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Alpelisib

Class: Antineoplastic Agents
Chemical Name: (2S)-N1-{4-Methyl-5-[1-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl]-1,3-thiazol-2-yl}pyrrolidine-1,2-dicarboxamide
Molecular Formula: C19H22F3N5O2S
CAS Number: 1217486-61-7
Brands: Piqray

Medically reviewed by Drugs.com on Aug 10, 2020. Written by ASHP.

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). Information on FDA-approved companion diagnostic tests for the detection of PIK3CA mutations in breast cancer is available at [Web].

Alpelisib Dosage and Administration

General

  • Confirm presence of PIK3CA mutation in tumor or plasma specimens by an FDA-approved diagnostic test prior to initiating alpelisib therapy. Patients with a negative plasma PIK3CA mutation result should be reevaluated for feasibility of tumor biopsy. (See Uses: 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 once daily with food. Take 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.

Dosage

Adults

Breast Cancer
Oral

300 mg (two 150-mg tablets) twice 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.

Dosage Modification for Toxicity
Oral

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

If dosage reduction from 300 mg once daily is necessary, reduce dosage to 250 mg (one 200-mg and one 50-mg tablet) once daily.

If dosage reduction from 250 mg once daily is necessary, reduce dosage to 200 mg (one 200-mg tablet) once daily.

If further dosage reduction is necessary, discontinue alpelisib.

Hyperglycemia
Oral

If grade 1 hyperglycemia (fasting plasma glucose exceeds ULN but ≤160 mg/dL) occurs, continue alpelisib at the same dosage. Initiate or intensify oral antidiabetic therapy (e.g., metformin, a thiazolidinedione, a dipeptidyl peptidase-4 [DPP-4] inhibitor). (See Hyperglycemia under Cautions.)

If grade 2 hyperglycemia (fasting plasma glucose >160 mg/dL but ≤250 mg/dL) occurs, continue alpelisib at the same dosage. Initiate or intensify oral antidiabetic therapy. If grade 2 hyperglycemia persists for >21 days despite oral antidiabetic therapy, reduce alpelisib dosage.

If grade 3 hyperglycemia (fasting plasma glucose >250 mg/dL but ≤500 mg/dL) occurs, interrupt alpelisib therapy, initiate or intensify oral antidiabetic therapy, and consider additional antidiabetic therapy (i.e., insulin) for 1–2 days until hyperglycemia improves. Administer IV fluids and administer appropriate treatment for electrolyte disorders, ketoacidosis, and/or hyperosmolar disturbances, if required. If hyperglycemia improves to grade 1 or less within 3–5 days, resume alpelisib at reduced dosage. If hyperglycemia does not improve to grade 1 or less within 3–5 days despite antidiabetic therapy, consultation with a clinician with expertise in the management of hyperglycemia recommended. If improvement to grade 1 or less does not occur within 21 days despite antidiabetic therapy, permanently discontinue alpelisib.

If grade 4 hyperglycemia (fasting plasma glucose >500 mg/dL) occurs, interrupt alpelisib therapy, initiate or intensify appropriate antidiabetic 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
Oral

If grade 1 dermatologic toxicity (active skin toxicity affecting <10% of body surface area [BSA]) occurs, continue alpelisib at the same dosage. Administer topical corticosteroids; consider an oral antihistamine.

If grade 2 dermatologic toxicity (active skin toxicity affecting 10–30% of BSA) occurs, continue alpelisib at the same dosage. Initiate or intensify topical corticosteroid and oral antihistamine therapy; consider low-dose systemic corticosteroid therapy.

If grade 3 dermatologic toxicity (severe rash not responsive to therapy; active skin toxicity affecting >30% of BSA) occurs, interrupt alpelisib therapy; initiate or intensify topical/systemic corticosteroid and oral antihistamine therapy. When the toxicity improves to grade 1 or less, resume alpelisib at the same dosage (for first occurrence) or at a reduced dosage (for second occurrence).

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, permanently discontinue alpelisib.

Diarrhea
Oral

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

If grade 2 diarrhea occurs, 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 3 or 4 diarrhea occurs, 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 a reduced dosage.

Pancreatitis
Oral

If grade 2 or 3 pancreatitis occurs, interrupt alpelisib therapy. When toxicity improves to grade 1 or less, resume alpelisib at a reduced dosage. Only one dosage reduction permitted for pancreatitis; if grade 2 or 3 pancreatitis recurs, permanently discontinue alpelisib.

Hepatic Toxicity
Oral

For grade 2 total bilirubin concentration elevations, interrupt alpelisib therapy. If toxicity improves to grade 1 or less within 14 days, resume alpelisib at the same dosage. If toxicity improves to grade 1 or less after 14 days, resume alpelisib at a reduced dosage.

Other Toxicity
Oral

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

If grade 3 adverse reactions occur, interrupt alpelisib therapy. When toxicity improves to grade 1 or less, resume alpelisib at a reduced dosage.

