KOMZIFTI- ziftomenib capsule

KOMZIFTI- ziftomenib capsule
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]

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Black Box Warning

WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete Boxed Warning. DIFFERENTIATION SYNDROME: (Differentiation syndrome, which can be fatal, has occurred with KOMZIFTI. Signs and symptoms may include fever, joint pain, hypotension, hypoxia, dyspnea, rapid weight gain or peripheral edema, pleural or pericardial effusions, pulmonary infiltrates, acute kidney injury, and rashes. If differentiation syndrome is suspected, interrupt KOMZIFTI and initiate oral or intravenous corticosteroids with hemodynamic and laboratory monitoring until symptom resolution; resume KOMZIFTI upon symptom improvement.)

Overview

KOMZIFTI- ziftomenib capsule is a menin inhibitor that is FDA approved for the treatment of relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 (NPM1) mutation in adult patients who have no satisfactory alternative treatment options.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include aspartate aminotransferase increase, 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 increase..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Relapsed or Refractory Acute Myeloid Leukemia with a Susceptible NPM1 Mutation

• 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.

Dosing Information

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 the Tables below.

Recommended Management and Dosage Modifications for KOMZIFTI for Adverse Reactions

Adverse Reactiona	Recommended Action
Differentiation syndrome	If differentiation syndrome is suspected, interrupt KOMZIFTI. Administer systemic corticosteroids and initiate hemodynamic monitoring until symptom resolution and for a minimum of 3 days and provide supportive care. Resume KOMZIFTI at the same dose level when signs and symptoms improve and are Grade ≤ 2b.
Noninfectious leukocytosis (e.g., sudden or significant white blood cell (WBC) increase, including WBC doubling within the first 2 weeks of administration or an absolute increase of 10 x 109/L)	Evaluate for differentiation syndrome. Initiate treatment with hydroxyurea, as per standard institutional practices, and leukapheresis if clinically indicated. Taper hydroxyurea only after leukocytosis improves or resolves. Interrupt KOMZIFTI if leukocytosis is not controlled with hydroxyurea within 48 hours. If interrupted, resume KOMZIFTI at the same dose level once WBC counts are controlled.
Nonhematological adverse reactions Grade ≥ 3b	Interrupt KOMZIFTI until recovery to Grade ≤ 2b. Resume KOMZIFTI at the same dose level. If the same Grade ≥ 3 toxicity recurs, interrupt KOMZIFTI until recovery to Grade ≤ 2b. Restart KOMZIFTI at a reduced dosec.

^a Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^b Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

^c See Table below for the reduced dose levels.

Recommended Dosage Reductions for KOMZIFTI for Adverse Reactions

	Recommended Dosage
First dose reduction	400 mg orally once daily
Second dose reduction	200 mg orally once daily

^*Permanently discontinue KOMZIFTI in patients unable to tolerate 200 mg orally once daily following second dose reduction.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of KOMZIFTI- ziftomenib capsule in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of KOMZIFTI- ziftomenib capsule in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding KOMZIFTI- ziftomenib capsule FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of KOMZIFTI- ziftomenib capsule in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of KOMZIFTI- ziftomenib capsule in pediatric patients.

Contraindications

None.

Warnings

WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete Boxed Warning. DIFFERENTIATION SYNDROME: (Differentiation syndrome, which can be fatal, has occurred with KOMZIFTI. Signs and symptoms may include fever, joint pain, hypotension, hypoxia, dyspnea, rapid weight gain or peripheral edema, pleural or pericardial effusions, pulmonary infiltrates, acute kidney injury, and rashes. If differentiation syndrome is suspected, interrupt KOMZIFTI and initiate oral or intravenous corticosteroids with hemodynamic and laboratory monitoring until symptom resolution; resume KOMZIFTI upon symptom improvement.)

Differentiation Syndrome

• 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.
• 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.
• Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment.

QTc Interval Prolongation

• KOMZIFTI can cause QT (QTc) interval prolongation.
• 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.
• 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).
• 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.

Embryo-Fetal Toxicity

• 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.

