INTEGRATED SAFETY SET

Adverse Reactions Observed in Clinical Trials

Serious adverse reactions and treatment discontinuation in clinical trials

  • The safety of XOSPATA was evaluated on the basis of 319 patients with relapsed or refractory AML treated with XOSPATA 120 mg daily in 3 clinical trials1
  • The median duration of exposure to XOSPATA was 3.6 months (range: 0.1 to 43.4 months)1
  • Fatal adverse reactions occurred in 2% of patients who received XOSPATA, including cardiac arrest (1%) and 1 case each of differentiation syndrome and pancreatitis1
  • The most frequent (≥5%) nonhematological serious adverse reactions reported in patients treated with XOSPATA were1:
    • 13% fever
    • 9% dyspnea
    • 8% renal impairment
    • 6% transaminase increased
    • 5% noninfectious diarrhea

Permanent discontinuations due to an adverse reaction occurred in 7% (n=22/319) of patients treated with XOSPATA1

  • The most common adverse reactions (>1%) leading to treatment discontinuation in the XOSPATA arm were AST increased (2%) and ALT increased (2%)1
  • Dose interruption due to an adverse reaction occurred in 29% of patients treated with XOSPATA (n=91/319)1
    • The most common adverse reactions leading to dose interruption were AST increased (6%), ALT increased (6%), and fever (4%)
  • Dose reduction due to an adverse reaction occurred in 6% of patients in the XOSPATA arm (n=20/319)1
Most Frequent (≥10%) Nonhematological Adverse Reactions (All Grades) Reported in Patients Treated With XOSPATA1
  • 51% transaminase increased
  • 50% myalgia/ arthralgia
  • 44% fatigue/ malaise
  • 41% fever
  • 41% mucositis
  • 40% edema
  • 36% rash
  • 35% noninfectious diarrhea
  • 35% dyspnea
  • 30% nausea
  • 28% cough
  • 28% constipation
  • 25% eye disorders
  • 24% headache
  • 22% dizziness
  • 22% hypotension
  • 21% vomiting
  • 21% renal impairment
  • 18% abdominal pain
  • 18% neuropathy
  • 15% insomnia
  • 11% dysgeusia
  • The most frequent (≥5%) Grade ≥3 nonhematological adverse reactions reported in patients treated with XOSPATA were1:
    • 21% transaminase increased
    • 12% dyspnea
    • 7% hypotension
    • 7% mucositis
    • 7% myalgia/arthralgia
    • 6% fatigue/malaise
  • Other clinically significant adverse reactions occurring in ≤10% of patients included1:
    • 9% prolonged QT interval
    • 8% hypersensitivity*
    • 5% pancreatitis*
    • 4% cardiac failure*
    • 4% pericardial effusion
    • 3% acute febrile neutrophilic dermatosis
    • 3% differentiation syndrome
    • 2% pericarditis/myocarditis*
    • 1% large intestine perforation
    • 1% PRES
  • Shifts to Grades 3 to 4 nonhematologic laboratory abnormalities included1:
    • 14% phosphate decreased
    • 13% ALT increased
    • 12% sodium decreased
    • 10% AST increased
    • 6% calcium decreased
    • 6% creatine kinase increased
    • 6% triglycerides increased
    • 3% creatinine increased
    • 2% alkaline phosphatase increased

*Grouped terms: cardiac failure (cardiac failure, cardiac failure congestive, cardiomegaly, cardiomyopathy, chronic left ventricular failure, and ejection fraction decreased), hypersensitivity (anaphylactic reaction, angioedema, dermatitis allergic, drug hypersensitivity, erythema multiforme, hypersensitivity, and urticaria), pancreatitis (amylase increased, lipase increased, pancreatitis, pancreatitis acute), pericarditis/myocarditis (myocarditis, pericardial hemorrhage, pericardial rub, and pericarditis).1

ADMIRAL TRIAL SAFETY

Safety Profile of XOSPATA vs Salvage Chemotherapy in the Preselected Low-Intensity Chemotherapy Subgroup

Adverse reactions reported in the first 30 days of treatment in the ADMIRAL trial were evaluated according to whether patients were preselected for high-intensity chemotherapy or low-intensity chemotherapy.1

  • All adverse reactions were grouped by events that were reported under different terms but were represented by the same phenomenon (eg, transaminase increased included: AST increased, ALT increased, blood alkaline phosphatase increased, and transaminases increased)1
    • Similarly, adverse reactions reported in more than one body system that appeared to represent a common pathophysiologic event were grouped together

Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grades 3-5†) of Patients With Relapsed or Refractory AML in the Preselected Low-Intensity Chemotherapy Subgroup in the First 30 Days of the ADMIRAL Trial1

Table of adverse reactions reported in the low-intensity chemotherapy subgroup in the ADMIRAL trial. Table of adverse reactions reported in the low-intensity chemotherapy subgroup in the ADMIRAL trial.

