b'6.2 Postmarketing Experienceexencephaly, and cleft palate were observed at 6.0 mg/m 2 . Increased The following adverse reactions have been identified during postapprovalincidence of foredigit defects was seen in fetuses at doses greater thanuse of intravenous decitabine. Because these reactions are reported3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb voluntarily from a population of uncertain size, it is not always possible toand hind-limb were noted at 6 mg/m2. reliably estimate their frequency or establish a causal relationship to drugThe effect of decitabine on postnatal development and reproductive capacity exposure.was evaluated in mice administered a single 3 mg/m2 intraperitoneal injection Blood and Lymphatic System Disorders: (approximately 7% the recommended daily clinical dose) on Day 10 ofDifferentiation syndrome Respiratory, Thoracic and Mediastinal Disorders: gestation. Body weights of males and females exposed in utero to decitabineInterstitial lung diseasewere significantly reduced relative to controls at all postnatal time points. 7 DRUG INTERACTIONSNo consistent effect on fertility was seen when female mice exposed in 7.1 Effects of INQOVI on Other Drugsutero were mated to untreated males. Untreated females mated to males Drugs Metabolized by Cytidine Deaminaseexposed in utero showed decreased fertility at 3 and 5 months of age (36% Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme.and 0% pregnancy rate, respectively). Follow up studies indicated that Coadministration of INQOVI with drugs that are metabolized by CDA maytreatment of pregnant mice with decitabine on gestation Day 10 was result in increased systemic exposure with potential for increased toxicityassociated with a reduced pregnancy rate resulting from effects on sperm of these drugs [see Clinical Pharmacology (12.3) in the full Prescribingproduction in the F1-generation. Information]. Avoid coadministration of INQOVI with drugs that are8.2 Lactation metabolized by CDA.Risk Summary 8 USE IN SPECIFIC POPULATIONSThere are no data on the presence of cedazuridine, decitabine, or their 8.1 Pregnancymetabolites in human milk or on their effects on the breastfed child or milk Risk Summaryproduction. Because of the potential for serious adverse reactions in the Based on findings from human data, animal studies, and its mechanism ofbreastfed child, advise women not to breastfeed during treatment with action [see Clinical Pharmacology (12.1) in the full Prescribing Information],INQOVI and for at least 2 weeks after the last dose. INQOVI can cause fetal harm when administered to a pregnant woman. A8.3 Females and Males of Reproductive Potential single published case report of intravenous decitabine use throughout theINQOVI can cause fetal harm when administered to a pregnant womanfirst trimester during pregnancy describes adverse developmental outcomes,[see Use in Specific Populations (8.1) in the full Prescribing Information]including major birth defects (structural abnormalities). In animal reproduction. studies, intravenous administration of decitabine to pregnant mice and ratsPregnancy Testing during organogenesis at doses approximately 7% of the recommendedVerify the pregnancy status in females of reproductive potential prior to human dose on a body surface area (mg/m2) basis caused adverseinitiating INQOVI. developmental outcomes, including increased embryo-fetal mortality,Contraception alterations to growth, and structural abnormalities (see Data). AdviseFemalespregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage forAdvise females of reproductive potential to use effective contraception the indicated population is unknown. All pregnancies have a backgroundduring treatment with INQOVI and for 6 months after the last dose. Malesrisk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects andBased on genotoxicity findings, advise males with female partners of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% toreproductive potential to use effective contraception during treatment with 20%, respectively.INQOVI and for 3 months after the last dose [see Nonclinical Toxicology (13.1) in the full Prescribing Information]Data. Human DataInfertility There are no available data on INQOVI use in pregnant women.Based on findings of decitabine and cedazuridine in animals, INQOVIA single published case report of intravenous decitabine pregnancy exposuremay impair male fertility [see Nonclinical Toxicology (13.1) in the full Prescribing Information]in a 39-year-old woman with a hematologic malignancy described multiple. The reversibility of the effect on fertility is structural abnormalities after 6 cycles of therapy in the 18th week of gestation.unknown. These abnormalities included holoprosencephaly, absence of nasal bone,8.4 Pediatric Use mid-facial deformity, cleft lip and palate, polydactyly, and rocker-bottomThe safety and effectiveness of INQOVI have not been established in feet. The pregnancy was terminated.pediatric patients. Animal Data8.5 Geriatric Use No reproductive or developmental toxicity studies have been conductedOf the 208 patients in clinical studies who received INQOVI, 75% werewith INQOVI or cedazuridine.age 65 years and older, while 36% were age 75 years and older. No overall In utero exposure to decitabine causes temporal-related defects in the ratdifferences in safety or effectiveness were observed between patientsand/or mouse, which include growth suppression, exencephaly, defectiveage 65 years and older, 75 years and older, and younger patients. skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia,8.6 Renal Impairment gastroschisis, and micromelia. Decitabine inhibits proliferation and increasesNo dosage modification of INQOVI is recommended for patients withapoptosis of neural progenitor cells of the fetal central nervous systemmild or moderate renal impairment (creatinine clearance [CLcr] of 30 to(CNS) and induces palatal clefting in the developing murine fetus. 89 mL/min based on Cockcroft-Gault). Due to the potential for increased Studies in mice have also shown that decitabine administration duringadverse reactions, monitor patients with moderate renal impairment (CLcr osteoblastogenesis (Day 10 of gestation) induces bone loss in offspring.30 to 59 mL/min) frequently for adverse reactions. INQOVI has not been In mice exposed to single intraperitoneal decitabine injections (0, 0.9 andstudied in patients with severe renal impairment (CLcr 15 to 29 mL/min)3.0 mg/m2, approximately 2% and 7% of the recommended daily clinicalor end-stage renal disease (ESRD: CLcr 15 mL/min) [see Clinical dose, respectively) over gestation Days 8, 9, 10 or 11, no maternal toxicityPharmacology (12.3) in the full Prescribing Information]. was observed, but reduced fetal survival was observed after treatment at 17 PATIENT COUNSELING INFORMATION 3 mg/m2 and decreased fetal weight was observed at both dose levels. TheAdvise the patient to read the FDA-approved patient labeling (Patient 3 mg/m2 dose elicited characteristic fetal defects for each treatment day,Information). including supernumerary ribs (both dose levels), fused vertebrae and ribs,Myelosuppression cleft palate, vertebral defects, hind-limb defects, and digital defects of Advise patients of the risk of myelosuppression and to report any symptoms fore- and hind-limbs.of fever, infection, anemia, or bleeding to their healthcare provider as soon In rats given a single intraperitoneal injection of 2.4, 3.6 or 6 mg/m2as possible. Advise patients for the need for laboratory monitoring [see decitabine (approximately 5, 8, or 13% the daily recommended clinical dose,Warnings and Precautions (5.1) in the full Prescribing Information]. respectively) on gestation Days 9-12, no maternal toxicity was observed.Embryo-Fetal Toxicity No live fetuses were seen at any dose when decitabine was injected onAdvise pregnant women of the potential risk to a fetus. Advise females of gestation Day 9. A significant decrease in fetal survival and reduced fetalreproductive potential to inform their healthcare provider of a known or weight at doses greater than 3.6 mg/m2 was seen when decitabine wassuspected pregnancy [see Warnings and Precautions (5.2), Use in Specific given on gestation Day 10. Increased incidences of vertebral and ribPopulations (8.1) in the full Prescribing Information]anomalies were seen at all dose levels, and induction of exophthalmia,.'