AYVAKIT Film-coated tablet Ref.[9993] Active ingredients:

5.1 Intracranial Hemorrhage

Intracranial hemorrhage (e.g., subdural hematoma, intracranial hemorrhage, and cerebral hemorrhage) occurred in 1% of the 267 patients with GIST and overall in 3% of the 335 patients who received AYVAKIT. Events of intracranial hemorrhage occurred in a range from 1.7 months to 19.3 months after initiating AYVAKIT. Overall, 0.9% of patients receiving AYVAKIT required permanent discontinuation for an intracranial hemorrhage; 1.2% required dosage interruption followed by dose reduction.

Withhold AYVAKIT and then resume at a reduced dose upon resolution, or permanently discontinue AYVAKIT based on severity [see Dosage and Administration (2.3)].

5.2 Central Nervous System Effects

A broad spectrum of central nervous system (CNS) adverse reactions can occur in patients receiving AYVAKIT. These include cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. CNS adverse reactions overall occurred in 58% of 335 patients who received AYVAKIT [see Adverse Reactions (6.1)]. Cognitive impairment occurred in 41% of the 335 patients who received AYVAKIT; 3.6% of these were severe (Grade 3 or 4). Dizziness occurred in 20% of patients; 0.6% of these events were severe. Sleep disorders occurred in 15% of patients; 0.3% of these events were severe. Mood disorders occurred in 13% of patients; 1.5% of these events were severe. Speech disorders occurred in 6% of patients; none of these events were severe. Hallucinations occurred in 2.1% of patients; none of these events were severe. The median time to onset of the first CNS adverse reaction was 6.1 weeks (range 1 day to 1.9 years). Overall, 3.9% of patients required permanent discontinuation of AYVAKIT for a CNS adverse reaction, 17% required a dosage interruption, and 10% required dose reduction.

Depending on the severity, withhold AYVAKIT and then resume at the same dose or at a reduced dose upon improvement, or permanently discontinue AYVAKIT [see Dosage and Administration (2.3)].

5.3 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 2.7 times the human exposure based on area under the curve (AUC) at the 300 mg dose. 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)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Intracranial hemorrhage [see Warnings and Precautions (5.1)]
• Central nervous system effects [see Warnings and Precautions (5.2)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to AYVAKIT at 30 mg to 600 mg orally once daily in 335 patients enrolled in one of three clinicals trials conducted in patients with advanced malignancies, including NAVIGATOR [see Clinical Studies (14.1)]. Among the 335 patients receiving AYVAKIT, 49% were exposed for 6 months or longer and 23% were exposed for greater than 1 year.

Gastrointestinal Stromal Tumors

Unresectable or Metastatic GIST

The safety of AYVAKIT in patients with unresectable or metastatic GIST was evaluated in NAVIGATOR [see Clinical Studies (14.1)]. The trial excluded patients with history of cerebrovascular accident or transient ischemic attacks, known risk of intracranial bleeding, and metastases to the brain. Patients received AYVAKIT 300 mg or 400 mg orally once daily (n=204). Among patients receiving AYVAKIT, 56% were exposed for 6 months or longer and 44% were exposed for greater than one year.

The median age of patients who received AYVAKIT was 62 years (range: 29 to 90 years), 60% were <65 years, 62% were male, and 69% were White. Patients had received a median of 3 prior kinase inhibitors (range: 0 to 7).

Serious adverse reactions occurred in 52% of patients receiving AYVAKIT. Serious adverse reactions occurring in ≥1% of patients who received AYVAKIT were anemia (9%), abdominal pain (3%), pleural effusion (3%), sepsis (3%), gastrointestinal hemorrhage (2%), vomiting (2%), acute kidney injury (2%), pneumonia (1%) and tumor hemorrhage (1%). Fatal adverse reactions occurred in 3.4% of patients. Fatal adverse reactions that occurred in more than one patient were sepsis and tumor hemorrhage (1% each).

Permanent discontinuation due to adverse reactions occurred in 16% of patients who received AYVAKIT. Adverse reactions requiring permanent discontinuation in more than one patient were fatigue, abdominal pain, vomiting, sepsis, anemia, acute kidney injury, and encephalopathy.

