ACN_7.4_Full Issue_Digital | Page 30

UKONIQ ( umbralisib ) tablets , for oral use
This is a brief summary . Before prescribing , please refer to the full Prescribing Information .
1.1 . Marginal Zone Lymphoma UKONIQ is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma ( MZL ) who have received at least one prior anti-CD20-based regimen .
This indication is approved under accelerated approval based on overall response rate [ see Clinical Studies ( 14.1 )]. Continued approval ����������������������������������������������������������������������� ����������������������������������������������
1.2 . Follicular Lymphoma UKONIQ is indicated for the treatment of adult patients with relapsed or refractory follicular lymphoma ( FL ) who have received at least three prior lines of systemic therapy .
This indication is approved under accelerated approval based on overall response rate [ see Clinical Studies ( 14.2 )]. Continued approval ����������������������������������������������������������������������� ���������������������������������������������
4 . CONTRAINDICATIONS None .
5 . WARNINGS AND PRECAUTIONS 5.1 . Infections Serious , including fatal , infections occurred in patients treated with UKONIQ . Grade 3 or higher infections occurred in 10 % of 335 patients , with fatal infections occurring in < 1 %. The most frequent ������������������������������������������������������������������ ������������������������������������������������������������������ months ( range : 1 day to 21 months ) [ see Adverse Reactions ( 6.1 )].
Monitor for any new or worsening signs and symptoms of infection . ���������������������������������������������������������������� resolved . Resume UKONIQ at the same or a reduced dose [ see Dosage and Administration ( 2.3 )].
Provide prophylaxis for Pneumocystis jirovecii pneumonia ( PJP ) during treatment with UKONIQ [ see Dosage and Administration ( 2.2 )]. Withhold UKONIQ in patients with suspected PJP of any grade and ������������������������������������������������������ [ see Dosage and Administration ( 2.2 )].
Monitor for cytomegalovirus ( CMV ) infection during treatment with UKONIQ in patients with a history of CMV infection . Consider prophylactic antivirals during treatment with UKONIQ to prevent CMV infection , including CMV reactivation [ see Dosage and Administration ( 2.2 )]. For clinical CMV infection or viremia , withhold UKONIQ until infection or viremia resolves . If UKONIQ is resumed , administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly [ see Dosage and Administration ( 2.2 )].
5.2 . Neutropenia Serious neutropenia occurred in patients treated with UKONIQ . Grade 3 neutropenia developed in 9 % of 335 patients and Grade ������������������������������ [ see Adverse Reactions ( 6.1 )]. The ��������������������������������������������������������������
����������������������������������������������������������������������� of UKONIQ and at least weekly in patients with neutrophil counts < 1 × 10 9 ���������������������������������������������������������� Withhold , reduce dose , or discontinue UKONIQ depending on the severity and persistence of neutropenia [ see Dosage and Administration ( 2.3 )].
5.3 . Diarrhea or Non-infectious Colitis Serious diarrhea or non-infectious colitis occurred in patients treated with UKONIQ . Any grade diarrhea or colitis occurred in 53 % of 335 patients and Grade 3 occurred in 9 % [ see Adverse Reactions ( 6.1 )]. The median time to onset for any grade diarrhea or colitis was 1 month ( range : 1 day to 23 months ), with 75 % of cases occurring by 2.9 months .
For patients with severe diarrhea ( Grade 3 , i . e ., > 6 stools per day over baseline ) or abdominal pain , stool with mucus or blood , change in bowel habits , or peritoneal signs , withhold UKONIQ until resolved and provide supportive care with antidiarrheals or enteric acting steroids as appropriate . Upon resolution , resume UKONIQ at a reduced dose . For recurrent Grade 3 diarrhea or recurrent colitis of any grade , discontinue UKONIQ . Discontinue UKONIQ for life-threatening diarrhea or colitis [ see Dosage and Administration ( 2.3 )].
5.4 . Hepatotoxicity Serious hepatotoxicity occurred in patients treated with UKONIQ . ������������������������������������������������������������������� 8 % and < 1 %, respectively , in 335 patients [ see Adverse Reactions ( 6.1 )]. The median time to onset for Grade 3 or higher transaminase ���������������������������������������������������������
Monitor hepatic function at baseline and during treatment with UKONIQ . For ALT / AST greater than 5 to less than 20 times ULN , withhold UKONIQ until return to less than 3 times ULN , then resume at a reduced dose . For ALT / AST elevation greater than 20 times ULN , discontinue UKONIQ [ see Dosage and Administration ( 2.3 )].
