PIQRAY
alpelisib
Quick Facts
Used For
PIQRAY is used with fulvestrant to treat adults with a specific type of advanced or...
Common Side Effects
Other Sections About Side Effects Severe allergic reactions, skin reactions, high blood...
What You Should Know
Patient Labeling Read the FDA-approved patient labeling (Patient Information). Severe Allergic Reactions Tell patients about...
Prescription
Not Required
Generic Available
No
Indications and Usage
PIQRAY is used with fulvestrant to treat adults with a specific type of advanced or metastatic breast cancer (HR-positive, HER2-negative, PIK3CA-mutated) that has gotten worse after endocrine therapy. A test must confirm this type of cancer before treatment begins.
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.
Dosage and Administration
Who Can Take This Medicine
Select patients with HR-positive, HER2-negative advanced or metastatic breast cancer. Your doctor will test your tumor tissue or blood (plasma) for PIK3CA mutations. If no mutation is found in blood, test tumor tissue instead.
How Much to Take
Take 300 mg (two 150 mg tablets) by mouth, once daily, with food. Take at about the same time each day. Swallow tablets whole. Do not chew, crush, or split tablets. Do not take a tablet that is broken, cracked, or damaged.
If You Miss a Dose
If you miss a dose and it has been less than 9 hours since your usual time, take it with food. If more than 9 hours have passed, skip that dose. Take your next dose at your regular time the next day.
If You Vomit
If you vomit after taking your dose, do not take another dose that day. Take your next dose at your usual time the next day.
If You Have Side Effects
If side effects occur, your doctor may lower your dose or pause treatment. Do not take a lower dose unless your doctor tells you to.
Skin Rash or Severe Skin Reactions
If you have a severe skin reaction, stop taking PIQRAY permanently. For less severe rash, your doctor may pause the medicine, treat the rash, and restart at a lower dose when improved.
High Blood Sugar (Hyperglycemia)
Before starting treatment, your doctor will check your blood sugar and may start you on metformin. During treatment, your doctor will check your blood sugar at least weekly for the first 2 weeks, then every 4 weeks. Your doctor may adjust your diabetes medicines as needed.
Diarrhea or Bowel Inflammation
For mild diarrhea, keep taking PIQRAY and tell your doctor. For moderate or severe diarrhea, your doctor may pause treatment until improved, then restart at a lower dose. For severe cases, treatment may be stopped permanently.
Other Side Effects
For other side effects, your doctor will decide if treatment needs to be paused or stopped based on severity.
Taking PIQRAY with Fulvestrant
When taken together, fulvestrant dose is 500 mg on Days 1, 15, and 29, then once monthly.
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
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)] .
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)] .
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
1 Grading according to CTCAE Version 5.0.
[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
1 Grading according to CTCAE Version 5.0.
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.
Dosage Forms and Strengths
Tablets
50 mg, 150 mg, and 200 mg
50 mg tablet
Light pink, round, curved tablet. Has “L7” on one side and “NVR” on the other side.
150 mg tablet
Pale red, oval-shaped, curved tablet. Has “UL7” on one side and “NVR” on the other side.
200 mg tablet
Light red, oval-shaped, curved tablet. Has “YL7” on one side and “NVR” on the other side.
Tablets: 50 mg, 150 mg, and 200 mg alpelisib
50 mg: Light pink, unscored, round and curved with beveled edges film-coated tablet, imprinted with “L7” on one side and “NVR” on the other side.
150 mg: Pale red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “UL7” on one side and “NVR” on the other side.
200 mg: Light red, unscored, ovaloid and curved with beveled edges film-coated tablet, imprinted with “YL7” on one side and “NVR” on the other side.
Contraindications
PIQRAY should not be used in patients who have severe allergies to it or any of its ingredients.
PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components [see Warnings and Precautions (5.1)] .
Warnings and Precautions
Severe Allergic Reactions
Severe allergic reactions, including anaphylaxis, can happen with PIQRAY. Signs include trouble breathing, redness in the face, rash, fever, or fast heartbeat. These reactions happened in less than 1% of patients. Tell your doctor right away if you have these symptoms. Stop taking PIQRAY completely if you have a severe allergic reaction.
Serious Skin Reactions
Serious skin problems can happen with PIQRAY, including Stevens-Johnson syndrome and other severe rashes. These skin reactions were reported in a small number of patients. If you notice a rash, fever, flu-like symptoms, mouth sores, or worsening skin problems, stop taking PIQRAY and call your doctor right away. You may need to see a skin doctor. Do not start taking PIQRAY again if you had a serious skin reaction.
High Blood Sugar
PIQRAY can cause high blood sugar. This happened in 65% of patients taking this medicine. High blood sugar can be serious. Signs include feeling very thirsty, urinating more than usual, or feeling hungry while losing weight. Your doctor will check your blood sugar before starting treatment and regularly during treatment. If you have high blood sugar, you may need medicine to control it. Tell your doctor if you have these symptoms.
