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, 56 ea)
Piqray (300 MG Daily Dose): 2 x 150 MG (28 ea)
Pharmacology
Mechanism of Action
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).
Pharmacokinetics/Pharmacodynamics
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 hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (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
Dosage and Administration
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 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.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Recommended alpelisib dosage reduction levels:
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.
Refer to fulvestrant monograph for information on fulvestrant toxicities.
Dermatologic toxicity: Rash: Consider dermatology consultation for all grades. Antihistamine administration prior to rash onset may decrease the rash incidence/severity.
Grade 1 (<10% body surface area [BSA] with active skin toxicity): No alpelisib dosage adjustment required. Initiate topical corticosteroid therapy; consider adding an oral antihistamine to manage symptoms.
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.
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. 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.
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 [FPG]/blood glucose values:
Grade 1 (FPG > ULN to 160 mg/dL): No alpelisib dosage adjustment required; initiate or intensify antidiabetic therapy as described below.
Grade 2 (FPG >160 to 250 mg/dL): No alpelisib dosage adjustment required; initiate or intensify antidiabetic therapy as described below. If FPG 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 FPG specific recommendations.
Grade 3 (FPG >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 FPG 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 FPG 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 FPG does not decrease to ≤160 mg/dL within 21 days following appropriate antidiabetic therapy.
Grade 4 (FPG >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. Re-check FPG within 24 hours (and as clinically indicated). If FPG decreases to ≤500 mg/dL, follow FPG value specific recommendations for grade 3 hyperglycemia. Permanently discontinue alpelisib if FPG 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).
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).
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 reactions, including Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) have been reported in a small percentage of patients. Do not initiate alpelisib in patients with a history of SJS, EM, or toxic epidermal necrolysis (TEN). If signs or symptoms of severe cutaneous reactions occur, interrupt alpelisib until the etiology of the reaction has been determined; a dermatology consultation is recommended. If SJS, TEN, or EM is confirmed, permanently discontinue alpelisib. Do not reinitiate alpelisib in patients who have experienced previous severe cutaneous reactions during alpelisib treatment. If SJS, TEN, or EM is not confirmed, alpelisib may require dose modifications, topical corticosteroids, and/or oral antihistamine treatment. Patients should be informed of the signs/symptoms of severe cutaneous reactions (eg, prodrome of fever, flu-like symptoms, mucosal lesions and/or progressive skin rash).
- Gastrointestinal 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. 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.
- Hyperglycemia: Severe hyperglycemia, including ketoacidosis, has been reported 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 blood glucose and/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 blood glucose and/or FPG 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. 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. 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) have been reported with alpelisib. 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, has been reported with alpelisib; 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. Patients should immediately report new or worsening respiratory symptoms.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
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 blood glucose and/or FBG 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 blood glucose and/or FPG 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.
Monitor for diarrhea; signs/symptoms of cutaneous reactions, hyperglycemia, hypersensitivity, respiratory symptoms (new or worsening) indicative of pneumonitis. Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to alpelisib may cause fetal harm.
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.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience hair loss, mouth sores, dry skin, weight loss, change in taste, headache, abdominal pain, heartburn, vomiting, nausea, or lack of appetite. Have patient report immediately to prescriber severe or persistent diarrhea, signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit), signs of infection, bruising, bleeding, severe loss of strength and energy, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), signs of a urinary tract infection (blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain), signs of fluid and electrolyte problems (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), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), swelling of arms or legs, vaginal dryness, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
