Ayvakit

AYVAKIT is a kinase inhibitor indicated for:

• the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. (
  1.1 PDGFRA Exon 18 Mutation-Positive Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST)

  AYVAKIT^®is indicated for the treatment of adults with unresectable or metastatic GIST harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations

  [see Dosage and Administration (2.2)]

  .
  ,
  2.2 GIST Harboring PDGFRA Exon 18 Mutations

  Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation

  [see Clinical Studies (14.1)]

  . An FDA-approved test for the detection of exon 18 mutations is not currently available.

  The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST

  .

  Continue treatment until disease progression or unacceptable toxicity.
  )

• the treatment of adult patients with AdvSM. AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). (
  1.2 Advanced Systemic Mastocytosis (AdvSM)

  AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes 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 less than 50 × 10⁹/L

  [see Warnings and Precautions (5.1)]

  .
  )
• Limitations of Use: AYVAKIT is not recommended for the treatment of patients with AdvSM with platelet counts of less than 50 × 10⁹/L (
  1.2 Advanced Systemic Mastocytosis (AdvSM)

  AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes 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 less than 50 × 10⁹/L

  [see Warnings and Precautions (5.1)]

  .
  )

• the treatment of adult patients with ISM. (
  1.3 Indolent Systemic Mastocytosis (ISM)

  AYVAKIT is indicated for the treatment of adult patients with indolent systemic mastocytosis (ISM).

  Limitations of Use

  :

  AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 × 10⁹/L

  [see Warnings and Precautions (5.1)]

  .
  )
• Limitations of Use: AYVAKIT is not recommended for the treatment of patients with ISM with platelet counts of less than 50 × 10⁹/L (
  1.2 Advanced Systemic Mastocytosis (AdvSM)

  AYVAKIT is indicated for the treatment of adult patients with advanced systemic mastocytosis (AdvSM). AdvSM includes 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 less than 50 × 10⁹/L

  [see Warnings and Precautions (5.1)]

  .
  )

• GIST: Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation. (
  2.2 GIST Harboring PDGFRA Exon 18 Mutations

  Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation

  [see Clinical Studies (14.1)]

  . An FDA-approved test for the detection of exon 18 mutations is not currently available.

  The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST

  .

  Continue treatment until disease progression or unacceptable toxicity.
  )
• GIST: The recommended dosage is 300 mg orally once daily. (
  2.2 GIST Harboring PDGFRA Exon 18 Mutations

  Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation

  [see Clinical Studies (14.1)]

  . An FDA-approved test for the detection of exon 18 mutations is not currently available.

  The recommended dosage of AYVAKIT is 300 mg orally once daily in patients with GIST

  .

  Continue treatment until disease progression or unacceptable toxicity.
  )
• AdvSM: The recommended dosage is 200 mg orally once daily. (
  2.3 Advanced Systemic Mastocytosis

  The recommended dosage of AYVAKIT is 200 mg orally once daily in patients with AdvSM. Continue treatment until disease progression or unacceptable toxicity.
  )
• ISM: The recommended dosage is 25 mg orally once daily. (
  2.4 Indolent Systemic Mastocytosis

  The recommended dosage of AYVAKIT is 25 mg orally once daily in patients with ISM.
  )
• Patients with severe hepatic impairment (Child-Pugh Class C): reduce dose of AYVAKIT. (
  2.7 Dosage Modifications for Severe Hepatic Impairment

  A modified starting dosage of AYVAKIT is recommended for patients with severe hepatic impairment (Child-Pugh Class C)

  [see Use in Specific Populations (8.7)]:

  • GIST: 200 mg orally once daily
  • AdvSM: 100 mg orally once daily
  • ISM: 25 mg orally every other day
  )

Tablets:

• 25 mg, round, white film-coated tablet with debossed text. One side reads "BLU" and the other side reads "25".
• 50 mg, round, white film-coated tablet with debossed text. One side reads "BLU" and the other side reads "50".
• 100 mg, round, white film-coated, printed with blue ink "BLU" on one side and "100" on the other side.
• 200 mg, capsule shaped, white film-coated, printed with blue ink "BLU" on one side and "200" on the other side.
• 300 mg, capsule shaped, white film-coated, printed with blue ink "BLU" on one side and "300" on the other side.

• Intracranial Hemorrhage
  : Permanently discontinue for any occurrence of any grade. (
  2.5 Dosage Modifications for Adverse Reactions

  The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2.