Adverse Reactions

Clinical Trials Experience

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Differentiation Syndrome
• QTc Interval Prolongation

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).
• Fatal adverse reactions occurred in 4 (4%) patients who received KOMZIFTI, including 2 with differentiation syndrome, 1 with infection, and 1 with sudden death.
• Serious adverse reactions were reported in 79% of patients who received KOMZIFTI.
• Serious adverse reactions occurring in ≥ 5% of patients included infection without an identified pathogen (29%), febrile neutropenia (18%), bacterial infection (16%), differentiation syndrome (16%), and dyspnea (6%).
• Dosage interruption of KOMZIFTI due to an adverse reaction occurred in 54% of patients.
• Adverse reactions that required dose interruption in ≥ 2% of patients included infection without an identified pathogen (15%), differentiation syndrome (13%), febrile neutropenia (5%), pyrexia (4%), electrocardiogram QT prolonged (4%), leukocytosis (4%), bacterial infection (3%), cardiac failure (2%), cholecystitis (2%), diarrhea (2%), pruritus (2%), and thrombosis (2%).
• 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.
• Adverse reactions that required permanent discontinuation of KOMZIFTI in ≥ 2% of patients were infection without an identified pathogen (8%), bacterial infection (4%), cardiac arrest (2%), and differentiation syndrome (2%).
• 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.
• The Table below summarizes the adverse reactions in KO-MEN-001.

Adverse Reactions Reported in ≥20% (Any Grade) or ≥5% (Grade 3 or 4) of Patients with Relapsed or Refractory AML

Adverse Reaction	KOMZIFTI N=112
	All Grades† (%)	Grade 3 or 4 (%)
Infections and infestations
Infection without identified pathogena	52	38
Bacterial infectionb	28	17
Viral infectionc	16	5
Vascular disorders
Hemorrhaged	38	8
Hypertension	11	5
Gastrointestinal disorders
Diarrheae*	36	5
Nauseaf*	35	2
General disorders and administration site conditions
Fatigueg	34	8
Edemah*	30	3
Musculoskeletal and connective tissue disorders
Musculoskeletal paini	28	4
Neoplasms benign, malignant, and unspecified (incl cysts and polyps)
Differentiation syndrome	26	13
Skin and subcutaneous
Pruritusj*	23	0
Blood and lymphatic system disorder
Febrile neutropenia	22	22
Leukocytosisk*	16	5
Investigations
Transaminases increasedl	21	8
Electrocardiogram QT prolonged*	12	8
Renal and urinary disorders
Renal impairmentm	19	6
Respiratory, thoracic, and mediastinal disorders
Hypoxia	9	5

^†Includes the following fatal adverse reactions: infection (n=1) and differentiation syndrome (n=2).

^*No Grade 4 events were reported for this adverse reaction.

^a Includes abdominal abscess, abscess limb, anal abscess, anorectal infection, bronchitis, conjunctivitis, device related infection, device related sepsis, diverticulitis, emphysematous cystitis, enterocolitis infectious, gingivitis, hordeolum, infection, large intestine infection, nail infection, necrotizing fasciitis, penile infection, periodontitis, perirectal abscess, peritonitis, pneumonia, postoperative abscess, respiratory tract infection, rhinitis, sepsis, septic shock, sinusitis, skin infection, soft tissue infection, tooth infection, upper respiratory tract infection, urosepsis, vaginal infection, vascular device infection, wound infection.

^b Includes bacteremia, bacterial infection, bacterial pyelonephritis, breast cellulitis, cellulitis, clostridial infection, clostridium difficile colitis, clostridium difficile infection, enterobacter sepsis, enterococcal bacteremia, erysipelas, escherichia bacteremia, escherichia infection, escherichia sepsis, escherichia urinary tract infection, klebsiella bacteremia, klebsiella infection, klebsiella urinary tract infection, paronychia, pneumonia bacterial, pneumonia klebsiella, pseudomonal bacteremia, staphylococcal bacteremia.

