclax for AML)Dose ReductionDosageFirst1 tablet orally once daily on Days 1, and 3Second1 tablet orally once daily on Days 1, and 5Third1 tablet orally once daily on Days and 2Manage persistent severe neutropenia and febrile neutropenia with supportive treatment [see Warnings and Precautions (5.1)]. Refer to the venetoclax prescribing information for dosage modifications for hematologic adverse reactions associated with venetoclax.Non-Hematologic Adverse ReactionsDose reductions of INQOVI for non-hematologic adverse reactions are provided in Table 2.Refer to the venetoclax prescribing information for dosage modifications for non-hematologic adverse reactions associated with venetoclax.. If hematologic recovery occurs (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, continue INQOVI at the same dose.. If hematologic recovery does not occur (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, Delay INQOVI for up to additional weeks ANDResume at reduced dose by administering INQOVI on Days through 4. Consider further dose reductions in the order listed in Table if myelosuppression persists after dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated. Delay INQOVI for up to additional weeks AND. Resume at reduced dose by administering INQOVI on Days through 4. Consider further dose reductions in the order listed in Table if myelosuppression persists after dose reduction. Maintain or increase dose in subsequent cycles as clinically indicated.. Serum creatinine mg/dL or greater. Serum bilirubin times upper limit of normal (ULN) or greater. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) times ULN or greater. Active or uncontrolled infection If hematologic recovery occurs (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, continue INQOVI at the same dose.. If hematologic recovery does not occur (ANC at least 1,000/uL and platelets at least 50,000/uL) within weeks of achieving remission, delay INQOVI for up to additional weeks and consider reducing the number of days of INQOVI per cycle according to Table 2.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1)] Myelosuppression [see Warnings and Precautions (5.1)] In MDS or CMML, the 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 or laboratory abnormalities (>= 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased. (6.1)In AML in combination with venetoclax, the most common adverse reactions (incidence >= 20%) are neutropenia, febrile neutropenia, thrombocytopenia, hemorrhage, anemia, infection (bacterial/viral), diarrhea, fatigue, mucositis, constipation, arthralgia, dyspnea, decreased appetite, edema, nausea, white blood cell count decreased, sepsis, pneumonia, rash, transaminitis, myalgia, arrhythmia, and abdominal pain. The most common Grade or laboratory abnormalities (>= 50%) were leukocytes decreased, lymphocytes decreased, platelets 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 drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.INQOVI Monotherapy for MDS or CMMLThe safety of INQOVI was evaluated in pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02 [see Clinical Studies (14.1)]. Patients were randomized to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through in Cycle and decitabine 20 mg/m2 intravenously on Days through in Cycle 2, or the reverse sequence, and then INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of each 28-day cycle in Cycles 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 months or longer and 24% were exposed to INQOVI for greater than 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 or laboratory abnormalities (>= 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.Table summarizes the adverse reactions in the pooled safety population. Table 3: Adverse Reactions (>=10%) in Patients Who Received INQOVI in Pooled Safety PopulationAdverse ReactionsINQOVI Cycle N=107Intravenous Decitabine Cycle N=106INQOVIIncludes adverse reactions that occurred during all cycles, including during treatment with cycle of intravenous decitabine. All Cycles N=208All Grades (%)Grades or (%)All Grades (%)Grades or (%)All Grades (%)Grades or (%)General disorders and administration site conditions FatigueIncludes fatigue, asthenia, and lethargy 292250555 HemorrhageIncludes 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 242170433 EdemaIncludes 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 100110300.5 Pyrexia7070191Gastrointestinal disorders ConstipationIncludes constipation and feces hard 200230440 MucositisIncludes 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 181242414 Nausea250160400.5 DiarrheaIncludes diarrhea and feces soft 160110371 Transaminase increasedIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, liver function test increased, and transaminases increased 12130213 Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower, epigastric discomfort, and abdominal discomfort 9070191 Vomiting5050150Musculoskeletal and connective tissue disorders MyalgiaIncludes 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 92161423 ArthralgiaIncludes arthralgia, back pain, neck pain, joint stiffness, pain in jaw, joint swelling, bursitis, joint range of motion decreased, and joint injury 91131403Respiratory, thoracic, and mediastinal disorders DyspneaIncludes dyspnea, dyspnea exertional, hypoxia, wheezing, chronic obstructive pulmonary disease, and tachypnoea 17393386 CoughIncludes cough and productive cough 7080280Blood lymphatic system disorders Febrile neutropenia101013133332Skin and subcutaneous tissue disorders RashIncludes 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 121111330.5Nervous system disorders DizzinessIncludes dizziness, vertigo, postural dizziness, and positional vertigo 161110332 HeadacheIncludes headache, sinus pain, and sinus headache 220130300 NeuropathyIncludes hypoesthesia, paresthesia, neuropathy peripheral, gait disturbance, peripheral sensory neuropathy, ataxia, balance disorder, brachial plexopathy, carpal tunnel syndrome, and radicular pain 4080130Metabolism and nutritional disorders Decreased appetite10160242Infections and infestations Upper respiratory tract infectionIncludes upper respiratory tract infection, nasopharyngitis, sinusitis, and viral upper respiratory tract infection 6030231 PneumoniaIncludes pneumonia, pneumonitis, atypical pneumonia, and lung infection 77752115 SepsisIncludes sepsis, bacteremia, septic shock, endocarditis, pseudomonal bacteremia, and staphylococcal bacteremia 66211411 CellulitisIncludes cellulitis, catheter site cellulitis, and infected bite 4132125Investigations Renal impairmentIncludes blood creatinine increased, acute kidney injury, blood urea increased, blood creatine increased, and renal failure 9081180 Weight decreased5030101Injury, poisoning, and procedural complications Fall4010121Psychiatric disorders Insomnia6020120.5Vascular disorders HypotensionIncludes hypotension, blood pressure decreased, and cardiogenic shock 4061112Cardiac Disorders ArrhythmiaIncludes sinus tachycardia, atrial fibrillation, bradycardia, tachycardia, atrial flutter, sinus bradycardia, and conduction disorder 3020111Clinically relevant adverse reactions in 10% of patients who received INQOVI included: Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%)Tumor lysis syndrome (0.5%)Table 4: Select Laboratory Abnormalities (>20%) Worsening from Baseline in Patients Who Received INQOVI in Pooled Safety PopulationLab AbnormalityIncludes any lab abnormalities that worsened by one or more grades. Grade 3-4 includes any lab abnormalities that worsened to Grade or Grade 4. INQOVI Cycle 1The 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 baseline value and at least one post-treatment