Lung Problems
PIQRAY can cause lung inflammation. This happened in about 2% of patients. Signs include cough, trouble breathing, or feeling short of breath. Tell your doctor right away if you have these symptoms. You may need to stop taking PIQRAY.
Diarrhea or Bowel Inflammation
Diarrhea is common with PIQRAY. It happened in 58% of patients. In some cases, it can be severe and lead to dehydration. Most patients needed medicine to treat diarrhea. Tell your doctor if you have diarrhea, stomach pain, or blood in your stool. Start diarrhea medicine right away and drink plenty of fluids.
Harm to Unborn Baby
PIQRAY can harm an unborn baby. Do not take PIQRAY if you are pregnant. Women who can become pregnant should use birth control during treatment and for 1 week after the last dose. Men with female partners who can become pregnant should use condoms during treatment and for 1 week after the last dose. Tell your doctor right away if you become pregnant.
5.1 Severe Hypersensitivity
Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms, including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia.
The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7% [see Adverse Reactions (6)] .
Angioedema has been reported in the postmarketing setting in patients treated with PIQRAY [see Adverse Reactions (6.2)] .
Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.
5.2 Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with PIQRAY.
In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively [see Adverse Reactions (6.1)] . Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with PIQRAY in the postmarketing setting [see Adverse Reactions (6.2)] .
If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If a SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous adverse reactions during PIQRAY treatment.
Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).
5.3 Hyperglycemia
Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Fatal cases of ketoacidosis have occurred in the postmarketing setting.
Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG > 250 to 500 mg/dL) and Grade 4 (FPG > 500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n = 2) treated with PIQRAY.
Among the patients who experienced Grade ≥ 2 (FPG 160 to 250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range, 5 to 517 days).
In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-hyperglycemic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-hyperglycemic medication [i.e., insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas]. In patients with Grade ≥ 2 hyperglycemia with at least 1 grade improvement (n = 153), median time to improvement from the first event was 8 days (range, 2 to 65 days).
In all patients with elevated FPG who continued fulvestrant treatment after discontinuing PIQRAY (n = 54), 96% (n = 52) of patients had FPG levels that returned to baseline.
Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. 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. Monitor fasting glucose more frequently for the first few weeks during treatment with PIQRAY in patients with risk factors for hyperglycemia, such as obesity (BMI ≥ 30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥ 75 [see Use in Specific Populations (8.5)] .
If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-hyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
The safety of PIQRAY in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of controlled Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes.
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. In the METALLICA study, use of metformin starting 7 days prior to the initiation of PIQRAY appeared to decrease the incidence and severity of hyperglycemia events, but increased the incidence and severity of nausea, vomiting, and diarrhea adverse reactions [see Adverse Reactions (6.1)] .
Advise patients of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).
5.4 Pneumonitis
Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, can occur in patients treated with PIQRAY.
Pneumonitis was reported in 1.8% of patients treated with PIQRAY.
In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms, such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.
Permanently discontinue PIQRAY in all patients with confirmed pneumonitis.
Advise patients to immediately report new or worsening respiratory symptoms.
5.5 Diarrhea or Colitis
Severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, can occur in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7% (n = 19) of patients. Among patients with Grade 2 or 3 diarrhea (n = 71), the median time to onset was 46 days (range, 1 to 442 days).
In clinical trials, 63% of patients who experienced diarrhea required antidiarrheal medications (e.g., loperamide) to manage symptoms. Dose reductions of PIQRAY were required in 6% of patients, and 2.8% of patients permanently discontinued PIQRAY due to diarrhea.
Colitis has been reported in the postmarketing setting in patients treated with PIQRAY [see Adverse Reactions (6.2)] .
Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY.
Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids.
5.6 Embryo-Fetal Toxicity
Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures based on area under the curve (AUC) that were ≥ 0.8 times the exposure in humans at the recommended dose of 300 mg/day. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)] .
Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
Adverse Reactions
Other Sections About Side Effects
Severe allergic reactions, skin reactions, high blood sugar, lung problems, and diarrhea or bowel inflammation are discussed in other parts of the label.
Clinical Trial Results (SOLAR-1)
This medicine was studied in 571 patients with a certain type of advanced breast cancer. Patients were split into two groups. One group got PIQRAY plus fulvestrant (284 patients), and the other got placebo plus fulvestrant (287 patients).
Two patients (0.7%) died while taking PIQRAY plus fulvestrant. One died from heart and lung problems, one from another cancer. These deaths were not thought to be caused by the study medicine.
Serious side effects happened in 35% of patients taking PIQRAY plus fulvestrant. The most common serious side effects were:
– High blood sugar (10%)
– Rash (3.5%)
– Diarrhea (2.8%)
– Kidney problems (2.5%)
– Stomach pain (2.1%)
– Low red blood cells (2.1%)
Jaw bone problems (ONJ) happened in 4.2% of patients (12 out of 284) taking PIQRAY plus fulvestrant, compared to 1.4% (4 out of 287) taking placebo. All patients with jaw bone problems had also taken other medicines for bone problems.
