Get your patient on Komzifti (Ziftomenib)

Select patients for the treatment of relapsed or refractory AML with KOMZIFTI based on the presence of an NPM1 mutation [see Clinical Studies (14 )] .

An FDA-approved test for the detection of NPM1 mutations is not currently available.

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.

• Administer KOMZIFTI once daily on an empty stomach (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3 )].
• 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.

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 [see Drug Interactions (7.1 )] . 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.

Manage any abnormalities promptly [see Warnings and Precautions (5.1 , 5.2 ) and Adverse Reactions (6.1 )] .

Interrupt or reduce dose for adverse reactions as per Table 1 and Table 2 .

Based on findings in animals and its mechanism of action, KOMZIFTI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1 )] .

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

Of the 112 patients with relapsed or refractory AML with an NPM1 mutation treated with KOMZIFTI, 70 (63%) patients were 65 years of age or older and 31 (28%) were 75 years or older.

No overall differences in effectiveness, safety, or pharmacokinetics of KOMZIFTI were observed between patients aged 65 years or older and younger patients [see Clinical Studies (14 ) and Clinical Pharmacology (12.3 )].

No dose adjustment is required for patients with mild or moderate (CL _Cr 30 to 89 mL/min) renal impairment. The effects of severe (CL _Cr less than 30 mL/min) renal impairment have not been studied [see Clinical Pharmacology (12.3 )].

No dose adjustment is required for patients with mild (bilirubin less than or equal to ULN and AST greater than ULN or bilirubin less than or equal to 1.5 x ULN) or moderate (bilirubin 1.5 to 3 x ULN) hepatic impairment. The effects of severe hepatic impairment (bilirubin greater than 3 x ULN) have not been studied [see Clinical Pharmacology (12.3 )] .

KOMZIFTI can cause fatal or life-threatening differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. Symptoms of differentiation syndrome, including those seen in patients treated with KOMZIFTI, may include fever, hypoxia, joint pain, hypotension, dyspnea, rapid weight gain or peripheral edema, pleural or pericardial effusions, acute kidney injury, and rashes.

In the clinical trial, differentiation syndrome occurred in 29 (26%) of 112 patients with relapsed or refractory AML with an NPM1 mutation who were treated with KOMZIFTI at the recommended dosage. Differentiation syndrome was Grade 3 in 13% and fatal in two patients. In broader evaluation of all patients with any genetic form of AML treated with KOMZIFTI monotherapy in clinical trials, differentiation syndrome occurred in 25% of patients. Four fatal cases of differentiation syndrome occurred out of 39 patients with KMT2A -rearranged AML treated with KOMZIFTI. KOMZIFTI is not approved for use in patients with KMT2A -rearranged AML.

In the 112 patients with an NPM1 mutation, differentiation syndrome was observed with and without concomitant hyperleukocytosis, in as early as 3 days and up to 46 days after KOMZIFTI initiation. The median time to onset was 15 days. Two patients experienced more than one differentiation syndrome event. Treatment was interrupted and resumed in 15 (13%) patients, while it was permanently discontinued in 2 (2%) patients [see Adverse Reactions (6.1 )] .

Prior to starting treatment with KOMZIFTI, reduce the WBC counts to less than 25 x 10⁹/L. If differentiation syndrome is suspected, interrupt KOMZIFTI, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) for a minimum of 3 days with hemodynamic and laboratory monitoring. Resume treatment with KOMZIFTI at the same dose level when signs and symptoms improve and are Grade 2 or lower. Taper corticosteroids over a minimum of 3 days after adequate control or resolution of symptoms [see Dosage and Administration (2.5 )] . Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment.

KOMZIFTI can cause QT (QTc) interval prolongation [see Clinical Pharmacology (12.2 ) ] . In the clinical trial, QTc interval prolongation was reported as an adverse reaction in 12% of 112 patients treated with KOMZIFTI at the recommended dosage for relapsed or refractory AML with an NPM1 mutation. QTc interval prolongation was Grade 3 in 8% of patients. The heart-rate corrected QT interval (using Fridericia's method) (QTcF) was greater than 500 msec in 9% of patients, and the increase from baseline QTcF was greater than 60 msec in 12% of patients. KOMZIFTI dose reduction was required for 1% of patients due to QTc interval prolongation [see Adverse Reactions (6.1 )] . QTc prolongation occurred in 14% of the 42 patients less than 65 years of age and in 10% of the 70 patients 65 years of age or older.

Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to treatment with KOMZIFTI. Perform an ECG prior to initiation of treatment with KOMZIFTI, and do not initiate KOMZIFTI in patients with QTcF > 480 msec. Perform an ECG at least once weekly for the first four weeks on treatment, and at least monthly thereafter. Interrupt KOMZIFTI if the QTc interval is > 500 ms or the change from baseline is > 60 ms (Grade 3) [see Dosage and Administration (2.5 )] . In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring may be necessary. Concomitant use of KOMZIFTI with drugs known to prolong the QTc interval may increase the risk of QTc interval prolongation [see Drug Interactions (7.1 ), Clinical Pharmacology (12.2 )] .

Based on findings in animals and its mechanism of action, KOMZIFTI can cause embryo-fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ziftomenib to pregnant mice during the period of organogenesis caused adverse developmental outcomes, including embryo-fetal mortality, structural abnormalities, and altered fetal growth at approximately 0.3 times the steady-state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose.

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3 )] .

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.

Ziftomenib is a menin inhibitor that blocks the interaction of menin and lysine [K]-specific methyltransferase 2A (KMT2A).

Acute leukemias can be driven by mutations in NPM1 that recruit the wild-type menin-KMT2A complex to promoters of leukemogenic genes. Susceptible NPM1 mutations are defined as those that result in loss of the nucleolar localization signal and the insertion of a new nuclear export signal leading to cytoplasmic accumulation of mutant NPM1 protein that disrupts normal cell function and drives leukemogenesis through altered gene expression.

Pharmacologic disruption of the menin-KMT2A protein-protein interaction by ziftomenib blocks oncogenic activity of mutant NPM1, which induces differentiation of leukemic cells as evidenced by increased expression of differentiation markers. In nonclinical studies, ziftomenib demonstrated in vitro and in vivo antitumor activity in models of NPM1 -mutant leukemia.

Ziftomenib exposure-response relationships have not been fully characterized and the time course of pharmacodynamic response is unknown.

Ziftomenib pharmacokinetics were characterized in patients with relapsed or refractory AML. Pharmacokinetic parameters are presented as mean (% CV), unless otherwise specified.

Carcinogenicity studies have not been conducted with ziftomenib. In a repeat dose toxicity study in mice treated with ziftomenib for 13 weeks, lymphoma was observed in multiple organs in one animal.

Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.

Fertility studies in animals have not been conducted with ziftomenib. In a repeat dose, 13-week toxicity study in dogs treated with twice daily oral administration of ziftomenib at 6, 20, or 60 mg/kg/day, changes were reported in male and female reproductive organs, including decreased mean testis weight, increased vacuolation of the seminiferous tubular epithelial cells, marked decrease in sperm in the epididymal lumen at ≥ 20 mg/kg/day, and fewer developing follicles in the ovaries at ≥ 60 mg/kg/day. At the dose of 20 mg/kg/day in dogs, exposures (AUC) were as low as 0.3 times the human exposure (AUC) at the recommended dose. At the dose of 60 mg/kg/day, exposures were as low as 1.2 times the human exposure at the recommended dose. Reversibility was not assessed at 20 mg/kg/day and findings were not reversible at 60 mg/kg/day after the 4-week recovery period.

In 13-week repeat-dose toxicity studies in mice and dogs, incidences of hyperplasia in a variety of organs occurred in several animals from both species. The findings in the mouse study were observed at ≥ 12 mg/kg/day at exposures as low as 0.3 times the AUC at the recommended dose, and the findings in the dog study were observed at ≥ 6 mg/kg/day at exposures as low as 0.05 times the AUC at the recommended dose.

How Supplied

KOMZIFTI 200 mg capsules are supplied as white capsules printed with “ZIF 200” in black ink.

KOMZIFTI capsules are available in white, induction-sealed, square, high-density polyethylene bottles of 90 capsules with child-resistant closure (NDC 84696-200-90).

Storage

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