value. Intravenous Decitabine Cycle INQOVI All Cycles All Grades (%)Grades or (%)All Grades (%)Grades or (%)All Grades (%)Grades or (%)HematologyLeukocytes decreased796577598781Platelet count decreased796577678276Neutrophil count decreased706562597371Hemoglobin decreased584159367155ChemistryGlucose increased190110547Albumin decreased221200452Alkaline phosphatase increased221120420.5Glucose decreased140170401Alanine aminotransferase increased13170372Sodium decreased9280304Calcium decreased160120302Aspartate aminotransferase increased6120302Creatinine increased7080290.5INQOVI in Combination with Venetoclax for AMLThe safety of INQOVI in combination with venetoclax (INQOVI+VEN) in adult patients 75 years of age and older or those who have comorbidities precluding the use of intensive induction chemotherapy was evaluated in Study ASTX727-07 (N=159) [see Clinical Studies (14.2)]. Patients received INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of the first 28-day cycle in combination with venetoclax given as ramp up on Day (100 mg) and Day (200 mg), followed by venetoclax 400 mg daily from Day onward.Among the patients who received INQOVI+VEN, the median duration of exposure was 5.5 months (range 0.2-28 months): 47% of patients were exposed to INQOVI for months or longer and 20% of patients were exposed to INQOVI for greater than year.Serious adverse reactions occurred in 82% of patients who received INQOVI+VEN. Serious adverse reactions in 5% of patients included febrile neutropenia (31%), sepsis (22%), pneumonia (15%), infection (bacterial/viral) (10%), hemorrhage (9%), and dyspnea (6%). Fatal adverse reactions occurred in 8% of patients who received INQOVI+VEN. These included sepsis (5%), dyspnea (2%), myocardial infarction (1%), hemolytic anemia (1%), and tumor lysis syndrome (1%).Permanent discontinuation of INQOVI due to an adverse reaction occurred in 9% of patients who received INQOVI+VEN. The most frequent adverse reaction resulting in permanent discontinuation in more than patient was hemorrhage (1%).Dosage interruptions of INQOVI due to an adverse reaction occurred in 55% of patients who received INQOVI+VEN. Adverse reactions requiring dosage interruptions in >= 5% of patients who received INQOVI+VEN included neutropenia (40%), febrile neutropenia (11%), infection (bacterial/viral) (8%), and thrombocytopenia (8%).Dose reductions of INQOVI due to an adverse reaction occurred in 6% of patients who received INQOVI+VEN. The most common adverse reactions requiring dosage reductions of INQOVI were neutropenia (4%), thrombocytopenia (1%), and infection (1%).The most common adverse reactions (>= 20%) were neutropenia, febrile neutropenia, thrombocytopenia, hemorrhage, anemia, infection (bacterial/viral), diarrhea, fatigue, mucositis, constipation, arthralgia, dyspnea, decreased appetite, edema, nausea, white blood cell count decreased, sepsis, pneumonia, rash, transaminitis, myalgia, arrhythmia, and abdominal pain. The most common Grade or laboratory abnormalities (>= 50%) were decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased hemoglobin.Table summarizes the adverse reactions in ASTX727-07.Table 5: Adverse Reactions (>= 20% All-Grades or >= 5% Grades 3-4) in Patients with AML Who Received INQOVI+VEN in ASTX727-07Adverse ReactionsPhase (N=159)All Grades (%)Grades 3-4 (%)Abbreviations: N=total number of patients; n=number of patients; SOC System Organ ClassGastrointestinal DisordersDiarrhea384MucositisConsists of multiple, related terms Includes gingivitis, mouth ulceration, stomatitis, oropharyngeal pain, aphthous ulcer, colitis, enterocolitis, gingival discomfort, gingival disorder, gingival injury, glossodynia, lip injury, neutropenic colitis, odynophagia, oesophagitis, oropharyngeal discomfort, pharyngeal inflammation, proctalgia, proctitis, pulpitis dental, tongue ulceration, ulcer, vulvovaginitis, enteritis 366Constipation 361Nausea310Abdominal Pain 213General Disorders and Administration Site ConditionsFatigue 368Edema 312Metabolism and Nutrition DisordersDecreased Appetite313Blood System and Lymphatic System DisordersNeutropenia 6058Febrile Neutropenia5252Thrombocytopenia 5250Anemia4136White Blood Cell Count Decreased2828Hepatobiliary DisordersTransaminitis 244Infections and InfestationsInfection (excludes fungal) 4013Sepsis 2818Pneumonia 2520Musculoskeletal and Connective Tissue DisordersArthralgia Includes arthralgia, back pain, bone pain, joint effusion, joint injury, joint range of motion decreased, neck pain, pain in extremity, pain in jaw, pelvic pain, polyarthritis, spinal osteoarthritis, spinal pain, periarthritis, osteoarthritis 356Myalgia Includes muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, non-cardiac chest pain, flank pain, musculoskeletal pain 234Cardiac DisordersArrhythmia Includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, atrioventricular block first degree, extrasystoles, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia 214Respiratory, Thoracic, and Mediastinal DisordersDyspnea Includes dyspnoea, dyspnoea exertional, hypoxia, wheezing, respiratory failure, acute respiratory failure 3012Renal and Urinary DisordersRenal Insufficiency 185Vascular DisordersHemorrhage 429Hypotension196Skin and Subcutaneous Tissue DisordersRash Includes actinic keratosis, catherter site erythema, catherter site rash, dermatitis, dermatitis acneiform, eczema, erythema, erythema multiforme, papule, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, seborrhoeic keratosis, skin disorder, skin exfoliation, skin hyperpigmentation, skin irritation, skin lesion, skin ulcer, and Stevens-Johnson Syndrome. 251Clinically relevant adverse reactions in 10% of patients who received INQOVI+VEN included:Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%)Tumor lysis syndrome (2%)Table summarizes the laboratory abnormalities identified in the combined AML safety population.Table 6:Select Laboratory Abnormalities (> 40% All Grade AEs) in Patients Who Received INQOVI+VEN in ASTX727-07Lab AbnormalityPhase (N=159)All Grades (%)Grades 3-4 (%)Hematology and CoagulationLymphocytes (109/L) Decreased9781Leukocytes (109/L) Decreased9191Platelets (109/L) Decreased7069Hemoglobin (g/L) Decreased5450Neutrophils (109/L) Decreased4848ChemistryAlbumin (g/L) Decreased607Bilirubin (umol/L) Increased547Alkaline Phosphatase (u/L) Increased431Creatinine (umol/L) Increased414Aspartate Aminotransferase (u/L) Increased413. Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%). Tumor lysis syndrome (0.5%). Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%). Tumor lysis syndrome (2%). 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of intravenous decitabine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: Differentiation syndromeRespiratory, Thoracic and Mediastinal Disorders: Interstitial lung diseaseCardiac Disorders: Cardiomyopathy.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Decitabine is nucleoside metabolic inhibitor that is believed to exert its effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in cancer cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.Cytidine deaminase (CDA) is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver degrade decitabine and limit its oral bioavailability. Cedazuridine is CDA inhibitor. Administration of cedazuridine with decitabine increases systemic exposure of decitabine.. 