duvelisib

General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

**REMS Drug**

Pronunciation:
doo-ve-lis-ib


Trade Name(s)

  • Copiktra

Ther. Class.

antineoplastics

Pharm. Class.

phosphatidylinositol-3-kinase inhibitors

Indications

Relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma in patients who have received ≥2 prior therapies.

Action

Inhibits phosphatidylinositol-3-kinase (PI3K) in malignant B cells, which leads to apoptosis and inhibition of proliferation of primary malignant B cell lines and primary CLL tumor cells.

Therapeutic Effect(s):

Decreased progression of CLL and small lymphocytic lymphoma.

Pharmacokinetics

Absorption: 42% absorbed after oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: 98%.

Metabolism and Excretion: Primarily metabolized by the liver by the CYP3A4 isoenzyme. 79% of drug excreted in feces (11% as unchanged drug), 14% in urine (<1% as unchanged drug).

Half-life: 4.7 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown1–2 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • OB:  Pregnancy;
  • Lactation: Lactation.

Use Cautiously in:

  • Rep:  Women of reproductive potential and men with female partners of reproductive potential;
  • Pedi:  Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: edema

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), rash, STEVENS-JOHNSON SYNDROME (SJS), TOXIC EPIDERMAL NECROLYSIS (TEN)

F and E: hyperkalemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia

GI: ↑ amylase, ↑ lipase, ↑ liver enzymes, abdominal pain, COLITIS, constipation, DIARRHEA, hypoalbuminemia, mucositis, nausea, vomiting, HEPATOTOXICITY, hyperbilirubinemia

GU: ↑ serum creatinine, ↓ fertility (men)

Hemat: anemia, leukopenia, lymphocytosis, lymphopenia, NEUTROPENIA, thrombocytopenia

Metabolic: ↓ appetite, weight loss

MS: arthralgia, pain

Neuro: fatigue, headache

Resp: cough, dyspnea, PNEUMONITIS

Misc: fever, DEATH, INFECTION

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Strong CYP3A inducers, including  rifampin, and  moderate CYP3A inducers, including  etravirine, may ↓ levels and effectiveness; avoid concurrent use. If concurrent use with moderate CYP3A inducer unavoidable, ↑ duvelisib dose on Day 12 of coadministration with moderate CYP3A inducer.
  •  Strong CYP3A inhibitors, including  ketoconazole, may ↑ levels and risk of toxicity; ↓ duvelisib dose.
  • May ↑ levels and risk of toxicity of  CYP3A substrates.

Route/Dosage

PO (Adults): 25 mg twice daily.  Concurrent use of strong CYP3A inhibitor: 15 mg twice daily;  Concurrent use of moderate CYP3A inducer and receiving dose of 25 mg twice daily: 40 mg twice daily;  Concurrent use of moderate CYP3A inducer and receiving dose of 15 mg twice daily: 25 mg twice daily

Availability

Capsules: 15 mg, 25 mg

Assessment

  • Monitor for signs and symptoms of infection (fever, chills) during therapy.  If ≥Grade 3 infections occur,  hold duvelisib until infection resolved. Resume as same or ↓ dose.  If clinical cytomegalovirus (CMV) infection or viremia (positive PCR or antigen test) occurs,  hold duvelisib until resolved. Resume at same or ↓ dose. If resumed, monitor patient for CMV reactions (by PCR or antigen test) at least monthly.  If Pneumocystis jirovecii pneumonia (PJP) occurs,  hold duvelisib until infections evaluated. If PJP confirmed, discontinue duvelisib.
  • Monitor for new or worsening noninfectious diarrhea or colitis.  For mild/moderate diarrhea (Grade 1–2, up to 6 stools per day over baseline) and responsive to antidiarrheal agents, OR asymptomatic (Grade 1) colitis,  continue duvelisib at same dose. Initiate antidiarrheal agents and monitor weekly until resolved.  For mild/moderate diarrhea (Grade 1–2, up to 6 stools per day over baseline) and unresponsive to antidiarrheal agents,  hold duvelisib until resolved. Start enteric-acting steroids (budesonide). Monitor weekly until resolved. Resume duvelisib at ↓ dose.  If abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, OR severe diarrhea (Grade 3, >6 stools per day over baseline) occurs,  hold duvelisib until resolved. Start enteric-acting steroids or systemic steroids. Monitor weekly until resolved.  For recurrent Grade 3 diarrhea or recurrent colitis of any grade, discontinue duvelisib.  If life-threatening diarrhea occurs, discontinue duvelisib.
  • Monitor for signs and symptoms of skin reactions (pruritic, erythematous, maculopapular) during therapy.  For Grade 1–2 skin reactions,  continue duvelisib dose. Begin therapy with emollients, antihistamines (for pruritus), or topical steroids. Monitor closely.  For Grade 3 skin reactions,  hold duvelisib until resolved. Begin therapy with emollients, antihistamines (for pruritus), or topical steroids. Monitor at least weekly until resolved. Resume duvelisib at ↓ dose. If skin reaction does not improve, worsens, or recurs, discontinue duvelisib.  If life-threatening skin reactions, SJS, TEN, or DRESS occur,  discontinue duvelisib.
  • Monitor for signs and symptoms of noninfectious pneumonitis (new or progressive cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, ↓ by >5% in oxygen saturation) during therapy.  For moderate (Grade 2) symptoms,  hold duvelisib. Treat with systemic steroids. If recovery to Grade 0–1, resume duvelisib at ↓ dose. If noninfectious pneumonitis recurs or no response to steroid therapy, discontinue duvelisib.  For severe (Grade 3) or life-threatening pneumonitis,  discontinue duvelisib and treat with systemic steroids.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

