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.
Note: Kidney function may be estimated with the Cockcroft-Gault formula.
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (effect on alpelisib pharmacokinetics is unknown).
Hepatic impairment at baseline: Child-Pugh classes A, B, or C: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant differences in pharmacokinetics are expected.
Hepatotoxicity during treatment: Grade 2 total bilirubin elevation: Interrupt alpelisib treatment until improvement to ≤ grade 1, then resume at the same dose level if resolved in ≤14 days or resume at the next lower dose level if improved in >14 days. For dosage adjustment levels and other toxicity grades, follow dosage adjustment for “other toxicities” (see Dosing – Adjustment for Toxicity).
Refer to adult dosing.
|
a Only one dose reduction is permitted for pancreatitis. | |
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b Refer to Fulvestrant monograph for information on fulvestrant toxicities. | |
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Initial (usual) dose |
300 mg once daily |
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First dose reduction level |
250 mg once daily |
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Second dose reduction level |
200 mg once daily |
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If further dose reductions are required, discontinue alpelisib. | |
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a SCARs = severe cutaneous adverse reactions. | |
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Dermatologic toxicity: Rash and SCARsa | |
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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. If active rash is not improved within 28 days of appropriate therapy, add a low-dose systemic corticosteroid. Permanently discontinue alpelisib if a SCAR is confirmed. |
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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. If rash improves to ≤ grade 1 within 10 days, systemic corticosteroid may be discontinued. Permanently discontinue alpelisib if a SCAR is confirmed. |
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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, interrupt alpelisib therapy. Once improved to ≤ grade 1, resume alpelisib at the next lower dosage level. Permanently discontinue alpelisib if a SCAR is confirmed. |
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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. |
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Consider dermatology consultation for all grades. Antihistamine administration prior to rash onset may decrease the rash incidence/severity. Do not reinitiate alpelisib if previous SCAR occurred during therapy. | |
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GI toxicity: Diarrhea | |
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Grade 1 |
No alpelisib dosage adjustment required; initiate appropriate medical therapy and monitor as clinically indicated. |
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Grade 2 |
Interrupt alpelisib treatment until improvement to ≤ grade 1, then resume at the same dose level. If ≥ grade 2 diarrhea recurs, interrupt alpelisib treatment until improvement to ≤ grade 1, then resume at the next lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. |
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Grade 3 |
Interrupt alpelisib treatment until improvement to ≤ grade 1, then resume at the next lower dose level. Initiate or intensify appropriate medical therapy and monitor as clinically indicated. |
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Grade 4 |
Permanently discontinue alpelisib. |
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Consider stopping lactose-containing foods, alcohol, laxatives, bulk fiber, stool softeners, and high-osmolar food supplements; encourage hydration and frequent small meals (Nunnery 2019). | |
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Hyperglycemia: Based on fasting plasma glucose/fasting blood glucose values. | |
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Grade 1 (fasting glucose >ULN to 160 mg/dL) |
No alpelisib dosage adjustment required; initiate or intensify antihyperglycemic therapy as described below. |
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Grade 2 (fasting glucose >160 to 250 mg/dL) |
No alpelisib dosage adjustment required; initiate or intensify antihyperglycemic therapy as described below. If fasting glucose does not decrease to ≤160 mg/dL within 21 days with appropriate antihyperglycemic therapy, reduce alpelisib dose by 1 dose level and continue to follow fasting glucose specific recommendations. |
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Grade 3 (fasting glucose >250 to 500 mg/dL) |
Interrupt alpelisib therapy; initiate or intensify antihyperglycemic therapy as described below and consider additional antihyperglycemic 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 antihyperglycemic 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 antihyperglycemic 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 antihyperglycemic therapy. |
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Grade 4 (fasting glucose >500 mg/dL) |
Interrupt alpelisib therapy; initiate or intensify antihyperglycemic 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. |
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Antihyperglycemic therapy recommendations |
Initiate or intensify antihyperglycemic therapy, including metformin, SGLT2 inhibitors, or 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). |
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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. |
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Consider consultation with a clinician with expertise in hyperglycemia management and lifestyle modifications. | |
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Hypersensitivity | |
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Severe |
Permanently discontinue alpelisib. |
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Pancreatitis | |
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Grades 2 and 3 |
Interrupt alpelisib treatment until improvement 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. |
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Pneumonitis | |
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New or worsening respiratory symptoms or suspected pneumonitis |
Immediately interrupt alpelisib treatment and evaluate for pneumonitis. |
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Confirmed |
Permanently discontinue alpelisib. Pneumonitis may also require systemic corticosteroids (Nunnery 2019). |
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Other toxicities | |
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Grade 1 or 2 |
No alpelisib dosage adjustment required; initiate appropriate medical therapy and monitor as clinically indicated. |
|
Grade 3 |
Interrupt alpelisib treatment until improvement to ≤ grade 1, then resume at the next lower dose level. |
|
Grade 4 |
Permanently discontinue alpelisib. |
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)
No
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 (56 ea)
Piqray (300 MG Daily Dose): 2 x 150 MG (56 ea)
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.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Alpelisib may cause teratogenicity and reproductive toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
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.
Alpelisib may be confused with abemaciclib, acalabrutinib, afatinib, Alecensa, alectinib, avapritinib, axitinib, copanlisib, duvelisib, idelalisib.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported with concomitant fulvestrant.