12.2 Pharmacodynamics. Decitabine induced hypomethylation both in vitro and in vivo. In patients administered the recommended dosage of INQOVI, the maximum change from baseline in the long interspersed nucleotide elements-1 (LINE-1) demethylation was observed at Day 8, with less than complete recovery of LINE-1 methylation to baseline at the end of the treatment cycle.Exposure-Response RelationshipsBased on the exposure-response analyses, relationship between an increase in 5-day cumulative daily decitabine exposure and greater likelihood of some adverse reactions (e.g., any grade neutropenias, thrombocytopenia) was observed in clinical studies.Cardiac ElectrophysiologyAt exposures twice the exposure from the maximum recommended dose, cedazuridine does not prolong the QTc interval to any clinically relevant extent.. 12.3 Pharmacokinetics. The pharmacokinetics of decitabine and cedazuridine were characterized following administration of INQOVI in patients with MDS CMML and AML are shown in Table 7.Approximately dose-proportional increases in peak concentrations (Cmax) and AUC over the dosing interval were 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.Following administration of the recommended dosage, 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 was 60% (90% confidence intervals (CI): 55, 65) [see Dosage and Administration (2.1)]. The GMR of decitabine AUC following consecutive once daily doses of INQOVI compared to that of intravenous decitabine on Day was 106% (90% CI: 98, 114) and the GMR of the 5-day cumulative decitabine AUC following consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106).Table 7: Pharmacokinetics of the Components of INQOVI at Recommended DosageMean (%CV), unless otherwise specified ParameterDecitabineCedazuridineAbbreviations: Cmax= maximum plasma concentration; AUC0-24h=area under the plasma concentration-time curve from time zero to 24 hours; CV=coefficient of variation; Tmax= Time to maximum concentration; V/F=apparent volume of distribution; CL/F=apparent clearanceGeneral Information With the recommended dosage of INQOVI for consecutive days: 5-day cumulative AUC, ng.hr/mL851 (50%)-- Day AUC, ng.hr/mL 103 (55%)2950 (49%) Steady state AUC, ng.hr/mL178 (53%)3291 (45%) Time to steady state, days22 Accumulation ratio based on AUC1.7 (42%)1.1 (63%) Cmax, ng/mL145 (55%)371 (52%)Absorption Bioavailability Cedazuridine increases oral decitabine exposure20% (23%) Tmax, hoursMedian (range) (0.3 to 3.0)3 (1.5 to 6.1)Effect of Food High-fat mealApproximately 800-1000 calories, with 50 of calories from fat AUC0-inf decreased to 50%, Cmax decreased to 25%AUC0-inf decreased to 92%, Cmax decreased to 99% Distribution V/F at steady state, L417 (54%)296 (51%) Fraction unbound, in vitro96% (4%) to 94% (2%) between 17 ng/mL to 342 ng/mL66% (6%) to 62% (2%) between 1000 ng/mL and 50000 ng/mLElimination Half-life at steady state, 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 degradationConversion to epimer by physicochemical degradationExcretionHealthy subjects Total (% unchanged) --46% (21%) in urine and 51% (27%) in fecesSpecific PopulationsAge (32 to 92 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 m2), 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 clinically meaningful effect on the pharmacokinetics of decitabine and cedazuridine after dosing with INQOVI.The effects of moderate (total bilirubin >1.5 to x 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 StudiesClinical StudiesDecitabine had no clinically meaningful effect on the pharmacokinetics of cedazuridine. Cedazuridine increased the exposure of decitabine.There were no drug-drug interactions observed between INQOVI and venetoclax in clinical Study ASTX727-07.The coadministration of INQOVI with proton pump inhibitors had no clinically meaningful effect on exposure to decitabine or cedazuridine.In vitro StudiesCYP Enzymes: Cedazuridine is not 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1INQOVI Monotherapy for MDS or CMML. Study ASTX727-01-BINQOVI was evaluated in Study ASTX727-01-B, an open-label, randomized, 2-cycle, 2-sequence crossover study (NCT02103478) that included 80 adult patients with MDS (International Prognostic Scoring System [IPSS] Intermediate-1, Intermediate-2, or high-risk) or CMML. Patients were randomized 1:1 to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally in Cycle and decitabine 20 mg/m2 intravenously in Cycle or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days through of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days through of each 28-day cycle until disease progression or unacceptable toxicity. Randomization was stratified by IPSS risk level. Twelve (15%) of the 80 patients went on to stem cell transplantation following INQOVI treatment.The baseline demographic and disease characteristics are shown in Table 8.Table 8: Demographics and Baseline Disease Characteristics for Study ASTX727-01-BCharacteristicN=80Age Median (min, max) (years)71 (32, 90)Sex (%) Male76 Female24Race (%) White93 Black or African American3 Asian1 Other or Not Reported4ECOG Performance Score (%) 044 148 29Disease Category IPSS (%) MDS INT-144 MDS INT-224 MDS High-Risk11 CMML21Prior HMA TherapyOne cycle only, per the Exclusion Criteria. (%) Prior Azacitidine4 Prior Decitabine4Transfusion DependenceDefined as documentation of >= units of transfusion within 56 days prior to the first day of study treatment. (%) RBC Transfusion Dependence48 Platelet Transfusion Dependence15Efficacy was established on the basis of complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence. Efficacy results are shown in Table 9. The median follow-up time was 24.0 months (range: 12.0 to 28.8 months) and median treatment duration was 6.6 months (range <0.1 to 27.9).Table 9: Efficacy Results in Patients with MDS or CMML from Study ASTX727-01-BEfficacy EndpointINQOVI N=80Complete Response (%) (95% CI)18 (10, 28)Median Duration of CR months (range)From start of CR until relapse or death. 8.7 (1.1, 18.2)Median Time to CR months (range) 4.8 (1.7, 10.0) Among the 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 20 (49%) became independent of RBC and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.Study ASTX727-02INQOVI was evaluated in ASTX727-02, an open-label, randomized, 2-cycle, 2-sequence crossover study (NCT03306264) that included 133 adult patients with MDS or CMML, including all French-American-British (FAB) classification criteria and IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores. Patients were randomized 1:1 to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally in Cycle and decitabine 20 mg/m2 intravenously in Cycle or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days through of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days through of each 28-day cycle until disease progression or unacceptable toxicity. No stratification was performed. Twenty-seven (20%) of the 133 patients went on to stem cell transplantation following INQOVI treatment.The baseline demographic and disease characteristics are shown in Table 10.Table 10: Demographics and Baseline Disease Characteristics for Study ASTX727-02CharacteristicN=133Age (years) Median (min, max)71 (44, 88)Sex (%) Male65 Female35Race (%) White91 Black or African American3 Asian2 Other or Not Reported4ECOG Performance Score (%) 041 159Disease Category IPSS (%) MDS INT-144 MDS INT-220 MDS High Risk16 MDS Low Risk8 CMML12Prior HMA TherapyOne cycle only, per the Exclusion Criteria. (%) Prior Azacitidine5 Prior Decitabine3Transfusion DependenceDefined as documentation of >= units of transfusion within 56 days prior to the first day of study treatment. (%) RBC Transfusion Dependence39 Platelet Transfusion Dependence8The primary outcome measure was comparison of the 5-day cumulative decitabine AUC between INQOVI and intravenous decitabine [see Clinical Pharmacology (12.3)]. Efficacy was established on the basis of complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence. Efficacy results are shown in Table 11. The median follow-up time was 12.6 months (range: 9.3 to 20.5) and median treatment duration was 8.2 months (range 0.2 to 19.7).Table 11: Efficacy Results in Patients with MDS or CMML from Study ASTX727-02Efficacy EndpointsINQOVI (N=133)Complete Response (%) (95% CI)21 (15, 29)Median Duration of CR months (range)From start of CR until relapse or death. 