Introduction

Antineoplastic agent; a selective inhibitor of the α isoform of phosphoinositide 3-kinase (PI3Kα).

Uses for Alpelisib

Breast Cancer

Used in combination with fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, advanced or metastatic breast cancer that has progressed during or following endocrine-based therapy in postmenopausal women and men with tumors harboring catalytic phosphatidylinositol-3-kinase subunit α (PIK3CA) mutations as detected by an FDA-approved diagnostic test (e.g., therascreen PIK3CA RGQ PCR Kit).

Guidelines generally recommend alpelisib in combination with fulvestrant in postmenopausal women and men with hormone receptor-positive, HER-2 negative, PIK3CA-mutated advanced or metastatic breast cancer previously treated with endocrine therapy (e.g., aromatase inhibitor with or without a cyclin-dependent kinase [CDK] 4/6 inhibitor).

Phosphatidylinositol-3-kinase Catalytic Subunit α (PIK3CA)-related Overgrowth Spectrum (PROS)

Treatment of PIK3CA-related overgrowth spectrum (PROS) in adults and pediatric patients ≥2 years of age (designated as an orphan drug for this use). Efficacy based on rate and duration of response; clinical benefit not established.

Traditional management of overgrowth syndromes has been conservative and limited to addressing complications as they arise; however, targeted therapies (e.g., alpelisib, sirolimus) have emerged as therapeutic options for various syndromes across the spectrum of PROS.

Alpelisib Dosage and Administration

General

Pretreatment Screening

• Breast cancer: Confirmation of at least one phosphatidylinositol-3-kinase catalytic subunit α (PIK3CA) mutation in tumor or plasma specimens by an FDA-approved diagnostic test is necessary prior to initiating therapy with alpelisib (Piqray). Reevaluate patients with a negative plasma PIK3CA mutation result for the feasibility of a tumor biopsy.

• Assess fasting plasma glucose and hemoglobin A_1c (HbA_1c); serum glucose levels should be normalized prior to initiation of the drug.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor fasting plasma glucose at least once per week for the first 2 weeks of therapy with alpelisib, then at least once every 4 weeks, and as clinically indicated. More frequent monitoring during the first few weeks may be necessary in patients with risk factors for hyperglycemia (e.g., obesity [body mass index ≥30 kg/m²], elevated fasting glucose, HbA_1c at or above the upper limit of normal, concomitant use of corticosteroids, ≥75 years of age).

• Monitor HbA_1c every 3 months and as clinically indicated.

• Monitor for signs or symptoms of hyperglycemia. Closely monitor patients with diabetes.

• If hyperglycemia following initiation of alpelisib therapy occurs, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with antihyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks, and as clinically indicated.

• Monitor for signs or symptoms of hypersensitivity reactions.

• Monitor for signs or symptoms of severe cutaneous adverse reactions (SCARs).

Premedication and Prophylaxis

• Prophylactic administration of an oral antihistamine may decrease incidence and severity of rash.

Other General Considerations

• Breast cancer: Consult manufacturer’s labeling for information on dosage adjustments, adverse effects, and contraindications of other antineoplastic agents used in combination regimens.

Administration

Oral Administration

Administer orally as tablets (Piqray, Vijoice) once daily with food at approximately the same time each day.

Swallow tablets whole; do not chew crush, or split. Do not use tablets that are cracked, broken, or otherwise not intact.

If a dose of alpelisib is missed and cannot be taken within 9 hours, do not take the missed dose; take the next dose at the regularly scheduled time.

If a dose is vomited, do not take an extra dose; take the next dose at the regularly scheduled time.

Preparation of Oral Suspension from Vijoice Tablets

In individuals who are unable to swallow the intact tablets, place appropriate dose of alpelisib (Vijoice) tablets in a glass container containing 2–4 ounces of water and allow to sit for approximately 5 minutes. Do not use any other liquid.

After allowing the tablets to sit for 5 minutes, use a spoon to crush the tablets in the water and to stir the suspension. Immediately administer resultant suspension. If immediate administration is not possible, discard suspension within 60 minutes of preparation.

Following administration of the dose, add 2–3 tablespoons of water to the glass container, stir the water with the same spoon to resuspend any remaining drug and administer the resultant suspension; repeat as necessary.

