PIQRAY

2 DOSAGE AND ADMINISTRATION Recommended Dose: 300 mg (two 150 mg tablets) taken orally once daily with food. ( 2.2 ) For adverse reactions, consider dose interruption, dose reduction, or discontinuation. ( 2.3 ) 2.1 Patient Selection Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with PIQRAY, based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens [see Clinical Studies (14)] . If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Dosage and Administration The recommended dose of PIQRAY is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food [see Clinical Pharmacology (12.3)] . Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)] . Patients should take their dose of PIQRAY at approximately the same time each day. Swallow PIQRAY tablets whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact. If a dose of PIQRAY is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take PIQRAY at the usual time. If the patient vomits after taking the dose, advise the patient not to take an additional dose on that day, and to resume the dosing schedule the next day at the usual time. When given with PIQRAY, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant. 2.3 Dose Modifications for Adverse Reactions The recommended dose modifications for adverse reactions are listed in Table 1. Table 1: PIQRAY Dose Reduction Guidelines for Adverse Reactions 1 1 Only one dose reduction is permitted for pancreatitis. 2 If further dose reduction below 200 mg once daily is required, discontinue PIQRAY. PIQRAY dose level Dose and schedule Number and strength of tablets Starting dose 300 mg once daily Two 150 mg tablets First-dose reduction 250 mg once daily One 200 mg tablet and one 50 mg tablet Second-dose reduction 200 mg once daily 2 One 200 mg tablet Tables 2, 3, 4, and 5 summarize recommendations for dose interruption, reduction, or discontinuation of PIQRAY in the management of specific adverse reactions. Cutaneous Adverse Reactions If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous SCAR during PIQRAY treatment [see Warnings and Precautions (5.2)] . Table 2: Dose Modification and Management for Rash and Severe Cutaneous Adverse Reactions (SCARs) 1 Grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 2 For all grades of rash, consider consultation with a dermatologist. 3 Antihistamines administered prior to rash onset may decrease incidence and severity of rash based on the SOLAR-1 trial. [see Warnings and Precautions (5.1, 5.2)] Grade 1,2 Recommendation 3 Grade 1 ( 30% BSA with active skin toxicity) Interrupt PIQRAY. Initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment. If the etiology is SCAR, permanently discontinue PIQRAY. If the etiology is not a SCAR, interrupt dose until improvement to Grade ≤ 1, then resume PIQRAY at next lower dose level. Grade 4 (e.g., severe bullous, blistering or exfoliating skin conditions) (any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences) Permanently discontinue PIQRAY. Hyperglycemia Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. Consider premedication with metformin prior to the initiation of PIQRAY in combination with fulvestrant based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)] . After initiating treatment with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Warnings and Precautions (5.3)] . Table 3: Dose Modification and Management for Hyperglycemia Abbreviation: ULN, upper limit of normal. 1 FPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2 Initiate applicable anti-hyperglycemic medications, including metformin, SGLT2 inhibitors or insulin sensitizers (such as thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500 mg once daily. Based on tolerability, metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1,000 mg with dinner, followed by further increase to 1,000 mg twice daily if needed [see Warnings and Precautions (5.3)] . 3 As recommended in the SOLAR-1 trial, insulin may be used for 1-2 days until hyperglycemia resolves. However, this may not be necessary in the majority of PIQRAY-induced hyperglycemia, given the short half-life of PIQRAY and the expectation of glucose levels normalizing after interruption of PIQRAY. [see Warnings and Precautions (5.3)] Fasting plasma glucose (FPG)/Fasting blood glucose values 1 Recommendation Dose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose). Grade 1 Fasting glucose > ULN -160 mg/dL or > ULN -8.9 mmol/L No PIQRAY dose adjustment required. Initiate or intensify anti-hyperglycemic treatment 2 . Grade 2 Fasting glucose > 160-250 mg/dL or > 8.9-13.9 mmol/L No PIQRAY dose adjustment required. Initiate or intensify anti-hyperglycemic treatment 2 . If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatment 2,3 , reduce PIQRAY dose by 1 dose level and follow fasting glucose value specific recommendations. Grade 3 > 250-500 mg/dL or > 13.9-27.8 mmol/L Interrupt PIQRAY. Initiate or intensify oral anti-hyperglycemic treatment 2 and consider additional anti-hyperglycemic medications 3 for 1-2 days until hyperglycemia improves, as clinically indicated. Administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances). If fasting glucose decreases to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate anti-hyperglycemic treatment, resume PIQRAY at 1 lower dose level. If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate anti-hyperglycemic treatment, consultation with a physician with expertise in the treatment of hyperglycemia is recommended. If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days following appropriate anti-hyperglycemic treatment 2,3 , permanently discontinue PIQRAY treatment. Grade 4 > 500 mg/dL or > 27.8 mmol/L Interrupt PIQRAY. Initiate or intensify appropriate anti-hyperglycemic treatment 2,3 (administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances)), re-check fasting glucose within 24 hours and as clinically indicated. If fasting glucose decreases to ≤ 500 mg/dL or 27.8 mmol/L, follow fasting glucose value-specific recommendations for Grade 3. If fasting glucose is confirmed at > 500 mg/dL or 27.8 mmol/L, permanently discontinue PIQRAY treatment. Diarrhea or Colitis Table 4: Dose Modification and Management for Diarrhea or Colitis 1 Grading according to CTCAE Version 5.0. 2 For Grade 2 and 3 colitis, consider additional treatment, such as enteric-acting and/or systemic steroids. [see Warnings and Precautions (5.5)] Grade 1 Recommendation Grade 1 No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated. Grade 2 Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the same dose level. For recurrent Grade ≥ 2, interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated 2 . Grade 3 Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated 2 . Grade 4 Permanently discontinue PIQRAY. Other Toxicities Table 5: Dose Modification and Management for Other Toxicities (Excluding Hyperglycemia, Rash and Severe Cutaneous Adverse Reactions, and Diarrhea or Colitis) 1 Grading according to CTCAE Version 5.0. 2 For Grade 2 and 3 pancreatitis, interrupt PIQRAY dose until improvement to Grade 14 days. Grade 1 Recommendation Grade 1 or 2 No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated 2,3 . Grade 3 Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose level. Grade 4 Permanently discontinue PIQRAY. Refer to the Full Prescribing Information of fulvestrant for dose modification guidelines in the event of toxicity and for other relevant safety information.

See official label

1 INDICATIONS AND USAGE PIQRAY is indicated in combination with fulvestrant for the treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.