7.5 (1.6, 17.5)Median Time to CR months (range) 4.3 (2.1, 15.2)Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 48 (63%) remained transfusion-independent during any 56-day post-baseline period.. 14.2INQOVI in Combination with Venetoclax for AML. Study ASTX727-07INQOVI in combination with venetoclax was evaluated in Study ASTX727-07, single arm, open-label, interventional study (NCT04657081) that included 101 adult patients with newly diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline ECOG performance status of 2-3, severe cardiac disorder or pulmonary comorbidity disorder, moderate hepatic impairment, CLcr >= 30 mL/min to 45 mL/min, or other comorbidity.Patients received INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of each cycle and venetoclax once daily as follows: 100 mg on Cycle Day 1, 200 mg on Cycle Day 2, 400 mg on Cycle Days through 28, and 400 mg on Cycles >= Days through 28 in each 28-day cycle until disease progression or unacceptable toxicity occurred.Bone marrow evaluations were, with minimal exceptions, performed within 7-day window prior to and including Day of treatment cycle to determine response to treatment and guide decisions on study treatment dosing.The baseline demographic and disease characteristics are shown in Table 12.Table 12: Demographics and Baseline Disease Characteristics for Study ASTX727-07CharacteristicINQOVI+VEN N=101Age (years) Median (min, max)78 (63, 88)Sex (%) Male61 Female40Race (%) White81 Black or African American3 Asian7 Other, Not Reported, or Unknown10ECOG Performance Score 0-179 218 33AML Disease History De novo AML37 Secondary AML63Mutation Analysis Detected TP5317 IDH1 or IDH218 FLT-312 NPM113Baseline Comorbidities Severe Cardiac Disease17 Moderate Hepatic Impairment5 Creatinine Clearance >= 30 and 45 mL/min18Risk ClassificationDefined using 2017 ELN genetic risk classification, (%) Favorable32 (32) Intermediate34 (34) Adverse30 (30) Unknown5 (5)Efficacy was established on the basis of complete remission (CR) and the duration of CR (DoCR). CR CRh (complete remission with partial hematologic recovery), DoCR+CRh, and rate of conversion from transfusion dependence to transfusion independence were also evaluated. Duration of remission (CR or CR CRh) was defined as time from first CR (or CRh) until disease relapse or death from any cause, whichever occurred first.The efficacy results are shown in Table 13. The median follow-up time was 11.2 months (range: 0.3 to 17.5 months).Table 13:Efficacy Results in Patients with AML from Study ASTX727-07 Part BEfficacy EndpointsINQOVI+VEN (N=101)Abbreviations: CI confidence interval; CR complete remission; CRh complete remission with partial hematologic recoveryRemission RateCR, (%)42 (41.6) (95% CI)Estimated using Clopper-Pearson method (31.9, 51.8)CR+CRh, (%)53 (52.5) (95% CI) (42.3, 62.5)Of the 42 patients who achieved CR, the median time to CR was 2.0 months (range: 0.4 to 15.3 months) with INQOVI in combination with venetoclax. Of the 53 patients who achieved CR or CRh, the median time to first response of CR or CRh was 1.9 months (range: 0.4 to 10.7 months). With median follow-up of 9.0 months among patients achieving CR, the median duration of CR was not reached (range: 0.5 to 16.3 months). With median follow-up of 8.9 months among patients achieving CR or CRh, the median duration of CR or CRh was not reached (range: 0.6 to 16.3 months).Transfusion independence was defined as no RBC or platelet transfusions for >= 56 consecutive days during active treatment with INQOVI in combination with venetoclax. Among the 44 patients who were transfusion dependent at baseline, 36.4% (16/44) became transfusion independent and 63.6% (28/44) remained transfusion dependent. Of the 57 patients who were transfusion independent at baseline, 43.9% (25/57) remained transfusion independent and 56.1% (32/57) became transfusion dependent.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.INQOVI Monotherapy for MDS or CMMLThe safety of INQOVI was evaluated in pooled safety population that includes patients enrolled in Study ASTX727-01-B and Study ASTX727-02 [see Clinical Studies (14.1)]. Patients were randomized to receive INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through in Cycle and decitabine 20 mg/m2 intravenously on Days through in Cycle 2, or the reverse sequence, and then INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of each 28-day cycle in Cycles 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 months or longer and 24% were exposed to INQOVI for greater than 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 or laboratory abnormalities (>= 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased.Table summarizes the adverse reactions in the pooled safety population. Table 3: Adverse Reactions (>=10%) in Patients Who Received INQOVI in Pooled Safety PopulationAdverse ReactionsINQOVI Cycle N=107Intravenous Decitabine Cycle N=106INQOVIIncludes adverse reactions that occurred during all cycles, including during treatment with cycle of intravenous decitabine. All Cycles N=208All Grades (%)Grades or (%)All Grades (%)Grades or (%)All Grades (%)Grades or (%)General disorders and administration site conditions FatigueIncludes fatigue, asthenia, and lethargy 292250555 HemorrhageIncludes 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 242170433 EdemaIncludes 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 100110300.5 Pyrexia7070191Gastrointestinal disorders ConstipationIncludes constipation and feces hard 200230440 MucositisIncludes 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 181242414 Nausea250160400.5 DiarrheaIncludes diarrhea and feces soft 160110371 Transaminase increasedIncludes alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, liver function test increased, and transaminases increased 12130213 Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower, epigastric discomfort, and abdominal discomfort 9070191 Vomiting5050150Musculoskeletal and connective tissue disorders MyalgiaIncludes 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 92161423 ArthralgiaIncludes arthralgia, back pain, neck pain, joint stiffness, pain in jaw, joint swelling, bursitis, joint range of motion decreased, and joint injury 91131403Respiratory, thoracic, and mediastinal disorders DyspneaIncludes dyspnea, dyspnea exertional, hypoxia, wheezing, chronic obstructive pulmonary disease, and tachypnoea 17393386 CoughIncludes cough and productive cough 7080280Blood lymphatic system disorders Febrile neutropenia101013133332Skin and subcutaneous tissue disorders RashIncludes 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 121111330.5Nervous system disorders DizzinessIncludes dizziness, vertigo, postural dizziness, and positional vertigo 161110332 HeadacheIncludes headache, sinus pain, and sinus headache 220130300 NeuropathyIncludes hypoesthesia, paresthesia, neuropathy peripheral, gait disturbance, peripheral sensory neuropathy, ataxia, balance disorder, brachial plexopathy, carpal tunnel syndrome, and radicular pain 4080130Metabolism and nutritional disorders Decreased appetite10160242Infections and infestations Upper respiratory tract infectionIncludes upper respiratory tract infection, nasopharyngitis, sinusitis, and viral upper respiratory tract infection 6030231 PneumoniaIncludes pneumonia, pneumonitis, atypical pneumonia, and