^c Includes adenovirus infection, COVID-19, genital herpes, herpes simplex reactivation, herpes virus infection, herpes zoster, nasal herpes, oral herpes, pneumonia influenzas, pneumonia parainfluenza viral, respiratory syncytial virus infection, rhinovirus infection.

^d Includes angina bullosa hemorrhagic, bladder tamponade, catheter site hematoma, conjunctival hemorrhage, contusion, disseminated intravascular coagulation, ecchymosis, epistaxis, gastric hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hematochezia, hematoma, hematuria, hemoptysis, hemorrhage, hemorrhoidal hemorrhage, hyperfibrinolysis, injection site hematoma, injection site hemorrhage, lower gastrointestinal hemorrhage, melaena, mouth hemorrhage, oral blood blister, petechiae, purpura, rectal hemorrhage, retinal hemorrhage, shock hemorrhagic, skin hemorrhage, subdural hematoma, tongue hemorrhage, traumatic hematoma, upper gastrointestinal hemorrhage, vaginal hemorrhage, vitreous hemorrhage.

^e Includes diarrhea, colitis, colitis erosive.

^f Includes nausea, vomiting.

^g Includes fatigue, asthenia, malaise.

^h Includes edema, edema peripheral, generalized edema, localized edema, peripheral swelling.

ⁱ Includes arthralgia, back pain, bone pain, flank pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity.

^j Includes pruritus, nasal pruritus.

^k Includes white blood cell count increased, leukocytosis, hyperleukocytosis.

^l Includes transaminases increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased, hypertransaminasemia.

^m Includes renal impairment: acute kidney injury, azotemia, blood creatinine increased, blood urea increased, chronic kidney disease, postrenal failure, renal failure.

• The Table below summarizes the laboratory abnormalities in KO-MEN-001.

Selected New or Worsening Laboratory Abnormalities in Patients with Relapsed or Refractory AML

Laboratory Abnormality	KOMZIFTI
	Grades 1-4* (%)	Grade 3-4* (%)
Aspartate aminotransferase increased	53	4
Potassium decreased	52	22
Albumin decreased	51	5
Alanine aminotransferase increased	50	6
Sodium decreased	49	3
Creatinine increased	45	4
Alkaline phosphatase increased	41	5
Bilirubin increased	27	6
Potassium increased	26	6

^*The denominator used to calculate the rate varied from 108 to 110 based on the number of patients with a baseline value and at least one post-baseline value.

Postmarketing Experience

There is limited information regarding KOMZIFTI- ziftomenib capsule Postmarketing Experience in the drug label.

Drug Interactions

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.
• Ziftomenib is primarily metabolized by CYP3A.
• Concomitant use of KOMZIFTI with strong or moderate CYP3A4 inducers may decrease ziftomenib exposure, which may reduce the efficacy of KOMZIFTI.

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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

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.
• 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 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

• Ziftomenib was administered orally twice daily to pregnant mice at doses of 6, 20, and 60 mg/kg/day during organogenesis (gestation days 6-15).
• 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of KOMZIFTI- ziftomenib capsule in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of KOMZIFTI- ziftomenib capsule during labor and delivery.

Nursing Mothers

Risk Summary

• There are no data on the presence of ziftomenib or its metabolites in human milk or the effects of ziftomenib or its metabolites on the breastfed child or milk production.
• Because of the potential for adverse reactions in the breastfed child, advise women not to breastfeed during treatment with KOMZIFTI and for 2 weeks after the last dose.

Pediatric Use

There is no FDA guidance on the use of KOMZIFTI- ziftomenib capsule in pediatric settings.

Geriatic Use

• 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.

Gender

There is no FDA guidance on the use of KOMZIFTI- ziftomenib capsule with respect to specific gender populations.

Race

There is no FDA guidance on the use of KOMZIFTI- ziftomenib capsule with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of KOMZIFTI- ziftomenib capsule in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of KOMZIFTI- ziftomenib capsule in patients with hepatic impairment.

Females of Reproductive Potential and Males

• Based on findings in animals and its mechanism of action, KOMZIFTI can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing

• Verify pregnancy status in females of reproductive potential prior to initiating KOMZIFTI.

