COPIKTRA

1 INDICATIONS AND USAGE COPIKTRA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines of systemic therapy. Limitations of Use: COPIKTRA is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased risk of treatment-related mortality. COPIKTRA is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior lines lines of systemic therapy. ( 1 ) Limitations of Use : COPIKTRA is not indicated or recommended for the treatment of any patients with CLL or SLL as initial or second line treatment due to an increased risk of treatment-related mortality. ( 1 )

2 DOSAGE AND ADMINISTRATION 25 mg orally, twice daily. Modify dosage for toxicity. ( 2.1 , 2.2 ) 2.1 Recommended Dosage The recommended dose of COPIKTRA is 25 mg administered as oral capsules twice daily (BID) with or without food. A cycle consists of 28 days. The capsules should be swallowed whole. Advise patients not to open, break, or chew the capsules. Advise patients that if a dose is missed by fewer than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time. 2.2 Recommended Prophylaxis Provide prophylaxis for Pneumocystis jirovecii (PJP) during treatment with COPIKTRA. Following completion of COPIKTRA treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold COPIKTRA in patients with suspected PJP of any grade, and discontinue if PJP is confirmed. Consider prophylactic antivirals during COPIKTRA treatment to prevent cytomegalovirus (CMV) infection including CMV reactivation. 2.3 Dosage Modifications for Adverse Reactions Manage toxicities per Table 1 with dose reduction, treatment hold, or discontinuation of COPIKTRA. Table 1. COPIKTRA Dose Modifications and Toxicity Management Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CMV = cytomegalovirus; DRESS = drug reaction with eosinophilia and systemic systems; PCR = polymerase chain reaction; PJP = Pneumocystis jirovecii; pneumonia; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; ULN = upper limit of normal Toxicity Adverse Reaction Grade Recommended Management Nonhematologic Adverse Reactions Infections Grade 3 or higher infection Withhold COPIKTRA until resolved Resume at the same or reduced dose (see Table 2 ) Clinical CMV infection or viremia (positive PCR or antigen test) Withhold COPIKTRA until resolved Resume at the same or reduced dose (see Table 2 ) If COPIKTRA is resumed, monitor patients for CMV reactivation (by PCR or antigen test) at least monthly PJP For suspected PJP, withhold COPIKTRA until evaluated For confirmed PJP, discontinue COPIKTRA Non-infectious Diarrhea or colitis Mild/moderate diarrhea (Grade 1-2, up to 6 stools per day over baseline) and responsive to antidiarrheal agents, OR Asymptomatic (Grade 1) colitis No change in dose Initiate supportive therapy with antidiarrheal agents as appropriate Monitor at least weekly until resolved Mild/moderate diarrhea (Grade 1-2, up to 6 stools per day over baseline) and unresponsive to antidiarrheal agents Withhold COPIKTRA until resolved Initiate supportive therapy with enteric acting steroids (e.g., budesonide) Monitor at least weekly until resolved Resume at a reduced dose (see Table 2 ) Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, OR Severe diarrhea (Grade 3, >6 stools per day over baseline) Withhold COPIKTRA until resolved Initiate supportive therapy with enteric acting steroids (e.g., budesonide) or systemic steroids Monitor at least weekly until resolved Resume at a reduced dose (see Table 2 ) For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue COPIKTRA Life-threatening Discontinue COPIKTRA Cutaneous reactions Grade 1-2 No change in dose Initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids Monitor closely Grade 3 Withhold COPIKTRA until resolved Initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids Monitor at least weekly until resolved Resume at reduced dose (see Table 2 ) If severe cutaneous reaction does not improve, worsens, or recurs, discontinue COPIKTRA Life-threatening Discontinue COPIKTRA SJS, TEN, DRESS (any grade) Discontinue COPIKTRA Pneumonitis without suspected infectious cause Moderate (Grade 2) symptomatic pneumonitis Withhold COPIKTRA Treat with systemic steroid therapy If pneumo…