Dosage

Pediatric Patients

PIK3CA-related Overgrowth Spectrum (PROS)

Oral

Initial dosage in pediatric patients 2–18 years of age: 50 mg orally once daily.

Subsequent dosage in patients ≥6 years of age: Consider increasing dosage of alpelisib to 125 mg once daily after 24 weeks of therapy.

Increased dosage not established in patients <6 years of age.

When a patient turns 18 years of age, consider gradually increasing dosage to the recommended adult dosage of 250 mg once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

Adults

Breast Cancer

Oral

300 mg (two 150-mg tablets) once daily; use in combination with fulvestrant 500 mg by IM injection on days 1, 15, and 29 and then once monthly thereafter.

Continue therapy until disease progression or unacceptable toxicity occurs.

PIK3CA-related Overgrowth Spectrum (PROS)

Oral

250 mg orally once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.

The following tables on Dosage Modifications for Alpelisib Toxicity indicate the recommended dosage modifications in adults and pediatric patients receiving alpelisib (see Table 1 and Table 2).

Hyperglycemia

If grade 1 hyperglycemia (fasting plasma glucose exceeds ULN but ≤160 mg/dL) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy (e.g., metformin, a sodium-glucose cotransporter 2 [SGLT2] inhibitor, a thiazolidinedione, a dipeptidyl peptidase-4 [DPP-4] inhibitor).

If grade 2 hyperglycemia (fasting plasma glucose >160 mg/dL but ≤250 mg/dL) occurs in adults, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib. If grade 2 hyperglycemia persists for >21 days despite oral antihyperglycemic therapy, reduce alpelisib dosage by one dose level.

If grade 2 hyperglycemia (fasting plasma glucose >160 mg/dL but ≤250 mg/dL) occurs in pediatric patients, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy. If grade 2 hyperglycemia persists for >21 days despite oral antihyperglycemic therapy, interrupt alpelisib therapy; when hyperglycemia improves to grade 1 or less, resume alpelisib at a dosage of 50 mg once daily.

If grade 3 hyperglycemia (fasting plasma glucose >250 mg/dL but ≤500 mg/dL) occurs in adults, interrupt alpelisib therapy, initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib. Administer IV fluids and administer appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. If hyperglycemia improves to ≤160 mg/dL within 3–5 days, resume alpelisib therapy at a dosage reduced by one dose level. If hyperglycemia does not improve to ≤160 mg/dL within 3–5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia recommended. If improvement to ≤160 mg/dL does not occur within 21 days despite antihyperglycemic therapy, permanently discontinue alpelisib.

If grade 3 hyperglycemia (fasting plasma glucose >250 mg/dL but ≤500 mg/dL) occurs in pediatric patients, interrupt alpelisib therapy, initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Administer IV fluids and appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. If hyperglycemia improves to ≤160 mg/dL within 3–5 days with appropriate antihyperglycemic therapy, resume alpelisib therapy at 50 mg once daily. If grade 3 hyperglycemia does not improve to ≤160 mg/dL within 3–5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia is recommended to determine if alpelisib may be resumed or permanently discontinued. If improvement to ≤160 mg/dL does not occur within 21 days despite oral antihyperglycemic therapy, permanently discontinue alpelisib. If grade 3 or greater hyperglycemia recurs, consider permanent discontinuance of drug.

If grade 4 hyperglycemia (fasting plasma glucose >500 mg/dL) occurs in adults or pediatric patients, interrupt alpelisib therapy, initiate or intensify appropriate antihyperglycemic therapy, administer IV fluids, and consider appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. Assess fasting plasma glucose within 24 hours and as clinically indicated. If hyperglycemia improves to grade 3 or less, follow recommendations for management of grade 3 hyperglycemia. If grade 4 hyperglycemia persists, permanently discontinue alpelisib.

Dermatologic Toxicity

If grade 1 dermatologic toxicity (active skin toxicity affecting <10% of body surface area [BSA]) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Administer topical corticosteroids; consider an oral antihistamine. If an active rash does not improve within 28 days of appropriate treatment, add a low dose systemic corticosteroid.

If grade 2 dermatologic toxicity (active skin toxicity affecting 10–30% of BSA) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate or intensify topical corticosteroid and oral antihistamine therapy; consider low-dose systemic corticosteroid therapy. If rash improves to grade 1 or less within 10 days, may discontinue systemic corticosteroid therapy.

