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Alpelisib

Medically reviewed by Drugs.com. Last updated on Jun 1, 2020.

Pronunciation

(AL pe LIS ib)

Index Terms

  • BYL719
  • Phosphoinositide 3-Kinase Inhibitor BYL719
  • PI3K Inhibitor BYL719

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Therapy Pack, Oral:

Piqray (200 MG Daily Dose): 200 mg (28 ea)

Piqray (250 MG Daily Dose): 200 mg tablets and 50 mg tablets (28 ea)

Piqray (300 MG Daily Dose): 2 x 150 MG (28 ea)

Brand Names: U.S.

  • Piqray (200 MG Daily Dose)
  • Piqray (250 MG Daily Dose)
  • Piqray (300 MG Daily Dose)

Pharmacologic Category

  • Antineoplastic Agent, Phosphatidylinositol 3-Kinase Inhibitor

Pharmacology

Alpelisib is a small-molecule phosphatidylinositol-3-kinase (PI3K) inhibitor with selective (and strong) activity against PI3Kα (André 2019). Mutations in the gene encoding the catalytic α-subunit of PI3K (PI3KCA) lead to activation of PI3Kα and Akt-signaling, cellular transformation, and tumor generation. Alpelisib inhibits phosphorylation of PI3K downstream targets (including Akt) and demonstrated activity in cell lines harboring a PIK3CA mutation. When compared with either agent alone, the combination of alpelisib with fulvestrant has synergistic antitumor activity in PIK3CA-mutated, estrogen receptor-positive models (André 2019).

Distribution

Vdss: 114 L

Metabolism

Primarily by chemical and enzymatic hydrolysis to form its metabolite BZG791, and to a lesser extent by CYP3A4

Excretion

Feces: 81% (36% as unchanged drug, 32% as BZG791); Urine: 14% (2% as unchanged drug, 7% as BZG791)

Clearance: 9.2 L/hour

Time to Peak

2 to 4 hours

Half-Life Elimination

8 to 9 hours

Protein Binding

89%

Use: Labeled Indications

Breast cancer, advanced or metastatic: Treatment (in combination with fulvestrant) of HR-positive, HER2-negative, PIK3CA-mutated (as detected by an approved test), advanced or metastatic breast cancer in males and postmenopausal females following progression on or after an endocrine-based regimen.

Contraindications

Severe hypersensitivity to alpelisib or any component of the formulation

Dosing: Adult

Breast cancer, advanced or metastatic (HR-positive, HER2-negative, PIK3CA-mutated): Males and postmenopausal females: Oral: 300 mg once daily (in combination with fulvestrant); continue until disease progression or unacceptable toxicity (André 2019).

Missed doses: A missed dose may administered (with food) within 9 hours after the usual administration time; if beyond 9 hours, skip the dose for that day and administer the dose for the next day at the usual time. If a dose is vomited, do not administer an additional dose on that day; resume the dosing schedule the next day at the usual time.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended Alpelisib Dosage Reduction Levelsa,b

aOnly one dose reduction is permitted for pancreatitis.

bRefer to Fulvestrant monograph for information on fulvestrant toxicities.

Initial (usual) dose

300 mg once daily

First dose reduction level

250 mg once daily

Second dose reduction level

200 mg once daily

If further dose reductions are required, discontinue alpelisib.

Dermatologic toxicity: Rash and severe cutaneous adverse reactions (SCARs): Consider dermatology consultation for all grades. Antihistamine administration prior to rash onset may decrease the rash incidence/severity.

Grade 1 (<10% BSA with active skin toxicity): No alpelisib dosage adjustment required. Initiate topical corticosteroid therapy; consider adding an oral antihistamine to manage symptoms. Permanently discontinue alpelisib if a SCAR is confirmed.

Grade 2 (10% to 30% BSA with active skin toxicity): No alpelisib dosage adjustment required. Initiate or intensify topical corticosteroid therapy and oral antihistamine treatment; consider low-dose systemic corticosteroid treatment. Permanently discontinue alpelisib if a SCAR is confirmed.

Grade 3 (eg, severe rash not responsive to medical management; >30% BSA with active skin toxicity): Interrupt alpelisib treatment; initiate or intensify topical/systemic corticosteroid therapy and oral antihistamine treatment. If the etiology is not a SCAR, once improved to ≤ grade 1, resume alpelisib at the same dose level for the first rash occurrence, or at the next lower dosage level for second rash occurrence. Permanently discontinue alpelisib if a SCAR is confirmed.

