Duvelisib

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# Black Box Warning

# Overview
Duvelisib is a kinase inhibitor that is FDA approved for the treatment of adult patients with:
- Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.
- Relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include diarrhea or colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory CLL or SLL after at least two prior therapies.
Follicular Lymphoma (FL)
- Duvelisib is indicated for the treatment of adult patients with relapsed or refractory FL after at least two prior systemic therapies.
- This indication is approved under accelerated approval based on overall response rate (ORR); continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- 25 mg orally, twice daily. Modify dosage for toxicity.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of duvelisib have not been established in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding duvelisib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding duvelisib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
None.

# Warnings
- Serious, including fatal (18/442; 4%), infections occurred in 31% of patients receiving duvelisib 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 duvelisib. Advise patients to report any new or worsening signs and symptoms of infection. For grade 3 or higher infection, withhold duvelisib until infection has resolved. Resume duvelisib at the same or reduced dose.
- Serious, including fatal, Pneumocystis jirovecii pneumonia (PJP) occurred in 1% of patients taking duvelisib. Provide prophylaxis for PJP during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/L. Withhold duvelisib in patients with suspected PJP of any grade, and permanently discontinue if PJP is confirmed.
- CMV reactivation/infection occurred in 1% of patients taking duvelisib. Consider prophylactic antivirals during duvelisib treatment to prevent CMV infection including CMV reactivation. For clinical CMV infection or viremia, withhold duvelisib until infection or viremia resolves. If duvelisib is resumed, administer the same or reduced dose and monitor patients for CMV reactivation by PCR or antigen test at least monthly.
- Serious, including fatal (1/442; <1%), diarrhea or colitis occurred in 18% of patients receiving duvelisib 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; 75th 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 duvelisib at the current dose, and monitor the patient at least weekly until the event resolves. If the diarrhea is unresponsive to antidiarrheal therapy, withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide). Monitor the patient at least weekly. Upon resolution of the diarrhea, consider restarting duvelisib at a reduced dose.
- For patients presenting with abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, or with severe diarrhea (Grade 3) (i.e. > 6 stools per day over baseline) withhold duvelisib and initiate supportive therapy with enteric acting steroids (e.g. budesonide) or systemic steroids. A diagnostic work-up to determine etiology, including colonoscopy, should be performed. Monitor at least weekly. Upon resolution of the diarrhea or colitis, restart duvelisib at a reduced dose. For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue duvelisib. Discontinue duvelisib for life-threatening diarrhea or colitis.
- Serious, including fatal (2/442; < 1%), cutaneous reactions occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Fatal cases included drug reaction with eosinophilia and systemic symptoms (DRESS) and toxic epidermal necrolysis (TEN). Median time to onset of any grade cutaneous reaction was 3 months (range: 1 day to 29 months, 75th percentile: 6 months), with a median event duration of 1 month (range: 1 day to 37 months, 75th percentile: 2 months).