Contraception

Females

• Advise females of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 6 months after the last dose.

Males

• Advise males with female partners of reproductive potential to use effective contraception during treatment with KOMZIFTI and for 3 months after the last dose.

Infertility

• Based on findings in animals, KOMZIFTI may impair fertility in females and males of reproductive potential.
• Findings in animals were not reversible after a 4-week recovery period.

Immunocompromised Patients

There is no FDA guidance one the use of KOMZIFTI- ziftomenib capsule in patients who are immunocompromised.

Administration and Monitoring

Administration

• 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.
• 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.

Monitoring

Recommended Dosage

• Do not start KOMZIFTI until the white blood cell (WBC) count is reduced to less than 25 x 10⁹/L.

Dosage Modifications for Adverse Reactions

• Manage any abnormalities promptly.

Differentiation Syndrome

• 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.

QTc Interval Prolongation

• 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).
• 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.

Strong or Moderate CYP3A4 Inhibitors

• Monitor patients more frequently for KOMZIFTI-associated adverse reactions.

Drugs that Prolong the QT Interval

• If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated.

IV Compatibility

There is limited information regarding the compatibility of KOMZIFTI- ziftomenib capsule and IV administrations.

Overdosage

There is limited information regarding KOMZIFTI- ziftomenib capsule overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding KOMZIFTI- ziftomenib capsule Pharmacology in the drug label.

Mechanism of Action

• 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.

Structure

• The chemical name is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile.
• The molecular formula is C33H42F3N9O2S2 and the molecular weight is 717.88 g/mol.

Add structure image.

• Ziftomenib is a white to off-white powder and is highly soluble in aqueous solution at pH 1.2 and practically insoluble at pH ≥4.
• Each KOMZIFTI capsule contains 200 mg ziftomenib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, and sodium lauryl sulfate.
• The capsule shells, imprinted with black ink, contain the following inactive ingredients: hypromellose and titanium dioxide.

Dosage Forms and Strengths

• Capsules of ziftomenib are available in 200 mg strength.
• The capsules are white and are imprinted with "ZIF 200" in black ink.

Pharmacodynamics

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

Cardiac Electrophysiology

• The effect of KOMZIFTI on the QTc interval was evaluated at 600 mg (the approved recommended dosage) in patients with relapsed or refractory acute myeloid leukemia in KO-MEN-001 (n=133).
• The increase in the QTc interval was concentration-dependent with the largest mean increase in QTc interval predicted to be 7.7 ms (upper confidence interval = 12.6 ms) after administration of ziftomenib 600 mg once daily.
• There were 9 subjects (7%) with QTcF > 500 ms and an increase in QTc > 60 ms over baseline.

Pharmacokinetics

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

Absorption
Tmax [Median (range)] (hours)	4.1 (0.5, 8.15)
Absolute Bioavailability	12.9%
Effect of Food
High-Fat Meal	AUC and Cmax increased 4-fold
Distribution
Apparent Volume of Distribution (L)	30100 (98%)
Protein Binding	99% (albumin)
Elimination
Half-Life (hours)	189.8 (23) [with CYP3A4 inhibitors] and 93.6 (21) [without CYP3A4 inhibitors]
Apparent Clearance (L/h)	41.5 (29) [with inhibitors] and 101.2 (27) [without inhibitors]
Metabolism
Primary Pathway	CYP3A
Excretion
Feces	86% (73% as unchanged drug)
Urine	0.5% (0.03% as unchanged drug)

Specific Populations

• No clinically significant differences in the pharmacokinetics of ziftomenib were observed based on age, sex, race, ethnicity, mild or moderate hepatic impairment, or mild to moderate renal impairment.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