Grade 4 (eg, severe bullous, blistering or exfoliating skin conditions; any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences): Permanently discontinue alpelisib.

Gastrointestinal toxicity: Diarrhea:

Grade 1: No alpelisib dosage adjustment required; initiate appropriate medical therapy and monitor as clinically indicated.

Grade 2: Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt alpelisib treatment until recovery to ≤ grade 1, then resume at the same dose level.

Grades 3 and 4: Initiate or intensify appropriate medical therapy and monitor as clinically indicated. Interrupt alpelisib treatment until recovery to ≤ grade 1, then resume at the next lower dose level.

Hyperglycemia: Fasting plasma glucose/fasting blood glucose values:

Grade 1 (fasting glucose > ULN to 160 mg/dL): No alpelisib dosage adjustment required; initiate or intensify antidiabetic therapy as described below.

Grade 2 (fasting glucose >160 to 250 mg/dL): No alpelisib dosage adjustment required; initiate or intensify antidiabetic therapy as described below. If fasting glucose does not decrease to ≤160 mg/dL within 21 days with appropriate antidiabetic therapy, reduce alpelisib dose by 1 dose level and continue to follow fasting glucose specific recommendations.

Grade 3 (fasting glucose >250 to 500 mg/dL): Interrupt alpelisib therapy; initiate or intensify antidiabetic therapy as described below and consider additional antidiabetic medications for 1 to 2 days (if needed; may not be necessary due to alpelisib half-life) until hyperglycemia improves. Administer IV hydration and consider appropriate intervention for electrolyte/ketoacidosis/hyperosmolar disturbances. If fasting glucose decreases to ≤160 mg/dL within 3 to 5 days with appropriate antidiabetic therapy, resume alpelisib with the dose reduced by 1 dose level. If fasting glucose does not decrease to ≤160 mg/dL within 3 to 5 days with appropriate antidiabetic therapy, consultation with a clinician with expertise in hyperglycemia management is recommended. Permanently discontinue alpelisib if fasting glucose does not decrease to ≤160 mg/dL within 21 days following appropriate antidiabetic therapy.

Grade 4 (fasting glucose >500 mg/dL): Interrupt alpelisib therapy; initiate or intensify antidiabetic therapy as described below. Administer IV hydration and consider appropriate intervention for electrolyte/ketoacidosis/hyperosmolar disturbances. Recheck fasting glucose within 24 hours (and as clinically indicated). If fasting glucose decreases to ≤500 mg/dL, follow fasting glucose value specific recommendations for grade 3 hyperglycemia. Permanently discontinue alpelisib if fasting glucose is confirmed at >500 mg/dL.

Antidiabetic therapy recommendations: Initiate or intensify antidiabetic therapy, including metformin and insulin sensitizers (eg, thiazolidinediones, dipeptidyl peptidase-4 inhibitors); short-term insulin (1 to 2 days) may also be considered until hyperglycemia resolves (although may not be necessary due to the short alpelisib half-life).

Metformin recommendations: Initiate metformin at 500 mg once daily; based on tolerance, may increase to 500 mg twice daily (with meals), and further increase to 500 mg with breakfast and 1,000 mg with dinner, followed by a further increase to 1,000 mg twice daily (with meals) if needed.

Hypersensitivity: Severe: Permanently discontinue alpelisib.

Pancreatitis: Grades 2 and 3: Interrupt alpelisib treatment until recovery to < grade 2, then resume at the next lower dose level. Only 1 dose reduction is permitted for pancreatitis. If toxicity recurs, permanently discontinue alpelisib.

Pneumonitis (confirmed): Permanently discontinue alpelisib.

Other toxicities:

Grade 1 or 2: No alpelisib dosage adjustment required; initiate appropriate medical therapy and monitor as clinically indicated.

Grade 3: Interrupt alpelisib treatment until recovery to ≤ grade 1, then resume at the next lower dose level.

Grade 4: Permanently discontinue alpelisib.

Administration

Oral: Administer with food at approximately the same time each day. Swallow tablets whole (tablets should be intact prior to ingestion); do not chew, crush, or split.

Storage

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F).

Drug Interactions

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

BCRP/ABCG2 Inhibitors: May increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

CYP2C9 Substrates (High risk with Inducers): Alpelisib may decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Alpelisib. Avoid combination

Adverse Reactions

Adverse reactions reported with concomitant fulvestrant.

