warnings and cautions
5 WARNINGS AND PRECAUTIONS Infections : Monitor for fever and any new or worsening signs and symptoms of infection. Evaluate promptly and treat as needed ( 5.1 ). Neutropenia : Monitor blood counts during treatment ( 5.2 ). Diarrhea or Non-infectious colitis : Monitor for the development of diarrhea or colitis and provide supportive care as appropriate ( 5.3 ). Hepatotoxicity : Monitor hepatic function ( 5.4 ). Severe cutaneous reactions : Withhold treatment, reduce dose, or discontinue treatment depending on severity and persistence of severe cutaneous reaction ( 5.5 ). 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 ( 5.6 ). Embryo-fetal toxicity : Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception ( 5.7 , 8.1 , 8.3 ). 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 Grade ≥3 infections included pneumonia, sepsis, and urinary tract infection. The median time to onset of Grade ≥3 infection was 2.4 months (range: 1 day to 21 months) [see Adverse Reactions ( 6.1 )]. Monitor for any new or worsening signs and symptoms of infection. For Grade 3 or 4 infection, withhold UKONIQ until infection has 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 permanently discontinue in patients with confirmed PJP [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 4 neutropenia developed in 9% [see Adverse Reactions ( 6.1 )]. The median time to onset of Grade 3 or 4 neutropenia was 45 days. Monitor neutrophil counts at least every 2 weeks for the first 2 months of UKONIQ and at least weekly in patients with neutrophil counts <1 ×10 9 /L (Grade 3-4). Consider supportive care as appropriate. 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 lifethreatening diarrhea or colitis [see Dosage and Administration ( 2.3 )]. 5.4 Hepatotoxicity Serious hepatotoxicity occurred in patients treated with UKONIQ. Grade 3 and 4 transaminase elevations (ALT and/or AST) occurred in 8% and <1%, respectively, in 335 patients [see Adverse Reactions ( 6.1 )]. The median time to onset for Grade 3 or higher transaminase elevations was 2.2 months (range: 15 days to 4.7 months). 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 higher cutaneous reaction was 15 days (range: 9 days to 6.4 months). 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 Based on findings in animals and its mechanism of action, UKONIQ 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 at the recommended dose of 800 mg. Advise pregnant women of the 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 [see Use in Specific Populations ( 8.1 , 8.3 )].