- Presenting features for the serious events were primarily described as pruritic, erythematous, or maculo-papular. Less common presenting features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash. Advise patients to report any new or worsening cutaneous reactions. Review all concomitant medications and discontinue any medications potentially contributing to the event. For patients presenting with mild or moderate (Grade 1-2) cutaneous reactions, continue duvelisib at the current dose, initiate supportive care with emollients, anti-histamines (for pruritus), or topical steroids, and monitor the patient closely. Withhold duvelisib for severe (Grade 3) cutaneous reaction until resolution. Initiate supportive care with steroids (topical or systemic) or anti-histamines (for pruritus). Monitor at least weekly until resolved. Upon resolution of the event, restart duvelisib at a reduced dose. Discontinue duvelisib if severe cutaneous reaction does not improve, worsens, or recurs. For life-threatening cutaneous reactions, discontinue duvelisib. In patients with SJS, TEN, or DRESS of any grade, discontinue duvelisib.
- Serious, including fatal (1/442; < 1%), pneumonitis without an apparent infectious cause occurred in 5% of patients receiving duvelisib 25 mg BID (N = 442). Median time to onset of any grade pneumonitis was 4 months (range: 9 days to 27 months), with 75% of cases occurring within 9 months). The median event duration was 1 month, with 75% of cases resolving by 2 months.
- Withhold duvelisib in patients who present with new or progressive pulmonary signs and symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation and evaluate for etiology. If the pneumonitis is infectious, patients may be restarted on duvelisib at the previous dose once the infection, pulmonary signs and symptoms resolve. For moderate non-infectious pneumonitis (Grade 2), treat with systemic corticosteroids, and resume duvelisib at a reduced dose upon resolution. If non-infectious pneumonitis recurs or does not respond to steroid therapy, discontinue duvelisib. For severe or life-threatening non-infectious pneumonitis, discontinue duvelisib and treat with systemic steroids.
- Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively, in patients receiving duvelisib 25 mg BID (N = 442). Two percent of patients had both an ALT or AST greater than 3 x ULN and total bilirubin greater than 2 x ULN. Median time to onset of any grade transaminase elevation was 2 months (range: 3 days to 26 months), with a median event duration of 1 month (range: 1 day to 16 months).
- Monitor hepatic function during treatment with duvelisib. For Grade 2 ALT/AST elevation (greater than 3 to 5  ULN), maintain duvelisib dose and monitor at least weekly until return to less than 3  ULN. For Grade 3 ALT/AST elevation (greater than 5 to 20  ULN), withhold duvelisib and monitor at least weekly until return to less than 3  ULN. Resume duvelisib at the same dose (first occurrence) or at a reduced dose for subsequent occurrence. For grade 4 ALT/AST elevation (greater than 20  ULN) discontinue duvelisib.
- Grade 3 or 4 neutropenia occurred in 42% of patients receiving duvelisib 25 mg BID (N = 442), with Grade 4 neutropenia occurring in 24% of all patients. The median time to onset of Grade  3 neutropenia was 2 months (range: 3 days to 31 months), with 75% of cases occurring within 4 months.
- Monitor neutrophil counts at least every 2 weeks for the first 2 months of duvelisib therapy, and at least weekly in patients with neutrophil counts  0.5 Gi/L, resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence.
- Based on findings in animals and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman. 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 approximately 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively. 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 at least 1 month after the last dose.