Treatment Stopped or Changed
– 4.6% of patients stopped both PIQRAY and fulvestrant completely
– 21% stopped PIQRAY alone
– 55% of patients needed to lower their dose
The most common reasons for stopping or lowering the dose were high blood sugar, rash, diarrhea, and fatigue.
Common Side Effects
The most common side effects (happening in 20% or more of patients) were:
– High blood sugar
– Kidney problems (increased creatinine)
– Diarrhea
– Rash
– Low lymphocyte count
– Nausea
– Liver problems (increased GGT and ALT)
– Fatigue
– Low hemoglobin
– Increased lipase
– Decreased appetite
– Mouth sores
– Vomiting
– Weight loss
– Low calcium
METALLICA Study
This study looked at using metformin (a diabetes medicine) before starting PIQRAY to help prevent high blood sugar.
Results showed:
– Patients with normal blood sugar: 33% had high blood sugar
– Patients with higher blood sugar: 70% had high blood sugar
Common side effects in this study were diarrhea (68%), nausea (68%), fatigue (46%), high blood sugar (44%), rash (38%), and vomiting (34%).
After Medicine Was Approved
Other side effects have been reported after the medicine was approved. These include:
– Eye inflammation (uveitis)
– Bowel inflammation (colitis)
– Severe high blood sugar condition
– Skin swelling
– Severe skin reaction with fever
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Severe Hypersensitivity [see Warnings and Precautions (5.1)]
Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)]
Hyperglycemia [see Warnings and Precautions (5.3)]
Pneumonitis [see Warnings and Precautions (5.4)]
Diarrhea or Colitis [see Warnings and Precautions (5.5)]
6.1 Clinical Trial Experience
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 safety of PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation [see Clinical Studies (14)] .
Patients received either PIQRAY 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15, and then at Day 1 of each 28-day cycle during treatment phase.
Two patients (0.7%) died while on treatment with PIQRAY plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment.
Serious adverse reactions occurred in 35% of patients receiving PIQRAY plus fulvestrant. Serious adverse reactions in > 2% of patients receiving PIQRAY plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the PIQRAY plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK-ligand inhibitor administration.
Among patients receiving PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and fulvestrant and 21% permanently discontinued PIQRAY alone, due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
Dose reductions due to adverse reactions occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent adverse reactions leading to dose reduction in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%).
The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma-glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia.
Grading according to CTCAE Version 4.03.
1 Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration.
2 Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower.
3 Fatigue: including fatigue, asthenia.
4 Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness.
5 Urinary tract infection: including UTI and single case of urosepsis.
6 Dysgeusia: including dysgeusia, ageusia, hypogeusia.
7 Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic.
8 Dry skin: including dry skin, skin fissures, xerosis, xeroderma.
PIQRAY plus fulvestrant
N = 284 Placebo plus fulvestrant
N = 287
% % % %
Gastrointestinal disorders
Diarrhea 58 7 16 0.3
Nausea 45 2.5 22 0.3
Stomatitis 1 30 2.5 6 0
Vomiting 27 0.7 10 0.3
Abdominal pain 2 17 1.4 11 1
Dyspepsia 11 0 6 0
General disorders and administration site conditions
Fatigue 3 42 5 29 1
Mucosal inflammation 19 2.1 1 0
Edema peripheral 15 0 5 0.3
Pyrexia 14 0.7 4.9 0.3 *
Mucosal dryness 4 12 0.4 4.2 0
Infections and infestations
Urinary tract infection 5 10 0.7 5 1
Investigations
Weight decreased 27 3.9 2.1 0
Metabolism and nutrition disorders
Decreased appetite 36 0.7 10 0.3
Nervous system disorders
Dysgeusia 6 18 0.4 3.5 0
Headache 18 0.7 13 0
Skin and subcutaneous tissue disorders
Rash 7 52 20 7 0.3
Alopecia 20 0 2.4 0
Pruritus 18 0.7 6 0
Dry skin 8 18 0.4 3.8 0
Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days. A subgroup of 86 patients received premedication, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.
1 Glucose increase is an expected laboratory abnormality of PI3K inhibition.
PIQRAY plus fulvestrant
N = 284 Placebo plus fulvestrant
N = 287
% % % %
Hematological parameters
Lymphocyte count decreased 52 8 40 4.5 *
Hemoglobin decreased 42 4.2 29 1
Activated partial thromboplastin time (aPTT) prolonged 21 0.7 16 0.3
Platelet count decreased 14 1.1 6 0 *
Biochemical parameters
Glucose increased 1 79 39 34 1
Creatinine increased 67 2.8 25 0.7
Gamma glutamyl transferase (GGT) increased 52 11 44 10
Alanine aminotransferase (ALT) increased 44 3.5 34 2.4 *
Lipase increased 42 7 25 6
Calcium (corrected) decreased 27 2.1 20 1.4
Glucose decreased 26 0.4 14 0 *
Potassium decreased 14 6 2.8 0.7 *
Albumin decreased 14 0 8 0
Magnesium decreased 11 0.4 4.2 0
Metformin Premedication for Hyperglycemia Adverse Reactions
The safety of PIQRAY and endocrine therapy with metformin premedication was evaluated in METALLICA (NCT04300790), a single-arm, two-cohort study in 68 patients with HR-positive, HER2-negative advanced breast cancer harboring PIK3CA mutation(s). The majority of patients (93%) received fulvestrant as endocrine therapy during the study. Cohort A enrolled patients with normal glycemic status (FPG < 100 mg/dl [< 5.6 mmol/L] and HbA1c < 5.7%) and Cohort B enrolled patients with impaired glycemic status (FPG 100–140 mg/dL [5.6–7.8 mmol/L] or HbA1c 5.7%–6.4%).