Dosage interruptions due to an adverse reaction occurred in 57% of patients who received AYVAKIT. Adverse reactions requiring dosage interruption in >2% of patients who received AYVAKIT were anemia, fatigue, nausea, vomiting, hyperbilirubinemia, memory impairment, diarrhea, cognitive disorder, and abdominal pain.

Dose reduction due to an adverse reaction occurred in 49% of patients who received AYVAKIT. Median time to dose reduction was 9 weeks. Adverse reactions requiring dosage reduction in more than 2% of patients who received AYVAKIT were fatigue, anemia, hyperbilirubinemia, memory impairment, nausea and periorbital edema.

The most common adverse reactions (≥20%) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Table 3 summarizes the adverse reactions observed in NAVIGATOR.

Table 3. Adverse Reactions (≥10%) in Patients Receiving AYVAKIT in NAVIGATOR:

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

* Edema includes face swelling, conjunctival edema, eye edema, eyelid edema, orbital edema, periorbital edema, face edema, mouth edema, pharyngeal edema, peripheral edema, edema, generalized edema, localized edema, peripheral swelling, testicular edema.
^† Abdominal pain includes abdominal pain, upper abdominal pain, abdominal discomfort, lower abdominal pain, abdominal tenderness, and epigastric discomfort.
^‡ Cognitive impairment includes memory impairment, cognitive disorder, confusional state, disturbance in attention, amnesia, mental impairment, mental status changes, encephalopathy, dementia, abnormal thinking, mental disorder, and retrograde amnesia.
^§ Sleep disorders includes insomnia, somnolence, and sleep disorder.
^¶ Taste effects include dysgeusia and ageusia.
^# Mood disorders includes agitation, anxiety, depression, depressed mood, dysphoria, irritability, mood altered, nervousness, personality change, and suicidal ideation.
^Þ Rash includes rash, rash maculo-papular, rash erythematous, rash macular, rash generalized, and rash papular.

Clinically relevant adverse reactions occurring in <10% of patients were:

Vascular: hypertension (8%)

Endocrine: thyroid disorders (hyperthyroid, hypothyroid) (3%)

Skin and subcutaneous: palmar-plantar erythrodysesthesia (1%)

Table 4 summarizes the laboratory abnormalities observed in NAVIGATOR.

Table 4. Select Laboratory Abnormalities (≥10%) Worsening from Baseline in Patients Receiving AYVAKIT in NAVIGATOR:

^* The denominator used to calculate the rate varied from 154 to 201 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effects of Other Drugs on AYVAKIT

Strong and Moderate CYP3A Inhibitors

Coadministration of AYVAKIT with a strong or moderate CYP3A inhibitor increases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate CYP3A inhibitor cannot be avoided, reduce the dose of AYVAKIT [see Dosage and Administration (2.4)].

Strong and Moderate CYP3A Inducers

Coadministration of AYVAKIT with a strong or moderate CYP3A inducer decreases avapritinib plasma concentrations [see Clinical Pharmacology (12.3)], which may decrease efficacy of AYVAKIT. Avoid coadministration of AYVAKIT with strong or moderate CYP3A inducers.

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 animals during the period of organogenesis was teratogenic and embryotoxic in rats at exposure levels approximately 2.7 times the human exposure based on AUC at the 300 mg dose (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 2.7 times the human exposure based on AUC at the 300 mg dose).

Risk Summary

There are no data on the presence of avapritinib or its metabolites in human milk or the effects of avapritinib on the breastfed child or milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose.

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.

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

Based on findings from animal studies, AYVAKIT may impair both male and female fertility [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of AYVAKIT in pediatric patients have not been established.

Of the 204 patients who received AYVAKIT in NAVIGATOR, 40% were 65 years or older, while 6% were 75 years and older. No overall differences in safety or efficacy were observed between these patients and younger adult patients.

No dose adjustment is recommended for patients with mild or moderate renal impairment [creatinine clearance (CLcr) 30 to 89 mL/min estimated by Cockcroft-Gault]. The recommended dose of AYVAKIT has not been established for patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease (CLcr <15 mL/min) [see Clinical Pharmacology (12.3)].

No dose adjustment is recommended for patients with mild [total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN or total bilirubin >1 to 1.5 times ULN and any AST] or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment. The recommended dose of AYVAKIT has not been established for patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].