If grade 4 adverse reactions occur, permanently discontinue alpelisib.

Prescribing Limits

Adults

Breast Cancer
Oral

Dosages <200 mg once daily not recommended.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)

Renal Impairment

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

Severe renal impairment (Clcr <30 mL/minute): Insufficient data to provide dosage recommendations. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)

Cautions for Alpelisib

Contraindications

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

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 dermatologic reactions (e.g., erythema multiforme, Stevens-Johnson syndrome) reported. Rash reported in 52% of patients receiving alpelisib; grade 3 rash reported in 20% of patients.

Avoid use in patients with a history of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis.

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, flu-like symptoms) occur, interrupt alpelisib therapy, evaluate etiology, and consult with a dermatologist. Dosage modification, corticosteroid and/or oral antihistamine therapy, or treatment discontinuance may be necessary. (See Dermatologic Toxicity under Dosage and Administration.)

If erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis is confirmed, permanently discontinue alpelisib.

Hyperglycemia

Severe hyperglycemia and ketoacidosis reported.

Hyperglycemia reported in 65% of patients receiving alpelisib; grade 3 or 4 hyperglycemia reported in 33 or 3.9%, respectively, of patients. Antidiabetic agents, usually metformin alone or in combination with other antidiabetic agents, administered to 87% of patients with hyperglycemia.

Assess fasting plasma glucose concentrations and glycosylated hemoglobin (hemoglobin A1c; HbA1c) and optimize blood glucose concentrations prior to initiation of therapy. Monitor blood glucose concentrations and/or fasting plasma glucose concentrations at least once weekly for the first 2 weeks of therapy, at least once monthly thereafter, and as clinically indicated. Monitor HbA1c once every 3 months and as clinically indicated.

If hyperglycemia occurs, assess fasting plasma glucose concentrations and/or blood glucose concentrations as clinically indicated and at least twice weekly until hyperglycemia resolves. Initiate or optimize antidiabetic agents as necessary; monitor fasting plasma glucose concentrations and/or blood glucose concentrations at least once weekly for 8 weeks after initiating antidiabetic 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. (See Hyperglycemia under Dosage and Administration.)

Monitor patients with a history of type 2 diabetes mellitus closely; intensified antidiabetic 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 interstitial lung disease (ILD)/pneumonitis 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. (See Diarrhea under Dosage and Administration.)

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 women of childbearing potential. Women of childbearing potential should use effective contraceptive methods while receiving the drug and for ≥1 week after discontinuance of therapy. Men who are partners of such women 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.

Impairment of Fertility

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

Specific Populations

Pregnancy

May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

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

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Geriatric patients ≥65 years of age: 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: Insufficient experience to determine whether efficacy and safety are similar to those in younger adults.

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 (Clcr 30–89 mL/minute). Effect of severe renal impairment (Clcr <30 mL/minute) on pharmacokinetics not established.

Common Adverse Effects

Diarrhea, rash, nausea, fatigue, decreased appetite, stomatitis, vomiting, decreased weight, alopecia, mucosal inflammation, dysgeusia, headache, pruritus, dry skin, abdominal pain, peripheral edema, pyrexia, mucosal dryness, dyspepsia, urinary tract infection, hyperglycemia, elevated Scr concentrations, elevated γ-glutamyltransferase (γ-glutamyltranspeptidase, GGT, GGTP) concentrations, lymphopenia, elevated ALT concentrations, decreased hemoglobin, elevated serum lipase concentrations, hypocalcemia, hypoglycemia, prolonged aPTT, decreased platelet counts, hypokalemia, hypoalbuminemia, hypomagnesemia.

Interactions for Alpelisib

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. (See Specific Drugs under Interactions.)

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. (See Absorption under Pharmacokinetics.)

Specific Drugs

Drug

Interaction

Comments

Bisphosphonates (e.g., alendronate, ibandronate, risedronate, zoledronic acid)

Possible increased risk of osteonecrosis of the jaw

Denosumab

Possible increased risk of osteonecrosis of the jaw

Everolimus

Clinically important pharmacokinetic interaction unlikely

Histamine H2-receptor antagonists (e.g., cimetidine, famotidine, ranitidine)

Possible decreased alpelisib solubility, resulting in decreased AUC

Ranitidine: Concomitant administration decreased alpelisib AUC and peak plasma concentration by 30 and 51%, respectively, in fasted state and by 21 and 36%, respectively, when administered with low-fat, low-calorie meal

May be administered concomitantly since alpelisib is administered with food and food has a more pronounced effect on alpelisib solubility than does gastric pH

Warfarin

Possible decreased AUC of warfarin

Monitor for reduced efficacy of warfarin

Alpelisib Pharmacokinetics

Absorption

Bioavailability

Bioavailability in the fasted state is limited by low solubility.

Peak plasma concentrations of alpelisib attained 2–4 hours following oral administration.

