Decitabine and cedazuridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Decitabine and cedazuridine is {{{aOrAn}}} inhibits cytidine deaminase that is FDA approved for the treatment of 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.. Common adverse reactions include Myelosuppression.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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.
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
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine and cedazuridine in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Decitabine and cedazuridine in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Decitabine and cedazuridine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Decitabine and cedazuridine in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Decitabine and cedazuridine in pediatric patients.
Contraindications
None
Warnings
Myelosuppression Fatal and serious myelosuppression can occur with INQOVI. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with Grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with Grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with Grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with Grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is 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 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with Grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 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.
Embryo-Fetal Toxicity Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to a 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 pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose
Adverse Reactions
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.
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/m2 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.
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%)
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
Drug Interactions
Effects of INQOVI on Other Drugs Drugs Metabolized by Cytidine Deaminase
Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme. Coadministration of INQOVI with drugs that are metabolized by CDA may result in increased systemic exposure with potential for increased toxicity of these drugs. Avoid coadministration of INQOVI with drugs that are metabolized by CDA.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Decitabine and cedazuridine in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Decitabine and cedazuridine in women who are pregnant.
Labor and Delivery
Based on findings from human data, animal studies, and its mechanism of action, INQOVI can cause fetal harm when administered to a pregnant woman. A 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 a 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 a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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.
Nursing Mothers
There 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 2 weeks after the last dose.
Pediatric Use
The safety and effectiveness of INQOVI have not been established in pediatric patients.
Geriatic Use
Of 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.
Gender
INQOVI can cause fetal harm when administered to a pregnant woman. Pregnancy Testing
Verify the pregnancy status in females of reproductive potential prior to initiating INQOVI.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose.
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose.
Infertility
Based 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.
Race
There is no FDA guidance on the use of Decitabine and cedazuridine with respect to specific racial populations.
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)
Hepatic Impairment
There is no FDA guidance on the use of Decitabine and cedazuridine in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Decitabine and cedazuridine in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Decitabine and cedazuridine in patients who are immunocompromised.
Administration and Monitoring
Administration
Do NOT substitute INQOVI for an intravenous decitabine product within a cycle.
Consider administering antiemetics prior to each dose to minimize nausea and vomiting
Monitoring
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.
- 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.
- Manage persistent severe neutropenia and febrile neutropenia with supportive treatment
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
IV Compatibility
There is limited information regarding the compatibility of Decitabine and cedazuridine and IV administrations.
Overdosage
There is limited information regarding Decitabine and cedazuridine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Decitabine and cedazuridine Pharmacology in the drug label.
Mechanism of Action
Decitabine is a 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 a CDA inhibitor. Administration of cedazuridine with decitabine increases systemic exposure of decitabine.
Structure
There is limited information regarding Decitabine and cedazuridine Structure in the drug label.
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.
Based on the exposure-response analyses, a relationship between an increase in 5-day cumulative daily decitabine exposure and a greater likelihood of some adverse reactions (e.g., any grade neutropenias, thrombocytopenia) was observed in clinical studies.
Pharmacokinetics
The pharmacokinetics of decitabine and cedazuridine following administration of INQOVI at the recommended dosage in patients with MDS and CMML.
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. 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 (Cmax) 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.
Nonclinical Toxicology
There is limited information regarding Decitabine and cedazuridine Nonclinical Toxicology in the drug label.
Clinical Studies
Study ASTX727-01-B
INQOVI 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 1 and decitabine 20 mg/m2 intravenously in Cycle 2 or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days 1 through 5 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.
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. 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).
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 ASTX727-02
INQOVI 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 1 and decitabine 20 mg/m2 intravenously in Cycle 2 or the reverse sequence. Both INQOVI and intravenous decitabine were administered once daily on Days 1 through 5 of the 28-day cycle. Starting with Cycle 3, all patients received INQOVI orally once daily on Days 1 through 5 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 primary outcome measure was comparison of the 5-day cumulative decitabine AUC between INQOVI and intravenous decitabine. 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. 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).
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.
How Supplied
INQOVI tablets are biconvex, oval-shaped, film-coated, red, and debossed with “H35” on one side.
The tablets are packaged in blisters and supplied as follows:
- NDC: 64842-0727-9; 5 tablets in one blister card in a child-resistant carton
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense medication in the original packaging.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
Myelosuppression
Advise patients of the risk of myelosuppression and to report any symptoms of fever, infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients for the need for laboratory monitoring.
Embryo-Fetal Toxicity
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with INQOVI and for 6 months after the last dose.
Advise males with female partners of reproductive potential to use effective contraception during treatment with INQOVI and for 3 months after the last dose.
Lactation
Advise women not to breastfeed during treatment with INQOVI and for 2 weeks after the last dose.
Administration
Advise patients to take INQOVI at approximately the same time each day on an empty stomach. Instruct patients to avoid eating for at least 2 hours before and 2 hours after taking INQOVI. Advise patients on what to do when a dose is missed or vomited.
Precautions with Alcohol
Alcohol-Decitabine and cedazuridine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
INQOVI
Look-Alike Drug Names
There is limited information regarding Decitabine and cedazuridine Look-Alike Drug Names in the drug label.
Price
References
The contents of this FDA label are provided by the National Library of Medicine.