Komzifti Drug Information

KOMZIFTI is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 ( NPM1 ) mutation who have no satisfactory alternative treatment options.

Patient Selection

Select patients for the treatment of relapsed or refractory AML with KOMZIFTI based on the presence of an NPM1 mutation. An FDA-approved test for the detection of NPM1 mutations is not currently available.

Recommended Dosage

The recommended dosage of KOMZIFTI is 600 mg taken orally once daily until disease progression or unacceptable toxicity. Do not start KOMZIFTI until the white blood cell (WBC) count is reduced to less than 25 x 10⁹/L. For patients without confirmed disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.

Administration Instructions Administer

KOMZIFTI once daily on an empty stomach (at least 1 hour before or 2 hours after a meal). Administer KOMZIFTI orally at about the same time each day. Swallow capsules whole.

Do not open, break, or chew the capsules. If a dose of KOMZIFTI is missed or not taken at the usual time, administer the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day.

Do not administer 2 doses within 12 hours.

Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of proton pump inhibitors (PPIs) with KOMZIFTI. Avoid concomitant use of a histamine-2 (H2) receptor antagonist or a locally acting antacid with KOMZIFTI. If concomitant use cannot be avoided: Take KOMZIFTI 2 hours before or 10 hours after administration of an H2 receptor antagonist.

Take KOMZIFTI 2 hours before or 2 hours after administration of a locally acting antacid.

Dosage Modifications for Adverse Reactions

Manage any abnormalities promptly. Interrupt or reduce dose for adverse reactions as per Table 1 and Table 2. Table 1 Recommended Management and Dosage Modifications for KOMZIFTI for Adverse Reactions Nonhematological adverse reactions Grade ≥ 3 b Interrupt KOMZIFTI until recovery to Grade ≤ 2 b.

Resume KOMZIFTI at the same dose level. Restart KOMZIFTI at a reduced dose c. Table 2 Recommended Dosage Reductions for KOMZIFTI for Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory AML with an NPM1 Mutation The safety of KOMZIFTI for the treatment of patients with relapsed or refractory AML with an NPM1 mutation was evaluated in KO-MEN-001. Patients received KOMZIFTI 600 mg once daily (n=112).

The median duration of exposure to KOMZIFTI was 2.2 months (range 0.1 to 21.5 months). Serious adverse reactions were reported in 79% of patients who received KOMZIFTI. Dosage interruption of KOMZIFTI due to an adverse reaction occurred in 54% of patients.

Dose reduction of KOMZIFTI due to an adverse reaction occurred in 4% of patients. Permanent discontinuation of KOMZIFTI due to an adverse reaction occurred in 21% of patients. The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were aspartate aminotransferase increased, infection without an identified pathogen, potassium decreased, albumin decreased, alanine aminotransferase increased, sodium decreased, creatinine increased, alkaline phosphatase increased, hemorrhage, diarrhea, nausea, fatigue, edema, bacterial infection, musculoskeletal pain, bilirubin increased, potassium increased, differentiation syndrome, pruritus, febrile neutropenia, and transaminases increased.

Table 3 summarizes the adverse reactions in KO-MEN-001. Table 4 Selected New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML 6

Effect of Other Drugs on KOMZIFTI Strong or Moderate CYP3A4 Inhibitors Monitor patients more frequently for KOMZIFTI-associated adverse reactions. Ziftomenib is primarily metabolized by CYP3A. Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inhibitors increases ziftomenib exposure, which may increase the risk of adverse reactions such as QT prolongation.

Strong or Moderate CYP3A4 Inducers Avoid concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers. Gastric Acid Reducing Agents Concomitant administration of ziftomenib with proton pump inhibitors (PPIs) decreases ziftomenib exposure, which may reduce the efficacy of KOMZIFTI. Avoid concomitant use of KOMZIFTI with PPIs.

Avoid concomitant use of KOMZIFTI with H2 receptor antagonists (H2RAs) or locally acting antacids. If concomitant use cannot be avoided, modify KOMZIFTI administration time. Drugs that Prolong the QT Interval Avoid concomitant use of KOMZIFTI with other product(s) with a known potential to prolong the QTc interval.

If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated. Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms. Ziftomenib causes QTc interval prolongation.

Concomitant use of KOMZIFTI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsades de pointes, other serious arrhythmias, and sudden death.

Pregnancy Risk Summary Based on findings in animals and its mechanism of action, KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on KOMZIFTI use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at maternal exposures approximately 0.3 times the human exposure (AUC) at the recommended dose (see Data ).

Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Decreased fetal body weight, embryo-fetal lethality, fetal external and skeletal malformations and variations (cleft palate, fused cervical arches, absent lumbar vertebrae fused and/or misaligned costal cartilage, absent or short rib, supernumerary site in the suture bone or split palatine of the skull, and/or fused, unossified, and/or incompletely ossified sternebrae) were noted at all doses.

At the dose of 6 mg/kg/day in mice, the maternal exposure was approximately 0.3 times the human exposure at the recommended dose of 600 mg once daily.

Pediatric Use Safety and effectiveness of KOMZIFTI in pediatric patients have not been established.