duvelisib (Rx)

Brand and Other Names:Copiktra
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 15mg
  • 25mg

Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Indicated for adults with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least 2 prior therapies

25 mg PO BID with or without food

Cycle consists of 28 days

Follicular Lymphoma

Indicated for adults with relapsed/refractory follicular lymphoma (FL) after at least 2 prior therapies

25 mg PO BID with or without food

Cycle consists of 28 days

Dosage Modifications

Renal impairment (CrCl 23-80 mL/min) and hepatic impairment (Child-Pugh Class A, B, and C) had no clinically significant effect on duvelisib

Dose modification levels

  • Dose reduction: 15 mg BID
  • Subsequent dose modification: Discontinue treatment if patient is unable to tolerate 15 mg BID

Infections

  • Grade ≥3: Withhold treatment until resolved; resume at same or reduced dose
  • Clinical CMV infection or viremia (positive PCR or antigen test)
    • Withhold treatment until resolved; resume at same or reduced dose; if treatment is resumed, monitor for CMV reactivation (by PCR or antigen test) at least monthly
  • Suspected Pneumocystis jirovecii pneumonia (PJP): Withhold treatment until evaluated
  • Confirmed PJP: Discontinue treatment

Noninfectious diarrhea or colitis

  • Grade 1-2 diarrhea (<6 stools/day over baseline) and responsive to antidiarrheal agents OR asymptomatic (Grade 1) colitis: Initiate supportive therapy with antidiarrheal agents if necessary; monitor at least weekly until resolved
  • Grade 1-2 diarrhea (<6 stools/day over baseline) and unresponsive to antidiarrheal agents: Withhold treatment until resolved; initiate supportive therapy with enteric-acting steroids (eg, budesonide); monitor at least weekly until resolved
  • Grade 3 diarrhea (>6 stools/day over baseline) OR abdominal pain, stool with mucus/blood, change in bowel habits, peritoneal signs
    • Withhold treatment until resolved
    • Initiate supportive therapy with enteric-acting steroids (eg, budesonide) or systemic steroids; monitor at least weekly until resolved; resume at a reduced dose
    • For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue treatment

Cutaneous reactions

  • Grade 1-2: Initiate supportive care with emollients, antihistamines (for pruritus), or topical steroids; monitor closely
  • Grade 3
    • Withhold treatment until resolved
    • Initiate supportive care with emollients, antihistamines, or topical steroids; monitor at least weekly until resolved; resume at reduced dose
    • If severe cutaneous reaction does not improve, worsens, or recurs, discontinue treatment
  • Life-threatening reaction or Steven Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), or toxic epidermal necrolysis (TEN) (any grade): Discontinue treatment

Pneumonitis without suspected infectious cause

  • Grade 2 symptomatic pneumonitis
    • Withhold treatment; treat with systemic steroid therapy
    • If pneumonitis recovers to Grade 0 or 1, resume at reduced dose
    • If noninfectious pneumonitis recurs or patient does not respond to steroid therapy, discontinue treatment

ALT/AST elevation

  • Grade 2 (3-5x upper limit of normal [ULN]): Maintain dose; monitor at least weekly until return to <3x ULN
  • Grade 3 (>5-20x ULN): Withhold treatment and monitor at least weekly until return to <3x ULN; resume at same dose (first occurrence) or at a reduced dose for subsequent occurrence
  • Grade 4 (>20x ULN): Discontinue treatment

Neutropenia

  • Absolute neutrophil count (ANC) 0.5-1 Gi/L: Maintain dose; monitor ANC at least weekly
  • ANC <0.5 Gi/L: Withhold treatment; monitor ANC until >0.5 Gi/L; resume at same dose (first occurrence) or at a reduced dose for subsequent occurrence

Concomitant use with CYP3A4 inhibitors or inducers

  • Strong CYP3A4 inhibitors: Reduce dose to 15 mg BID
  • Strong CYP3A4 inducers: Avoid

Dosing Considerations

Indication for relapsed/refractory FL is approved under accelerated approval based on overall response rate; continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials

Recommended prophylaxis

  • Provide prophylaxis for PJP during treatment
  • Following completion of treatment, continue PJP prophylaxis until absolute CD4+ T-cell count is >200 cells/microL
  • Consider prophylactic antivirals during treatment to prevent CMV infection, including CMV reactivation

Safety and efficacy not established

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Interactions

Interaction Checker

and duvelisib

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            Neutropenia (67%)

            Diarrhea or colitis (57%)

            Anemia (55%)

            Neutropenia, Grade ≥3 (49%)

            Thrombocytopenia (43%)

            ALT increased (42%)

            Lipase increased (37%)

            AST increased (36%)

            Phosphate decreased (34%)

            Hyperkalemia (31%)

            Hyponatremia (31%)

            Amylase increased (31%)

            Hypoalbuminemia (31%)

            Lymphocytosis (30%)

            Pyrexia (29%)

            Creatinine increased (29%)

            Upper respiratory tract infection (28%)

            Pneumonia (27%)

            Rash (27%)

            Alkaline phosphatase increased (27%)

            Hypocalcemia (25%)

            Fatigue (25%)

            Diarrhea or colitis, Grade ≥3 (25%)

            Nausea (23%)

            Cough (23%)

            Lymphocytosis, Grade ≥3 (22%)

            Pneumonia, Grade ≥3 (22%)

            Anemia, Grade ≥3 (20%)

            Hypokalemia (20%)

            Lower respiratory tract infection (18%)

            Constipation (17%)

            Musculoskeletal pain (17%)

            Abdominal pain (16%)

            Vomiting (15%)

            Decreased appetite (13%)

            Dyspnea (12%)

            Lipase increased, Grade ≥3 (12%)

            Edema (11%)

            Transaminase elevation (11%)