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor hepatic function. ( 5.6 ) Neutropenia: Monitor blood counts. ( 5.7 ) Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.8 ) 5.1 Treatment-related Mortality In a randomized controlled study in patients with relapsed or refractory CLL or SLL, treatment with COPIKTRA caused increased treatment-related mortality [see Clinical Studies ( 14 )] . With extended follow-up with a median of 63 months, treatment-related deaths occurred in 15% (23/158) of those patients in the overall population. In the indicated patient population, patients with relapsed or refractory CLL or SLL after at least two prior lines of systemic therapy, treatment-related deaths following treatment with COPIKTRA occurred in 14% (13/93) of patients. The most common cause of the treatment-related deaths were infections, which occurred in 9% and 11% of patients with relapsed or refractory CLL following at least one or two prior systemic therapies, respectively [see Adverse Reactions ( 6.1 )] . COPIKTRA is not indicated and is not recommended for any patients in the initial or second-line treatment setting [see Indications and Usage ( 1 )] . 5.2 Infections Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving COPIKTRA 25 mg BID (N = 442). The most common serious infections were pneumonia, sepsis, and lower respiratory infections. Median time to onset of any grade infection was 3 months (range: 1 day to 32 months), with 75% of cases occurring within 6 months. Treat infections prior to initiation of COPIKTRA. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold COPIKTRA until infection has resolved. Resume COPIKTRA at the same or reduced dose [see Dosage and Administration ( 2.3 )] . Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking COPIKTRA. Provide prophylaxis for PJP during treatment with COPIKTRA. Following completion of COPIKTRA treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/µL. Withhold COPIKTRA in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed. CMV reactivation/infection occurred in 1% of patients taking COPIKTRA. Consider prophylactic antivirals during COPIKTRA treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold COPIKTRA until infection or viremia resolves. If COPIKTRA 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 ( 2.3 )] . 5.3 Diarrhea or Colitis Serious, including fatal (1/442; 0.2%), diarrhea or colitis occurred in 18% of patients receiving COPIKTRA 25 mg BID (N = 442). The median time to onset of any grade diarrhea or colitis was 4 months (range: 1 day to 33 months), with 75% of cases occurring by 8 months. The median event duration was 0.5 months (range: 1 day to 29 months; 75 th percentile: 1 month). Advise patients to report any new or worsening diarrhea. For non-infectious diarrhea or colitis, follow the guidelines below: For patients presenting with mild or moderate diarrhea (Grade 1-2) (i.e., up to 6 stools per day over baseline) or asymptomatic (Grade 1) colitis, initiate supportive care with antidiarrheal agents as appropriate, continue COPIKTRA at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold COPIKTRA and initiate supportive therapy with enteric acting steroids (e.g., budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting COPIKTRA at a reduced dose. For patients prese…

4 CONTRAINDICATIONS None. None.

7 DRUG INTERACTIONS CYP3A4 inhibitors: Reduce COPIKTRA dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors. ( 2.4 , 7.1 , 12.3 ) Strong CYP3A4 inducers: Avoid coadministration. ( 2.5 , 7.1 , 12.3 ) Moderate CYP3A4 inducers: Avoid coadministration. If coadministration cannot be avoided, increase the dose of COPIKTRA. ( 2.5 , 7.1 , 12.3 ) CYP3A4 substrates: Monitor for signs of toxicities when co-administering COPIKTRA with sensitive CYP3A substrates. ( 7.2 ) 7.1 Effects of Other Drugs on COPIKTRA Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases duvelisib AUC [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of COPIKTRA toxicities. Reduce COPIKTRA dosage when co-administered with a strong CYP3A4 inhibitor [see Dosage and Administration ( 2.4 )] . Strong and Moderate CYP3A4 Inducers Coadministration with a strong or moderate CYP3A4 inducer decreases duvelisib area under the curve (AUC) [see Clinical Pharmacology ( 12.3 )] , which may reduce COPIKTRA efficacy. Avoid coadministration of strong or moderate CYP3A4 inducers with COPIKTRA. If coadministration with a moderate CYP3A4 inducer cannot be avoided, increase the COPIKTRA dose. [see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )]. 7.2 Effects of COPIKTRA on Other Drugs CYP3A4 Substrates Coadministration with COPIKTRA increases AUC of a sensitive CYP3A4 substrate [see Clinical Pharmacology ( 12.3 )] which may increase the risk of toxicities of these drugs. Consider reducing the dose of the sensitive CYP3A4 substrate and monitor for signs of toxicities of the co-administered sensitive CYP3A4 substrate.

