ASH Clinical News ACN_4.9_Digital_Issue | Page 39

associated skeletal malformations ( not ossified metacarpal , misaligned phalanx and metacarpal , absent digit , not ossified phalanx , and short not ossified or bent tibia ), moderate dilation of the lateral ventricle in the brain , abnormal placement of the right subclavian artery , absent intermediate lobe in the lungs , low-set kidney , altered liver morphology , incompletely or not ossified pelvis , an increased average for supernumerary thoracic ribs , and a reduced average for ossified tarsals . No maternal toxicity was observed at the low dose ( 10 mg / kg / day ) that resulted in cardiac anomalies in fetuses ; this dose resulted in an exposure ( AUC ) approximately equal to that reported in humans at the recommended dose of 4 mg / day . Additional embryo-fetal toxicity included increased resorption .

Following daily oral administration of pomalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits , fetal plasma pomalidomide concentrations were approximately 50 % of the maternal C max at all dosages ( 5 to 250 mg / kg / day ), indicating that pomalidomide crossed the placenta .

8.2 Lactation Risk Summary There is no information regarding the presence of pomalidomide in human milk , the effects of POMALYST on the breastfed child , or the effects of POMALYST on milk production . Pomalidomide was excreted in the milk of lactating rats [ see Data ]. Because many drugs are excreted in human milk and because of the potential for adverse reactions in a breastfed child from POMALYST , advise women not to breastfeed during treatment with POMALYST .

Data Animal Data Following a single oral administration of pomalidomide to lactating rats approximately 14 days postpartum , pomalidomide was transferred into milk , with milk to plasma ratios of 0.63 to 1.46 .

8.3 Females and Males of Reproductive Potential Pregnancy Testing POMALYST can cause fetal harm when administered during pregnancy [ see Use in Specific Populations ( 8.1 )]. Verify the pregnancy status of females of reproductive potential prior to initiating POMALYST therapy and during therapy . Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy , while taking POMALYST , during dose interruptions and for at least 4 weeks after completing therapy .

Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST . The first test should be performed within 10-14 days , and the second test within 24 hours prior to prescribing POMALYST . Once treatment has started and during dose interruptions , pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use , then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles . If menstrual cycles are irregular , the pregnancy testing should occur every 2 weeks . Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding . POMALYST treatment must be discontinued during this evaluation .

Contraception Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously : one highly effective form of contraception – tubal ligation , IUD , hormonal ( birth control pills , injections , hormonal patches , vaginal rings , or implants ), or partner ’ s vasectomy , and 1 additional effective contraceptive method – male latex or synthetic condom , diaphragm , or cervical cap . Contraception must begin 4 weeks prior to initiating treatment with POMALYST , during therapy , during dose interruptions , and continuing for 4 weeks following discontinuation of POMALYST therapy . Reliable contraception is indicated even where there has been a history of infertility , unless due to hysterectomy . Females of reproductive potential should be referred to a qualified provider of contraceptive methods , if needed .

Males Pomalidomide is present in the semen of males who take POMALYST . Therefore , males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST , even if they have undergone a successful vasectomy . Male patients taking POMALYST must not donate sperm .

Infertility Based on findings in animals , female fertility may be compromised by treatment with POMALYST [ see Nonclinical Toxicology ( 13.1 )].

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients .

8.5 Geriatric Use No dosage adjustment is required for POMALYST based on age .

Of the total number of patients in clinical studies of POMALYST , 44 % were aged older than 65 years , while 10 % were aged older than 75 years . No overall differences in effectiveness were observed between these patients and younger patients . In these studies , patients older than 65 years were more likely than patients less than or equal to 65 years of age to experience pneumonia .

8.6 Renal Impairment In patients with severe renal impairment requiring dialysis , the AUC of pomalidomide increased by 38 % and the rate of SAE increased by 64 % relative to patients with normal renal function ; therefore , starting dose adjustment is recommended . For patients with severe renal impairment requiring dialysis , POMALYST should be administered after the completion of hemodialysis on dialysis days because exposure of pomalidomide could be significantly decreased during dialysis [ see Dosage and Administration ( 2.4 )].

8.7 Hepatic Impairment Pomalidomide is metabolized primarily by the liver . Following single dose administration , the AUC of pomalidomide increased 51 %, 58 %, and 72 % in subjects with mild ( Child-Pugh class A ), moderate ( Child-Pugh class B ), and severe ( Child-Pugh class C ) hepatic impairment compared to subjects with normal liver function . Dose adjustment is recommended in patients with hepatic impairment [ see Dosage and Administration ( 2.5 )].

8.8 Smoking Tobacco Cigarette smoking reduces pomalidomide AUC by 32 % due to CYP1A2 induction . Advise patients that smoking may reduce the efficacy of pomalidomide .

10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide . Hemodialysis can remove pomalidomide from circulation .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis , Mutagenesis , Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted . One of 12 monkeys dosed with 1 mg / kg of pomalidomide ( an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg / day ) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study .

Pomalidomide was not mutagenic or clastogenic in a battery of tests , including the bacteria reverse mutation assay ( Ames test ), the in vitro assay using human peripheral blood lymphocytes , and the micronucleus test in orally treated rats administered doses up to 2000 mg / kg / day .

In a fertility and early embryonic development study in rats , drug-treated males were mated with untreated or treated females . Pomalidomide was administered to males and females at doses of 25 to 1000 mg / kg / day . When treated males were mated with treated females , there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels . There were no other effects on reproductive functions or the number of pregnancies . The lowest dose tested in animals resulted in an exposure ( AUC ) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg / day . When treated males in this study were mated with untreated females , all uterine parameters were comparable to the controls . Based on these results , the observed effects were attributed to the treatment of females .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).

Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [ see Boxed Warning and Contraindications ( 4 )]. POMALYST is a thalidomide analogue and may cause serious birth defects or death to a developing baby [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )].

• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy .

• Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test .

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception , including at least 1 highly effective form , simultaneously during POMALYST therapy , during dose interruptions , and for 4 weeks after she has completely finished taking POMALYST . Highly effective forms of contraception other than tubal ligation include IUD and hormonal ( birth control pills , injections , patch , or implants ) and a partner ’ s vasectomy . Additional effective contraceptive methods include latex or synthetic condom , diaphragm , and cervical cap .

• Instruct patient to immediately stop taking POMALYST and contact her healthcare provider if she becomes pregnant while taking this drug , if she misses her menstrual period or experiences unusual menstrual bleeding , if she stops taking birth control , or if she thinks FOR ANY REASON that she may be pregnant .

• Advise patient that if her healthcare provider is not available , she should call Celgene Customer Care Center at 1-888-423-5436 [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST , even if they have undergone a successful vasectomy .

• Advise male patients taking POMALYST that they must not donate sperm [ see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.3 )].

• All patients must be instructed to not donate blood while taking POMALYST and for 4 weeks following discontinuation of POMALYST [ see Warnings and Precautions ( 5.1 )].

POMALYST REMS Program Because of the risk of embryo-fetal toxicity , POMALYST is only available through a restricted program called POMALYST REMS [ see Warnings and Precautions ( 5.2 )].

• Patients must sign a Patient-Physician Agreement Form and comply with the requirements to receive POMALYST . In particular , females of reproductive potential must comply with the pregnancy testing , contraception requirements , and participate in monthly telephone surveys . Males must comply with the contraception requirements [ see Use in Specific Populations ( 8.3 )].

• POMALYST is available only from pharmacies that are certified in POMALYST REMS program . Provide patients with the telephone number and website for information on how to obtain the product .