• Gastric Acid Reducing Agents: Administration of PPIs reduced ziftomenib AUC_0-inf by 53% and C_max by 70%.
• Strong, Moderate, or Weak CYP3A4 Inhibitors: Itraconazole, voriconazole, and posaconazole (strong CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 3-fold and C_max by up to 2-fold.
• Erythromycin, fluconazole, and isavuconazole (moderate CYP3A4 inhibitors) are estimated to increase ziftomenib AUC by up to 2-fold and C_max by up to 2-fold.
• Cimetidine (weak CYP3A inhibitor) is estimated to increase ziftomenib AUC and C_max by up to 1.4-fold.
• Strong, Moderate, or Weak CYP3A4 Inducers: Rifampin (strong CYP3A4 inducer) is estimated to decrease ziftomenib AUC by up to 80% and C_max by up to 70%.
• Efavirenz (moderate CYP3A4 inducer) is estimated to decrease ziftomenib AUC and C_max by up to 70%.
• Dexamethasone (weak CYP3A4 inducer) is estimated to decrease ziftomenib AUC and C_max by up to 40%.
• CYP3A4 Substrates: Ziftomenib is predicted to increase the AUC and C_max of midazolam (CYP3A4 substrate) up to 1.9- and 1.4-fold, respectively, when ziftomenib is administered alone.
• Other Drugs: Ziftomenib is not predicted to have clinically significant effects on the exposure of repaglinide (CYP2C8 substrate), (S)-warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and raltegravir (UGT1A1 substrate).

In Vitro Studies

• Cytochrome P450 (CYP450) Enzymes: Ziftomenib does not inhibit CYP1A2 or CYP2D6. Ziftomenib induces CYP1A2 but not CYP2B6 or CYP3A4.
• UDP-Glucuronosyltransferase (UGT): Ziftomenib inhibits UGT1A9 and UGT2B17.
• Transporter Systems: Ziftomenib is a substrate of P-gp and BCRP, but not BSEP or MRP. Ziftomenib does not inhibit P-gp, BCRP, OAT1, OAT3, OCT2, MATE1, MATE2-K, OATP1B1, OATP1B3, BSEP, or MRP2.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• 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.

Animal Toxicology and/or Pharmacology

• 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.

Clinical Studies

• The efficacy of KOMZIFTI was evaluated in an open-label, single-arm, multicenter clinical trial (Study KO-MEN-001, NCT04067336; KOMET-001) in 112 adult patients with relapsed or refractory AML with an NPM1 mutation identified using next-generation sequencing or polymerase chain reaction.
• Patients with NPM1 mutations, including Type A, B, and D mutations and other NPM1 mutations likely to result in cytoplasmic localization of the NPM1 protein, were enrolled.
• Other eligibility criteria included creatinine clearance ≥ 30 mL/min, total bilirubin ≤ 1.5 x the upper limit of normal (ULN), aminotransferases ≤ 2 x ULN, QTcF ≤ 480 msec, and Eastern Cooperative Oncology Group performance status score of 0-2.
• KOMZIFTI was given orally at a dose of 600 mg once daily until disease progression or unacceptable toxicity.
• Patients were permitted to resume treatment with KOMZIFTI following hematopoietic stem cell transplant (HSCT).
• Four (3.6%) of the 112 patients underwent stem cell transplantation following KOMZIFTI treatment.
• The baseline demographic and disease characteristics for the 112 treated patients are shown in the Table below.

Baseline Demographic and Disease Characteristics

Demographics and Disease Characteristics	KOMZIFTI (600 mg once daily) N=112
Demographics
Median Age (years) (Range)	69 (22, 86)
Age Categories, n (%)
<65 years	42 (38)
≥65 years	70 (63)
Sex, n (%)
Male	49 (44)
Female	63 (56)
Race, n (%)
White	88 (79)
Black or African American	2 (2)
Asian	4 (4)
Other	2 (2)
Unknown	16 (14)
Ethnicity, n (%)
Hispanic or Latino	3 (3)
Not Hispanic or Latino	87 (78)
Unknown	22 (20)
Disease Characteristics
Type of AML, n (%)
De novo AML	95 (85)
Secondary AML	17 (15)
Disease status, n (%)
Primary Refractory	7 (6)
Refractory Relapse	37 (33)
Untreated Relapse	68 (61)
Median number of prior lines of therapy (range)	2 (1, 7)
Prior stem cell transplantation, n (%)	26 (23)

• Efficacy was established based on the rate of complete remission (CR) plus CR with partial hematological recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence.
• The median follow-up was 4.2 months (range, 0.1 to 41.2 months).
• The efficacy results are shown in the Table below.