8.1 Pregnancy Risk Summary Based on findings from animal studies and the mechanism of action, COPIKTRA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (resorptions, post-implantation loss, and decreased viable fetuses), alterations to growth (lower fetal weights) and structural abnormalities (malformations) at maternal doses 10 times and 39 times the MRHD of 25 mg BID in rats and rabbits, respectively (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals received daily oral doses of duvelisib of 0, 10, 50, 150 and 275 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 50 mg/kg/day resulted in adverse developmental outcomes including reduced fetal weights and external abnormalities (bent tail and fetal anasarca), and doses ≥ 150 mg/kg/day resulted in maternal toxicity including mortality and no live fetuses (100% resorption) in surviving dams. In another study in pregnant rats receiving oral doses of duvelisib up to 35 mg/kg/day during the period of organogenesis, no maternal or embryo-fetal effects were observed. The dose of 50 mg/kg/day in rats is approximately 10 -times the MRHD of 25 mg BID. In an embryo-fetal development study in rabbits, pregnant animals received daily oral doses of duvelisib of 0, 25, 100, and 200 mg/kg/day during the period of organogenesis. Administration of duvelisib at doses ≥ 100 mg/kg/day resulted in maternal toxicity (body weight losses or lower mean body weights and increased mortality) and adverse developmental outcomes (increased resorptions and post-implantation loss, abortion, and decreased numbers of viable fetuses). In another study in pregnant rabbits receiving oral doses of duvelisib up to 75 mg/kg/day, no maternal or embryo-fetal effects were observed. The dose of 100 mg/kg/day in rabbits is approximately 39 times the MRHD of 25 mg BID.

6 ADVERSE REACTIONS The following adverse reactions have been associated with COPIKTRA in clinical trials and are discussed in greater detail in other sections of the prescribing information: Treatment-related Mortality [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Diarrhea or Colitis [see Warnings and Precautions ( 5.3 )] Cutaneous Reactions [see Warnings and Precautions ( 5.4 )] Pneumonitis [see Warnings and Precautions ( 5.5 )] Hepatotoxicity [see Warnings and Precautions ( 5.6 )] Neutropenia [see Warnings and Precautions ( 5.7 )] The most common adverse reactions ( > 20%) are diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Secura Bio, Inc. (Secura Bio) at 1-844-973-2872, or U.S. Food and Drug Administration (FDA) at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in practice. Summary of Clinical Trial Experience in B-cell Malignancies The data described below reflect exposure to COPIKTRA in two single-arm, open-label clinical trials, one open-label extension clinical trial, and one randomized, open-label, actively controlled clinical trial totaling 442 patients with previously treated hematologic malignancies primarily including CLL/SLL (69%) and FL (22%). Patients were treated with COPIKTRA 25 mg BID until unacceptable toxicity or progressive disease. The median duration of exposure was 9 months (range: 0.1 to 53 months), with 36% (160/442) of patients having at least 12 months of exposure. For the 442 patients, the median age was 67 years (range: 30 to 90 years), 65% were male, 92% were White, and 93% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patients had a median of 2 prior therapies. The trials required hepatic transaminases at least ≤ 3 times upper limit of normal (ULN), total bilirubin ≤ 1.5 times ULN, and serum creatinine ≤ 1.5 times ULN. Patients were excluded for prior exposure to a PI3K inhibitor within 4 weeks. Fatal adverse reactions within 30 days of the last dose occurred in 36 patients (8%) treated with COPIKTRA 25 mg BID. Serious adverse reactions were reported in 289 patients (65%). The most frequent serious adverse reactions that occurred were infection (31%), diarrhea or colitis (18%), pneumonia (17%), rash (5%), and pneumonitis (5%). Adverse reactions resulted in treatment discontinuation in 156 patients (35%), most often due to diarrhea or colitis, infection, and rash. COPIKTRA was dose reduced in 104 patients (24%) due to adverse reactions, most often due to diarrhea or colitis and transaminase elevation. The median time to first dose modification or discontinuation was 4 months (range: 0.1 to 27 months), with 75% of patients having their first dose modification or discontinuation within 7 months. Common Adverse Reactions Table 4 summarizes common adverse reactions in patients receiving COPIKTRA 25 mg BID, and Table 5 summarizes the treatment-emergent laboratory abnormalities. The most common adverse reactions (reported in ≥ 20% of patients) were diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. Table 4. Common Adverse Reactions (≥ 10% Incidence) in Patients with B-cell Malignancies Receiving COPIKTRA † Grouped term for reactions with multiple preferred terms a Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative, diarrhea, diarrhea hemorrhagic b Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransfe…