Avapritinib-(AYVAKIT)- (Jan 2020)- @-Gastrointestinal Stromal TumorDrug Name:
Avapritinib-(AYVAKIT)- (Jan 2020)- @-Gastrointestinal Stromal Tumor
List Of Brands:
Indication Type Description:
Pregnancy and lactation
DRUG INTERACTIONS- summary
• Strong and Moderate CYP3A Inhibitors: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inhibitors. If coadministration of AYVAKIT with a moderate inhibitor cannot be avoided, reduce dose of AYVAKIT.
• Strong and Moderate CYP3A Inducers: Avoid coadministration of AYVAKIT with strong and moderate CYP3A inducers.
U.S. FDA APPROVED DRUGS DURING 2020
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AYVAKIT safely and effectively. See full prescribing information for AYVAKIT.
AYVAKIT (avapritinib) tablets, for oral use
Initial U.S. Approval: 2020
INDICATIONS AND USAGE
AYVAKIT is a kinase inhibitor indicated for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations.
DOSAGE AND ADMINISTRATION
• Select patients for treatment with AYVAKIT based on the presence of a PDGFRA exon 18 mutation.
• The recommended dosage is 300 mg orally once daily on an empty stomach, at least one hour before and two hours after a meal.
DOSAGE FORMS AND STRENGTHS Tablets: 100 mg, 200 mg and 300 mg.
The most common adverse reactions (incidence = 20%) are edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness
WARNINGS AND PRECAUTIONS
• Intracranial Hemorrhage: Withhold AYVAKIT for Grade 1 or 2 reactions until resolution and then resume at a reduced dose.
Permanently discontinue for recurrent Grade 1 or 2 reactions or first occurrence of Grade 3 or 4 reactions.
• Central Nervous System (CNS) Effects: CNS adverse reactions include cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations.
Depending on the severity, continue AYVAKIT at same dose, withhold and then resume at same or reduced dose upon improvement, or permanently discontinue.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Intracranial Hemorrhage Advise patients to contact their healthcare provider immediately if experiencing neurological signs and symptoms that may be associated with intracranial hemorrhage
Central Nervous System Effects Advise patients and caretakers to notify their healthcare provider if they experience new or worsening CNS symptoms.
Advise patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions
Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy
Use in Specific Populations Advise females of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose
Advise males with female partners of reproductive potential to use effective contraception during treatment with AYVAKIT and for 6 weeks after the final dose
Lactation Advise women not to breastfeed during treatment with AYVAKIT and for 2 weeks following the final dose
Infertility Advise females and males of reproductive potential that AYVAKIT may impair fertility [se
Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products
Administration Advise patients to take AYVAKIT on an empty stomach, at least 1 hour before and at least 2 hours after a meal
Manufactured for: Blueprint Medicines Corporation, Cambridge, MA 02139, USA
1.Mechanism of Action Avapritinib is a tyrosine kinase inhibitor that targets PDGFRA and PDGFRA D842 mutants as well as multiple KIT exon 11, 11/17 and 17 mutants with half maximal inhibitory concentrations (IC50s) less than 25 nM.
2. Pharmacodynamics Exposure-Response Relationships Based on the data from NAVIGATOR, exposure-response relationships for any Grade 3 or 4 adverse reaction were observed at higher exposures with a faster time to onset for adverse reactions with increasing avapritinib exposure.
Cardiac Electrophysiology The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered dose of 300 mg or 400 mg (1.3 times the approved recommended dose) once daily. No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (Cmax) of 899 ng/mL.
3. Pharmacokinetics Avapritinib Cmax and AUC increased proportionally over the dose range of 30 mg to 400 mg once daily (0.1 to 1.33 times the recommended dose).
At the recommended dosage of 300 mg once daily, the mean (CV%) steady state Cmax of avapritinib was 813 ng/mL (52%) and the mean steady state area under the concentration-time curve (AUC0-24h) was 15400 h•ng/mL (48%).
Steady state concentration of avapritinib was reached by day 15 following daily dosing and the mean accumulation ratio was 3.1 to 4.6 after repeated dosing.
Absorption The median time to peak concentration (Tmax) ranged from 2.0 to 4.1 hours following single doses of avapritinib 30 mg to 400 mg (0.1 to 1.33 times the approved recommended dose).
Effect of Food The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state.
Distribution The mean apparent volume of distribution of avapritinib is 1200 L (43%). In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood-to-plasma ratio is 0.95.
Elimination The mean plasma elimination half-life of avapritinib was 32 hours to 57 hours following single doses of avapritinib 30 mg to 400 mg (0.1 to 1.33 times the approved recommended dose).
The steady state mean apparent oral clearance of avapritinib is 19.5 L/h (48%).
Metabolism Avapritinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C9 in vitro.
Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds.
Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.
Excretion Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged).
Specific Populations No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin = ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment.
The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on the pharmacokinetics of avapritinib is unknown.
Drug Interaction Studies Clinical Studies and Model-Informed Approaches
Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg once daily (a strong CYP3A inhibitor) is predicted to increase avapritinib AUC by 600% at steady state.
Coadministration of AYVAKIT 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 210% at steady state
Effect of Strong and Moderate CYP3A Inducers on Avapritinib: Coadministration of AYVAKIT 400 mg as a single dose with rifampin 600 mg once daily (a strong CYP3A inducer) decreased avapritinib Cmax by 74% and AUC0-INF by 92%.
Coadministration of AYVAKIT 300 mg once daily with efavirenz 600 mg once daily (a moderate CYP3A inducer) is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady-state
Effect of Acid-Reducing Agents on Avapritinib: No clinically significant differences in the pharmacokinetics of avapritinib were identified when coadministered with gastric acid reducing agents in patients with GIST.
In Vitro Studies Cytochrome P450 (CYP) Enzymes: In vitro studies indicate that avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A at clinically relevant concentrations.
Avapritinib is an inhibitor of CYP2C9 at clinically relevant concentrations.
Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations. Avapritinib is not an inducer of CYP1A2 or CYP2B6.
Avapritinib is a substrate of CYP3A.
M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9 at clinically relevant concentrations. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Transporter Systems: Avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal BCRP, MATE1, MATE2-K, and BSEP, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. Avapritinib is not a substrate of P-gp or BCRP.
The effect of M499 on transporter systems is unknown.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on findings from animal studies and its mechanism of action,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
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.
2. Lactation 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.
3. Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating AYVAKIT
Contraception AYVAKIT can cause fetal harm when administered to pregnant women
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
4. Pediatric Use The safety and effectiveness of AYVAKIT in pediatric patients have not been established.
5. Geriatric Use 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.
6. Renal Impairment 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)
7. Hepatic Impairment 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