# Adverse Reactions

## Clinical Trials 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 duvelisib 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 duvelisib 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 duvelisib 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. Duvelisib 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 3 summarizes common adverse reactions in patients receiving duvelisib 25 mg BID, and TABLE 4 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.
- Grade 4 adverse reactions occurring in  2% of recipients of duvelisib included neutropenia (18%), thrombocytopenia (6%), sepsis (3%), hypokalemia and increased lipase (2% each), and pneumonia and pneumonitis (2% each).
- Grade 4 laboratory abnormalities developing in  2% of patients included neutropenia (24%), thrombocytopenia (7%), lipase increase (4%), lymphocytopenia (3%), and leukopenia (2%).
Summary of Clinical Trial Experience in CLL/SLL 
Study 1
- The safety data below reflects exposure in a randomized, open-label, actively controlled clinical trial for adult patients with CLL or SLL who received at least one prior therapy. Of 313 patients treated, 158 received duvelisib monotherapy and 155 received ofatumumab. The 442-patient safety analysis above includes patients from Study 1.
- Duvelisib was administered at 25 mg BID in 28-day treatment cycles until unacceptable toxicity or progressive disease. The comparator group received 12 doses of ofatumumab with an initial dose of 300 mg intravenous (IV) on Day 1 followed a week later by 7 weekly doses of 2000 mg IV, followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses.
- In the total study population, the median age was 69 years (range: 39 to 90 years), 60% were male, 92% were White, and 91% had an ECOG performance status of 0 to 1. Patients had a median of 2 prior therapies, with 61% of patients having received 2 or more prior therapies. The trial required a hemoglobin  8 g/dL and platelets  10,000 L with or without transfusion support, hepatic transaminases  3 times upper limit of normal (ULN), total bilirubin  1.5 times ULN, and serum creatinine  2 times ULN. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Brutons tyrosine kinase (BTK) inhibitor, and uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
- During randomized treatment, the median duration of exposure to duvelisib was 11.6 months with 72% (114/158) exposed for  6 months and 49% (77/158) exposed for  1 year. The median duration of exposure to ofatumumab was 5.3 months, with 77% (120/155) receiving at least 10 of 12 doses.
- Fatal adverse reactions within 30 days of the last dose occurred in 12% (19/158) of patients treated with duvelisib and in 4% (7/155) of patients treated with ofatumumab.
- Serious adverse reactions were reported in 73% (115/158) of patients treated with duvelisib and most often involved infection (38% of patients; 60/158) and diarrhea or colitis (23% of patients; 36/158).
- Duvelisib was discontinued in 57 patients (36%), most often due to diarrhea or colitis, infection, and rash. Duvelisib was dose reduced in 46 patients (29%) due to adverse reactions, most often due to diarrhea or colitis and rash.
Common Adverse Reactions
- TABLE 5 summarizes selected adverse reactions in Study 1, and TABLE 6 summarizes treatment-emergent laboratory abnormalities. The most common adverse reactions with duvelisib (reported in  20% of patients) were diarrhea or colitis, neutropenia, pyrexia, upper respiratory tract infection, pneumonia, rash, fatigue, nausea, anemia and cough.
- Grade 4 laboratory abnormalities that developed in  2% of duvelisib treated patients included neutropenia (32%), thrombocytopenia (6%), lymphopenia (3%), and hypokalemia (2%).
- The data above are not an adequate basis for comparison of rates between the study drug and the active control.
Summary of Clinical Trial Experience in FL
- The data described below reflect the exposure to duvelisib 25 mg BID in 96 patients with relapsed or refractory FL. These patients were included in the 442-patient safety analysis presented above. The median duration of treatment was 24 weeks, with 46% of patients exposed for  6 months and 19% exposed for  1 year.
- The median age was 64 years (range: 30 to 82 years), and 93% had an ECOG performance status of 0 to 1. Patients had a median of 3 prior systemic therapies.
- Serious adverse reactions were reported in 58% and most often involved diarrhea or colitis, pneumonia, renal insufficiency, rash, and sepsis. The most common adverse reactions ( 20% of patients) were diarrhea or colitis, nausea, fatigue, musculoskeletal pain, rash, neutropenia, cough, anemia, pyrexia, headache, mucositis, abdominal pain, vomiting, transaminase elevation, and thrombocytopenia.
- Adverse reactions resulted in duvelisib discontinuation in 29% of patients, most often due to diarrhea or colitis and rash. Duvelisib was dose reduced in 23% due to adverse reactions, most often due to transaminase elevation, diarrhea or colitis, lipase increased, and infection.

## Postmarketing Experience
There is limited information regarding Duvelisib Postmarketing Experience in the drug label.

# Drug Interactions
CYP3A Inducers
- Co-administration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce duvelisib efficacy. Avoid co-administration of duvelisib with strong CYP3A4 inducers.
CYP3A Inhibitors
- Co-administration with a strong CYP3A inhibitor increases duvelisib AUC, which may increase the risk of duvelisib toxicities. Reduce duvelisib dose to 15 mg BID when co-administered with a strong CYP3A4 inhibitor.
CYP3A Substrates
- Co-administration with duvelisib increases AUC of a sensitive CYP3A4 substrate 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 CYP3A substrate.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- Based on findings from animal studies and the mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman.
- 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.
- 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.
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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Duvelisib in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Duvelisib during labor and delivery.

### Nursing Mothers
Risk Summary
- There are no data on the presence of duvelisib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions from duvelisib in a breastfed child, advise lactating women not to breastfeed while taking duvelisib and for at least 1 month after the last dose.

### Pediatric Use
- Safety and effectiveness of duvelisib have not been established in pediatric patients. Pediatric studies have not been conducted.