            Decreased weight (11%)

            Rash, Grade ≥3 (11%)

            1-10% (Grade ≥3)

            Hypokalemia (8%)

            Hyponatremia (7%)

            ALT increased (7%)

            Transaminase elevation (6%)

            Amylase increased (5%)

            Lower respiratory tract infection (4%)

            Fatigue (4%)

            Hyperkalemia (4%)

            AST increased (3%)

            Phosphate decreased (3%)

            Dyspnea (3%)

            Pyrexia (3%)

            Abdominal pain (3%)

            Hypoalbuminemia (2%)

            Hypocalcemia (1%)

            Creatinine increased (1%)

            Cough (1%)

            Musculoskeletal pain (1%)

            Edema (1%)

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            Warnings

            Black Box Warnings

            Fatal and serious toxicities

            • Fatal and or serious infections, diarrhea, colitis, cutaneous reactions, and pneumonitis have occurred
            • In duvelisib-treated patients, fatal and/serious toxicities (infections [31%]; diarrhea or colitis [18%]; cutaneous reactions [5%]) occurred
            • Monitor for symptoms; withhold treatment if listed toxicity is suspected

            Contraindications

            None

            Cautions

            Serious, including fatal (4%), infections occurred in 31%; most common serious infections were pneumonia, sepsis, and lower respiratory tract infections; median time to onset of any grade infection was 3 months, with 75% of cases occurring within 6 months

            CMV reactivation/infection and serious/fatal PJP occurred in 1% of treated patients; consider prophylactic antivirals during treatment

            Treat infections prior to initiation of therapy; advise patients to report any new or worsening signs and symptoms of infection

            Serious, including fatal (≤1%), cutaneous reactions occurred in 5%; fatal cases included DRESS and TEN; median time to onset of any grade cutaneous reaction was 3 months, with a median event duration of 1 month; presenting features for serious events include pruritic, erythematous, or maculopapular rash; less common features include exanthem, desquamation, erythroderma, skin exfoliation, keratinocyte necrosis, and papular rash

            Serious, including fatal (<1%), pneumonitis without an apparent infectious cause occurred in 5%; median time to onset of any grade pneumonitis was 4 months, with 75% of cases occurring within 9 months; median event duration was 1 month, with 75% of cases resolving by 2 months

            Grade 3 and 4 ALT and/or AST elevation developed in 8% and 2%, respectively; median time to onset of any grade transaminase elevation was 2 months, with a median event duration of 1 month; monitor hepatic function during treatment

            Grade 3 or 4 neutropenia occurred in 42%; median time to onset of Grade ≥3 neutropenia was 2 months, with 75% of cases occurring within 4 months; monitor neutrophil counts at least every 2 weeks for first 2 months of therapy, and at least weekly in patients with neutrophil counts <1 Gi/L (Grade 3-4)

            Based on findings in animals and its mechanism of action, fetal harm may occur when administered to a pregnant woman (see Pregnancy)

            Drug interactions overview

            • Effects of other drugs on duvelisib
              • Strong CYP3A4 inducers: Coadministration with a strong CYP3A inducer decreases duvelisib area under the curve (AUC), which may reduce the efficacy of duvelisib
              • Moderate CYP3A4 inducers: Not studied
              • Strong CYP3A inhibitors: Coadministration with a strong CYP3A inhibitor increases duvelisib AUC, which may increase the risk of duvelisib toxicities
              • Mild or moderate CYP3A4 inhibitors: No effect based on physiologically based pharmacokinetic modeling and simulation
            • Effects of duvelisib on other drugs
              • Sensitive CYP3A substrates: Coadministration 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 coadministered sensitive CYP3A substrate
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            Pregnancy

            Pregnancy

            There are no available data in pregnant women to inform the drug-associated risk

            Based on findings from animal studies and its mechanism of action, duvelisib can cause fetal harm when administered to a pregnant woman

            Conduct pregnancy testing before initiation of treatment

            Animal data

            • In animal reproduction studies, administration of duvelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryofetal mortality (eg, resorptions, postimplantation loss, decreased viable fetuses), alterations to growth, and structural abnormalities (malformations) at maternal doses 10 times and 39 times the maximum recommended human dose (MRHD) of 25 mg BID in rats and rabbits, respectively

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 1 month after last dose
            • Males: Male patients with female partners of reproductive potential should use effective contraception during treatment and for at least 1 month after last dose

            Infertility

            • Based on testicular findings in animals, male fertility may be impaired by treatment; no data available on drug effects of on human fertility

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma

            This PI3K inhibitor induces growth inhibition and reduces viability in cell lines derived from malignant B cells and in primary CLL tumor cells; inhibits several key cell-signaling pathways (eg, B cell receptor signaling, 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 macrophage

            Absorption

            Peak plasma concentration: 1.5 mcg/mL

            Median peak plasma time: 1-2 hr

            Absolute bioavailability: 42% (healthy adults)

            Distribution

            Protein binding: >98%

            Mean blood-to-plasma ratio: 0.5

            Vd (steady-state): 28.5 L

            P-glycoprotein substrate and BCRP substrate

            Metabolism

            Metabolized by CYP3A4

            Elimination

            Clearance: 4.2 L/hr

            Half-life: 4.7 hr

            Excretion: Feces (11% unchanged); urine (<1% unchanged)

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            Administration

            Oral Administration

            Administer with or without food

            Swallow capsules whole; do not to open, break, or chew capsules

            Missed dose

            • Missed dose <6 hr: Take missed dose right away and take next dose as usual
            • Missed dose >6 hr: Wait and take next dose at usual time

            Storage

            Store at 20-25°C (68-77°F), with excursions permitted to 15-30°C (59-86°F)

            Retain in original package until dispensing; dispense blister packs in original container

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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