5.5 . Severe Cutaneous Reactions Severe cutaneous reactions , including a fatal case of exfoliative dermatitis , occurred in patients treated with UKONIQ . Grade 3 cutaneous reactions occurred in 2 % of 335 patients and included exfoliative dermatitis , erythema , and rash ( primarily maculo-papular ) [ see Adverse Reactions ( 6.1 )]. The median time to onset of Grade 3 or
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Monitor patients for new or worsening cutaneous reactions . Review all concomitant medications and discontinue any potentially contributing medications . Withhold UKONIQ for severe ( Grade 3 ) cutaneous reactions until resolution . Monitor at least weekly until resolved . Upon resolution , resume UKONIQ at a reduced dose . Discontinue UKONIQ if severe cutaneous reaction does not improve , worsens , or recurs . Discontinue UKONIQ for life-threatening cutaneous reactions or SJS , TEN , or DRESS of any grade [ see Dosage and Administration ( 2.3 )]. Provide supportive care as appropriate .
5.6 Allergic Reactions Due to Inactive Ingredient FD & C Yellow No . 5 UKONIQ contains FD & C Yellow No . 5 ( tartrazine ), which may cause allergic-type reactions ( including bronchial asthma ) in certain susceptible persons . Although the overall incidence of FD & C Yellow No . 5 ( tartrazine ) sensitivity in the general population is low , it is frequently seen in patients who also have aspirin hypersensitivity .
5.7 Embryo-Fetal Toxicity ���������������������������������������������������������������� can cause fetal harm when administered to a pregnant woman . In animal reproduction studies , administration of umbralisib to pregnant mice during the period of organogenesis caused adverse developmental outcomes including embryo-fetal mortality and fetal malformations at maternal exposures comparable to those in patients ���������������������������������������������������������������� potential risk to a fetus . Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for one month after the last dose ������������������������������������������� .
6 . ADVERSE REACTIONS �������������������������������������������������������������������� elsewhere in the labeling :
• Infections [ see Warnings and Precautions ( 5.1 )]
• Neutropenia [ see Warnings and Precautions ( 5.2 )]
• Diarrhea and Non-infectious Colitis [ see Warnings and Precautions ( 5.3 )]
• Hepatotoxicity [ see Warnings and Precautions ( 5.4 )]
• Severe Cutaneous Reactions [ see Warnings and Precautions ( 5.5 )]
6.1 . Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not ������������������������������������������������������������
The pooled safety population described in WARNINGS AND ����������������������������������������������������������� dosage of 800 mg orally once daily in 335 adults with hematologic malignancies in studies TGR-1202-101 , TGR-1202-202 , UTX-TGR-205 , and UTX-TGR-501 . Among these 335 patients who received UKONIQ , 52 % were exposed for 6 months or longer and 30 % were exposed for greater than one year .
Relapsed or Refractory Follicular Lymphoma and Marginal Zone Lymphoma
The safety of UKONIQ was evaluated in a pooled safety population that included 221 adults with marginal zone lymphoma ( 37 %) and follicular lymphoma ( 63 %) enrolled in three single-arm , open-label trials ( Study TGR-1202-101 , TGR-1202-202 , and UTX-TGR-205 ) and one open-label extension trial ( Study UTX-TGR-501 ) [ see Clinical ��������������������� . These trials required hepatic transaminases ��������������������������������������������������������������������� ����������������������������������������������������������������� exposure to a PI3K inhibitor . Patients received UKONIQ 800 mg orally once daily . Among these 221 patients who received UKONIQ , 60 % ������������������������������������������������������������� greater than one year .
�������������������������������������������������������������� female , and 97 % had an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 to 1 . Race was reported in 92 % of patients ; of these patients , 89 % were White , 6 % were Black , and 3 % were Asian . Patients had a median of 2 prior therapies ( range 1 to 10 ).
Serious adverse reactions occurred in 18 % of patients who received ������������������������������������������������������������������� ��������������������������������������������������������������������� tract infection ( 2 %). Fatal adverse reactions occurred in < 1 % of patients who received UKONIQ , including exfoliative dermatitis .
