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Duvelisib Capsules

TABLE OF CONTENTS

1. DESCRIPTION 7. DRUG INTERACTIONS
2. INDICATIONS AND USAGE 8. USE IN SPECIFIC POPULATIONS
3. DOSAGE AND ADMINISTRATION 10. MECHANISM OF ACTION
4. CONTRAINDICATIONS 11. PHARMACODYNAMICS
5. WARNINGS AND PRECAUTIONS 12. PHARMACOKINETICS
6. ADVERSE REACTIONS 13. HOW SUPPLIED/STORAGE AND HANDLING

 


WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS

• Fatal and/or serious infections occurred in 31% of duvelisib-treated patients. Monitor for signs and symptoms of infection. Withhold duvelisib if infection is suspected [see Warnings and Precautions (5.1)].

• Fatal and/or serious diarrhea or colitis occurred in 18% of duvelisib-treated patients. Monitor for the development of severe diarrhea or colitis. Withhold duvelisib [see Warnings and Precautions (5.2)].

• Fatal and/or serious cutaneous reactions occurred in 5% of duvelisib-treated patients. Withhold duvelisib [see Warnings and Precautions (5.3)].

• Fatal and/or serious pneumonitis occurred in 5% of duvelisib-treated patients. Monitor for pulmonary symptoms and interstitial infiltrates. Withhold duvelisib [see Warnings and Precautions (5.4)].


 

1. DESCRIPTION

Duvelisib is a dual inhibitor of phosphatidylinositol 3-kinases PI3K-δ and PI3K-γ.

Duvelisib is a white-to-off-white crystalline solid. Hydration can vary with relative humidity. Duvelisib contains a single chiral center as (S) enantiomer. Duvelisib is soluble in ethanol and practically insoluble in water. Duvelisib is described chemically as a hydrate of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and has the following chemical structure:

Empirical formula: C22H17ClN6O•H2O - Molecular weight: 434.88 g/mol

Duvelisib capsules are for oral administration and are supplied as white to off-white opaque and Swedish orange opaque capsules (25 mg, on anhydrous basis) or pink opaque capsules (15 mg, on anhydrous basis), and contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. Capsule shells contain gelatin, titanium dioxide, black ink, and red iron oxide.

2. INDICATIONS AND USAGE

2.1 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.

2.2 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) [see Clinical Studies]; continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

3. DOSAGE AND ADMINISTRATION

3.1 Dosing

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.

3.2 Recommended Prophylaxis

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/μL.

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.

3.3 Dose Modifications for Adverse Reactions

Manage toxicities per Table 1 with dose reduction, treatment hold, or discontinuation of duvelisib.

Table 1. Duvelisib 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

Recommended dose modification levels for duvelisib are presented in Table 2.

Table 2. Dose Modification Levels

3.4 Dose Modification for Concomitant Use with CYP3A4 Inhibitors

Reduce duvelisib dose to 15 mg twice daily when co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole) [see Drug Interactions (7.1)].

4. CONTRAINDICATIONS

None.

5. WARNINGS AND PRECAUTIONS

5.1 Infections

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 [see Dosage and Administration (3.3)].

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/μL. 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 [see Dosage and Administration (3.3)].

5.2 Diarrhea or Colitis

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 [see Dosage and Administration (3.3)].

5.3 Cutaneous Reactions

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 [see Dosage and Administration (3.3)].

5.4 Pneumonitis

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 [see Dosage and Administration (3.3)].

5.5 Hepatotoxicity

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 [see Dosage and Administration (3.3)].

5.6 Neutropenia

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 < 1.0 Gi/L (Grade 3-4). Withhold duvelisib in patients presenting with neutrophil counts < 0.5 Gi/L (Grade 4). Monitor until ANC is > 0.5 Gi/L, resume duvelisib at same dose for the first occurrence or a reduced dose for subsequent occurrence [see Dosage and Administration (3.3)].

5.7 Embryo-Fetal Toxicity

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 [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology].

6. ADVERSE REACTIONS

The following adverse reactions have been associated with duvelisib in clinical trials and are discussed in greater detail in other sections of the prescribing information:

• Infections [see Warnings and Precautions (5.1)]

• Diarrhea or Colitis [see Warnings and Precautions (5.2)]

• Cutaneous Reactions [see Warnings and Precautions (5.3)]

• Pneumonitis [see Warnings and Precautions (5.4)]

• Hepatotoxicity [see Warnings and Precautions (5.5)]

• Neutropenia [see Warnings and Precautions (5.6)]

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 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.