If grade 3 dermatologic toxicity (severe rash not responsive to therapy; active skin toxicity affecting >30% of BSA) occurs in adults or pediatric patients, interrupt alpelisib therapy; initiate or intensify topical/systemic corticosteroid and oral antihistamine therapy. If the etiology is not a severe cutaneous adverse reaction (SCAR) in adults, may resume alpelisib therapy at a dosage reduced by one dose level when the toxicity improves to grade 1 or less. If the etiology is not a SCAR in pediatric patients, may resume alpelisib therapy at 50 mg once daily while continuing oral antihistamine therapy when the toxicity improves to grade 1 or less or permanently discontinue alpelisib. Permanently discontinue alpelisib in pediatric patients if a rash of grade 3 or higher recurs or if the patient was already receiving an optimal dosage of an antihistamine at the time of rash onset.

If the etiology of any dermatologic reaction is confirmed to be a SCAR in adults or pediatric patients, permanently discontinue alpelisib. Do not reinitiate therapy with alpelisib in patients who have previously experienced SCAR during alpelisib therapy.

If grade 4 dermatologic toxicity (severe bullous, blistering, or exfoliating skin conditions; involvement of any percentage of BSA accompanied by extensive superinfection requiring IV anti-infective therapy; life-threatening consequences) occurs in adults or pediatric patients, permanently discontinue alpelisib.

Diarrhea

If grade 1 diarrhea occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate appropriate therapy for diarrhea and additional monitoring as clinically indicated.

If grade 2 diarrhea occurs in adults, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, resume alpelisib at the same dosage. If grade 2 diarrhea recurs, interrupt alpelisib therapy; resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less.

If grade 2 diarrhea occurs in pediatric patients, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, may resume alpelisib at the same dosage. If grade 2 diarrhea recurs, interrupt alpelisib therapy; resume alpelisib at 50 mg once daily when the toxicity improves to grade 1 or less.

If grade 3 diarrhea occurs in adults, interrupt alpelisib therapy; resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated.

If grade 3 diarrhea occurs in pediatric patients, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, may resume alpelisib at 50 mg once daily or permanently discontinue drug. If grade 3 or greater diarrhea recurs, consider permanently discontinuing drug.

If grade 4 diarrhea occurs in adults or pediatric patients, permanently discontinue alpelisib.

Pancreatitis

If grade 2 or 3 pancreatitis occurs in adults, interrupt alpelisib therapy. When toxicity improves to less than grade 2, resume alpelisib at a reduced dosage. Only one dosage reduction permitted for pancreatitis; if pancreatitis recurs, permanently discontinue alpelisib.

If grade 2 pancreatitis occurs in pediatric patients, interrupt alpelisib; may resume alpelisib at a dosage of 50 mg once daily when the toxicity improves to less than grade 2. If pancreatitis recurs or grade 3 pancreatitis occur, permanently discontinue alpelisib.

If grade 4 pancreatitis occurs in adults or pediatric patients, permanently discontinue alpelisib.

Pneumonitis

If pneumonitis is suspected in adults or pediatric patients, interrupt alpelisib therapy.

If pneumonitis of any grade is confirmed, permanently discontinue alpelisib.

Hepatic Toxicity

For grade 2 total bilirubin concentration elevations in adults, interrupt alpelisib therapy. If toxicity improves to grade 1 or less in ≤14 days, resume alpelisib at the same dosage. If toxicity improves to grade 1 or less in >14 days, resume alpelisib at a dosage reduced by one dose level.

For grade 2 total bilirubin concentration elevations in pediatric patients, interrupt alpelisib therapy. If toxicity improves to grade 1 or less in ≤14 days, resume alpelisib at the same dosage. If toxicity improves to grade 1 or less in >14 days, resume alpelisib at 50 mg once daily.

Other Toxicity

If other grade 1 or 2 adverse reactions occur in adults or pediatric patients, continue alpelisib at the same dosage. Initiate appropriate therapy and additional monitoring as clinically indicated.

If other grade 3 adverse reactions occur in adults, interrupt alpelisib therapy; may resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less. Initiate appropriate therapy and additional monitoring as clinically indicated.