### Geriatic Use
- Clinical trials of duvelisib included 270 patients (61%) that were 65 years of age and older and 104 (24%) that were 75 years of age and older. No major differences in efficacy or safety were observed between patients less than 65 years of age and patients 65 years of age and older.

### Gender
There is no FDA guidance on the use of Duvelisib with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Duvelisib with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Duvelisib in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Duvelisib in patients with hepatic impairment.

### Females of Reproductive Potential and Males
Pregnancy Testing
- Duvelisib can cause fetal harm when administered to a pregnant woman. Conduct pregnancy testing before initiation of duvelisib treatment.
Contraception 
Females
- Based on animal studies, duvelisib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Males
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Infertility
- Based on testicular findings in animals, male fertility may be impaired by treatment with duvelisib. There are no data on the effect of duvelisib on human fertility.

### Immunocompromised Patients
There is no FDA guidance one the use of Duvelisib in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- The recommended dose of duvelisib 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.
- Provide prophylaxis for Pneumocystis jirovecii (PJP) during treatment with duvelisib. Following completion of duvelisib treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater than 200 cells/L.
- Withhold duvelisib in patients with suspected PJP of any grade, and discontinue if PJP is confirmed.
- Consider prophylactic antivirals during duvelisib treatment to prevent cytomegalovirus (CMV) infection including CMV reactivation.
- Manage toxicities per TABLE 1 with dose reduction, treatment hold, or discontinuation of duvelisib.
- Recommended dose modification levels for duvelisib are presented in TABLE 2.
- Reduce duvelisib dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole).

### Monitoring
There is limited information regarding Duvelisib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Duvelisib and IV administrations.

# Overdosage
There is limited information regarding Duvelisib overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K- and PI3K- isoforms expressed in normal and malignant B-cells. Duvelisib induced growth inhibition and reduced viability in cell lines derived from malignant B-cells and in primary CLL tumor cells. Duvelisib inhibits several key cell-signaling pathways, including B-cell receptor signaling and CXCR12-mediated chemotaxis of malignant B-cells. Additionally, duvelisib inhibits CXCL12-induced T cell migration and M-CSF and IL-4 driven M2 polarization of macrophages.

## Structure
- Duvelisib is a white-to-off-white crystalline solid with the empirical formula C22H17ClN6OH2O and a molecular weight of 434.88 g/mol.

## Pharmacodynamics
- At the recommended dose of 25 mg BID, reductions in levels of phosphorylated AKT (a downstream marker for PI3K inhibition) were observed in patients treated with duvelisib.
Cardiac Electrophysiology
- The effect of multiple doses of duvelisib 25 and 75 mg BID on the QTc interval was evaluated in patients with previously treated hematologic malignancies. Increases of > 20 ms in the QTc interval were not observed.