  • Monitor hepatic function during therapy.  If AST/ALT ↑ to 3–5 times upper limit of normal (ULN) (Grade 2), continue duvelisib dose. Monitor AST and ALT at least weekly until return to <3 × ULN.  If AST/ALT ↑ to 5–20 × ULN (Grade 3),  hold duvelisib and monitor AST and ALT at least weekly until return to <3 × ULN. Resume duvelisib at same dose for 1st occurrence or ↓ dose for subsequent occurrences.  If AST/ALT ↑ to >20 × ULN (Grade 4),  discontinue duvelisib.
  • Monitor neutrophil counts at least every 2 wk for first 2 mo of therapy and at least weekly in patients with Grade 3 or 4 neutrophil counts.  If ANC 0.5–1 mm3 /L, continue duvelisib dose. Monitor ANC at least weekly.  If ANC <0.5 mm3 /L,  hold duvelisib. Monitor ANC until >0.5 mm3 /L. Resume duvelisib at same dose for 1st occurrence or ↓ dose for subsequent recurrence.
  • Monitor platelet count during therapy.  If platelet count 25–<50 mm3 /L (Grade 3) with Grade 1 bleeding,  continue duvelisib dose. Monitor platelet counts at least weekly.  If platelet count 25–<50 mm3 /L (Grade 3) with Grade 2 bleeding or platelet count <25 mm3 /L (Grade 4),  hold duvelisib. Monitor platelet counts until ≤25 mm3 /L and bleeding resolves. Resume duvelisib at same dose for 1st occurrence or reduced dose for subsequent recurrence.

Implementation

  • Provide prophylaxis for PJP during therapy with duvelisib. Once therapy is completed, continue PJP prophylaxis until absolute CD4+ T-cell count >200 cells/mm3 .
  • PO Administer twice daily without regard to food.  DNC: Swallow capsules whole; do not open, crush, or chew.  

Patient/Family Teaching

  • Explain purpose and side effects of medication to patient. Advise patient to read  Patient Information  before starting therapy.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications.
  • Instruct patient to take duvelisib as directed. Take missed doses as soon as remembered if within 6 hr of missed dose and take next dose as usual. If >6 hr, skip dose and take next dose as scheduled.
  • Explain need for continued medical follow-up to assess effectiveness and possible side effects of medication. Periodic lab tests will be needed.
  • Advise patient to notify health care professional immediately if signs and symptoms of infections, diarrhea (any new or worsening diarrhea, stool with mucus or blood, abdominal pain), new or worsening skin rash (painful sores or ulcers on skin, lips, or in mouth; severe rash with blisters or peeling skin; rash with itching; rash with fever), or lung inflammation occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking any new medications.
  • Advise patient to report signs or symptoms of decline in liver function (fatigue, swelling, nausea, vomiting, dark urine, clay-colored stools, jaundice).
  • Rep:  May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception and avoid breastfeeding during and for ≥1 mo after last dose of duvelisib. Advise patient to notify health care professional immediately if pregnancy is suspected. May impair male fertility.

Evaluation/Desired Outcomes

Decreased progression of CLL and small lymphocytic lymphoma.