Hyperglycemia adverse reactions occurred in 33% (16/48) and 70% (14/20 patients) in Cohort A and Cohort B, respectively. Grade 3-4 hyperglycemia occurred in 2.1% (1/48) of patients in Cohort A and 15% (3/20) of patients in Cohort B. The incidence of nausea, vomiting, and diarrhea adverse reactions, including Grade 3 diarrhea, increases with metformin premedication [see Warnings and Precautions (5.3)] .
Serious adverse reactions occurred in 22% of patients in the METALLICA study and serious adverse reactions ≥ 2% included diarrhea (3%), rash (3%) and vomiting (3%).
The most common Grade 3-4 adverse reactions (≥ 5%) were rash (16%), diarrhea (13%), and hyperglycemia (6%).
Permanent discontinuation of PIQRAY due to adverse reactions in the METALLICA study occurred in 19% of patients, and dose modification or interruption of PIQRAY due to adverse reactions occurred in 56% of patients, of which 28% were dose reductions.
The most common adverse reactions (≥ 30%) in the METALLICA study were diarrhea (68%), nausea (68%), fatigue (46%), hyperglycemia (44%), rash (38%), and vomiting (34%).
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of PIQRAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Eye disorders: Uveitis
Gastrointestinal disorders: Colitis
Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).
Skin and subcutaneous tissue disorders: Angioedema, Drug reaction with eosinophilia and systemic symptoms (DRESS).
Drug Interactions
CYP3A4 Inducers
Taking PIQRAY with a strong CYP3A4 inducer lowers the amount of alpelisib in your body. This may make PIQRAY less effective. Do not take PIQRAY with strong CYP3A4 inducers. Use a different medicine instead.
BCRP Inhibitors
Taking PIQRAY with a breast cancer resistance protein (BCRP) inhibitor raises the amount of alpelisib in your body. This may increase side effects. Do not take BCRP inhibitors with PIQRAY. If you must take them together, your doctor will watch for more side effects.
7.1 Effect of Other Drugs on PIQRAY
CYP3A4 Inducer
Coadministration of PIQRAY with a strong CYP3A4 inducer decreases alpelisib concentration [see Clinical Pharmacology (12.3)] , which may reduce alpelisib efficacy. Avoid concomitant use of strong CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4.
Breast Cancer Resistance Protein Inhibitors
Coadministration of PIQRAY with a breast cancer resistance protein (BCRP) inhibitor may increase alpelisib concentration [see Clinical Pharmacology (12.3)] , which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, when PIQRAY is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.
Pregnancy
Risk Summary
PIQRAY is used with fulvestrant. PIQRAY can harm an unborn baby.
Studies in pregnant animals showed that this medicine can cause:
– Loss of pregnancy
– Smaller babies
– Birth defects
These problems happened at doses similar to the human dose. Pregnant women should not take this medicine.
Data
Animal studies were done in rats and rabbits. Pregnant animals received up to 30 mg/kg per day during pregnancy.
In rats:
– At 30 mg/kg, all babies died
– At 10 mg/kg, babies were smaller and had bone problems
In rabbits:
– At 30 mg/kg, all babies died
– At 15 mg/kg or higher, babies died or had deformities
Risk Summary
PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.
Based on animal data and mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman[see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures ≥ 0.8 times the exposure in humans based on AUC at the recommended dose of 300 mg/day(see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.
Data
Animal Data
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib up to 30 mg/kg/day during the period of organogenesis.
In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At a dose of 10 mg/kg/day (approximately 0.8 times the exposure in humans at the recommended dose of 300 mg/day based on AUC), toxicities included reduced fetal weight and increased incidences of skeletal malformations (bent scapula and thickened or bent long bones) and fetal variations (enlarged brain ventricle, decreased bone ossification).
In a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (post-implantation loss). Doses ≥ 15 mg/kg/day resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head. At 15 mg/kg/day in rabbits, the maternal exposure was approximately 5 times the exposure achieved at the recommended human dose of 300 mg/day based on AUC.
Lactation
Breastfeeding
PIQRAY is used with fulvestrant. See the fulvestrant label for breastfeeding information.
It is not known if alpelisib passes into breast milk. There is no information on how it affects milk production or breastfed children. Because of possible serious reactions in the breastfed child, women should not breastfeed during treatment with PIQRAY and for 1 week after the last dose.
PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.
There is no data on the presence of alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with PIQRAY and for 1 week after the last dose.
Pediatric Use
We do not know if PIQRAY is safe or works well in children.
The safety and efficacy of PIQRAY in pediatric patients have not been established.
Geriatric Use
Older Patients in the Study
Of 284 patients in the study, 117 were 65 years or older and 34 were 75 years or older.
Side Effects in Older Patients
When taken with fulvestrant, high blood sugar was more common in patients 65 years or older (44%) than in younger patients (32%).
In patients 75 years or older, high blood sugar happened more often (74% vs 66%) and serious high blood sugar was also more common (56% vs 36%) compared to patients under 75.
How Well It Works
The medicine worked about the same in patients 65 years or older as it did in younger patients.
Patients 75 Years or Older
There were not enough patients 75 years or older to know if the medicine is safer or works differently for them.
Of 284 patients who received PIQRAY in the SOLAR-1 trial, 117 patients were ≥ 65 years of age and 34 patients were ≥ 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was a higher incidence of Grade 3-4 hyperglycemia in patients ≥ 65 years of age (44%) compared to patients < 65 years of age (32%). No overall differences in effectiveness of PIQRAY were observed between patients ≥ 65 years of age compared to younger patients. There are an insufficient number of patients ≥ 75 years of age to assess whether there are differences in safety or effectiveness. However, in the SOLAR-1 trial, an increase in the hyperglycemia adverse reactions (74% vs 66%) and Grade 3-4 (56% vs 36%) hyperglycemia were observed in patients ≥ 75 years of age compared to patients < 75 years of age, respectively[see Warnings and Precautions (5.3)].
Hepatic Impairment
Severe Kidney Problems
The effect of severe kidney problems on alpelisib is not known.
Mild to Moderate Kidney Problems
No dose change is needed for patients with mild to moderate kidney problems.
The effect of severe renal impairment (CLcr < 30 mL/min) on alpelisib pharmacokinetics is unknown[see Clinical Pharmacology (12.3)].
No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min).
Description
What PIQRAY Is
PIQRAY (alpelisib) is a kinase inhibitor. Alpelisib is a white to almost white powder. The molecular formula for alpelisib is C19H22F3N5O2S and the molecular weight is 441.47 g/mol.
Available Strengths
PIQRAY film-coated tablets are supplied for oral use in three strengths: 50 mg, 150 mg, and 200 mg.
Tablet Ingredients
The tablets also contain hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. The tablet coating contains hypromellose, iron oxide black, iron oxide red, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.
PIQRAY (alpelisib) is a kinase inhibitor. The chemical name of alpelisib is (2S)- N 1 -[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide. Alpelisib is a white to almost white powder. The molecular formula for alpelisib is C 19 H 22 F 3 N 5 O 2 S and the relative molecular mass is 441.47 g/mol. The chemical structure of alpelisib is shown below:
PIQRAY film-coated tablets are supplied for oral administration with three strengths that contain 50 mg, 150 mg and 200 mg of alpelisib. The tablets also contain hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. The film-coating contains hypromellose, iron oxide black, iron oxide red, macrogol/polyethylene glycol (PEG) 4000, talc, and titanium dioxide.
Mechanism of Action
How This Medicine Works
Alpelisib is a drug that blocks a protein called PI3K. This protein can help cancer cells grow and divide. Some breast cancers have changes in a gene called PIK3CA that makes PI3K too active. Alpelisib stops this activity.
Effects on Cancer Cells
In lab tests, alpelisib blocked signals that help cancer grow. It worked on cancer cells with PIK3CA gene changes. In animals with human breast tumors, alpelisib slowed tumor growth.
Combining with Other Treatments
Alpelisib may increase estrogen receptor activity in breast cancer cells. When combined with fulvestrant (another breast cancer drug), it worked better than either drug alone in lab and animal models.
Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.
In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
Pharmacodynamics
How It Affects the Heart
Heart tests (ECGs) were done to check if alpelisib changes heart rhythm in patients with advanced cancer. The 300 mg dose did not cause a large effect on heart rhythm with or without fulvestrant.
Cardiac Electrophysiology
Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of alpelisib on the QTcF interval in patients with advanced cancer. An analysis of clinical ECG data demonstrates the absence of a large effect (i.e., > 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant.
Pharmacokinetics
How the Body Processes Alpelisib
Alpelisib (PIQRAY) has been studied in healthy people and patients with tumors. The amount of drug in the blood increases with higher doses. The drug builds up slightly in the body over time. Steady levels are reached within 3 days of daily dosing.
Absorption
The drug reaches its highest level in the blood 2 to 4 hours after taking it.
Effect of Food
Taking alpelisib with food increases how much drug gets into your body. A high-fat meal (985 calories) increases total drug exposure by 73% and peak levels by 84%. A low-fat meal (334 calories) increases total exposure by 77% and peak levels by 145%. Always take alpelisib with food as directed.
