Ziftomenib

Ziftomenib is a prescription medication 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.

• Ziftomenib is available under the following different brand names: Komzifti

Common side effects of Ziftomenib include:

• iznfections, including bacterial infections 
• bleeding 
• diarrhea  
• nausea 
• fatigue
• edema
• musculoskeletal pain
• itching
• differentiation syndrome
• febrile neutropenia
• increased aspartate aminotransferase (AST)
• increased alanine aminotransferase (ALT)
• increased or decreased potassium
• increased bilirubin
• increased creatinine
• increased alkaline phosphatase
• decreased sodium
• decreased albumin

Serious side effects of Ziftomenib include:

• differentiation syndrome
• infection without an identified pathogen
• febrile neutropenia
• bacterial infection
• dyspnea

Rare side effects of Ziftomenib include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Capsule

• 200 mg

Acute Myeloid Leukemia

Adult dosage

• 600 mg orally once daily
• Continue until disease progression or unacceptable toxicity
• For patients without confirmed disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for clinical response

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your doctor has directed you to use this medication, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

Drug interaction overview

• Moderately sensitive CYP3A4 substrate
• Weak CYP3A4 inhibitor
• Strong or moderate CYP3A4 inducers
  • Avoid coadministration with strong or moderate CYP3A4 inducers, which may decrease ziftomenib systemic exposure, and thereby reduce efficacy
• Strong or moderate CYP3A4 inhibitors
  • Monitor patients more frequently for ziftomenib-associated adverse reactions (eg, QT prolongation)
  • Concomitant use with strong or moderate CYP3A4 inhibitors increases ziftomenib systemic exposure, which may increase the risk of adverse reactions
• Gastric acid-reducing agents
  • Proton pump inhibitors: Avoid coadministration; reduces ziftomenib efficacy
  • H2 receptor antagonists or locally acting antacids: Avoid coadministration; if unable to avoid, modify ziftomenib administration time 
•  Drug that prolong QT interval

Ziftomenib causes QTc interval prolongation; concomitant use with other products that prolong the QTc interval may result in a greater increase in QTc interval and adverse reactions associated with QTc interval prolongation, including Torsades de pointes, other serious arrhythmias, and sudden death

Avoid coadministration with other product(s) with a known potential to prolong QTc interval

If unable to avoid, obtain ECGs when initiating, during concomitant use, and as clinically indicated

Interrupt dosing if the QTc interval is more than 500 ms or change from baseline is above 60 ms

Contraindications

• None

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Ziftomenib?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Ziftomenib?”

Cautions

• Differentiation syndrome
  • Can cause fatal or life-threatening differentiation syndrome
  • Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells
  • Symptoms may include fever, hypoxia, joint pain, hypotension, dyspnea, rapid weight gain, peripheral edema, pleural or pericardial effusions, acute kidney injury, and rashes
  • Before initiating treatment, reduce WBC counts to below 25 x 10^9/L
  • If differentiation syndrome is suspected, interrupt dosing, initiate oral or IV corticosteroids (eg, dexamethasone 10 mg every 12 hours) for greater than 3 days with hemodynamic and laboratory monitoring
  • Resume dosing at the same dose level when signs and symptoms improve and are Grade less than 2
  • Taper corticosteroids over greater than 3 days after adequate control or resolution of symptoms
  • Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment
• QTc interval prolongation
  • Can cause QT (QTc) interval prolongation
  • Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, before initiating treatment
  • Perform an ECG before initiating and do not initiate in patients with a QTc above 480 msec
  • Perform an ECG at least once weekly for the first 4 weeks, and at least monthly thereafter
  • Interrupt dosing if the QTc interval is above 500 ms or a change from baseline is above 60 ms (Grade 3)
• Embryofetal toxicity
• Based on findings in animals and their mechanism of action, it can cause embryofetal harm when administered during pregnancy
• Advise pregnant women of the potential risk to the fetus
• Advise females of reproductive potential to use effective contraception during treatment with and for 6 months after the last dose
• Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose

Pregnancy and Lactation

Based on findings in animals and their mechanism of action, ziftomenib can cause embryofetal harm when administered during pregnancy

Advise pregnant women of potential fetal risk

Verify pregnancy status in females of reproductive potential before initiating

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for 6 months after last dose
• Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months after the last dose

Infertility

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

Lactation

• Data are unavailable regarding the presence of ziftomenib or its metabolites in human milk or its effects on breastfed children or milk production
• Owing to potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 2 weeks after the last dose