>10%:

Cardiovascular: Peripheral edema (15%)

Central nervous system: Fatigue (42%), headache (18%)

Dermatologic: Skin rash (52%), alopecia (20%), pruritus (18%), xeroderma (18%)

Endocrine & metabolic: Hyperglycemia (65%), increased gamma-glutamyl transferase (52%), decreased serum calcium (27%), weight loss (27%), decreased serum glucose (26%), decreased serum albumin (14%), decreased serum potassium (14%), decreased serum magnesium (11%)

Gastrointestinal: Diarrhea (58%), nausea (45%), increased serum lipase (42%), decreased appetite (36%), stomatitis (19% to 30%; grades 3/4: 2% to 3%), vomiting (27%), dysgeusia (18%), abdominal pain (17%), dry mucous membranes (12%), dyspepsia (11%)

Hematologic & oncologic: Lymphocytopenia (52%; grades 3/4: 8%), prolonged partial thromboplastin time (21%; grades 3/4: <1%), decreased platelet count (14%; grades 3/4: 1%)

Hepatic: Increased serum alanine aminotransferase (44%)

Renal: Increased serum creatinine (67%)

Miscellaneous: Fever (14%)

1% to 10%:

Dermatologic: Erythema multiforme (1%)

Gastrointestinal: Severe diarrhea (3%)

Genitourinary: Urinary tract infection (10%)

Hematologic & oncologic: Anemia (2%)

Neuromuscular & skeletal: Osteonecrosis of the jaw (4%)

Renal: Acute renal failure (3%)

Respiratory: Pneumonitis (2%)

Frequency not defined:

Dermatologic: Skin fissure

Gastrointestinal: Ageusia, xerostomia

Genitourinary: Vaginal dryness

Neuromuscular & skeletal: Asthenia

<1%, postmarketing, and/or case reports: Anaphylactic shock, anaphylaxis, interstitial pneumonitis, interstitial pulmonary disease, ketoacidosis, severe dermatological reaction, severe hypersensitivity reaction, Stevens-Johnson syndrome, urinary tract infection with sepsis

Warnings/Precautions

Concerns related to adverse effects:

• Dermatologic toxicity: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms may occur. If signs or symptoms of SCARs occur, interrupt alpelisib until the etiology of the reaction has been determined; a dermatology consultation is recommended. If a SCAR is confirmed, permanently discontinue alpelisib. Do not reinitiate alpelisib in patients who have experienced previous severe cutaneous reactions during alpelisib treatment. If a SCAR is not confirmed, alpelisib may require dose modifications, topical corticosteroids, and/or oral antihistamine treatment. Patients should be informed of the signs/symptoms of SCARs (eg, prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, lymphadenopathy). Maculopapular rash (with or without pruritus and dry skin) is the most commonly occurring rash; rash generally develops within the initial 2 months of treatment and may be managed with supportive medication (topical corticosteroids and/or oral antihistamines), and if needed, treatment interruption (Nunnery 2019).

• GI toxicity: Severe diarrhea may commonly occur with alpelisib, sometimes with dehydration and acute kidney injury. Grade 3 diarrhea has been reported. The median time to onset of grade 2 or 3 diarrhea was 46 days (range: 1 to 442 days). Antidiarrheal medication (eg, loperamide) was required to manage symptoms in a majority of patients who experienced diarrhea. Diarrhea may require treatment interruption, dose reduction, and/or discontinuation. Consider stopping lactose-containing foods, alcohol, laxatives, bulk fiber, stool softeners, and high-osmolar food supplements; encourage hydration and frequent small meals (Nunnery 2019). Patients should be instructed to initiate antidiarrheal treatment, increase oral fluids, and notify their health care provider if diarrhea occurs during alpelisib treatment. Nausea and vomiting (usually mild) and stomatitis may also occur. Pancreatitis may require treatment interruption, dose reduction, and/or discontinuation.