## Pharmacokinetics
- Duvelisib exposure increased in a dose-proportional manner over a dose range of 8 mg to 75 mg twice daily (0.3 to 3 times the recommended dosage).
- At steady state following 25 mg BID administration of duvelisib in patients, the geometric mean (CV%) maximum concentration (Cmax) was 1.5 (64%) g/mL and AUC was 7.9 (77%) gh/mL.
Absorption
- The absolute bioavailability of 25 mg duvelisib after a single oral dose in healthy volunteers was 42%. The median time to peak concentration (Tmax) was observed at 1 to 2 hours in patients.
Effect of Food
- Duvelisib may be administered without regard to food. The administration of a single dose of duvelisib with a high-fat meal (fat accounted for approximately 50% of the total caloric content of the meal) decreased Cmax by approximately 37% and decreased the AUC by approximately 6%, relative to fasting conditions.
Distribution
- Protein binding of duvelisib is greater than 98% with no concentration dependence. The mean blood-to-plasma ratio was 0.5. The geometric mean (CV%) apparent volume of distribution at steady state (Vss/F) is 28.5 L (62%). Duvelisib is a substrate of P-glycoprotein (P-gp) and BCRP in vitro.
Elimination
- The geometric mean (CV%) apparent systemic clearance at steady-state is 4.2 L/hr (56%) in patients with lymphoma or leukemia. The geometric mean (CV%) terminal elimination half-life of duvelisib is 4.7 hours (57%).
Metabolism
- Duvelisib is primarily metabolized by cytochrome P450 CYP3A4.
Excretion
- Following a single 25 mg oral dose of radiolabeled duvelisib, 79% of the radioactivity was excreted in feces (11% unchanged) and 14% was excreted in the urine (< 1% unchanged).
Specific Populations
- Age (18 to 90 years), sex, race, renal impairment (creatinine clearance 23 to 80 mL/ min), hepatic impairment (Child Pugh Class A, B, and C) and body weight (40 to 154 kg) had no clinically significant effect on the exposure of duvelisib.
Drug Interaction Studies 
Strong and Moderate CYP3A Inhibitors
- Co-administration of strong CYP3A inhibitor ketoconazole (at 200 mg BID for 5 days), a strong inhibitor of CYP3A4, with a single oral 10 mg dose of duvelisib in healthy adults (n= 16) increased duvelisib Cmax by 1.7-fold and AUC by 4-fold. Based on physiologically-based pharmacokinetic (PBPK) modeling and simulation, the increase in exposure to duvelisib is estimated to be ~2-fold at steady state when concomitantly used with strong CYP3A4 inhibitors such as ketoconazole. PBPK modeling and simulation estimated no effect on duvelisib exposures from concomitantly used mild or moderate CYP3A4 inhibitors.
Strong and Moderate CYP3A4 Inducers
- Co-administration of 600 mg once daily rifampin, a strong CYP3A inducer, for 7 days with a single oral 25 mg duvelisib dose in healthy adults (N = 13) decreased duvelisib Cmax by 66% and AUC by 82%.
- The effect of moderate CYP3A4 induction has not been studied.
CYP3A4 Substrates
- Co-administration of multiple doses of duvelisib 25 mg BID for 5 days with single oral 2 mg midazolam, a sensitive CYP3A4 substrate, in healthy adults (N = 14), increased in the midazolam AUC by 4.3-fold and Cmax by 2.2-fold.
In Vitro Studies
- Duvelisib is a substrate of P-glycoprotein (P-gp) and breast cancer-resistant protein (BCRP).
- Duvelisib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BCRP, or P-gp.

## Nonclinical Toxicology
- Carcinogenicity studies have not been conducted with duvelisib.
- Duvelisib did not cause genetic damage in in vitro or in vivo assays.
- Fertility studies with duvelisib were not conducted. Histological findings in male and female rats were observed in the repeat dose toxicity studies and included testis (seminiferous epithelial atrophy, decreased weight, soft testes), and epididymis (small size, oligo/aspermia) in males and ovary (decreased weight) and uterus (atrophy) in females.