lung infection 77752115 SepsisIncludes sepsis, bacteremia, septic shock, endocarditis, pseudomonal bacteremia, and staphylococcal bacteremia 66211411 CellulitisIncludes cellulitis, catheter site cellulitis, and infected bite 4132125Investigations Renal impairmentIncludes blood creatinine increased, acute kidney injury, blood urea increased, blood creatine increased, and renal failure 9081180 Weight decreased5030101Injury, poisoning, and procedural complications Fall4010121Psychiatric disorders Insomnia6020120.5Vascular disorders HypotensionIncludes hypotension, blood pressure decreased, and cardiogenic shock 4061112Cardiac Disorders ArrhythmiaIncludes sinus tachycardia, atrial fibrillation, bradycardia, tachycardia, atrial flutter, sinus bradycardia, and conduction disorder 3020111Clinically relevant adverse reactions in 10% of patients who received INQOVI included: Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%)Tumor lysis syndrome (0.5%)Table 4: Select Laboratory Abnormalities (>20%) Worsening from Baseline in Patients Who Received INQOVI in Pooled Safety PopulationLab AbnormalityIncludes any lab abnormalities that worsened by one or more grades. Grade 3-4 includes any lab abnormalities that worsened to Grade or Grade 4. INQOVI Cycle 1The 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 baseline value and at least one post-treatment value. Intravenous Decitabine Cycle INQOVI All Cycles All Grades (%)Grades or (%)All Grades (%)Grades or (%)All Grades (%)Grades or (%)HematologyLeukocytes decreased796577598781Platelet count decreased796577678276Neutrophil count decreased706562597371Hemoglobin decreased584159367155ChemistryGlucose increased190110547Albumin decreased221200452Alkaline phosphatase increased221120420.5Glucose decreased140170401Alanine aminotransferase increased13170372Sodium decreased9280304Calcium decreased160120302Aspartate aminotransferase increased6120302Creatinine increased7080290.5INQOVI in Combination with Venetoclax for AMLThe safety of INQOVI in combination with venetoclax (INQOVI+VEN) in adult patients 75 years of age and older or those who have comorbidities precluding the use of intensive induction chemotherapy was evaluated in Study ASTX727-07 (N=159) [see Clinical Studies (14.2)]. Patients received INQOVI (35 mg decitabine and 100 mg cedazuridine) orally once daily on Days through of the first 28-day cycle in combination with venetoclax given as ramp up on Day (100 mg) and Day (200 mg), followed by venetoclax 400 mg daily from Day onward.Among the patients who received INQOVI+VEN, the median duration of exposure was 5.5 months (range 0.2-28 months): 47% of patients were exposed to INQOVI for months or longer and 20% of patients were exposed to INQOVI for greater than year.Serious adverse reactions occurred in 82% of patients who received INQOVI+VEN. Serious adverse reactions in 5% of patients included febrile neutropenia (31%), sepsis (22%), pneumonia (15%), infection (bacterial/viral) (10%), hemorrhage (9%), and dyspnea (6%). Fatal adverse reactions occurred in 8% of patients who received INQOVI+VEN. These included sepsis (5%), dyspnea (2%), myocardial infarction (1%), hemolytic anemia (1%), and tumor lysis syndrome (1%).Permanent discontinuation of INQOVI due to an adverse reaction occurred in 9% of patients who received INQOVI+VEN. The most frequent adverse reaction resulting in permanent discontinuation in more than patient was hemorrhage (1%).Dosage interruptions of INQOVI due to an adverse reaction occurred in 55% of patients who received INQOVI+VEN. Adverse reactions requiring dosage interruptions in >= 5% of patients who received INQOVI+VEN included neutropenia (40%), febrile neutropenia (11%), infection (bacterial/viral) (8%), and thrombocytopenia (8%).Dose reductions of INQOVI due to an adverse reaction occurred in 6% of patients who received INQOVI+VEN. The most common adverse reactions requiring dosage reductions of INQOVI were neutropenia (4%), thrombocytopenia (1%), and infection (1%).The most common adverse reactions (>= 20%) were neutropenia, febrile neutropenia, thrombocytopenia, hemorrhage, anemia, infection (bacterial/viral), diarrhea, fatigue, mucositis, constipation, arthralgia, dyspnea, decreased appetite, edema, nausea, white blood cell count decreased, sepsis, pneumonia, rash, transaminitis, myalgia, arrhythmia, and abdominal pain. The most common Grade or laboratory abnormalities (>= 50%) were decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased hemoglobin.Table summarizes the adverse reactions in ASTX727-07.Table 5: Adverse Reactions (>= 20% All-Grades or >= 5% Grades 3-4) in Patients with AML Who Received INQOVI+VEN in ASTX727-07Adverse ReactionsPhase (N=159)All Grades (%)Grades 3-4 (%)Abbreviations: N=total number of patients; n=number of patients; SOC System Organ ClassGastrointestinal DisordersDiarrhea384MucositisConsists of multiple, related terms Includes gingivitis, mouth ulceration, stomatitis, oropharyngeal pain, aphthous ulcer, colitis, enterocolitis, gingival discomfort, gingival disorder, gingival injury, glossodynia, lip injury, neutropenic colitis, odynophagia, oesophagitis, oropharyngeal discomfort, pharyngeal inflammation, proctalgia, proctitis, pulpitis dental, tongue ulceration, ulcer, vulvovaginitis, enteritis 366Constipation 361Nausea310Abdominal Pain 213General Disorders and Administration Site ConditionsFatigue 368Edema 312Metabolism and Nutrition DisordersDecreased Appetite313Blood System and Lymphatic System DisordersNeutropenia 6058Febrile Neutropenia5252Thrombocytopenia 5250Anemia4136White Blood Cell Count Decreased2828Hepatobiliary DisordersTransaminitis 244Infections and InfestationsInfection (excludes fungal) 4013Sepsis 2818Pneumonia 2520Musculoskeletal and Connective Tissue DisordersArthralgia Includes arthralgia, back pain, bone pain, joint effusion, joint injury, joint range of motion decreased, neck pain, pain in extremity, pain in jaw, pelvic pain, polyarthritis, spinal osteoarthritis, spinal pain, periarthritis, osteoarthritis 356Myalgia Includes muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal stiffness, myalgia, non-cardiac chest pain, flank pain, musculoskeletal pain 234Cardiac DisordersArrhythmia Includes arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, atrioventricular block first degree, extrasystoles, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia 214Respiratory, Thoracic, and Mediastinal DisordersDyspnea Includes dyspnoea, dyspnoea exertional, hypoxia, wheezing, respiratory failure, acute respiratory failure 3012Renal and Urinary DisordersRenal Insufficiency 185Vascular DisordersHemorrhage 429Hypotension196Skin and Subcutaneous Tissue DisordersRash Includes actinic keratosis, catherter site erythema, catherter site rash, dermatitis, dermatitis acneiform, eczema, erythema, erythema multiforme, papule, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, seborrhoeic keratosis, skin disorder, skin exfoliation, skin hyperpigmentation, skin irritation, skin lesion, skin ulcer, and Stevens-Johnson Syndrome. 251Clinically relevant adverse reactions in 10% of patients who received INQOVI+VEN included:Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%)Tumor lysis syndrome (2%)Table summarizes the laboratory abnormalities identified in the combined AML safety population.Table 6:Select Laboratory Abnormalities (> 40% All Grade AEs) in Patients Who Received INQOVI+VEN in ASTX727-07Lab AbnormalityPhase (N=159)All Grades (%)Grades 3-4 (%)Hematology and CoagulationLymphocytes (109/L) Decreased9781Leukocytes (109/L) Decreased9191Platelets (109/L) Decreased7069Hemoglobin (g/L) Decreased5450Neutrophils (109/L) Decreased4848ChemistryAlbumin (g/L) Decreased607Bilirubin (umol/L) Increased547Alkaline Phosphatase (u/L) Increased431Creatinine (umol/L) Increased414Aspartate Aminotransferase (u/L) Increased413. Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%). Tumor lysis syndrome (0.5%). Acute febrile neutrophilic dermatosis (Sweets syndrome) (1%). Tumor lysis syndrome (2%).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of decitabine and cedazuridine were characterized following administration of INQOVI in patients with MDS CMML and AML are shown in Table 7.Approximately dose-proportional increases in peak concentrations (Cmax) and AUC over the dosing interval were 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.Following administration of the recommended dosage, 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 was 60% (90% confidence intervals (CI): 55, 65) [see Dosage and Administration (2.1)]. The GMR of decitabine AUC following consecutive once daily doses of INQOVI compared to that of intravenous decitabine on Day was 106% (90% CI: 98, 114) and the GMR of the 5-day cumulative decitabine AUC following consecutive once daily doses of INQOVI compared to that of intravenous decitabine was 99% (90% CI: 93, 106).Table 7: Pharmacokinetics of the Components of INQOVI at Recommended DosageMean (%CV), unless otherwise specified ParameterDecitabineCedazuridineAbbreviations: Cmax= maximum plasma concentration; AUC0-24h=area under the plasma concentration-time curve from time zero to 24 hours; CV=coefficient of variation; Tmax= Time to maximum concentration; V/F=apparent volume of distribution; CL/F=apparent clearanceGeneral Information With the recommended dosage of INQOVI for consecutive days: 5-day cumulative AUC, ng.hr/mL851 (50%)-- Day AUC, ng.hr/mL 103 (55%)2950 (49%) Steady state AUC, ng.hr/mL178 (53%)3291 (45%) Time to steady state, days22 Accumulation ratio based on AUC1.7 (42%)1.1 (63%) Cmax, ng/mL145 (55%)371 (52%)Absorption Bioavailability Cedazuridine increases oral decitabine exposure20% (23%) Tmax, hoursMedian (range) (0.3 to 3.0)3 (1.5 to 6.1)Effect of Food High-fat mealApproximately 800-1000 calories, with 50 of calories from fat AUC0-inf decreased to 50%, Cmax decreased to 25%AUC0-inf decreased to 92%, Cmax decreased to 99% Distribution V/F at steady state, L417 (54%)296 (51%) Fraction unbound, in vitro96% (4%) to 94% (2%) between 17 ng/mL to 342 ng/mL66% (6%) to 62% (2%) between 1000 ng/mL and 50000 ng/mLElimination Half-life at steady state, 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 degradationConversion to epimer by physicochemical degradationExcretionHealthy subjects Total (% unchanged) --46% (21%) in urine and 51% (27%) in fecesSpecific PopulationsAge (32 to 92 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 m2), 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 clinically meaningful effect on the pharmacokinetics of decitabine and cedazuridine after dosing with INQOVI.The effects of moderate (total bilirubin >1.5 to x 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 StudiesClinical StudiesDecitabine had no clinically meaningful effect on the pharmacokinetics of cedazuridine. Cedazuridine increased the exposure of decitabine.There were no drug-drug interactions observed between INQOVI and venetoclax in clinical Study ASTX727-07.The coadministration of INQOVI with proton pump inhibitors had no clinically meaningful effect on exposure to decitabine or cedazuridine.In vitro StudiesCYP Enzymes: Cedazuridine is not 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION INQOVI(R) (IN KOE VEE) (decitabine and cedazuridine) tabletsThis Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 5/2026What is INQOVIINQOVI is prescription medicine used: to treat adults with myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML). Your healthcare provider will determine if INQOVI can treat your type of MDS.in combination with venetoclax to treat adults with newly diagnosed acute myeloid leukemia (AML) who: are 75 years of age or older, orhave other medical conditions that prevent the use of standard chemotherapy. It is not known if INQOVI is safe and effective in children.Before taking INQOVI, tell your healthcare provider about all of your medical conditions, including if you:have kidney problemsare pregnant or plan to become pregnant. INQOVI can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with INQOVI.Use effective birth control (contraception) during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INQOVI. Males with female partners who are able to become pregnant: Use effective birth control during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options. are breastfeeding or plan to breastfeed. It is not known if INQOVI passes into breast milk. Do not breastfeed during treatment with INQOVI and for weeks after the last dose of INQOVI.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. INQOVI may affect the way certain other medicines work and may cause side effects. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take INQOVITake INQOVI exactly as your healthcare provider tells you to.Do not change your dose or stop taking INQOVI unless your healthcare provider tells you to.Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking INQOVI if you get certain side effects.Take INQOVI one time day at about the same time each day.Take INQOVI on an empty stomach at least hours before or hours after eating.Swallow INQOVI tablets whole. Do not cut, crush, or chew the tablet.If you take INQOVI in combination with venetoclax for AML:take INQOVI at least hours before or hours after taking venetoclax. Do not take INQOVI and venetoclax at the same time.read the venetoclax Medication Guide for additional information.If you miss dose of INQOVI take your dose as soon as possible if it is within 12 hours of your usual time. Then, continue taking INQOVI at your scheduled time. If you missed dose by more than 12 hours, do not take additional doses to make up for the missed dose. Take your next scheduled dose on the following day at your usual time.If you vomit after taking dose of INQOVI, do not take another dose. Take your next scheduled dose at your usual time.Your healthcare provider may prescribe medicine to reduce nausea and vomiting before each dose of INQOVI.What are the possible side effects of INQOVIINQOVI may cause serious side effects, including:Low blood cell counts. Low blood counts (white blood cells, platelets, and red blood cells) are common with INQOVI but can also be serious and lead to infections that may be life-threatening. If your blood cell counts are too low, your healthcare provider may need to delay treatment with INQOVI, lower your dose of INQOVI, or in some cases give you medicine to help treat low blood cell counts. Your healthcare provider may need to give you antibiotic medicines to prevent or treat infections or fever while your blood cell counts are low. Your healthcare provider will check your blood cell counts before you start treatment and regularly during treatment with INQOVI. Tell your healthcare provider right away if you get any of the following signs and symptoms during treatment with INQOVI: feverchillsbody achestirednessbruising more easily than usualThe most common side effects of INQOVI in adults with MDS or CMML include:low white blood cell counts (leukopenia, neutropenia)low platelets in your blood (thrombocytopenia)low red blood cell count (anemia)tirednessconstipationbleedingmuscle painpain or sores in your mouth or throatjoint painnauseashortness of breathdiarrhearashdizzinessfever with low white blood cell count (febrile neutropenia)swelling of arms or legsheadachecoughdecreased appetiteupper respiratory tract infectionpneumoniachanges in liver function testsThe most common side effects of INQOVI in adults with AML in combination with venetoclax include:low white blood cell counts (leukopenia, lymphocytopenia, neutropenia)low platelets in your blood (thrombocytopenia)fever with low white blood cell count (febrile neutropenia)bleedinglow red blood cell count (anemia)infectiondiarrheatirednesspain or sores in your mouth or throatconstipationjoint paindecreased appetiteswelling of arms or legsnauseashortness of breathsepsispneumoniarashchanges in liver function testsmuscle painabnormal heart rhythmstomach-area (abdomen) pain, dizziness or feeling lightheadeddecreased kidney functionINQOVI may affect fertility in men, which may affect your ability to have children. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of INQOVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store INQOVIStore INQOVI at room temperature between 68F and 77F (20C and 25C).INQOVI comes in blister card in child-resistant carton.Do not store INQOVI outside of the original blisters.Talk to your healthcare provider about how to safely throw away (dispose of) INQOVI.Keep INQOVI and all medicines out of the reach of children.General information about the safe and effective use of INQOVIMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use INQOVI for condition for which it was not prescribed. Do not give INQOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about INQOVI that is written for health professionals.What are the ingredients in INQOVIActive ingredients: decitabine and cedazuridineInactive ingredients: lactose monohydrate, hypromellose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The film coating material contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red.Manufactured for: Taiho Pharmaceutical Co., Ltd. Japan Distributed by: Taiho Oncology, Inc., Princeton, NJ 08540 USA INQOVI is registered trademark of Taiho Pharmaceutical Co., Ltd. For more information, go to www.INQOVI.com or call 1-888-878-2446.. to treat adults with myelodysplastic syndromes (MDS), including chronic myelomonocytic leukemia (CMML). Your healthcare provider will determine if INQOVI can treat your type of MDS.. in combination with venetoclax to treat adults with newly diagnosed acute myeloid leukemia (AML) who: are 75 years of age or older, orhave other medical conditions that prevent the use of standard chemotherapy. are 75 years of age or older, or. have other medical conditions that prevent the use of standard chemotherapy.. have kidney problems. are pregnant or plan to become pregnant. INQOVI can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with INQOVI.Use effective birth control (contraception) during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INQOVI. Males with female partners who are able to become pregnant: Use effective birth control during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options. Your healthcare provider will check to see if you are pregnant before you start treatment with INQOVI.. Use effective birth control (contraception) during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with INQOVI.. Use effective birth control during treatment with INQOVI and for months after the last dose of INQOVI. Talk to your healthcare provider if you have questions about birth control options.. are breastfeeding or plan to breastfeed. It is not known if INQOVI passes into breast milk. Do not breastfeed during treatment with INQOVI and for weeks after the last dose of INQOVI.. Take INQOVI exactly as your healthcare provider tells you to.. Do not change your dose or stop taking INQOVI unless your healthcare provider tells you to.. Your healthcare provider may tell you to decrease your dose, temporarily stop, or completely stop taking INQOVI if you get certain side effects.. Take INQOVI one time day at about the same time each day.. Take INQOVI on an empty stomach at least hours before or hours after eating.. Swallow INQOVI tablets whole. Do not cut, crush, or chew the tablet.. If you take INQOVI in combination with venetoclax for AML:take INQOVI at least hours before or hours after taking venetoclax. Do not take INQOVI and venetoclax at the same time.read the venetoclax Medication Guide for additional information.. take INQOVI at least hours before or hours after taking venetoclax. Do not take INQOVI and venetoclax at the same time.. read the venetoclax Medication Guide for additional information.. If you miss dose of INQOVI take your dose as soon as possible if it is within 12 hours of your usual time. Then, continue taking INQOVI at your scheduled time. If you missed dose by more than 12 hours, do not take additional doses to make up for the missed dose. Take your next scheduled dose on the following day at your usual time.. If you vomit after taking dose of INQOVI, do not take another dose. Take your next scheduled dose at your usual time.. Your healthcare provider may prescribe medicine to reduce nausea and vomiting before each dose of INQOVI.. Low blood cell counts. Low blood counts (white blood cells, platelets, and red blood cells) are common with INQOVI but can also be serious and lead to infections that may be life-threatening. If your blood cell counts are too low, your healthcare provider may need to delay treatment with INQOVI, lower your dose of INQOVI, or in some cases give you medicine to help treat low blood cell counts. Your healthcare provider may need to give you antibiotic medicines to prevent or treat infections or fever while your blood cell counts are low. Your healthcare provider will check your blood cell counts before you start treatment and regularly during treatment with INQOVI. Tell your healthcare provider right away if you get any of the following signs and symptoms during treatment with INQOVI: fever. chills. body aches. tiredness. bruising more easily than usual. low white blood cell counts (leukopenia, neutropenia). low platelets in your blood (thrombocytopenia). low red blood cell count (anemia). tiredness. constipation. bleeding. muscle pain. pain or sores in your mouth or throat. joint pain. nausea. shortness of breath. diarrhea. rash. dizziness. fever with low white blood cell count (febrile neutropenia). swelling of arms or legs. headache. cough. decreased appetite. upper respiratory tract infection. pneumonia. changes in liver function tests. low white blood cell counts (leukopenia, lymphocytopenia, neutropenia). low platelets in your blood (thrombocytopenia). fever with low white blood cell count (febrile neutropenia). bleeding. low red blood cell count (anemia). infection. diarrhea. tiredness. pain or sores in your mouth or throat. constipation. joint pain. decreased appetite. swelling of arms or legs. nausea. shortness of breath. sepsis. pneumonia. rash. changes in liver function tests. muscle pain. abnormal heart rhythm. stomach-area (abdomen) pain, dizziness or feeling lightheaded. decreased kidney function. Store INQOVI at room temperature between 68F and 77F (20C and 25C).. INQOVI comes in blister card in child-resistant carton.. Do not store INQOVI outside of the original blisters.. Talk to your healthcare provider about how to safely throw away (dispose of) INQOVI.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Infertility: Can impair fertility. (8.3) Lactation: Advise not to breastfeed. (8.2). Infertility: Can impair fertility. (8.3) 8.1 Pregnancy. Risk SummaryBased on findings from human data, animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], INQOVI can cause fetal harm when administered to pregnant woman. single published case report of intravenous decitabine use throughout the first trimester during pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities). In animal reproduction studies, intravenous administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose on body surface area (mg/m2) basis caused adverse developmental outcomes, including increased embryo-fetal mortality, alterations to growth, and structural abnormalities (see Data). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataHuman DataThere are no available data on INQOVI use in pregnant women.A single published case report of intravenous decitabine pregnancy exposure in 39-year-old woman with hematologic malignancy described multiple structural abnormalities after cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly, and rocker-bottom feet. The pregnancy was terminated.Animal DataNo reproductive or developmental toxicity studies have been conducted with INQOVI or cedazuridine.In utero exposure to decitabine causes temporal-related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, and micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal central nervous system (CNS) and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (Day 10 of gestation) induces bone loss in offspring.In mice exposed to single intraperitoneal decitabine injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation Days 8, 9, 10, or 11, no maternal toxicity was observed, but reduced fetal survival was observed after treatment at mg/m2 and decreased fetal weight was observed at both dose levels. The mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects, and digital defects of fore- and hind-limbs.In rats given single intraperitoneal injection of 2.4, 3.6, or mg/m2 decitabine (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation Days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation Day 9. significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation Day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hind-limb were noted at mg/m2.The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered single mg/m2 intraperitoneal injection (approximately 7% the recommended daily clinical dose) on Day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at and months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation Day 10 was associated with reduced pregnancy rate resulting from effects on sperm production in the F1-generation.. 8.2 Lactation. Risk SummaryThere are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk or on their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with INQOVI and for weeks after the last dose.. 8.3 Females and Males of Reproductive Potential. INQOVI can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status in females of reproductive potential prior to initiating INQOVI.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with INQOVI and for months after the last dose.MalesBased on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for months after the last dose [see Nonclinical Toxicology (13.1)].InfertilityBased on findings of decitabine and cedazuridine in animals, INQOVI may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of the effect on fertility is unknown.. 8.4 Pediatric Use. The safety and effectiveness of INQOVI have not been established in pediatric patients.. 8.5 Geriatric Use. Myelodysplastic Syndromes/Chronic Myelomonocytic LeukemiaOf the 208 patients in clinical studies who received INQOVI, 75% were age 65 years and older, while 36% were age 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 years and older, 75 years and older, and younger patients.Acute Myeloid LeukemiaOf the 159 patients in the clinical study who received INQOVI in combination with venetoclax, 30% were age under 75 years old, while 70% were age 75 years and older. No overall differences in safety or effectiveness were observed in patients under 75 years of age versus 75 years and older.. 8.6 Renal Impairment. No dosage modification of INQOVI is recommended for patients with mild or moderate renal impairment (creatinine clearance [CLcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (CLcr 30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (ESRD: CLcr <15 mL/min) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelosuppression: Severe myelosuppression, including fatal adverse reactions and infectious complications can occur. Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor for response and toxicity. Delay the next cycle and resume at the same or reduced dose as recommended. (2.3, 5.1)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). Myelosuppression: Severe myelosuppression, including fatal adverse reactions and infectious complications can occur. Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor for response and toxicity. Delay the next cycle and resume at the same or reduced dose as recommended. (2.3, 5.1). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). 5.1 Myelosuppression. INQOVI Monotherapy for MDS or CMMLIn patients with MDS or CMML, INQOVI can cause severe myelosuppression, including fatal adverse reactions. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade or occurring in 76%. Neutropenia occurred in 73% of patients, with Grade or occurring in 71%. Anemia occurred in 71% of patients, with Grade or occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade or occurring in 32%. Thrombocytopenia, neutropenia, anemia, and febrile neutropenia are the most frequent cause of INQOVI dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.Fatal and serious infectious complications can occur with INQOVI. Pneumonia occurred in 21% of patients, with Grade or occurring in 15%. Sepsis occurred in 14% of patients, with Grade or occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1% [see Adverse Reactions (6.1)].Obtain complete blood cell counts prior to initiation of INQOVI, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended [see Dosage and Administration (2.4)].INQOVI in Combination with Venetoclax for AMLIn patients with AML, INQOVI can cause severe myelosuppression, including fatal adverse reactions, when given in combination with venetoclax. Based on laboratory values in Study ASTX727-07 Phase new or worsening thrombocytopenia occurred in 70% of patients, with Grade or occurring in 69%. Neutropenia occurred in 48% of patients, with Grade or occurring in 48%. Anemia occurred in 54% of patients, with Grade or occurring in 50%. Febrile neutropenia occurred in 52% of patients, with Grade or occurring in 52%. Thrombocytopenia, neutropenia, anemia, and febrile neutropenia were frequent cause of INQOVI and/or venetoclax dose reduction or interruption. Dose reductions of INQOVI due to neutropenia and thrombocytopenia occurred in 4% and 1% of patients, respectively. Dose interruptions of INQOVI due to neutropenia, febrile neutropenia, thrombocytopenia, and anemia occurred in 40%, 11%, 8%, and 2% of patients, respectively.Fatal and serious infectious complications can occur during treatment with INQOVI and venetoclax. Pneumonia occurred in 25% of patients, with Grade or occurring in 20%. Sepsis occurred in 28% of patients with Grade or occurring in 18%. Fatal pneumonia occurred in 2% of patients and fatal sepsis in 8% [see Adverse Reactions (6.1)].Obtain complete blood cell counts prior to initiation of INQOVI with venetoclax, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended [see Dosage and Administration (2.4)].. 5.2 Embryo-Fetal Toxicity. Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to pregnant woman. In nonclinical studies with decitabine in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic at doses less than the recommended human dose.Advise patients of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for months after the last dose [see Use in Specific Populations (8.1, 8.3)].