If other grade 3 adverse reactions occur in pediatric patients, interrupt alpelisib therapy; when the toxicity improves to grade 1 or less, may resume alpelisib at 50 mg once daily or permanently discontinue drug. Initiate appropriate therapy and additional monitoring as clinically indicated. If the adverse reaction recurs at grade 3 or greater severity, consider permanent discontinuance of the drug and consultation with a clinician with expertise in a field related to the adverse reaction.

If other grade 4 adverse reactions occur in adults or pediatric patients, permanently discontinue alpelisib.

Prescribing Limits

Pediatric Patients

PROS

Oral

Dosages <50 mg once daily not recommended.

Adults

Breast Cancer

Oral

Dosages <200 mg once daily not recommended.

PROS

Oral

Dosages <50 mg once daily not recommended.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): Insufficient data to provide dosage recommendations.

Geriatric Patients

No specific dosage recommendations at this time.

Contraindications

• History of serious hypersensitivity reactions (e.g., anaphylaxis) to alpelisib or any ingredient in the formulation.

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity reactions (e.g., anaphylaxis, anaphylactic shock) reported. Manifestations may include dyspnea, flushing, rash, fever, and tachycardia.

If severe hypersensitivity reaction occurs, permanently discontinue alpelisib and institute supportive treatment.

Dermatologic Effects

Rash (i.e., generalized, macular, maculopapular, papular, or pruritic) and severe cutaneous adverse reactions (SCARs) (e.g., erythema multiforme, Stevens-Johnson syndrome) reported. Rash reported in 52% of patients receiving alpelisib; grade 3 rash reported in 20% of patients. Drug reaction with eosinophilia and systemic symptoms reported in postmarketing surveillance.

Prophylactic administration of an oral antihistamine may decrease incidence and severity of rash.

If rash (any grade) occurs, consider consultation with a dermatologist. If signs and symptoms of severe dermatologic reactions (e.g., progressive rash, mucosal lesions, fever, lymphadenopathy, flu-like symptoms) occur, interrupt alpelisib therapy, evaluate etiology, and consult with a dermatologist. Permanently discontinue alpelisib if SCARs are confirmed; do not reinitiate in patients who previously experienced SCARs during treatment with alpelisib. If SCARs are not confirmed, dosage modification, corticosteroid and/or oral antihistamine therapy, or treatment discontinuance may be necessary.

Hyperglycemia

Severe hyperglycemia (including ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome), sometimes fatal, reported.

Hyperglycemia reported in 65% of patients receiving alpelisib for breast cancer; grade 3 or 4 hyperglycemia reported in 33 or 3.9% of patients, respectively. Antihyperglycemic agents, usually metformin alone or in combination with other antihyperglycemic agents, administered to 87% of patients with hyperglycemia. Hyperglycemia reported in 12% of patients receiving alpelisib for phosphatidylinositol-3-kinase catalytic subunit α-related overgrowth spectrum (PROS).

Assess fasting plasma glucose concentrations and glycosylated hemoglobin (hemoglobin A_1c; HbA_1c) and optimize blood glucose concentrations prior to initiation of therapy. Monitor fasting plasma glucose concentrations at least once weekly for the first 2 weeks of therapy, at least once monthly thereafter, and as clinically indicated. More frequent monitoring may be necessary in patients with risk factors for hyperglycemia. Monitor HbA_1c once every 3 months and as clinically indicated.

If hyperglycemia occurs, assess fasting plasma glucose concentrations as clinically indicated and at least twice weekly until hyperglycemia resolves. Initiate or optimize antihyperglycemic agents as necessary; monitor fasting plasma glucose concentrations and/or blood glucose concentrations at least once weekly for 8 weeks after initiating antihyperglycemic therapy and then at least once every 2 weeks and as clinically indicated. Consider consultation with a clinician with expertise in the management of hyperglycemia. Temporary interruption of therapy, dosage reduction, or treatment discontinuance may be necessary.

Monitor patients with a history of type 2 diabetes mellitus closely; intensified antihyperglycemic therapy may be required. Safety not established in patients with type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus.

Pneumonitis

Severe adverse pulmonary reactions consistent with acute interstitial pneumonitis and interstitial lung disease (ILD) reported.

If new or progressive respiratory manifestations (e.g., cough, dyspnea, hypoxia, interstitial infiltrates) occur, interrupt alpelisib therapy and evaluate patient for pneumonitis or other causes of respiratory symptoms.

