ACN_7.4_Full Issue_Digital | Page 31

������������������������������������������������������������������� kg / day during the period of organogenesis . Malformations were ���������������������������������������������������������������� ����������������������������������������������������������������� occurred starting at the dose of 100 mg / kg / day and included folded ������������������������������������������������������������������� resorptions , and increased post-implantation loss . The exposure ( AUC ) at a dose of 100 mg / kg / day in mice is approximately equivalent to the human exposure at the recommended dose of 800 mg .
In an embryo-fetal development study in rabbits , pregnant animals ������������������������������������������������������������������ �������������������������������������������������������������������� kg / day resulted in maternal toxicity ( decreased food consumption and body weight ) and reduced fetal weights . The exposure ( AUC ) at ��������������������������������������������������������������������� human patients at the recommended dose of 800 mg .
8.2 . Lactation Risk Summary
There are no data on the presence of umbralisib in human milk or the effects on the breastfed child or milk production . Because of the potential for serious adverse reactions from umbralisib in the breastfed child , advise women not to breastfeed during treatment with UKONIQ and for one month after the last dose .
8.3 . Females and Males of Reproductive Potential UKONIQ may cause fetal harm when administered to a pregnant woman �������������������������������������� .
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating UKONIQ .
Contraception Females
Advise female patients of reproductive potential to use highly effective contraception during treatment with UKONIQ and for at least ������������������������������
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with UKONIQ and for one month after the last dose .
Infertility Males
���������������������������������������������������������������� fertility [ see Nonclinical Toxicology ( 13.1 )]. Trend for reversibility was noted in dogs 30 days after the last dose .
8.4 . Pediatric Use Safety and effectiveness of UKONIQ have not been established in pediatric patients .
8.5 . Geriatric Use Of the 221 patients with MZL or FL who received UKONIQ in clinical studies , 56 % of patients were 65 years of age and older , while 19 % were 75 years of age and older . No overall differences in effectiveness or pharmacokinetics were observed between these patients and younger patients . In patients 65 years of age and older , 23 % experienced serious adverse reactions compared to 12 % in patients younger than 65 years of age . There was a higher incidence of infectious serious adverse reactions in patients 65 years of age or older �������������������������������������������������������������
8.6 . Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment ( creatinine clearance [ CLcr ] 30 to 89 mL / min estimated by Cockcroft-Gault equation ) [ see Clinical Pharmacology ( 12.3 )]. UKONIQ has not been studied in patients with severe renal impairment ([ CLcr ] < 30 mL / min ).
8.7 . Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic �������������������������������������������������������������������� ULN or total bilirubin > 1 to 1.5 × ULN and any AST ) [ see Clinical Pharmacology ( 12.3 )]. UKONIQ has not been studied in patients with moderate ( total bilirubin > 1.5 to 3 × ULN and any AST ) or severe hepatic impairment ( total bilirubin > 3 × ULN and any AST ).
14 . CLINICAL STUDIES 14.1 . Marginal Zone Lymphoma �������������������������������������������������������������������� UTX-TGR-205 ( NCT02793583 ), an open-label , multi-center , multi-cohort trial . Patients with MZL were required to have received at least one prior therapy , including an anti-CD20 containing regimen . The trial excluded patients with prior exposure to a PI3K inhibitor . Patients received UKONIQ 800 mg orally once daily until disease progression or unacceptable toxicity .
A total of 69 patients with MZL [ extranodal ( N = 38 ), nodal ( N = 20 ), and splenic ( N = 11 )] were enrolled in this cohort . The median age was 67 ������������������������������������������������������������������� were Black , 3 % were Asian , 7 % were Other , and 97 % had a baseline ECOG performance status of 0 or 1 . Patients had a median number of prior lines of therapy of 2 ( range : 1 to 6 ), with 26 % being refractory to their last therapy .
������������������������������������������������������������� Independent Review Committee ( IRC ) using criteria adopted from the International Working Group criteria for malignant lymphoma . The median follow-up time was 20.3 months ( range : 15.0 to 28.7 �����������������������������������������������
��������������������������������������������������������� Endpoint
�������������
ORR , n (%) a
��������
95 % CI 37.0 , 61.6 CR , n (%) 11 ( 16 ) PR , n (%) 23 ( 33 ) DOR Median , months ( 95 % CI ) b NR ( 9.3 , NE ) Range , months 0.0 + , 21.8 +
���������������������������������������������������������������������������������� Independent Review Committee ; ORR , overall response rate ; NE , not evaluable ; NR , not reached ; PR , partial response . a
Per IRC according to Revised International Working Group Criteria b
Based on Kaplan-Meier estimation
+
Denotes censored observation
The median time to response was 2.8 months ( range : 1.8 to 21.2 ����������������������������������������������������������������� the 3 MZL sub-types ( extranodal , nodal , and splenic , respectively ).