• Hepatitis B virus reactivation: The American Society of Clinical Oncology hepatitis B screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends hepatitis B virus (HBV) screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

• Hyperglycemia: Severe hyperglycemia, including ketoacidosis, may occur with alpelisib. Hyperglycemia was reported in nearly two-thirds of patients. Grade 3 hyperglycemia occurred in one-third of patients; grade 4 hyperglycemia and ketoacidosis have been reported in a small percentage of patients. Among patients who experienced grade 2 or higher hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range: 5 to 517 days). Most hyperglycemia events were managed with antidiabetic medication, with a majority utilizing metformin (either as single agent or in combination with other antidiabetic medications (eg, insulin, dipeptidyl peptidase-4 inhibitors, sulfonylureas). The median time from ≥ grade 2 hyperglycemia to at least 1 grade improvement was 8 days (range: 2 to 65 days). Most patients who continued fulvestrant but discontinued alpelisib (due to hyperglycemia) had fasting plasma glucose (FPG) levels that returned to baseline. Optimize blood glucose prior to initiating alpelisib treatment. Monitor FPG and HbA1c prior to alpelisib treatment initiation; monitor fasting glucose or FPG at least once each 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. If hyperglycemia occurs, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with antidiabetic 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 clinician with expertise in hyperglycemia management and counsel patients on lifestyle modifications. Patients with type 1 or uncontrolled type 2 diabetes were excluded from the clinical trial; the safety of alpelisib in these patients has not been established. Patients with a history of type 2 diabetes were included in the clinical trial; closely monitor patients with diabetes as they may require intensified antidiabetic therapy. Hyperglycemia may require treatment interruption, dose reduction, and/or discontinuation. Aggressive hydration and electrolyte management may also be indicted (Nunnery 2019). Patients should be aware of signs/symptoms of hyperglycemia (eg, excessive thirst, frequent urination, increased urine volume, increased appetite with weight loss).

• Hypersensitivity: Severe hypersensitivity reactions (including anaphylaxis and anaphylactic shock) may occur. Manifestations of severe hypersensitivity reactions included dyspnea, flushing, rash, fever, or tachycardia. Grade 3 and 4 hypersensitivity reactions have occurred rarely. Monitor for signs/symptoms of severe hypersensitivity reactions. Permanently discontinue alpelisib if severe hypersensitivity occurs.

• Pulmonary toxicity: Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, may occur; pneumonitis was reported in a small percentage of patients. Immediately interrupt alpelisib treatment and evaluate for pneumonitis in patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis. Consider a diagnosis of noninfectious pneumonitis in patients with nonspecific respiratory signs/symptoms (eg, hypoxia, cough, dyspnea, interstitial infiltrates on radiologic exams) and in whom infectious, neoplastic, and other causes have been appropriately excluded. Permanently discontinue alpelisib with confirmed pneumonitis. Pneumonitis may also require systemic corticosteroids (Nunnery 2019). Patients should immediately report new or worsening respiratory symptoms.

Special populations:

• Elderly: Patients ≥65 years of age experienced a higher incidence of grades 3 and 4 hyperglycemia.

Other warnings/precautions:

• PIK3CA mutation status: Select patients for treatment based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens; if no mutation is detected in a plasma specimen, test tumor tissue. Information on tests approved for detection of PIK3CA mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics.

Monitoring Parameters

PIK3CA mutation status; pregnancy test (prior to treatment in females of reproductive potential)

Hyperglycemia: Monitor fasting plasma glucose (FPG) and HbA1c prior to alpelisib treatment initiation; monitor fasting glucose or fasting blood glucose at least once each 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. If hyperglycemia occurs, monitor fasting glucose as clinically indicated, and at least twice weekly until blood glucose or FPG decreases to normal levels. During treatment with antidiabetic medication, continue monitoring blood glucose or FPG at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated.

Hepatitis B virus screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning systemic anticancer therapy (ASCO [Hwang 2020]).

Monitor for diarrhea; signs/symptoms of severe cutaneous adverse reactions, hyperglycemia, hypersensitivity, respiratory symptoms (new or worsening) indicative of pneumonitis. Monitor adherence.

Reproductive Considerations

Evaluate pregnancy status prior to use in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for 1 week after the last alpelisib dose. Males with female partners of reproductive potential should use condoms and effective contraception during therapy and for 1 week after the last dose of alpelisib.

Also refer to the fulvestrant monograph for additional information.

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to alpelisib may cause fetal harm.

Also refer to the fulvestrant monograph for additional information.

Patient Education

What is this drug used for?

• It is used to treat breast cancer.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hair loss

• Mouth sores

• Dry skin

• Weight loss

• Change in taste

• Headache

• Abdominal pain

• Heartburn

• Vomiting

• Nausea

• Lack of appetite

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Severe or persistent diarrhea

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.

• Infection

• Bruising

• Bleeding

• Severe loss of strength and energy

• Lung problems like shortness of breath or other trouble breathing, cough that is new or worse

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.

• Fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness, passing out, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting.

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Swelling of arms or legs

• Vaginal dryness

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.