  Table 1: Recommended Dosage Reductions for AYVAKIT for Adverse Reactions

  Dose Reduction Level	Dosage in patients with GISTPermanently discontinue AYVAKIT in patients with GIST who are unable to tolerate a dose of 100 mg once daily.	Dosage in patients with AdvSMPermanently discontinue AYVAKIT in patients with AdvSM who are unable to tolerate a dose of 25 mg once daily.
  First dose reduction	200 mg once daily	100 mg once daily
  Second dose reduction	100 mg once daily	50 mg once daily
  Third dose reduction	-	25 mg once daily

  Table 2: Recommended Dosage Modifications for AYVAKIT for Adverse Reactions

  Adverse Reaction	SeveritySeverity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0	Dosage Modification
  Patients with GIST or AdvSM
  Intracranial Hemorrhage [see Warnings and Precautions (5.1)]	Any grade	Permanently discontinue AYVAKIT.
  Cognitive Effects [see Warnings and Precautions (5.2)]	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.
  Other [see Adverse Reactions (6.1)]	Grade 3 or Grade 4	Withhold AYVAKIT until improvement to less than or equal to Grade 2. Resume at same dose or reduced dose, as clinically appropriate.
  Patients with AdvSM
  Thrombocytopenia [see Warnings and Precautions (5.1)]	<50 × 109/L	Interrupt AYVAKIT until platelet count is ≥ 50 × 109/L, then resume at reduced dose (per Table 1). If platelet counts do not recover above 50 × 109/L, consider platelet support.
  ,
  5.1 Intracranial Hemorrhage

  Serious intracranial hemorrhage may occur with AYVAKIT treatment; fatal events occurred in less than 1% of patients. Overall, intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 2.9% of the 749 patients with GIST or AdvSM who received AYVAKIT in clinical trials. No events of intracranial hemorrhage occurred in the 246 patients with ISM who received any dose of AYVAKIT in the PIONEER study

  .

  Monitor patients closely for risk factors of intracranial hemorrhage which may include history of vascular aneurysm, intracranial hemorrhage or cerebrovascular accident within the prior year, concomitant use of anticoagulant drugs, or thrombocytopenia.

  Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, vision changes, or altered mental status. Advise patients to seek immediate medical attention for signs or symptoms of intracranial hemorrhage.

  Permanently discontinue AYVAKIT if intracranial hemorrhage of any grade occurs

  [see Dosage and Administration (2.5)]

  .

  Gastrointestinal Stromal Tumors

  Intracranial hemorrhage occurred in 3 of 267 patients (1.1%). Two (0.7%) of the events were Grade ≥ 3 and resulted in discontinuation of study drug. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating AYVAKIT.

  Advanced Systemic Mastocytosis

  In patients with AdvSM who received AYVAKIT at 200 mg daily, intracranial hemorrhage occurred in 2 of 75 patients (2.7%) who had platelet counts ≥ 50 × 10⁹/L prior to initiation of therapy and in 3 of 80 patients (3.8%) regardless of platelet counts.

  In patients with AdvSM, a platelet count must be performed prior to initiating therapy; AYVAKIT is not recommended in patients with AdvSM with platelet counts < 50 × 10⁹/L. Following treatment initiation, platelet counts must be performed every 2 weeks for the first 8 weeks regardless of baseline platelet count. After 8 weeks of treatment, monitor platelet counts every 2 weeks (or more frequently as clinically indicated) if values are less than 75 × 10⁹/L, every 4 weeks if values are between 75 and 100 × 10⁹/L, and as clinically indicated if values are greater than 100 × 10⁹/L.

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

  [see Dosage and Administration (2.5)]

  . Dose-interruptions and dose-reductions for thrombocytopenia occurred in 20% and 22% of AYVAKIT-treated patients, respectively. Thrombocytopenia was generally reversible by reducing or interrupting AYVAKIT.
  )
• Cognitive Effects
  : A broad spectrum of cognitive adverse reactions can occur in patients receiving AYVAKIT. In patients with GIST, AdvSM, or ISM depending on the severity, continue AYVAKIT at same dose, withhold and then resume at same or reduced dose upon improvement, or permanently discontinue. (
  2.5 Dosage Modifications for Adverse Reactions

  The recommended dosage reductions and modifications for adverse reactions are provided in Tables 1 and 2.

  Table 1: Recommended Dosage Reductions for AYVAKIT for Adverse Reactions

  Dose Reduction Level	Dosage in patients with GISTPermanently discontinue AYVAKIT in patients with GIST who are unable to tolerate a dose of 100 mg once daily.	Dosage in patients with AdvSMPermanently discontinue AYVAKIT in patients with AdvSM who are unable to tolerate a dose of 25 mg once daily.
  First dose reduction	200 mg once daily	100 mg once daily
  Second dose reduction	100 mg once daily	50 mg once daily
  Third dose reduction	-	25 mg once daily

  Table 2: Recommended Dosage Modifications for AYVAKIT for Adverse Reactions

  Adverse Reaction	SeveritySeverity as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0	Dosage Modification
  Patients with GIST or AdvSM
  Intracranial Hemorrhage [see Warnings and Precautions (5.1)]	Any grade	Permanently discontinue AYVAKIT.
  Cognitive Effects [see Warnings and Precautions (5.2)]	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.
  Other [see Adverse Reactions (6.1)]	Grade 3 or Grade 4	Withhold AYVAKIT until improvement to less than or equal to Grade 2. Resume at same dose or reduced dose, as clinically appropriate.
  Patients with AdvSM
  Thrombocytopenia [see Warnings and Precautions (5.1)]	<50 × 109/L	Interrupt AYVAKIT until platelet count is ≥ 50 × 109/L, then resume at reduced dose (per Table 1). If platelet counts do not recover above 50 × 109/L, consider platelet support.
  ,
  5.2 Cognitive Effects

  Cognitive adverse reactions can occur in patients receiving AYVAKIT. These cognitive adverse reactions occurred in 33% of the 995 patients with GIST, AdvSM or ISM who received AYVAKIT in clinical trials. These adverse reactions were managed with dose interruption and/or reduction when needed.