If pneumonitis is confirmed, permanently discontinue alpelisib.

Diarrhea

Diarrhea, sometimes severe and resulting in dehydration or acute kidney injury, reported.

If diarrhea occurs, initiate appropriate therapy (e.g., antidiarrhea agents, fluid replacement). Temporary interruption, dosage reduction, or treatment discontinuance of alpelisib may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Teratogenicity, embryofetal mortality, and reduced fetal weight demonstrated in animals.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of alpelisib in females of reproductive potential. Females of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥1 week after discontinuance of therapy. Males who are partners of such females should use condoms and effective contraception during treatment and for ≥1 week after discontinuance of therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether alpelisib distributes into milk or affects breast-fed infants or milk production. Discontinue breast-feeding during therapy and for ≥1 week after the last dose.

Females and Males of Reproductive Potential

Females of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥1 week after discontinuance of therapy.

Males who are partners of such females should use condoms and effective contraception during treatment and for ≥1 week after discontinuance of therapy.

Results of animal studies suggest that alpelisib may impair male and female fertility.

Pediatric Use

Safety and efficacy not established in breast cancer.

Safety and efficacy not established in pediatric patients <2 years of age with PROS.

Geriatric Use

Geriatric patients ≥65 years of age with breast cancer: No overall differences in efficacy relative to younger adults; however, increased incidence of grade 3 or 4 hyperglycemia in geriatric patients.

Geriatric patients ≥75 years of age with breast cancer: Insufficient experience to determine whether efficacy and safety are similar to those in younger adults; however, incidence of hyperglycemia, including grade 3–4 hyperglycemia, increased in patients ≥75 years of age.

No adults ≥65 years of age were enrolled in the EPIK-P1 study evaluating alpelisib in patients with PROS.

Hepatic Impairment

Pharmacokinetics of alpelisib not altered in patients with hepatic impairment (Child-Pugh class A, B, or C).

Renal Impairment

Pharmacokinetics of alpelisib not altered in patients with mild to moderate renal impairment (Cl_cr 30–89 mL/minute). Effect of severe renal impairment (Cl_cr <30 mL/minute) on pharmacokinetics not established.

Common Adverse Effects

Adverse effects reported in ≥20% of patients with breast cancer: Increased serum glucose, increased serum creatinine, diarrhea, rash, decreased lymphocyte count, increased gamma glutamyl transferase, nausea, increased alanine aminotransferase, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, decreased weight, decreased calcium, decreased glucose, prolonged activated partial thromboplastin time, alopecia.

Adverse effects reported in ≥10% of patients with PROS: Diarrhea, stomatitis, hyperglycemia.

General

Pretreatment Screening

• Breast cancer: Confirmation of at least one phosphatidylinositol-3-kinase catalytic subunit α (PIK3CA) mutation in tumor or plasma specimens by an FDA-approved diagnostic test is necessary prior to initiating therapy with alpelisib (Piqray). Reevaluate patients with a negative plasma PIK3CA mutation result for the feasibility of a tumor biopsy.

• Assess fasting plasma glucose and hemoglobin A_1c (HbA_1c); serum glucose levels should be normalized prior to initiation of the drug.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor fasting plasma glucose at least once per week for the first 2 weeks of therapy with alpelisib, then at least once every 4 weeks, and as clinically indicated. More frequent monitoring during the first few weeks may be necessary in patients with risk factors for hyperglycemia (e.g., obesity [body mass index ≥30 kg/m²], elevated fasting glucose, HbA_1c at or above the upper limit of normal, concomitant use of corticosteroids, ≥75 years of age).

• Monitor HbA_1c every 3 months and as clinically indicated.

• Monitor for signs or symptoms of hyperglycemia. Closely monitor patients with diabetes.

• If hyperglycemia following initiation of alpelisib therapy occurs, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with antihyperglycemic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks, and as clinically indicated.

• Monitor for signs or symptoms of hypersensitivity reactions.

• Monitor for signs or symptoms of severe cutaneous adverse reactions (SCARs).

Premedication and Prophylaxis

• Prophylactic administration of an oral antihistamine may decrease incidence and severity of rash.

