The safety of AYVAKIT® (avapritinib) was evaluated in clinical trials for Advanced SM

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AYVAKIT was generally well tolerated in clinical trials1

Majority of adverse reactions were Grade 1 or 21

The safety of AYVAKIT was evaluated in 148 patients in EXPLORER and PATHFINDER. Patients received a starting dose of AYVAKIT ranging from 30 mg to 400 mg orally once daily and were centrally confirmed to have Advanced SM (N=131), including 80 patients who received the recommended starting dose of 200 mg once daily.
Among patients receiving AYVAKIT, 70% were treated for ≥6 months and 37% were exposed for >1 year.

Fatal adverse reactions occurred in 2.5% [2/80] of patients receiving the recommended starting dose of 200 mg.1 No specific adverse reaction leading to death was reported in more than 1 patient.1

10% of patients permanently discontinued due to any adverse reaction at the recommended starting dose of 200 mg.1

Serious adverse reactions were seen in 34% of patients receiving the recommended starting dose of 200 mg (N=80).1 

The most common adverse reactions (≥20%) were edema, diarrhea, nausea, and fatigue/asthenia.1

Adverse reactions and lab abnormalities (≥10%) for patients receiving 200 mg once-daily starting dose in EXPLORER and PATHFINDER (N=80)1*a

Adverse Reaction All Grades % Grade ≥3 %
General
Edemab 79 5
Fatigue/asthenia 23 4
Gastrointestinal
Diarrhea 28 1
Nausea 24 1
Vomiting 18 3
Abdominal painc 14 1
Constipation 11 0
Nervous system
Headache 15 0
Cognitive effectsd 14 1
Taste effectse 13 0
Dizziness 13 0
Musculoskeletal and connective tissue
Arthralgia 10 1
Respiratory, thoracic and mediastinal
Epistaxis 11 0
Laboratory Abnormality All Grades % Grade ≥3 %
Hematology
Decreased platelets 64 21
Decreased hemoglobin 55 23
Decreased neutrophils 54 25
Decreased lymphocytes 34 11
Increased activated partial thromboplastin time 14 1
Increased lymphocytes 10 0
Chemistry
Decreased calcium 50 3
Increased bilirubin 41 3
Increased aspartate aminotransferase 38 1
Decreased potassium 26 4
Increased alkaline phosphatase 24 5
Increased creatinine 20 0
Increased alanine aminotransferase 18 1
Decreased sodium 18 1
Decreased albumin 15 1
Decreased magnesium 14 1
Increased potassium 11 0
Clinically relevant adverse reactions occurring in <10% of patients were: cardiac failure (2.5%), cardiac failure congestive (1.3%), ascites (5%), gastrointestinal hemorrhage (1.3%), large intestine perforation (1.3%), cholelithiasis (1.3%), upper respiratory tract infection (6%), urinary tract infection (6%), herpes zoster (2.5%), flushing (3.8%), hypertension (3.8%), hypotension (3.8%), hot flush (2.5%), insomnia (6%), pain in extremity (6%), dyspnea (9%), cough (2.5%), rash† (8%), alopecia (9%), pruritus (8%), hair color changes (6%), decreased appetite (8%), lacrimation increased (9%), and decreased phosphate (9%).

*Per National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) versions 4.03 and 5.0.

†Grouped term including rash and rash maculopapular.

aSelect laboratory abnormalities (≥10%) worsening from baseline in patients with Advanced SM.

bEdema includes face swelling, eyelid edema, orbital edema, periorbital edema, face edema, peripheral edema, edema, generalized edema, and peripheral swelling.

cAbdominal pain includes abdominal pain, upper abdominal pain, and abdominal discomfort.

dCognitive effects include memory impairment, cognitive disorder, confusional state, delirium, and disorientation.

eTaste effects include dysgeusia.

Warnings and precautions1

Intracranial hemorrhage 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 Advanced SM 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.

Cognitive effectsCognitive adverse reactions can occur in patients receiving AYVAKIT. Cognitive adverse reactions occurred in 39% of 749 patients who received AYVAKIT, and in 28% of 148 Advanced 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.

Photosensitivity
AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=803), photosensitivity reactions occurred in 2.5% of patients.

Advise patients to limit direct ultraviolet exposure during treatment with AYVAKIT and for one week after discontinuation of treatment.

Embryo-fetal toxicityBased on findings from animal studies and its mechanism of action, AYVAKIT can cause fetal harm when administered to pregnant women.

INDICATION

INDICATION & IMPORTANT SAFETY INFORMATION

AYVAKIT® (avapritinib) 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.

IMPORTANT SAFETY INFORMATION

Intracranial Hemorrhage—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 Effects—Cognitive adverse reactions can occur in patients receiving AYVAKIT. Cognitive adverse reactions occurred in 39% of 749 patients and in 28% of 148 AdvSM 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.

Photosensitivity—AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=803), photosensitivity reactions occurred in 2.5% of patients. Advise patients to limit direct ultraviolet exposure during treatment with AYVAKIT and for one week after discontinuation of treatment.

Embryo-Fetal Toxicity—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.

Adverse Reactions—The most common adverse reactions (≥20%) were edema, diarrhea, nausea, and fatigue/asthenia.

Drug Interactions—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® (avapritinib) 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; March 2023.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Systemic Mastocytosis V. 2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed February 15, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
  3. Gilreath JA et al. Clin Pharmacol. 2019;11:77-92.
  4. Verstovsek S. Eur J Haematol. 2013;90(2):89-98.
  5. Garcia-Montero AC et al. Blood. 2006;108(7):‍2366-2372.
  6. Data on file. Blueprint Medicines Corporation, Cambridge, MA. 2021.
  7. Gotlib J et al. Blood. 2013;121(13):‍2393-2401.
  8. Valent P et al. Blood. 2017;129(11):1420-1427.
  9. Pardanani A et al. Am J Hematol. 2019;94(3):‍363-377.
  10. Theoharides TC et al. N Engl J Med. 2015;373(2):163-172.
  11. Pardanani A et al. Blood. 2009;114(18):‍3769-3772.
  12. Passamonti F, Maffioli M. Hematology Am Soc Hematol Educ Program. 2016;2016(1):534-542.
  13. Stoecker MM, Wang E. Arch Pathol Lab Med. 2012;136(7):832-838.
  14. Arber DA et al. Blood. 2016;127(20):‍2391-2405.
  15. Greiner G et al. Clin Chem. 2018;64(3):547-555.
  16. Gotlib J et al. Nat Med. 2021;27(12):‍2192-2199.
  17. Kwon J. Blood Res. 2021;56(suppl 1):S5-S16.
  18. Meggendorfer M et al. Blood. 2012;120(15):‍3080-3088.
  19. Greenberg PL et al. Blood. 2012;120(12):‍2454-2465.
  20. Malcovati L et al. Blood. 2020;136(2):157-170.

INDICATION

AYVAKIT® (avapritinib) 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.

See the recommended dosing instructions for AYVAKIT, including guidance for patient monitoring and dose and therapy management for adverse reactions.

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