Permanent discontinuation of UKONIQ due to an adverse reaction ����������������������������������������������������������������� ���������������������������������������������������������������� diarrhea-colitis ( 6 %) and transaminase elevation ( 5 %).
Dose reductions of UKONIQ due to an adverse reaction occurred in 11 % of patients . Adverse reactions which required dose reductions in ������������������������������������������������
Dosage interruptions of UKONIQ due to an adverse reaction occurred ������������������������������������������������������������ ����������������������������������������������������������������� transaminase elevation ( 7 %), neutropenia ( 5 %), vomiting ( 5 %), and upper respiratory tract infection ( 5 %).
��������������������������������������������������������������� abnormalities , were increased creatinine , diarrhea-colitis , fatigue , nausea , neutropenia , transaminase elevation , musculoskeletal pain , anemia , thrombocytopenia , upper respiratory tract infection , vomiting , abdominal pain , decreased appetite , and rash .
Table 3 provides the adverse reactions in the pooled safety population of 221 patients with marginal zone lymphoma and follicular lymphoma who received the recommended dosage .
������������������������������������������������������������ Marginal Zone Lymphoma and Follicular Lymphoma Who Received UKONIQ in Pooled Safety Population
UKONIQ N = 221
Adverse Reactions
All Grades ����
Grade 3 or ������
Gastrointestinal Disorders Diarrhea
58
10
Nausea
38
< 1
Vomiting
21
< 1
Abdominal pain a
19
3
General Disorders and Administration Site Conditions
Fatigue b
���
3
Edema c
���
< 1
Pyrexia
10
0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain d
27
2
Infections Upper respiratory tract infection e
21
< 1
Metabolism and Nutrition Disorders Decreased appetite
19
2
Skin and Subcutaneous Tissue Disorders
Rash f
18
3
Psychiatric Disorders Insomnia
���
< 1
a
Abdominal pain includes Abdominal pain , abdominal pain upper , abdominal
pain lower , abdominal discomfort
b
Fatigue includes Fatigue , asthenia , lethargy
c
�������������������������������������������������������������������
overload , generalized edema
d
Musculoskeletal pain includes Back pain , myalgia , pain in extremity ,
musculoskeletal pain , neck pain , spinal pain , musculoskeletal chest pain ,
musculoskeletal discomfort
e
Upper respiratory tract infection includes Upper respiratory tract infection ,
sinusitis , nasopharyngitis , rhinitis
f
Rash includes Rash , rash maculo-papular , rash erythematous , rash pruritic , rash
macular , exfoliative dermatitis
Clinically relevant adverse reactions in < 10 % of patients who
received UKONIQ included urinary tract infection ( 9 %), dyspnea ( 7 %),
pneumonia ( 6 %), sepsis ( 3 %), colitis ( 2 %), pneumonitis (< 1 %), and
exfoliative dermatitis (< 1 %).
�������������������������������������������������������������������
population of 221 patients with marginal zone lymphoma and
follicular lymphoma who received the recommended dosage .
������������������������������������������������
That Worsened from Baseline in Patients with Marginal
Zone Lymphoma and Follicular Lymphoma Who Received
UKONIQ in Pooled Safety Population
UKONIQ N = 221
Laboratory Parameter
Any Grades a ����
Grade 3 or 4 b �����
Hematologic Neutrophil decreased
33
16
Hemoglobin decreased
27
3
Platelets decreased
26
��
Chemistry Creatinine increased
79
0
Alanine aminotransferase
33
8
increased
Aspartate aminotransferase
32
7
increased
Potassium decreased
21
��
a
Laboratory values were categorized using the National Cancer Institute Common
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8 . USE IN SPECIFIC POPULATIONS
8.1 . Pregnancy
Risk Summary
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[ see Clinical Pharmacology ( 12.1 )], UKONIQ can cause fetal harm when
administered to a pregnant woman . There are no available data on
UKONIQ use in pregnant women to evaluate for a drug-associated
risk . In animal reproduction studies , administration of umbralisib
to pregnant mice during organogenesis resulted in adverse
developmental outcomes , including alterations to growth , embryo-fetal
mortality , and structural abnormalities at maternal exposures ( AUC )
comparable to those in patients at the recommended dose of 800 mg
( see Data ). Advise pregnant women of the potential risk to a fetus .
In the U . S . general population , the estimated background risk
of major birth defects and miscarriage in clinically recognized
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Data
Animal Data
In an embryo-fetal development study in mice , pregnant animals