Distribution
The drug spreads through the body with a volume of about 114 liters. It binds to proteins in the blood (89% bound).
How Long Alpelisib Stays in the Body
The drug stays in the body for about 8 to 9 hours (half-life). The body clears about 9.2 liters per hour.
How Alpelisib is Broken Down
The body breaks down alpelisib mainly through chemical breakdown and liver enzymes. This forms a substance called BZG791. The liver enzyme CYP3A4 also helps break it down further.
How Alpelisib Leaves the Body
Most of the drug leaves the body through bowel movements (81%). About 36% leaves as unchanged drug, and 32% as BZG791. About 14% leaves through urine. Only 2% leaves as unchanged drug in urine.
Effects in Different Patients
Age, sex, race, body weight, mild to moderate kidney problems, or mild to severe liver problems do not significantly change how alpelisib works. The effect of severe kidney problems is unknown.
Drug Interactions
Acid-reducing medicines (like ranitidine) decrease how much alpelisib gets into your body. Take alpelisib with food as directed.
Alpelisib does not significantly affect other drugs processed by liver enzymes CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6.
Rifampin (a strong liver enzyme inducer) decreases alpelisib levels significantly. Avoid using rifampin with alpelisib.
Ketoconazole (a strong liver enzyme blocker) may increase alpelisib levels slightly.
Efavirenz (a moderate liver enzyme inducer) may decrease alpelisib levels slightly.
Alpelisib can affect some drug transporters. It may affect P-gp and BCRP transporters at treatment doses.
Absorption
The median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.
Effect of food
A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and Cmaxby 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and Cmaxby 145% following a single dose of PIQRAY. No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.
Distribution
The mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 L (46%). Protein binding of alpelisib is 89% and is independent of concentration.
Elimination
The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (% CV) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.
Metabolism
Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and followed by CYP3A4 mediated hydroxylation.
Excretion
Following a single oral dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.
Specific Populations
No clinically significant differences in the pharmacokinetics of alpelisib were predicted based on age (21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renal impairment (CLcr 30 to < 90 mL/min based on the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of alpelisib is unknown.
Drug Interaction Studies
Clinical Studies
Acid Reducing Agents:PIQRAY can be coadministered with acid reducing agents, since PIQRAY should be taken with food. Food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH value.
Coadministration of the H2receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib decreased the absorption and overall exposure of alpelisib. In the presence of a low-fat low-calorie meal, AUC was decreased on average by 21% and Cmaxby 36% with ranitidine. Under the fasted state, AUC was decreased on average by 30% and Cmaxby 51% with ranitidine.
CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 Substrates:Coadministration of repeated doses of alpelisib 300 mg with a single-dose of sensitive substrates of CYP3A4 (midazolam), CYP2C8 (repaglinide), CYP2C9 (warfarin), CYP2C19 (omeprazole) and CYP2B6 (bupropion), administered as a cocktail did not show clinically significant pharmacokinetic interactions. No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when coadministered with alpelisib.
Effect of CYP3A4 Inducers on Alpelisib:Coadministration of repeat doses of rifampin (a strong CYP3A4 inducer) with a single 300 mg dose of alpelisib decreased alpelisib Cmaxby 38% and AUC by 57%, respectively. Coadministration of rifampin with repeat doses of 300 mg alpelisib decreased alpelisib Cmaxby 59% and AUC by 74%, respectively.
Model-Informed Approaches
Coadministration of repeat doses of ketoconazole (a strong CYP3A4 inhibitor) with a single 300 mg dose of alpelisib is expected to increase alpelisib AUC by 37% or less.
Coadministration of repeat doses of efavirenz (a moderate CYP3A4 inducer) with a single 300 mg dose of alpelisib is expected to decrease alpelisib AUC by 30% or less.
In Vitro Studies
Effect of Transporter on Alpelisib:Alpelisib is a substrate of BCRP.
Effect of Alpelisib on Transporters:Alpelisib is an inhibitor of P-gp. Alpelisib has a low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations.
Clinical Studies
Study Overview
SOLAR-1 was a clinical trial that tested PIQRAY plus fulvestrant versus placebo plus fulvestrant in 572 patients with a type of advanced breast cancer (HR-positive, HER2-negative). Patients had cancer that got worse after receiving aromatase inhibitor treatment. Patients were not included if they had inflammatory breast cancer, Type 1 diabetes, uncontrolled Type 2 diabetes, or pneumonitis.
About 60% of patients had tumors with PIK3CA mutations. Half had cancer that spread to liver or lungs. Very few (6%) had previously received CDK4/6 inhibitor treatment.
Who Was in the Study
The study included 341 patients with PIK3CA mutations and 231 patients without these mutations. Most patients were women (99.8%). The median age was 63 years (range 25 to 92). Most were white (66%), followed by Asian (22%).
Treatment Given
Patients received PIQRAY (300 mg) or placebo by mouth once daily, plus fulvestrant (500 mg) as an injection. Treatment continued until cancer got worse or side effects became too severe. Tumor scans were done every 8 weeks for the first 18 months, then every 12 weeks.