Other General Considerations

• Breast cancer: Consult manufacturer’s labeling for information on dosage adjustments, adverse effects, and contraindications of other antineoplastic agents used in combination regimens.

Administration

Oral Administration

Administer orally as tablets (Piqray, Vijoice) once daily with food at approximately the same time each day.

Swallow tablets whole; do not chew crush, or split. Do not use tablets that are cracked, broken, or otherwise not intact.

If a dose of alpelisib is missed and cannot be taken within 9 hours, do not take the missed dose; take the next dose at the regularly scheduled time.

If a dose is vomited, do not take an extra dose; take the next dose at the regularly scheduled time.

Preparation of Oral Suspension from Vijoice Tablets

In individuals who are unable to swallow the intact tablets, place appropriate dose of alpelisib (Vijoice) tablets in a glass container containing 2–4 ounces of water and allow to sit for approximately 5 minutes. Do not use any other liquid.

After allowing the tablets to sit for 5 minutes, use a spoon to crush the tablets in the water and to stir the suspension. Immediately administer resultant suspension. If immediate administration is not possible, discard suspension within 60 minutes of preparation.

Following administration of the dose, add 2–3 tablespoons of water to the glass container, stir the water with the same spoon to resuspend any remaining drug and administer the resultant suspension; repeat as necessary.

Dosage

Pediatric Patients

PIK3CA-related Overgrowth Spectrum (PROS)

Oral

Initial dosage in pediatric patients 2–18 years of age: 50 mg orally once daily.

Subsequent dosage in patients ≥6 years of age: Consider increasing dosage of alpelisib to 125 mg once daily after 24 weeks of therapy.

Increased dosage not established in patients <6 years of age.

When a patient turns 18 years of age, consider gradually increasing dosage to the recommended adult dosage of 250 mg once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

Adults

Breast Cancer

Oral

300 mg (two 150-mg tablets) once daily; use in combination with fulvestrant 500 mg by IM injection on days 1, 15, and 29 and then once monthly thereafter.

Continue therapy until disease progression or unacceptable toxicity occurs.

PIK3CA-related Overgrowth Spectrum (PROS)

Oral

250 mg orally once daily.

Continue treatment until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Adverse effects may require temporary interruption, dosage reduction, and/or permanent discontinuance.

The following tables on Dosage Modifications for Alpelisib Toxicity indicate the recommended dosage modifications in adults and pediatric patients receiving alpelisib (see Table 1 and Table 2).

Hyperglycemia

If grade 1 hyperglycemia (fasting plasma glucose exceeds ULN but ≤160 mg/dL) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy (e.g., metformin, a sodium-glucose cotransporter 2 [SGLT2] inhibitor, a thiazolidinedione, a dipeptidyl peptidase-4 [DPP-4] inhibitor).

If grade 2 hyperglycemia (fasting plasma glucose >160 mg/dL but ≤250 mg/dL) occurs in adults, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib. If grade 2 hyperglycemia persists for >21 days despite oral antihyperglycemic therapy, reduce alpelisib dosage by one dose level.

If grade 2 hyperglycemia (fasting plasma glucose >160 mg/dL but ≤250 mg/dL) occurs in pediatric patients, continue alpelisib at the same dosage. Initiate or intensify oral antihyperglycemic therapy. If grade 2 hyperglycemia persists for >21 days despite oral antihyperglycemic therapy, interrupt alpelisib therapy; when hyperglycemia improves to grade 1 or less, resume alpelisib at a dosage of 50 mg once daily.

If grade 3 hyperglycemia (fasting plasma glucose >250 mg/dL but ≤500 mg/dL) occurs in adults, interrupt alpelisib therapy, initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Most patients experiencing alpelisib-induced hyperglycemia may not require insulin therapy because of the short half-life of alpelisib. Administer IV fluids and administer appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. If hyperglycemia improves to ≤160 mg/dL within 3–5 days, resume alpelisib therapy at a dosage reduced by one dose level. If hyperglycemia does not improve to ≤160 mg/dL within 3–5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia recommended. If improvement to ≤160 mg/dL does not occur within 21 days despite antihyperglycemic therapy, permanently discontinue alpelisib.

