Dosing and administration information for patients with Advanced SM taking AYVAKIT® (avapritinib)1

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Starting AYVAKIT—one tablet, once-daily dosing1

The recommended dosage of AYVAKIT for Advanced SM is 200 mg orally once daily.

AYVAKIT SHOULD BE TAKEN1:

One tablet
orally

One time
each day

On an empty stomach, at least 1 hour before or 2 hours after a meal

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Do not initiate AYVAKIT in patients with platelet counts <50 x 109/L.

Treatment should continue until disease progression or unacceptable toxicity.

Do not take an additional dose if vomiting occurs after AYVAKIT has been taken, but continue with the next scheduled dose.

AYVAKIT is also available in dose strengths of 100 mg, 50 mg, and 25 mg for dose modification for adverse reactions or drug interactions (for example, CYP3A inhibitors).

Avoid concomitant use of AYVAKIT with strong or moderate CYP3A inhibitors. If concomitant use with a moderate CYP3A inhibitor cannot be avoided, the recommended starting dosage of AYVAKIT is 50 mg orally once daily.

 

Below is helpful information for starting treatment, monitoring treatment response, and recommended dose modifications for adverse reactions if necessary.

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Patient monitoring for initiating and continuing treatment with AYVAKIT1

PLATELET MONITORING

A platelet count must be performed prior to initiation of therapy, during the first 8 weeks of treatment, and potentially longer depending on what is clinically indicated. AYVAKIT is not recommended for patients with platelet counts <50 x 109/L.1

Time on therapy Monitoring plan Treatment plan
Prior to initiation Perform platelet count. AYVAKIT is not recommended in Advanced SM patients with platelet counts <50 x 109/L.
First 8 weeks Perform platelet count every 2 weeks regardless of baseline platelet count.

If platelet count <50 x 109/L occurs, interrupt AYVAKIT until platelet count is 50 x 109/L, then resume at reduced dose.

If platelet counts do not recover above 50 x 109/L, consider platelet support.

After 8 weeks Monitor platelet counts:
  • Every 2 weeks if values are <75 x 109/L (or more frequently as clinically indicated)
  • Every 4 weeks if values are 75-100 x 109/L
  • As clinically indicated if values are >100 x 109/L

Monitor patients closely for the risk of ICH, including those with thrombocytopenia, vascular aneurysm or a history of intracranial hemorrhage or cerebrovascular accident within the prior year. 

If any ICH occurs, permanently discontinue AYVAKIT.

Manage platelet counts of <50 x 109/L by treatment interruption or dose reduction of AYVAKIT. Platelet support may be necessary.

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It was common to modify AYVAKIT dosage1

Many patients in the EXPLORER and PATHFINDER trials had their dose reduced or interrupted due to adverse reactions1

AYVAKIT dose reductions and interruptions in clinical trials1

Among patients with Advanced SM in clinical trials who started at 200 mg (N=80), many patients had their dose modified.

Dose
interruption

Dose reduction
(median time to
reduction:
6.9 weeks)6

Permanent
discontinuation due
to adverse reaction

Adverse reactions requiring dosage interruption or dose reduction in >2% of patients who received AYVAKIT at 200 mg once daily:

  • Thrombocytopenia
  • Neutropenia
  • Anemia
  • Elevated blood alkaline phosphatase
  • Cognitive disorder
  • Peripheral edema
  • Periorbital edema
  • Fatigue
  • Arthralgia

Recommended dose reductions from the 200 mg once-daily starting dose1

Recommended dose reductions for adverse reactions
Dose Reduction Starting Dose (200 mg)a
First 100 mg once daily
Second 50 mg once daily
Third 25 mg once daily

aPermanently discontinue AYVAKIT in patients who are unable to tolerate a dose of 25 mg daily.

Recommended dose modifications for patients experiencing adverse reactions1

Adverse Reaction Severityb Dosage Modification
Intracranial Hemorrhage Any Grade Permanently discontinue AYVAKIT.
Cognitive Effects Grade 1 Continue AYVAKIT at same dose or reduced dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose.
Grade 2 or Grade 3 Withhold AYVAKIT until improvement to baseline, Grade 1, or resolution. Resume at same dose or reduced dose.
Grade 4 Permanently discontinue AYVAKIT.
Thrombocytopenia <50 x 109/L Interrupt AYVAKIT until platelet count is 50 x 109/L, then resume at reduced dose per the recommended reductions. If platelet counts do not recover above 50 x 109/L, consider platelet support.
Other Grade 3 or Grade 4 Withhold AYVAKIT until improvement to Grade 2. Resume at same dose or reduced dose, as clinically appropriate.

bSeverity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

For further information on dose modifications and patient monitoring, review the Prescribing Information and download the AYVAKIT Dosing and Administration Guide

For patients experiencing adverse reactions, dose modification may be necessary1
For patients who experience certain adverse reactions, additional information is provided below and in the AYVAKIT Prescribing Information to help guide in modifying and managing their treatment.

ICH may occur with AYVAKIT treatment.

In clinical trials:

  • ICH occurred in 2 of 75 patients (2.7%) with Advanced SM who received AYVAKIT at 200 mg daily and had platelet counts 50 x 109/L prior to initiation of therapy
  • For all patients with Advanced SM receiving AYVAKIT at 200 mg daily, 3 of 80 (3.8%) experienced ICH regardless of platelet counts

Monitor patients closely for the risk of ICH including those with thrombocytopenia, vascular aneurysm or a history of ICH or cerebrovascular accident within the prior year.

Permanently discontinue AYVAKIT if ICH of any grade occurs.

Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with ICH (ie, severe headache, vomiting, drowsiness, dizziness, confusion, slurred speech, or paralysis).

