DRUG INTERACTIONS-summary

Drugs Metabolized by Cytidine Deaminase:                                                                 Avoid coadministration with INQOVI.

BRIEF SUMMARY

DECITABINE AND CEDAZURIDINE-(July 2020)

Indn-      To treat Adult Patients with Myelodyplastic Syndrome     

Comp-     Tablets: 35 mg decitabine and 100 mg cedazuridine.The recommended dosage  is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle.  

CI-   None. 

 WARNINGS-                                                                                                                       ­ • Myelosuppression: Fatal and serious myelosuppression and infectiou. Obtain complete blood cell counts prior to initiation

Pat Inform-

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 potentia.

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U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  28

ADVERSE REACTIONS

Most common adverse reactions (incidence = 20%) are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased.

The most common Grade 3 or 4 laboratory abnormalities (= 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased. 

 WARNINGS AND PRECAUTIONS

­ • Myelosuppression: Fatal and serious myelosuppression 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. 

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

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.

Manufactured for: Otsuka Pharmaceutical Co., Ltd. Japan Distributed by: Taiho Oncology, Inc. Princeton, NJ 08540 USA

 CLINICAL PHARMACOLOGY

1. 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

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.

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.

3. Pharmacokinetics-                                                                                                   The pharmacokinetics of decitabine and cedazuridine following administration of INQOVI at the recommended dosage in patients with MDS and CMML are given below

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..

 Pharmacokinetics of the Components of INQOVI* Parameter Decitabine Cedazuridine General Information-                                                                                                With the recommended dosage of INQOVI for 5 consecutive days: 5-day cumulative AUC, ng.hr/mL 851 (50%) -­ Day 1 AUC, ng·hr/mL 103 (55%) 2950 (49%) Steady state AUC, ng·hr/mL 178 (53%) 3291 (45%) Time to steady state, days 2 2 14 Reference ID: 4636876 Accumulation ratio based on AUC 1.7 (42%) 1.1 (63%) Cmax, ng/mL 145 (55%) 371 (52%)

Absorption-                                                                                                            Bioavailability- Cedazuridine increases oral decitabine exposure 20% (23%) Tmax, hours‡ 1 (0.3 to 3.0) 3 (1.5 to 6.1) Distribution V/F at steady state, L 417 (54%) 296 (51%) Fraction unbound, in vitro 96% (4%) to 94% (2%) between 17 ng/mL to 342 ng/mL 66% (6%) to 62% (2%) between 1000 ng/mL and 50000 ng/mL

Elimination-                                                                                                                   Half-life at steady state† , hours 1.5 (27%) 6.7 (19%) CL/F at steady state, L/hours 197 (53%) 30.3 (46%)

Metabolism -                                                                                                         

 Primary Pathways- Primarily by cytidine deaminase (CDA) and by physicochemical degradation Conversion to epimer by physicochemical degradation

Excretion§ Total (% unchanged) -­ 46% (21%) in urine and 51% (27%) in feces Cmax= maximum plasma concentration; AUC0-24h=area under the plasma concentration-time curve from time zero to 24 hours; CV=coefficient of variation; SD=standard deviation; Tmax= Time to maximum concentration; V/F=apparent volume of distribution; CL/F=apparent clearance * Mean (%CV) † Mean (SD) ‡ Median (range) §

Healthy subjects Specific Populations-                                                                     Age (32 to 90 years), sex, and mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN or AST > ULN) did not have an effect on the pharmacokinetics of decitabine or cedazuridine after dosing with INQOVI.

Decitabine exposure (AUC) increased with decreasing body surface area or body weight, and cedazuridine exposure increased with decreasing CLcr; however, body surface area (1.3 to 2.9 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 a clinically meaningful effect on the pharmacokinetics of decitabine and cedazuridine after dosing with INQOVI.

Drug Interaction Studies-                                                                                               Clinical Studies Decitabine had no clinically meaningful effect on the pharmacokinetics of cedazuridine. Cedazuridine increased the exposure of decitabine.

The coadministration of INQOVI with proton pump inhibitors had no clinically meaningful effect on exposure to decitabine or cedazuridine.

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

Based on findings from human data, animal studies, and its mechanism of action

INQOVI can cause fetal harm when administered to a pregnant woman.

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. 

2. Lactation Risk Summary-                                                                                         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 at least 2 weeks after the last dose.

3. Females and Males of Reproductive Potential -                                                       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. The reversibility of the effect on fertility is unknown.

4. Pediatric Use-                                                                                                              The safety and effectiveness of INQOVI have not been established in pediatric patients.

5. Geriatric 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.

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)