Table 3. Common Adverse Reactions (≥ 10% Incidence) in Patients with B-cell Malignancies Receiving Duvelisib

† 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 aminotransferase increased, transaminases increased, hypertransaminasemia, hepatocellular injury, hepatotoxicity

c Pneumonia includes the preferred terms: All preferred terms containing "pneumonia" except for "pneumonia aspiration"; bronchopneumonia, bronchopulmonary aspergillosis

d Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic, pustular), toxic epidermal necrolysis and toxic skin eruption, drug reaction with eosinophilia and systemic symptoms, drug eruption, Stevens-Johnson syndrome

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).

Table 4. Most Common New or Worsening Laboratory Abnormalities (≥ 20% Any Grade) in Patients with B-cell Malignancies Receiving Duvelisib

a Includes laboratory abnormalities that are new or worsening in grade or with worsening from baseline unknown.

b Percentages are based on number of patients with at least one post-baseline assessment; not all patients were evaluable.

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 μL 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 Bruton’s 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 treatmentemergent 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.

Table 5. Common Nonhematologic Adverse Reactions (≥ 10% Incidence) in Patients with CLL/SLL Receiving Duvelisib (Study 1)

Grades were obtained per CTCAE version 4.03.

† Grouped term for reactions with multiple preferred terms

a Diarrhea or colitis includes the preferred terms: colitis, enterocolitis, colitis microscopic, colitis ulcerative, diarrhea

b Pneumonia includes the preferred terms: All preferred term containing "pneumonia" except for "pneumonia aspiration"; bronchopneumonia, bronchopulmonary aspergillosis

c Rash includes the preferred terms: dermatitis (including allergic, exfoliative, perivascular), erythema (including multiforme), rash (including exfoliative, erythematous, follicular, generalized, macular & papular, pruritic, pustular), toxic skin eruption, drug eruption

d Transaminase elevation includes the preferred terms: alanine aminotransferase increased, aspartate aminotransferase increased, transaminases increased, hepatotoxicity

Table 6. Most Common New or Worsening Laboratory Abnormalities (≥ 20% Any Grade) in Patients with CLL/SLL Receiving Duvelisib (Study 1)

Grades were obtained per CTCAE version 4.03.

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.

7. DRUG INTERACTIONS

7.1 Effects of Other Drugs on Duvelisib

CYP3A Inducers

Co-administration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC) [see Clinical Pharmacology], which may reduce duvelisib efficacy. Avoid coadministration of duvelisib with strong CYP3A4 inducers.

CYP3A Inhibitors

Co-administration with a strong CYP3A inhibitor increases duvelisib AUC [see Clinical Pharmacology], which may increase the risk of duvelisib toxicities. Reduce duvelisib dose to 15 mg BID when co-administered with a strong CYP3A4 inhibitor [see Dosage and Administration (3.4)].

7.2 Effects of Duvelisib on Other Drugs

CYP3A Substrates

Co-administration with duvelisib increases AUC of a sensitive CYP3A4 substrate [see Clinical Pharmacology] 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 coadministered sensitive CYP3A substrate.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal studies and the mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology].

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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Duvelisib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. 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 [see Nonclinical Toxicology]. There are no data on the effect of duvelisib on human fertility.

8.4 Pediatric Use

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

8.5 Geriatric 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.

10. MECHANISM OF ACTION

Duvelisib is an inhibitor of PI3K with inhibitory activity predominantly against PI3K-δ and PI3K-γ 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.

11. 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.

12. 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%) μg/mL and AUC was 7.9 (77%) μg•h/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 [see Dosage and Administration (3.3) and Drug Interactions (7.1)]. 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 [see Drug Interactions (7.1)].

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 [see Drug Interactions (7.2)].

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.

13. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied:

COPIKTRA (duvelisib) capsules are supplied as follows:

Abbreviations: HDPE = high-density polyethylene; NDC = National Drug Code; no. = number

Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Retain in original package until dispensing. Dispense blister packs in original container.

Rx only

Rev 09/18