†Grades 3 to 5 include serious, life-threatening, and fatal adverse reactions.1

Safety Profile of XOSPATA vs Salvage Chemotherapy in the Preselected High-Intensity Chemotherapy Subgroup

  • All adverse reactions were grouped by events that were reported under different terms but were represented by the same phenomenon (eg, myalgia/arthralgia included: arthralgia, back pain, bone pain, flank pain, limb discomfort, medial tibial stress syndrome, myalgia, muscle twitching, musculoskeletal discomfort, musculoskeletal pain, muscle spasms, neck pain, noncardiac chest pain, pain, and pain in extremity)1:
    • Similarly, adverse reactions reported in more than one body system that appeared to represent a common pathophysiologic event were grouped together
Table of adverse reactions reported in the high-intensity chemotherapy subgroup in the ADMIRAL trial. Table of adverse reactions reported in the high-intensity chemotherapy subgroup in the ADMIRAL trial.

‡Grades 3 to 5 include serious, life-threatening, and fatal adverse reactions.1

ADMIRAL TRIAL SAFETY

Laboratory Abnormalities Observed by Preselected High-Intensity and Low-Intensity Chemotherapy in the First 30 Days of the ADMIRAL Trial

Selected post-baseline laboratory values were observed in the first 30 days of treatment in the ADMIRAL trial.1

Table of laboratory abnormalities observed in the ADMIRAL trial. Table of laboratory abnormalities observed in the ADMIRAL trial.

Drug Interactions
With XOSPATA

Effect of Other Drugs on XOSPATA1§

Co-administered Drugs

Combined P-gp and strong CYP3A inducers

Effect on XOSPATA

Concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer decreases the exposure of XOSPATA, which may decrease the efficacy of XOSPATA

Recommendation

Avoid concomitant use of XOSPATA with combined P-gp and strong CYP3A inducers

Co-administered Drugs

Strong CYP3A inhibitors

Effect on XOSPATA

Concomitant use of XOSPATA with a strong CYP3A inhibitor increases the exposure of XOSPATA

Recommendation

  • Consider alternative therapies that are not strong CYP3A inhibitors
  • If concomitant use of strong CYP3A inhibitors is considered essential for the care of the patient, monitor the patient more frequently for adverse reactions with XOSPATA
  • Interrupt and reduce dose of XOSPATA in patients with serious or life-threatening toxicity

Effect of XOSPATA on Other Drugs1

Co-administered Drugs

Drugs that target the 5HT2B receptor or the sigma nonspecific receptor

Effect on Other Drugs

Concomitant use of XOSPATA may reduce the effects of drugs that target the 5HT2B receptor or the sigma nonspecific receptor (eg, escitalopram, fluoxetine, sertraline)

Recommendation

Avoid concomitant use of these drugs with XOSPATA unless their use is considered essential for the care of the patient<

P-gp, BCRP, and OCT1 Substrates

Based on in vitro data, gilteritinib is a P-gp, breast cancer resistant protein (BCRP), and organic cation transporter 1 (OCT1) inhibitor. Coadministration of gilteritinib may increase the exposure of P-gp, BCRP, and OCT1 substrates, which may increase the incidence and severity of adverse reactions of these substrates

For P-gp, BCRP, or OCT1 substrates where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such substrate and monitor for adverse reactions as recommended in the respective prescribing information

§Refer to Section 12.3 in the Full Prescribing Information for more information on concomitant use of XOSPATA with a combined P-gp and strong CYP3A inducer (eg, rifampin) or strong CYP3A inhibitors (eg, itraconazole). Gilteritinib inhibits BCRP, P-gp, and OCT1 at clinically relevant concentrations.1

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5HT2B=5-hydroxytryptamine receptor 2B; ALT=alanine aminotransferase; AML=acute myeloid leukemia; AST=aspartate aminotransferase; BCRP=breast cancer resistant protein; CYP3A=cytochrome P450 family 3 subfamily A; OCT1= organic cation transporter 1; P-gp=P-glycoprotein; PRES=posterior reversible encephalopathy syndrome; QT=cardiac ventricular repolarization.

Reference: 1. XOSPATA [package insert]. Northbrook, IL: Astellas Pharma US, Inc.