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

Sr.No-  1

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. 

ADVERSE REACTIONS

 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

CONTRAINDICATIONS                                                                                                 None.

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

 CLINICAL PHARMACOLOGY 

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. 

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