If grade 3 hyperglycemia (fasting plasma glucose >250 mg/dL but ≤500 mg/dL) occurs in pediatric patients, interrupt alpelisib therapy, initiate or intensify oral antihyperglycemic therapy, and consider additional antihyperglycemic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Administer IV fluids and appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. If hyperglycemia improves to ≤160 mg/dL within 3–5 days with appropriate antihyperglycemic therapy, resume alpelisib therapy at 50 mg once daily. If grade 3 hyperglycemia does not improve to ≤160 mg/dL within 3–5 days despite antihyperglycemic therapy, consultation with a clinician with expertise in the management of hyperglycemia is recommended to determine if alpelisib may be resumed or permanently discontinued. If improvement to ≤160 mg/dL does not occur within 21 days despite oral antihyperglycemic therapy, permanently discontinue alpelisib. If grade 3 or greater hyperglycemia recurs, consider permanent discontinuance of drug.

If grade 4 hyperglycemia (fasting plasma glucose >500 mg/dL) occurs in adults or pediatric patients, interrupt alpelisib therapy, initiate or intensify appropriate antihyperglycemic therapy, administer IV fluids, and consider appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. Assess fasting plasma glucose within 24 hours and as clinically indicated. If hyperglycemia improves to grade 3 or less, follow recommendations for management of grade 3 hyperglycemia. If grade 4 hyperglycemia persists, permanently discontinue alpelisib.

Dermatologic Toxicity

If grade 1 dermatologic toxicity (active skin toxicity affecting <10% of body surface area [BSA]) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Administer topical corticosteroids; consider an oral antihistamine. If an active rash does not improve within 28 days of appropriate treatment, add a low dose systemic corticosteroid.

If grade 2 dermatologic toxicity (active skin toxicity affecting 10–30% of BSA) occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate or intensify topical corticosteroid and oral antihistamine therapy; consider low-dose systemic corticosteroid therapy. If rash improves to grade 1 or less within 10 days, may discontinue systemic corticosteroid therapy.

If grade 3 dermatologic toxicity (severe rash not responsive to therapy; active skin toxicity affecting >30% of BSA) occurs in adults or pediatric patients, interrupt alpelisib therapy; initiate or intensify topical/systemic corticosteroid and oral antihistamine therapy. If the etiology is not a severe cutaneous adverse reaction (SCAR) in adults, may resume alpelisib therapy at a dosage reduced by one dose level when the toxicity improves to grade 1 or less. If the etiology is not a SCAR in pediatric patients, may resume alpelisib therapy at 50 mg once daily while continuing oral antihistamine therapy when the toxicity improves to grade 1 or less or permanently discontinue alpelisib. Permanently discontinue alpelisib in pediatric patients if a rash of grade 3 or higher recurs or if the patient was already receiving an optimal dosage of an antihistamine at the time of rash onset.

If the etiology of any dermatologic reaction is confirmed to be a SCAR in adults or pediatric patients, permanently discontinue alpelisib. Do not reinitiate therapy with alpelisib in patients who have previously experienced SCAR during alpelisib therapy.

If grade 4 dermatologic toxicity (severe bullous, blistering, or exfoliating skin conditions; involvement of any percentage of BSA accompanied by extensive superinfection requiring IV anti-infective therapy; life-threatening consequences) occurs in adults or pediatric patients, permanently discontinue alpelisib.

Diarrhea

If grade 1 diarrhea occurs in adults or pediatric patients, continue alpelisib at the same dosage. Initiate appropriate therapy for diarrhea and additional monitoring as clinically indicated.

If grade 2 diarrhea occurs in adults, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, resume alpelisib at the same dosage. If grade 2 diarrhea recurs, interrupt alpelisib therapy; resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less.

If grade 2 diarrhea occurs in pediatric patients, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, may resume alpelisib at the same dosage. If grade 2 diarrhea recurs, interrupt alpelisib therapy; resume alpelisib at 50 mg once daily when the toxicity improves to grade 1 or less.

If grade 3 diarrhea occurs in adults, interrupt alpelisib therapy; resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated.

If grade 3 diarrhea occurs in pediatric patients, interrupt alpelisib therapy. Initiate or intensify appropriate therapy for diarrhea and additional monitoring as clinically indicated. When the toxicity improves to grade 1 or less, may resume alpelisib at 50 mg once daily or permanently discontinue drug. If grade 3 or greater diarrhea recurs, consider permanently discontinuing drug.

