Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications . The background risk of major birth defects and miscarriage for the indicated population is unknown . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % -4% and 15 % -20%, respectively .
Data Animal Data Enasidenib administered to pregnant rats at a dose of 30 mg / kg twice daily during organogenesis ( gestation days 6-17 ) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss , resorptions , decreased viable fetuses , lower fetal birth weights , and skeletal variations . These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg / day .
In pregnant rabbits treated during organogenesis ( gestation days 7-19 ), enasidenib was maternally toxic at doses equal to 5 mg / kg / day or higher ( exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose ) and caused spontaneous abortions at 5 mg / kg / day ( exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose ).
8.2 Lactation Risk Summary There are no data on the presence of enasidenib or its metabolites in human milk , the effects on the breastfed infant , or the effects on milk production . Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants , advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose .
8.3 Females and Males of Reproductive Potential Pregnancy Testing Based on animal embryo-fetal toxicity studies , IDHIFA can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations ( 8.1 )].
Obtain a pregnancy test on females of reproductive potential prior to starting treatment with IDHIFA .
Contraception Females Advise females of reproductive potential to avoid becoming pregnant while receiving IDHIFA . Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose . Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives . The clinical significance of this potential drug interaction is unknown at this time .
Males Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA .
Infertility Based on findings in animals , IDHIFA may impair fertility in females and males of reproductive potential . It is not known whether these effects on fertility are reversible [ see Nonclinical Toxicology ( 13.1 )].
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established .
8.5 Geriatric Use No dosage adjustment is required for IDHIFA based on age . In the clinical study , 61 % of 214 patients were aged 65 years or older , while 24 % were older than 75 years . No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients .
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility Carcinogenicity studies have not been performed with enasidenib .
Enasidenib was not mutagenic in an in vitro bacterial reverse mutation ( Ames ) assay . Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay , or in an in vivo rat bone marrow micronucleus assay .
Fertility studies in animals have not been conducted with enasidenib . In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90-days in duration , changes were reported in male and female reproductive organs including seminiferous tubular degeneration , hypospermia , atrophy of the seminal vesicle and prostate , decreased corpora lutea and increased atretic follicles in the ovaries , and atrophy in the uterus .
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).
Differentiation Syndrome Advise patients on the risks of developing differentiation syndrome as early as 10 days and during the first 5 months on treatment . Ask patients to immediately report any symptoms suggestive of differentiation syndrome , such as fever , cough or difficulty breathing , bone pain , rapid weight gain or swelling of their arms or legs , to their healthcare provider for further evaluation [ see Boxed Warning and Warnings and Precautions ( 5.1 )].
Tumor Lysis Syndrome Advise patients on the risks of developing tumor lysis syndrome . Advise patients on the importance of maintaining high fluid intake , and the need for frequent monitoring of blood chemistry values [ see Dosage and Administration ( 2.3 ) and Adverse Reactions ( 6.1 )].
Gastrointestinal Adverse Reactions Advise patients on risk of experiencing gastrointestinal reactions such as diarrhea , nausea , vomiting , decreased appetite , and changes in their sense of taste . Ask patients to report these events to their healthcare provider , and advise patients how to manage them [ see Adverse Reactions ( 6.1 )].
Elevated Blood Bilirubin Inform patients that taking IDHIFA may cause elevated blood bilirubin , which is due to its mechanism of action , and not due to liver damage . Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation [ see Adverse Reactions ( 6.1 )].
Embryo-Fetal Toxicity and Use of Contraceptives Advise female patients with reproductive potential to use effective contraceptive methods while receiving IDHIFA and to avoid pregnancy while on treatment and for 1 month after completion of treatment . Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during IDHIFA treatment . Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA . Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives . The clinical significance of this potential drug interaction is unknown at this time [ see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.3 )].
Lactation Advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the final dose [ see Use in Specific Populations ( 8.2 )].
Dosing and Storage Instructions
• Advise patients not to chew or split the tablets but swallow whole with a cup of water .
• Instruct patients that if they miss a dose or vomit after a dose of IDHIFA , to take it as soon as possible on the same day and return to normal schedule the following day . Warn patients not to take 2 doses to make up for the missed dose [ see Dosage and Administration ( 2.2 )].
• Keep IDHIFA in the original container . Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture .
Manufactured for and marketed by : Celgene Corporation Summit , NJ 07901
Licensed from : Agios Pharmaceuticals Cambridge , MA 02139
Trademarks are the property of their respective owners . IDHIFA ® is a registered trademark of Celgene Corporation . Pat . www . celgene . com / therapies
© 2016-2017 Celgene Corporation All Rights Reserved . IDH _ HCP _ BS _ v01 _ 08-2017