Efficacy Results in Patients with Relapsed or Refractory AML

Endpoint	KOMZIFTI (600 mg once daily) N=112
CRa+CRhb, n (%)	24 (21.4)
95% CI	(14.2, 30.2)
Median DOCR+CRhc (months)	5.0
95% CI	(1.9, 8.1)
CRa, n (%)	19 (17.0)
95% CI	(10.5, 25.2)
Median DOCRd (months)	5.0
95% CI	(2.8, 8.1)
CRhb, n (%)	5 (4.5)
95% CI	(1.5, 10.1)
Observed DOCRhe (months)	0.0+, 1.5+, 1.5, 1.6, 11.4

CI: confidence interval; the 95% CI rate was calculated using the exact method based on binomial distribution; NE: not estimable; +: censor.

^a CR is defined as bone marrow blasts <5%, absolute neutrophil count (ANC) > 1.0 x 10⁹/L, and platelet count > 100 x 10⁹/L.

^b CRh is defined as bone marrow blasts <5%, (ANC) > 0.5 x 10⁹/L; platelet count > 50 x 10⁹/L.

^c Duration of CR+CRh (DO_CR+CRh) is defined as the time from first CR/CRh to the first documented relapse or death, whichever occurs first.

^d Duration of CR (DO_CR) is defined as the time from first CR to the first documented relapse or death, whichever occurs first.

^e Duration of CRh (DO_CRh) is defined as the time from first CRh to the first documented relapse or death, whichever occurs first.

• For patients who achieved a CR or CRh, the median time to first response was 2.7 months (range, 0.9 to 15 months).
• Of the 24 patients who achieved a response of CR or CRh, 21 (88%) patients did so within 6 months of initiating KOMZIFTI.
• Among the 66 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 14 (21.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period.
• Of the 46 patients who were independent of both RBC and platelet transfusions at baseline, 12 (26.1%) patients remained transfusion independent during any 56-day post-baseline period.

How Supplied

• Capsules of ziftomenib are available in 200 mg strength.
• The capsules are white and are imprinted with "ZIF 200" in black ink.
• 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).

Images

Drug Images

Package and Label Display Panel

PD panel 1

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Differentiation Syndrome

• Advise patients of the risk of developing differentiation syndrome as early as 3 days after the start of therapy and during treatment.
• Instruct patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, joint or bone pain, dizziness, shortness of breath or difficulty breathing, cough, chest pain, rapid weight gain, rash, decreased urinary output, or swelling in the hands, feet, ankles, or legs, to their healthcare provider for further evaluation.

Prolonged QT Interval

• Advise patients to consult their healthcare provider immediately if they feel faint, lose consciousness, or have signs or symptoms suggestive of arrhythmia.
• Advise patients with a history of hypokalemia or hypomagnesemia of the importance of monitoring their electrolytes.

Embryo-Fetal Toxicity

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy.
• 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.

Lactation

• Advise women not to breastfeed during treatment with KOMZIFTI and for 2 weeks after the last dose.

Drug Interactions

• Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and supplements.

Dosing Instructions

• Advise patients to take KOMZIFTI once daily, at around the same time each day, on an empty stomach, at least 1 hour before or 2 hours after a meal.
• Advise patients to swallow KOMZIFTI capsules whole.
• Do not open, break, or chew the capsules.
• Instruct patients, if they miss a dose of KOMZIFTI, to take the dose as soon as possible on the same day and at least 12 hours prior to the next scheduled dose and return to the normal schedule the following day.
• Advise patients not to take 2 doses within 12 hours to make up for the missed dose.

Precautions with Alcohol

Alcohol-KOMZIFTI- ziftomenib capsule interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Komzifti

Look-Alike Drug Names

There is limited information regarding KOMZIFTI- ziftomenib capsule Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.