14.2 . Follicular Lymphoma �������������������������������������������������������������� Study UTX-TGR-205 , an open-label , multi-center , multi-cohort trial ( NCT02793583 ). Patients with relapsed or refractory FL were required to have received at least two prior systemic therapies , including an anti-CD20 monoclonal antibody and an alkylating agent . The trial excluded patients with Grade 3b FL , large cell transformation , prior allogeneic transplant , history of CNS lymphoma , and prior exposure to a PI3K inhibitor . Patients received UKONIQ 800 mg orally once daily until disease progression or unacceptable toxicity .
A total of 117 patients with FL were enrolled in this cohort . The median age was 65 years ( range : 29 to 87 years ), 38 % were female , 80 % were ������������������������������������������������������������������ disease and 97 % had a baseline ECOG performance status of 0 to 1 . Patients had a median of 3 prior lines of therapy ( range : 1 to 10 ), with 36 % refractory to their last therapy .
������������������������������������������������������������� Independent Review Committee ( IRC ) using criteria adopted from the International Working Group criteria for malignant lymphoma . The median follow-up time was 20.1 months ( range : 13.5 to 29.6 �����������������������������������������������
��������������������������������������������������� ����������������������������
Endpoint ��������������
ORR , n (%) a
�������� 95 % CI 33.6 , 52.2
CR , n (%) ��������
PR , n (%) ��������
DOR Median months ( 95 % CI ) b ����������������� Range , months 0.0 + , 20.9 +
��������������������������������������������������������������������������������� Independent Review Committee ; ORR , overall response rate ; PR , partial response . a
Per IRC according to Revised International Working Group Criteria b
Based on Kaplan-Meier estimation
+
Denotes censored observation
���������������������������������������������������������� �������������
17 . PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ��������������������
Infections Advise patients that UKONIQ can cause serious infections that may be fatal . Advise patients to immediately report any signs or symptoms of infection ( e . g ., fever , chills , weakness ) [ see Warnings and Precautions ( 5.1 )].
Neutropenia Advise patients of the need for periodic monitoring of blood counts and to notify their healthcare provider immediately if they develop a fever or any signs of infection [ see Warnings and Precautions ( 5.2 )].
Diarrhea or Non-infectious Colitis Advise patients that they may experience loose stools or diarrhea and should contact their healthcare provider with any persistent or worsening diarrhea . Advise patients to maintain adequate hydration [ see Warnings and Precautions ( 5.3 )].
Advise patients of the possibility of colitis and to notify their healthcare provider of any abdominal pain / distress [ see Warnings and Precautions ( 5.3 )].
Hepatotoxicity ��������������������������������������������������������������������� enzymes and the need for periodic monitoring of liver tests . Advise patients to report symptoms of liver dysfunction including jaundice ( yellow eyes or yellow skin ), abdominal pain , bruising , or bleeding [ see Warnings and Precautions ( 5.4 )].
Severe Cutaneous Reactions Advise patients that UKONIQ may cause a severe skin rash and to notify their healthcare provider immediately if they develop a new or worsening skin rash [ see Warnings and Precautions ( 5.5 )].
Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential 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 contraceptive during treatment with UKONIQ and for one month after the last dose �������������������������������������� .
Advise males with female partners of reproductive potential to use effective contraceptive during treatment with UKONIQ and for one month after the last dose �������������������������������������� .
Lactation Advise women not to breastfeed during treatment with UKONIQ and for one month after the last dose �������������������������������������� .
Infertility Advise males of reproductive potential that UKONIQ may impair fertility �������������������������������������� .
Allergic Reactions Due to Inactive Ingredient FD & C Yellow No . 5 Advise patients that UKONIQ contains FD & C Yellow No . 5 ( tartrazine ), which may cause allergic-type reactions in certain susceptible persons [ see Warnings and Precautions ( 5.6 )].
Administration Inform patients to take UKONIQ orally once daily at approximately the same time each day with food and how to make up a missed or vomited dose . Advise patients to swallow tablets whole . Advise patients not to crush , break , cut or chew tablets [ see Dosage and Administration ( 2.1 )].
You are encouraged to report negative side effects of prescription drugs to the FDA . Visit MedWatch or call 1-800-FDA-1088 .
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