Systemic exposure to alpelisib is dose proportional over a dose range of 30–450 mg in the fed state.

Accumulation ratio is 1.3–1.5 with once-daily administration. Steady-state concentrations achieved within 3 days.

Food

High-fat, high-calorie meal increased AUC and peak plasma concentrations of alpelisib by 73 and 84%, respectively, compared with administration in the fasted state.

Low fat, low-calorie meal increased AUC and peak plasma concentrations of alpelisib by 77 and 145%, respectively, compared with administration in the fasted state.

Distribution

Extent

Not known whether alpelisib is distributed into human milk.

Plasma Protein Binding

89%.

Elimination

Metabolism

Metabolized by chemical and enzymatic hydrolysis to major metabolite BZG791. Metabolized to a lesser extent by CYP3A4.

Elimination Route

Eliminated in feces (81% [36% as unchanged drug and 32% as BZG791]) and urine (14% [2% as unchanged drug and 7% as BZG791]); approximately 12% of dose recovered as metabolites formed by CYP3A4-mediated metabolism.

Half-life

8–9 hours.

Special Populations

In a pharmacokinetic population analysis, age (21–87 years), sex, race, body weight (37–181 kg), mild to severe hepatic impairment, and mild or moderate renal impairment did not have clinically important effects on alpelisib pharmacokinetics.

Not studied in patients with severe renal impairment.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

  • Selectively inhibits the α isoform of phosphatidylinositol-3-kinase (PI3Kα). Mutations in the gene that encodes PI3Kα (i.e., PIK3CA) are expressed in approximately 40% of hormone receptor-positive, HER2-negative breast cancers and result in PI3Kα/Akt signaling, cellular transformation, and generation of tumors.

  • Inhibited phosphorylation of PI3K/Akt downstream targets in breast cancer cell lines and exhibited activity in cell lines harboring a PIK3CA mutation.

  • Blocked PI3K/Akt signaling and decreased tumor growth in xenograft models of PI3Kα-dependent tumors in mice.

  • PI3K inhibition by alpelisib shown to induce estrogen receptor transcription in breast cancer cells.

  • Combination of alpelisib and the estrogen antagonist fulvestrant demonstrated increased antitumor activity compared with either drug alone in xenograft models of PIK3CA-mutated, estrogen receptor-positive breast cancer.

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.

  • Importance of advising patients to take alpelisib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician. Importance of advising patients to swallow alpelisib tablets whole and not to chew, crush, or split tablets; importance of not using tablets that are cracked, broken, or otherwise damaged. Importance of taking the drug with food.

  • Importance of advising patients that a missed dose should be taken as soon as it is remembered, up to 9 hours after the scheduled administration time; if a dose is missed by more than 9 hours, the missed dose should be omitted and the next dose taken at the regularly scheduled time. If a dose is vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a vomited dose.

  • Risk of serious hypersensitivity reactions, including anaphylaxis. Importance of immediately contacting a clinician if signs or symptoms of a hypersensitivity reaction (e.g., dyspnea, flushing, rash, fever, tachycardia) occur.

  • Risk of serious dermatologic reactions. Importance of immediately contacting a clinician if signs or symptoms of a severe dermatologic reaction (e.g., severe or progressive rash; redness; flu-like symptoms; blistering or peeling skin; blistering of the lips, eyes, or mouth) occur.

  • Risk of hyperglycemia. Importance of periodic blood glucose monitoring and of immediately reporting signs or symptoms of hyperglycemia (e.g., excessive thirst, dry mouth, frequent urination, increased appetite with weight loss).

  • Risk of interstitial lung disease or pneumonitis. Importance of immediately contacting a clinician if any new or worsening respiratory symptoms (e.g., cough, shortness of breath, difficulty breathing, chest pain) occur.

  • Risk of diarrhea; potential for dehydration and acute kidney injury if diarrhea is severe. Importance of advising patients on how to manage diarrhea (e.g., oral hydration, antidiarrhea agents) at the first sign of loose stools. Importance of informing clinician if diarrhea occurs.

  • Risk of fetal harm. Necessity of advising women of childbearing potential to use effective contraceptive methods while receiving alpelisib and for ≥1 week after discontinuance of therapy. Necessity of advising men who are partners of such women to use condoms and effective contraception during treatment and for ≥1 week after discontinuance of therapy. Importance of women informing clinicians if they are or plan to become pregnant. Apprise patient of potential fetal hazard if used during pregnancy.

  • Importance of advising women to discontinue nursing during therapy and for ≥1 week after discontinuance of the drug.

  • Importance of advising patients with reproductive potential that alpelisib may impair male and female fertility.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., diabetes mellitus). Importance of close monitoring if certain interacting drugs must be used concomitantly. (See Interactions.)

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Alpelisib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg

Piqray

Novartis

150 mg

Piqray

Novartis

200 mg

Piqray

Novartis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 10, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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