Asciminib – Uses, Dosage, Side Effects, Interaction

Asciminib Hydrochloride is the hydrochloride salt form of asciminib, an orally bioavailable, allosteric Bcr-Abl1 tyrosine kinase inhibitor, with antineoplastic activity. Upon administration, asciminib targets and binds to the myristoyl pocket of the Bcr-Abl1 fusion protein at a location that is distinct from the ATP-binding domain, thereby inhibiting the activity of both wild-type Bcr-Abl and certain mutation forms, including the T315I mutation. This binding results in the inhibition of Bcr-Abl1-mediated proliferation and enhanced apoptosis of Philadelphia chromosome-positive (Ph+) hematological malignancies. The Bcr-Abl1 fusion protein tyrosine kinase is an abnormal enzyme produced by leukemia cells that contain the Philadelphia chromosome.

Use in Cancer

Asciminib hydrochloride is approved to treat adults with:

• Chronic myelogenous leukemia (CML) is in chronic phase and is Philadelphia chromosome positive. It is used:
  • In patients who have received at least two tyrosine kinase inhibitors.¹
  • In patients whose CML has the T315I mutation.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that asciminib hydrochloride provides a clinical benefit in these patients.

Asciminib hydrochloride is also being studied in the treatment of other types of cancer.

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

• anemia
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• high blood pressure
• pregnancy
• a patient who is producing milk and breastfeeding
• pancreatitis
• high blood levels of the lipase enzyme
• high blood levels of the amylase enzyme

Dosage

Strengths: 20 mg; 40 mg

Chronic Myelogenous Leukemia

Philadelphia chromosome-positive chronic myeloid leukemia I chronic phase (Ph+ CML-CP):

• Ph+ CML-CP Previously Treated with 2 or More TKIs (tyrosine kinase inhibitors): 80 mg orally once a day OR 40 mg orally every 12 hours
• Duration of therapy: Continue as long as clinical benefit is observed or until unacceptable toxicity occurs
• Ph+ CML-CP with the T315I Mutation: 200 mg orally every 12 hours
• Mild to severe renal impairment (eGFR 15 to 89 mL/min/1.73 m2): No adjustment recommended
• ESRD (eGFR less than 15 mL/min/1.73 m2) Data not available

Dose Adjustments

Dose Reductions for Adverse Reactions:

Ph+ CML-CP Previously treated with 2 or more TKIs:

• FIRST REDUCTION: 40 mg once a day OR 20 mg twice a day
• SUBSEQUENT REDUCTION: Permanently discontinue in patients unable to tolerate a reduced dose

Ph+ CML-CP with T315I Mutation:

• FIRST REDUCTION: 160 mg twice a day
• SUBSEQUENT REDUCTION: Permanently discontinue in patients unable to tolerate a reduced dose

THROMBOCYTOPENIA and/or NEUTROPENIA: Absolute Neutrophil Count (ANC) less than 1 x 10(9)/L and or Platelets (PLT) less than 50 x 10(9)/L:

• HOLD therapy until resolved to ANC of 1 x 10(9)/L or greater and/or PLT of 50 x 10(9)/L or greater
• If resolved within 2 weeks: Resume at the starting dose
• If resolved after more than 2 weeks: Resume at a reduced dose

For recurrent severe thrombocytopenia and/or neutropenia, hold until resolved ANC is 1 x 10(9)/L or greater and PLT is 50 x 10(9)/L or greater, then resume at a reduced dose
ASYMPTOMATIC AMYLASE and/or LIPASE ELEVATION: Elevation greater than 2 x ULN:

• HOLD until resolved to less than 1.5 x ULN
• If resolved, restart at a reduced dose; if the event recurs at a reduced dose, permanently discontinue
• If not resolved, permanently discontinue; perform diagnostic tests to exclude pancreatitis

NON-HEMATOLOGIC ADVERSE REACTIONS: Grade 3 or higher:

• HOLD until recovery to Grade 1 or less
• If resolved, resume at a reduced dose
• If not resolved, permanently discontinue

Side Effects

The Most Common

• muscle, bone or joint pain
• tiredness
• nausea
• diarrhea
• unexpected bleeding or easy bruising, blood in urine or stools
• fever or signs of an infection
• sudden stomach pain or discomfort, nausea or vomiting
• confusion, headaches, dizziness, chest pain, or shortness of breath
• rash, difficulty breathing or swallowing, swelling of face, lips or tongue, rash or skin flushing, dizziness or feeling faint, fever, fast heartbeat
• shortness of breath, chest pain or pressure, feeling of rapid or irregular heart beat, ankle or feet swelling, weight gain, numbness or weakness on one side of the body, decreased vision or loss of vision, trouble talking, pain in arms, legs, back, neck or jaw

More Common

• heart problems–pain in your arms, legs, back, neck or jaw, numbness or weakness on one side of your body, problems with speech or vision, dizziness, headache, swelling in your ankles or feet, chest pain, irregular heartbeat, rapid weight gain, feeling short of breath, severe stomach pain;
• high blood pressure–severe headache, blurred vision, pounding in your neck or ears;
• low blood cell counts–fever, chills, tiredness, flu-like symptoms, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet; or
• pancreas problems–sudden stomach pain or discomfort, nausea, or vomiting.
• cold symptoms such as stuffy nose, sneezing, sore throat;
• muscle, bone, or joint pain;
• tiredness;
• nausea, diarrhea;
• rash; or
• abnormal blood tests.

Rare’

• Bladder pain
• bloating
• bloody or cloudy urine
• burning urination
• coughing up blood
• frequent urge to urinate
• increased menstrual flow or vaginal bleeding
• indigestion
• nosebleeds
• pains in the chest, groin, or legs, especially calves of the legs
• pains in the stomach, side, or abdomen, possibly radiating to the back
• paralysis
• prolonged bleeding from cuts
• severe headaches of sudden onset
• sudden loss of coordination
• sudden onset of slurred speech
• sudden vision changes
• vomiting
• yellow eyes or skin

Drug Interaction

Pregnancy and Lactation

Pregnancy

Based on findings from animal studies and the mechanism of action, SCEMBLIX can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on SCEMBLIX use in pregnant women to evaluate a drug-associated risk.

Animal reproduction studies in pregnant rats and rabbits demonstrated that oral administration of asciminib during
organogenesis-induced structural abnormalities, embryo-fetal mortality, and alterations to growth. Advise pregnant women and females of reproductive potential 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.

Lactation

There are no data on the presence of asciminib or its metabolites in human milk, the effects on the breastfed child, or milk
production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during
treatment with SCEMBLIX and for 1 week after the last dose.

References

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