If grade 4 diarrhea occurs in adults or pediatric patients, permanently discontinue alpelisib.

Pancreatitis

If grade 2 or 3 pancreatitis occurs in adults, interrupt alpelisib therapy. When toxicity improves to less than grade 2, resume alpelisib at a reduced dosage. Only one dosage reduction permitted for pancreatitis; if pancreatitis recurs, permanently discontinue alpelisib.

If grade 2 pancreatitis occurs in pediatric patients, interrupt alpelisib; may resume alpelisib at a dosage of 50 mg once daily when the toxicity improves to less than grade 2. If pancreatitis recurs or grade 3 pancreatitis occur, permanently discontinue alpelisib.

If grade 4 pancreatitis occurs in adults or pediatric patients, permanently discontinue alpelisib.

Pneumonitis

If pneumonitis is suspected in adults or pediatric patients, interrupt alpelisib therapy.

If pneumonitis of any grade is confirmed, permanently discontinue alpelisib.

Hepatic Toxicity

For grade 2 total bilirubin concentration elevations in adults, interrupt alpelisib therapy. If toxicity improves to grade 1 or less in ≤14 days, resume alpelisib at the same dosage. If toxicity improves to grade 1 or less in >14 days, resume alpelisib at a dosage reduced by one dose level.

For grade 2 total bilirubin concentration elevations in pediatric patients, interrupt alpelisib therapy. If toxicity improves to grade 1 or less in ≤14 days, resume alpelisib at the same dosage. If toxicity improves to grade 1 or less in >14 days, resume alpelisib at 50 mg once daily.

Other Toxicity

If other grade 1 or 2 adverse reactions occur in adults or pediatric patients, continue alpelisib at the same dosage. Initiate appropriate therapy and additional monitoring as clinically indicated.

If other grade 3 adverse reactions occur in adults, interrupt alpelisib therapy; may resume alpelisib at a dosage reduced by one level when the toxicity improves to grade 1 or less. Initiate appropriate therapy and additional monitoring as clinically indicated.

If other grade 3 adverse reactions occur in pediatric patients, interrupt alpelisib therapy; when the toxicity improves to grade 1 or less, may resume alpelisib at 50 mg once daily or permanently discontinue drug. Initiate appropriate therapy and additional monitoring as clinically indicated. If the adverse reaction recurs at grade 3 or greater severity, consider permanent discontinuance of the drug and consultation with a clinician with expertise in a field related to the adverse reaction.

If other grade 4 adverse reactions occur in adults or pediatric patients, permanently discontinue alpelisib.

Prescribing Limits

Pediatric Patients

PROS

Oral

Dosages <50 mg once daily not recommended.

Adults

Breast Cancer

Oral

Dosages <200 mg once daily not recommended.

PROS

Oral

Dosages <50 mg once daily not recommended.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute): No dosage adjustment required.

Severe renal impairment (Cl_cr <30 mL/minute): Insufficient data to provide dosage recommendations.

Geriatric Patients

No specific dosage recommendations at this time.

Metabolized principally by chemical and enzymatic hydrolysis and to a lesser extent by CYP3A4.

In vitro, inhibits CYP3A4. Induces CYP isoenzymes 2B6, 2C9, and 3A4.

In vitro, inhibits P-glycoprotein (P-gp); low potential to inhibit breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), bile salt export pump (BSEP), organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) transporter 1, and MATE2-K.

In vitro, substrate of BCRP.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inducers: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, alpelisib. Avoid concomitant use.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2C9 substrates: Possible decreased systemic exposure to, and decreased efficacy of, the substrate drug. If alpelisib used concomitantly with a CYP2C9 substrate for which activity is sensitive to decreases in plasma concentration, monitor for reduced efficacy of the substrate drug.

Drugs Affecting Breast Cancer Resistance Protein

BCRP inhibitors: Possible increased systemic exposure to alpelisib and increased risk of alpelisib toxicity. Avoid concomitant use. If concomitant use cannot be avoided, monitor for adverse effects.

Drugs Affecting Gastric Acidity

Drugs that increase pH of upper GI tract: Possible decreased solubility of alpelisib, resulting in decreased plasma alpelisib concentrations. May be administered concomitantly since alpelisib is administered with food and food has a more pronounced effect on alpelisib solubility than does gastric pH.

Specific Drugs