In an ad hoc analysis of patients starting at the 200 mg recommended dose (N=80)6:
  • 18/80 (23%) of patients experienced a Grade 3 adverse event of thrombocytopenia or platelet count decrease
  • Median time to onset: 3.1 weeks
  • Median time to improvement: 3.3 weeks*

Thrombocytopenia was generally reversible by reducing or interrupting treatment with AYVAKIT. Dose interruptions and dose reductions for thrombocytopenia occurred in 20% and 22% of AYVAKIT-treated patients, respectively.

If your patient experiences platelet counts <50 x 109/L: Interrupt AYVAKIT until platelet count is 50 x 109/L, then resume at reduced dose per the recommended reductions.

If platelet counts do not recover above 50 x 109/L, consider platelet support.

Use with caution in patients with potential increased risk of ICH. AYVAKIT is not recommended for use in patients with platelet counts <50 x 109/L.1

*Defined as improvement to Grade 0-2. Not all patients showed improvement; 4 patients were censored.

Get more details on platelet monitoring

Cognitive adverse reactions can occur in patients taking AYVAKIT.

In clinical trials:

  • Cognitive adverse reactions occurred in 28% of 148 patients with SM (3% were Grade 3). These reactions included:
    • Memory impairment (16%)
    • Cognitive disorder (10%)
    • Confusional state (6%)
    • Other cognitive effects that occurred in <2% of patients
  • Median time to onset of first cognitive adverse reaction was 13.3 weeks (range: 1 day to 1.8 years)
  • Median time to improvement for patients experiencing cognitive effects Grade 2 to Grade 1 or complete resolution was 8.1 weeks

Dose modifications in clinical trials due to cognitive adverse reactions:

  • 2% of patients required permanent discontinuation
  • 8.1% of patients required dose interruption
  • 8.8% of patients required dose reduction

Dose modifications for cognitive effects

Grade 1Continue AYVAKIT at same dose or reduced dose or withhold until improvement to baseline or resolution. Resume at same dose or reduced dose.
Grade 2 or Grade 3Withhold AYVAKIT until improvement to baseline, Grade 1, or resolution. Resume at same dose or reduced dose.
Grade 4Permanently discontinue AYVAKIT.

Advise patients and caregivers to notify their healthcare provider if they experience new or worsening cognitive symptoms. Patients should not drive or operate hazardous machinery if they are experiencing cognitive adverse reactions.

In clinical trials:
  • Serious adverse reactions occurred in 34% of patients receiving the recommended starting dose of 200 mg once daily
  • Serious reactions occurring in 1% of patients were: anemia (5%), subdural hematoma (4%), pleural effusion, ascites, and pneumonia (3% each), acute kidney injury, gastrointestinal hemorrhage, intracranial hemorrhage, encephalopathy, gastric hemorrhage, large intestine perforation, pyrexia, and vomiting (2% each)
If your patient experiences a Grade 3 or Grade 4 adverse reaction: Withhold AYVAKIT until improvement to Grade 2. Resume at same dose or reduced dose, as clinically appropriate.
See hypothetical profiles of
patients taking AYVAKIT
Patient
portrayals

IMPORTANT SAFETY INFORMATION

There are no contraindications for AYVAKIT.

Serious intracranial hemorrhage (ICH) may occur with AYVAKIT treatment; fatal events occurred in <1% of patients. Overall, ICH (eg, subdural hematoma, ICH, and cerebral hemorrhage) occurred in 2.9% of 749 patients who received AYVAKIT. In AdvSM patients who received AYVAKIT at 200 mg daily, ICH occurred in 2 of 75 patients (2.7%) who had platelet counts 50 x 109/L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts. Monitor patients closely for risk of ICH including those with thrombocytopenia, vascular aneurysm or a history of ICH or cerebrovascular accident within the prior year. Permanently discontinue AYVAKIT if ICH of any grade occurs. A platelet count must be performed prior to initiating therapy. AYVAKIT is not recommended in AdvSM patients with platelet counts <50 x 109/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks. After 8 weeks of treatment, monitor platelet counts every 2 weeks or as clinically indicated based on platelet counts. Manage platelet counts of <50 x 109/L by treatment interruption or dose reduction.

Cognitive adverse reactions can occur in patients receiving AYVAKIT. Cognitive adverse reactions occurred in 39% of 749 patients and in 28% of 148 SM patients (3% were Grade >3). Memory impairment occurred in 16% of patients; all events were Grade 1 or 2. Cognitive disorder occurred in 10% of patients; <1% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Other events occurred in < 2% of patients. Depending on the severity, withhold AYVAKIT and then resume at same dose or at a reduced dose upon improvement, or permanently discontinue.

AYVAKIT can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use an effective method of contraception during treatment with AYVAKIT and for 6 weeks after the final dose of AYVAKIT. Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks after the final dose.

The most common adverse reactions (20%) at all doses were edema, diarrhea, nausea and fatigue/asthenia.

Avoid coadministration of AYVAKIT with strong and moderate CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose of AYVAKIT. Avoid coadministration of AYVAKIT with strong and moderate CYP3A inducers.

To report suspected adverse reactions, contact Blueprint Medicines Corporation at 1-888-258-7768 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please click here to see the full Prescribing Information for AYVAKIT.

INDICATION

AYVAKIT is indicated for the treatment of adult patients with Advanced SM (AdvSM) including patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of <50 x 109/L.

References:

  1. AYVAKIT [prescribing information]. Cambridge, MA: Blueprint Medicines Corporation; June 2021.
  2. Gilreath JA, et al. Clin Pharmacol. 2019;11:77-92.
  3. Garcia-Montero AC, et al. Blood. 2006;108(7):2366-2372.
  4. Verstovsek S. Eur J Haematol. 2013;90(2):89-98.