The median time on treatment was 8.2 months, with 59% of patients receiving treatment for more than 6 months.
Results
For patients with PIK3CA mutations:
– PIQRAY plus fulvestrant: Median PFS 11.0 months
– Placebo plus fulvestrant: Median PFS 5.7 months
– The treatment group had a 35.7% response rate versus 16.2% in the placebo group
No significant difference in overall survival was found between the two groups. Patients without PIK3CA mutations did not benefit from the treatment.
SOLAR-1 (NCT02437318) was a randomized, double-blind, placebo-controlled trial of PIQRAY plus fulvestrant versus placebo plus fulvestrant in 572 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment (with or without CDK4/6 combination). Patients were excluded if they had inflammatory breast cancer, diabetes mellitus Type 1 or uncontrolled Type 2, or pneumonitis. Randomization was stratified by presence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s). Overall, 60% of enrolled patients had tumors with one or more PIK3CA mutations in tissue, 50% had liver/lung metastases, and 6% had previously been treated with a CDK4/6 inhibitor.
There were 341 patients enrolled by tumor tissue in the cohort with a PIK3CA mutation and 231 enrolled in the cohort without a PIK3CA mutation. Of the 341 patients in the cohort with a PIK3CA mutation, 336 (99%) patients had one or more PIK3CA mutations confirmed in tumor tissue using the FDA-approved therascreen ® PIK3CA RGQ PCR Kit. Out of the 336 patients with PIK3CA mutations confirmed in tumor tissue, 19 patients had no plasma specimen available for testing with the FDA-approved therascreen ® PIK3CA RGQ PCR Kit. Of the remaining 317 patients with PIK3CA mutations confirmed in tumor tissue, 177 patients (56%) had PIK3CA mutations identified in plasma specimen, and 140 patients (44%) did not have PIK3CA mutations identified in plasma specimen.
Patients received either PIQRAY (300 mg) or placebo orally once daily on a continuous basis, plus fulvestrant (500 mg) administered intramuscularly on Cycle 1, Days 1 and 15, and then on Day 1 of every 28-day cycle. Patients received treatment until radiographic disease progression or unacceptable toxicity. Tumor assessments were performed every 8 weeks for the first 18 months and every 12 weeks thereafter.
Patient demographics for those with PIK3CA-mutated tumors were generally representative of the broader study population. The median duration of exposure to PIQRAY plus fulvestrant was 8.2 months with 59% of patients exposed for > 6 months.
The majority of patients (98%) received prior hormonal therapy as the last treatment (48% metastatic setting, 52% adjuvant setting). Primary endocrine resistance, defined as relapsed within 24 months on adjuvant endocrine therapy or progression within 6 months on endocrine therapy for advanced disease, was observed in 13% of patients and secondary endocrine resistance, defined as relapsed after 24 months on adjuvant endocrine therapy, relapsed within 12 months of the end of adjuvant endocrine therapy, or progression after 6 months on endocrine therapy for advanced disease, was observed in 72% of patients.
The major efficacy outcome was investigator-assessed progression-free survival (PFS) in the cohort with a PIK3CA mutation per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were overall response rate (ORR) and overall survival (OS) in the cohort with a PIK3CA mutation.
No benefit was observed in patients whose tumors did not have a PIK3CA tissue mutation (PFS: HR = 0.85, 95% CI: 0.58, 1.25; OS: HR = 0.92, 95% CI: 0.65, 1.29).
Abbreviation: CI, confidence interval.
1 p-value obtained from the two-sided stratified log-rank test, stratified by prior CDK4/6 inhibitor usage and presence of lung/liver metastases. P-value was compared to prespecified Haybittle-Peto efficacy boundary (two-sided p ≤ 0.0398).
2 ORR = percentage of patients with confirmed complete response or partial response with measurable disease at baseline.
PIQRAY plus fulvestrant Placebo plus fulvestrant
Progression-free survival N = 169 N = 172
Median PFS months (95% CI) 11.0 (7.5, 14.5) 5.7 (3.7, 7.4)
Hazard ratio (95% CI) 0.65 (0.50, 0.85)
p-value 1 0.0013
Overall response rate N = 126 N = 136
ORR 2 (95% CI) 35.7 (27.4, 44.7) 16.2 (10.4, 23.5)
Figure 1: Progression Free Survival in SOLAR-1 (Per Investigator Assessment of Patients with a PIK3CA Tumor Mutation)
Patient Counseling Information
Patient Labeling
Read the FDA-approved patient labeling (Patient Information).
Severe Allergic Reactions
Tell patients about signs of allergic reactions. Advise patients to call their healthcare provider right away for signs of allergic reactions.
Severe Skin Reactions
Tell patients about signs of serious skin reactions. Advise patients to call their healthcare provider right away for signs of serious skin reactions.