  Overall, 10% led to dose interruptions, 7% led to dose reductions and 2.2% led to permanent discontinuation of AYVAKIT treatment in patients with GIST, AdvSM or ISM.

  Depending on the severity and indication, withhold AYVAKIT and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue AYVAKIT

  [see Dosage and Administration (2.5)]

  .

  Indolent Systemic Mastocytosis

  Cognitive adverse reactions occurred in 7.8% of patients with ISM who received AYVAKIT + best supportive care versus 7% of patients who received placebo + best supportive care in the PIONEER study; <1% were Grade 3. The median time to onset of the first cognitive adverse reaction was 2.3 months (range: 0 to 5.4 months). Median time to improvement to Grade 1 or complete resolution was 2.1 months (range: 0.4 to 2.1 months).

  Gastrointestinal Stromal Tumors

  Cognitive adverse reactions occurred in 41% of 601 patients with GIST who received AYVAKIT; 5% were Grade ≥ 3. Memory impairment occurred in 21% of patients; <1% of these events were Grade 3. Cognitive disorder occurred in 12% of patients; 1.2% of these events were Grade 3. Confusional state occurred in 6% of patients; <1% of these events were Grade 3. Amnesia occurred in 3% of patients; <1% of these events were Grade 3. Somnolence and speech disorder occurred in 2% of patients; none of these events were Grade 3. Other events occurred in less than 2% of patients.

  The median time to onset of the first cognitive adverse reaction was 8.4 weeks (range: 1 day to 4 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 7.9 weeks. Overall, 2.7% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 13.5% required a dosage interruption, and 8.5% required dose reduction.

  Advanced Systemic Mastocytosis

  Cognitive adverse reactions occurred in 28% of 148 patients with AdvSM who received AYVAKIT; 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 less than 2% of patients.

  The median time to onset of the first cognitive adverse reaction was 13.3 weeks (range: 1 day to 1.8 years). Among patients who experienced a cognitive effect of Grade 2 or worse (impacting activities of daily living), the median time to improvement to Grade 1 or complete resolution was 8.1 weeks. Overall, 2% of all patients who received AYVAKIT required permanent discontinuation for a cognitive adverse reaction, 8.1% required a dosage interruption, and 8.8% required dose reduction.
  )
• Photosensitivity:
  May cause photosensitivity reactions. Advise patients to limit direct ultraviolet exposure. (
  5. 3 Photosensitivity

  AYVAKIT may cause photosensitivity reactions. In all patients treated with AYVAKIT in clinical trials (n=1049), 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
  : Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.4 Embryo-Fetal Toxicity

  Based on findings from animal studies and its mechanism of action, AYVAKIT can cause fetal harm when administered to pregnant women. Oral administration of avapritinib during the period of organogenesis was teratogenic and embryotoxic in rats at exposures approximately 31.4, 6.3 and 2.7 times the human exposure based on area under the curve (AUC) at the 25 mg, 200 mg, and 300 mg dose, respectively.

  Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose

  [see Use in Specific Populations (8.1, 8.3)]

  .
  ,
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and its mechanism of action

  [see Clinical Pharmacology (12.1)]

  , AYVAKIT can cause fetal harm when administered to a pregnant woman. There are no available data on AYVAKIT use in pregnant women. Oral administration of avapritinib to pregnant rats during the period of organogenesis was teratogenic and embryotoxic at exposure levels approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively

  (see Data)

  . 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 2-4% and 15-20%, respectively.

  Data

  Animal Data

  In a reproductive toxicity study, administration of avapritinib to rats during the period of organogenesis resulted in decreased fetal body weights, post-implantation loss, and increases in visceral (hydrocephaly, septal defect, and stenosis of the pulmonary trunk) and skeletal (sternum) malformations at doses greater than or equal to 10 mg/kg/day (approximately 31.4, 6.3 and 2.7 times the human exposure based on AUC at the 25 mg, 200 mg and 300 mg dose, respectively).
  ,
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to initiating AYVAKIT

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  AYVAKIT can cause fetal harm when administered to pregnant women

  [see Use in Specific Populations (8.1)].

  Females

  Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose

  [see Drug Interactions (7.2)].

  Males

  Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose.

  Infertility

  Females

  Based on findings from animal studies, AYVAKIT may impair female fertility. These findings were not reversible within a two month recovery period

  [see Nonclinical Toxicology (13.1)].

  Males

  Based on findings from animal studies, AYVAKIT may impair male fertility. These findings were not reversible within a two month recovery period

  [see Nonclinical Toxicology (13.1)]

  .
  )