>10%:
Cardiovascular: Peripheral edema (15%)
Dermatologic: Alopecia (20%), pruritus (18%), skin rash (52%), xeroderma (18%)
Endocrine & metabolic: Decreased serum albumin (14%), decreased serum calcium (27%), decreased serum glucose (26%), decreased serum magnesium (11%), decreased serum potassium (14%), hyperglycemia (65%; including severe hyperglycemia), increased gamma-glutamyl transferase (52%), weight loss (27%)
Gastrointestinal: Abdominal pain (17%), decreased appetite (36%), diarrhea (58%), dry mucous membranes (12%), dysgeusia (18%), dyspepsia (11%), increased serum lipase (42%), nausea (45%), stomatitis (19% to 30%; grades 3/4: 2% to 3%), vomiting (27%)
Hematologic & oncologic: Decreased platelet count (14%; grades 3/4: 1%), lymphocytopenia (52%; grades 3/4: 8%), prolonged partial thromboplastin time (21%; grades 3/4: <1%)
Hepatic: Increased serum alanine aminotransferase (44%)
Nervous system: Fatigue (42%), headache (18%)
Renal: Increased serum creatinine (67%)
Miscellaneous: Fever (14%)
1% to 10%:
Dermatologic: Erythema multiforme (1%)
Gastrointestinal: Severe diarrhea (3%)
Genitourinary: Urinary tract infection (10%; including urinary tract infection with sepsis)
Hematologic & oncologic: Anemia (2%)
Neuromuscular & skeletal: Osteonecrosis of the jaw (4%)
Renal: Acute kidney injury (3%)
Respiratory: Pneumonitis (2%)
<1%:
Dermatologic: Stevens-Johnson syndrome
Endocrine & metabolic: Ketoacidosis
Hypersensitivity: Severe hypersensitivity reaction (grades 3/4)
Postmarketing:
Endocrine & metabolic: Hyperglycemic hyperosmolar syndrome
Immunologic: Drug reaction with eosinophilia and systemic symptoms
Severe hypersensitivity to alpelisib or any component of the formulation
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. Inform patients 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 (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. Instruct patients to initiate antidiarrheal treatment, increase oral fluids, and notify their health care provider if diarrhea occurs during alpelisib treatment.
• Hyperglycemia: Severe hyperglycemia, occasionally associated with hyperglycemic hyperosmolar nonketotic syndrome (HHNKS) or 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 (including fatal ketoacidosis cases) 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 antihyperglycemic medication, with a majority utilizing metformin (either as single agent or in combination with other antihyperglycemic 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. 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 controlled type 2 diabetes were included in the clinical trial. 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.
• Pulmonary toxicity: Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, may occur; pneumonitis was reported in a small percentage of patients. 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.
Substrate of BCRP/ABCG2, CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: 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. Risk D: Consider therapy modification
CYP2C9 Substrates (High risk with Inducers): Alpelisib may decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Alpelisib. Risk X: Avoid combination
Gilteritinib: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Lasmiditan: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Voxilaprevir: May increase the serum concentration of BCRP/ABCG2 Substrates BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Following a single alpelisib dose, a high-fat and high-calorie meal (985 calories with 58.1 g of fat) increased the alpelisib AUC and Cmax by 73% and 84%, respectively; a low-fat and low-calorie meal (334 calories with 8.7 g of fat) increased the alpelisib AUC and Cmax by 77% and 145%, respectively.
Evaluate pregnancy status prior to use in patients who may become pregnant. Patients who may become pregnant should use effective contraception during therapy and for 1 week after the last alpelisib dose. Patients with partners who may become pregnant 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.
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.
It is not known if alpelisib is present in breast milk.
Due to the potential for adverse events in a breastfed infant, breastfeeding is not recommended during therapy and for 1 week after the last alpelisib dose.
Also refer to the Fulvestrant monograph for additional information.
PIK3CA mutation status. Evaluate pregnancy status (prior to treatment in patients who may become pregnant).
Hyperglycemia: Monitor fasting plasma glucose (FPG) and HbA1c prior to alpelisib treatment initiation; monitor fasting plasma 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. Monitor fasting glucose more closely in patients with risk factors for hyperglycemia. 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 antihyperglycemic 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.
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, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen 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.
Monitor for diarrhea; signs/symptoms of severe cutaneous adverse reactions, hyperglycemia, hypersensitivity, respiratory symptoms (new or worsening) indicative of pneumonitis. Monitor adherence.
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
Protein binding: 89%
Metabolism: Primarily by chemical and enzymatic hydrolysis to form its metabolite BZG791, and to a lesser extent by CYP3A4
Half-life elimination: 8 to 9 hours
Time to peak: 2 to 4 hours
Excretion: Feces: 81% (36% as unchanged drug, 32% as BZG791); Urine: 14% (2% as unchanged drug, 7% as BZG791)
Clearance: 9.2 L/hour
Tablet Therapy Pack (Piqray (200 MG Daily Dose) Oral)
200 mg (per each): $802.37
Tablet Therapy Pack (Piqray (250 MG Daily Dose) Oral)
200 & 50 mg (per each): $401.19
Tablet Therapy Pack (Piqray (300 MG Daily Dose) Oral)
2 x 150 mg (per each): $401.19
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