High Blood Sugar
Advise patients that PIQRAY may cause high blood sugar and the need to check fasting blood sugar regularly during treatment. Advise patients to call their healthcare provider right away for signs of high blood sugar.
Lung Problems
Tell patients that PIQRAY may cause lung problems and to call their healthcare provider right away if they have breathing problems.
Diarrhea or Stomach Problems
Advise patients that PIQRAY may cause diarrhea, which may be severe. Start anti-diarrhea medicine, drink more fluids, and call your healthcare provider if diarrhea occurs while taking PIQRAY.
Advise patients that PIQRAY may cause stomach problems. Tell your healthcare provider right away if you have stomach pain or mucus or blood in your stool while taking PIQRAY.
Eye Problems
Advise patients to call their healthcare provider right away for signs of eye problems.
Pregnancy Risks
Tell pregnant women and females who can become pregnant about the possible risk to a baby. Advise females to tell their healthcare provider if they are pregnant or think they may be pregnant.
Advise females who can become pregnant to use effective birth control during treatment with PIQRAY and for 1 week after the last dose.
Advise male patients with female partners who can become pregnant to use condoms and effective birth control during treatment with PIQRAY and for 1 week after the last dose.
See the Full Prescribing Information for fulvestrant for pregnancy and birth control information.
Breastfeeding
Advise women not to breastfeed during treatment with PIQRAY and for 1 week after the last dose. See the Full Prescribing Information for fulvestrant for breastfeeding information.
Fertility Problems
Advise males and females who can become pregnant that PIQRAY may cause fertility problems. See the Full Prescribing Information for fulvestrant for fertility information.
Drug Interactions
Advise patients to avoid using strong CYP3A4 inducers while taking PIQRAY. Advise patients to avoid using BCRP inhibitors while taking PIQRAY. If unable to use other drugs, your doctor will closely watch for increased side effects. No dose change is needed when taking PIQRAY with CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP2B6 medicines.
How to Take PIQRAY
Tell patients to take PIQRAY at about the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split before swallowing).
Advise patients to take PIQRAY with food.
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. Do not take 2 doses to make up for a missed dose.
If you vomit after taking PIQRAY, do not take an additional dose that day. Take your next dose at the usual time the next day.
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Severe Hypersensitivity
Inform patients of the signs and symptoms of hypersensitivity. Advise patients to contact their healthcare provider immediately for signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)] .
Severe Cutaneous Adverse Reactions
Inform patients of the signs and symptoms of severe cutaneous adverse reactions (SCARs). Advise patients to contact their healthcare provider immediately for signs and symptoms of SCARs [see Warnings and Precautions (5.2)] .
Hyperglycemia
Advise patients that PIQRAY may cause hyperglycemia and the need to monitor fasting blood glucose periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia [see Warnings and Precautions (5.3)] .
Pneumonitis
Inform patients that PIQRAY may cause pneumonitis and to immediately contact their healthcare provider if they experience respiratory problems [see Warnings and Precautions (5.4)] .
Diarrhea or Colitis
Advise patients that PIQRAY may cause diarrhea, which may be severe, and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY [see Warnings and Precautions (5.5)] .
Advise patients that PIQRAY may cause colitis and to notify their healthcare provider immediately of any symptoms of colitis, such as abdominal pain and mucus or blood in stool, while taking PIQRAY [see Warnings and Precautions (5.5)] .
Uveitis
Advise patients to contact their healthcare provider immediately for signs and symptoms of uveitis [see Adverse Reactions (6.2)] .
Embryo-Fetal Toxicity
Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)] .
Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose [see Use in Specific Populations (8.3)] .
Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose [see Use in Specific Populations (8.3)] .
Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
Lactation
Advise women not to breastfeed during treatment with PIQRAY and for 1 week after the last dose [see Use in Specific Populations (8.2)] . Refer to the Full Prescribing Information of fulvestrant for lactation information.
Infertility
Advise males and females of reproductive potential that PIQRAY may impair fertility [see Use in Specific Populations (8.3)] . Refer to the Full Prescribing Information of fulvestrant for infertility information.
Drug Interactions
Advise patients to avoid the use of strong CYP3A4 inducers in patients treated with PIQRAY. Advise patients to avoid the use of BCRP inhibitors while taking PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions. No dose adjustment is required when coadministering PIQRAY with CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates [see Drug Interactions (7.1, 7.2)] .
Dosing
Instruct patients to take PIQRAY at approximately the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split prior to swallowing) [see Dosage and Administration (2.2)] .
Advise patients to take PIQRAY with food [see Clinical Pharmacology (12.3)] .
Instruct patients that 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. Instruct patients not to take 2 doses to make up for a missed dose.
Instruct patients that if they vomit after taking the dose of PIQRAY, they should not take an additional dose on that day, and to resume the usual dosing schedule the next day at the usual time [see Dosage and Administration (2.2)] .
© Novartis
T2024-03
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References
PIQRAY (alpelisib) [prescribing information]. March 2026. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b20b4e18-7a4b-4500-a08f-06c6dab0ee5b
Accessed: March 27, 2026