# Clinical Studies
Study 1
- A randomized, multicenter, open-label trial (Study 1; NCT02004522) compared duvelisib versus ofatumumab in 319 adult patients with CLL (N = 312) or SLL (N = 7) after at least one prior therapy. The trial excluded patients with prior autologous transplant within 6 months or allogeneic transplant, prior exposure to a PI3K inhibitor or a Brutons tyrosine kinase (BTK) inhibitor. The trial required hepatic transaminases  3 times upper limit of normal (ULN), total bilirubin  1.5 times ULN, and serum creatinine  2 times ULN.
- The study randomized patients with a 1:1 ratio to receive either duvelisib 25 mg BID until disease progression or unacceptable toxicity or ofatumumab for 7 cycles. Ofatumumab was administered intravenously at an initial dose of 300 mg, followed one week later by 2000 mg once weekly for 7 doses, and then 2000 mg once every 4 weeks for 4 additional doses.
- The approval of duvelisib was based on efficacy and safety analysis of patients with at least 2 prior lines of therapy, where the benefit:risk appeared greater in this more heavily pretreated population compared to the overall trial population.
- In this subset (95 randomized to duvelisib, 101 to ofatumumab), the median patient age was 69 years (range: 40 to 90 years), 59% were male, and 88% had an ECOG performance status of 0 or 1. Forty-six percent received 2 prior lines of therapy, and 54% received 3 or more prior lines. At baseline, 52% of patients had at least one tumor  5 cm, and 22% of patients had a documented 17p deletion.
- During randomized treatment, the median duration of exposure to duvelisib was 13 months (range: 0.2 to 37), with 80% of patients receiving at least 6 months and 52% receiving at least 12 months of duvelisib. The median duration of exposure to ofatumumab was 5 months (range: < 0.1 to 6).
- Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC). Other efficacy measures included overall response rate. Efficacy of duvelisib compared to ofatumumab specifically in patients treated with at least two prior therapies is presented in TABLE 8 and FIGURE 1.
Study 2
- Efficacy of duvelisib in patients with previously treated FL is based on a single-arm, multicenter trial (Study 2; NCT02204982). In this study, duvelisib 25 mg BID was administered in patients with FL (N = 83) who were refractory to rituximab and to either chemotherapy or radioimmunotherapy. Refractory disease was defined as less than a partial remission or relapse within 6 months after the last dose. The trial excluded patients with Grade 3b FL, large cell transformation, prior allogeneic transplant, and prior exposure to a PI3K inhibitor or to a Brutons tyrosine kinase inhibitor.
- The median age was 64 years (range: 30 to 82 years), 68% were male, and 37% had bulky disease assessed at baseline (target lesion  5 cm). Patients had a median of 3 prior lines of therapy (range: 1 to 10), with 94% being refractory to their last therapy and 81% being refractory to 2 or more prior lines of therapy. Most patients (93%) had an ECOG performance status of 0 or 1.
- The median duration of exposure to duvelisib was 5 months (range: 0.4 to 24), with 41% of patients receiving at least 6 months and 10% receiving at least 12 months of duvelisib.
- Efficacy was based on overall response rate and duration of response as assessed by an IRC (TABLE 9).

# How Supplied
- Duvelisib capsules are supplied as follows:

## Storage
- Store at 20 to 25C (68 to 77F), with excursions permitted at 15 to 30C (59 to 86F) . Retain in original package until dispensing. Dispense blister packs in original container.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
- Physicians and healthcare professionals are advised to discuss the following with patients prior to treatment with duvelisib:
Infections
- Advise patients that duvelisib can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. fever, chills).
Diarrhea or Colitis
- Advise patients that duvelisib can cause serious diarrhea or colitis (inflammation of the gut) that may be fatal, and to notify their healthcare provider immediately about any new or worsening diarrhea, stool with mucus or blood, or abdominal pain.
Cutaneous Reactions
- Advise patients that duvelisib can cause a serious skin rash that may be fatal, and to notify their healthcare provider immediately if they develop a new or worsening skin rash.
Pneumonitis
- Advise patients that duvelisib may cause pneumonitis (inflammation of the lungs) that may be fatal, and to report any new or worsening respiratory symptoms including cough or difficulty breathing.
Hepatotoxicity
- Advise patients that duvelisib may cause significant elevations in liver enzymes, and that monitoring of liver tests is needed. Advise patients to report symptoms of liver dysfunction including jaundice (yellow eyes or yellow skin), abdominal pain, bruising, or bleeding.
Neutropenia
- Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any sign of infection.
Embryo-Fetal Toxicity
- Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of duvelisib.
- Advise males with female partners of reproductive potential to use effective contraception during treatment with duvelisib and for at least 1 month after the last dose.
Lactation
- Advise lactating women not to breastfeed during treatment with duvelisib and for at least 1 month after the last dose.
- Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products, before and during treatment with duvelisib.
Instructions for Taking Duvelisib
- Advise patients to take duvelisib exactly as prescribed. Duvelisib may be taken with or without food; the capsules should be swallowed whole.
- 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.

# Precautions with Alcohol
Alcohol-Duvelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Copiktra

# Look-Alike Drug Names
There is limited information regarding Duvelisib Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price