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Piqray

Generic Name: Alpelisib
Class: Antineoplastic Agents
Chemical Name: (2S)-1-N-[4-methyl-5-[2-(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: 1217486-47-9

Medically reviewed by Drugs.com. Last updated on Jun 10, 2019.

Introduction

Alpelisib is an antineoplastic agent.

Uses for Piqray

Alpelisib has the following uses:

Alpelisib is a kinase inhibitor indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.1

Piqray Dosage and Administration

General

Alpelisib is available in the following dosage form(s) and strength(s):

Tablets: 50 mg, 150 mg, 200 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • Recommended dose: 300 mg (two 150 mg tablets) taken orally once daily with food.1

  • For adverse reactions, consider dose interruption, dose reduction, or discontinuation.1

  • Consult manufacturer’s labeling for specific recommendations.1

Cautions for Piqray

Contraindications

Severe hypersensitivity to alpelisib or to any of its components.1

Warnings/Precautions

Severe Hypersensitivity

Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, were reported in patients treated with alpelisib. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia.1

The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7%.1

Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue alpelisib in the event of severe hypersensitivity.1

Severe Cutaneous Reactions

Severe cutaneous reactions, including Stevens-Johnson Syndrome (SJS) and Erythema Multiforme (EM) were reported in patients treated with alpelisib.1

SJS and EM were reported in 0.4% and 1.1% of patients, respectively. Do not initiate alpelisib treatment in patients with a history of SJS, EM, or Toxic Epidermal Necrolysis (TEN).1

If signs or symptoms of severe cutaneous reactions occur, interrupt alpelisib until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. 1

If SJS, TEN, or EM is confirmed, permanently discontinue alpelisib. Do not reintroduce alpelisib in patients who have experienced previous severe cutaneous reactions during alpelisib treatment.1

If SJS, TEN, or EM is not confirmed, alpelisib may require dose modifications, topical corticosteroids, or oral antihistamine treatment.1

Advise patients of the signs and symptoms of severe cutaneous reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash).1

Hyperglycemia

Severe hyperglycemia, including ketoacidosis, has been reported in patients treated with alpelisib. Hyperglycemia was reported in 65% of patients treated with alpelisib. Grade 3 (fasting plasma glucose [FPG] >250–500 mg/dL) and Grade 4 (FPG >500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n=2) treated with alpelisib.1

Among the patients who experienced Grade ≥2 (FPG 160–250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range: 5 to 517 days).1

In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-diabetic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-diabetic medication (i.e., insulin, dipeptidyl peptidase-4 [DPP-4] inhibitors, and sulfonylureas). In patients with Grade ≥2 hyperglycemia with at least 1 grade improvement (n = 153), median time to improvement from the first event was 8 days (range: 2 to 65 days).1

In all patients with elevated FPG who continued fulvestrant treatment after discontinuing alpelisib (n=54), 96% (n=52) of patients had FPG levels that returned to baseline. 1

Before initiating treatment with alpelisib, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with alpelisib, monitor blood glucose and/or FPG at least once every 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.1

If a patient experiences hyperglycemia after initiating treatment with alpelisib, 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 anti-diabetic 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 healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.1

The safety of alpelisib in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.1

Based on the severity of the hyperglycemia, alpelisib may require dose interruption, reduction, or discontinuation.1

Advise patients of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).1

Pneumonitis

Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has been reported in patients treated with alpelisib.1

Pneumonitis was reported in 1.8% of patients treated with alpelisib.1

In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt alpelisib immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.1

Permanently discontinue alpelisib in all patients with confirmed pneumonitis.1

Advise patients to immediately report new or worsening respiratory symptoms.1

Diarrhea

Severe diarrhea, including dehydration and acute kidney injury, occurred in patients treated with alpelisib. Most patients (58%) experienced diarrhea during treatment with alpelisib. Grade 3 diarrhea occurred in 7% (n=19) of patients. Among patients with Grade 2 or 3 diarrhea (n=71), the median time to onset was 46 days (range: 1 to 442 days).1

Dose reductions of alpelisib were required in 6% of patients and 2.8% of patients permanently discontinued alpelisib due to diarrhea. In the 164 patients that experienced diarrhea, anti-diarrheal medications (e.g., loperamide) were required to manage symptoms in 63% (104/164) of these patients.1

Based on the severity of the diarrhea, alpelisib may require dose interruption, reduction, or discontinuation.1

Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking alpelisib.1

Embryo-fetal Toxicity

Based on findings in animals and its mechanism of action, alpelisib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures based on area under the curve (AUC) that were ≥0.8 times the exposure in humans at the recommended dose of 300 mg/day. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with alpelisib and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with alpelisib and for 1 week after the last dose.1

Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.1

Specific Populations

Pregnancy

Risk Summary: Alpelisib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.1

Based on animal data and mechanism of action, alpelisib can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures ≥0.8 times the exposure in humans based on AUC at the recommended dose of 300 mg/day). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. 1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.1

Animal Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib up to 30 mg/kg/day during the period of organogenesis.1

In rats, oral administration of alpelisib resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At a dose of 10 mg/kg/day (approximately 0.8 times the exposure in humans at the recommended dose of 300 mg/day based on AUC), toxicities included reduced fetal weight and increased incidences of skeletal malformations (bent scapula and thickened or bent long bones) and fetal variations (enlarged brain ventricle, decreased bone ossification).1

In a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (post-implantation loss). Doses ≥15 mg/kg/day resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head. At 15 mg/kg/day in rabbits, the maternal exposure was approximately 5 times the exposure achieved at the recommended human dose of 300 mg/day based on AUC.1

Lactation

Alpelisib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information. 1

There is no data on the presence of alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with alpelisib and for 1 week after the last dose.1

Females and Males of Reproductive Potential

Alpelisib is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.1

Verify the pregnancy status in females of reproductive potential prior to initiating alpelisib.1

Alpelisib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with alpelisib and for 1 week after the last dose.1

Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with alpelisib and for 1 week after the last dose. 1

Based on findings from animal studies, alpelisib may impair fertility in males and females of reproductive potential.1

Pediatric Use

The safety and efficacy of alpelisib in pediatric patients have not been established.1

Geriatric Use

Of 284 patients who received alpelisib in the SOLAR-1 trial, 117 patients were ≥65 years of age and 34 patients were ≥75 years of age. In patients treated with alpelisib plus fulvestrant, there was a higher incidence of Grade 3–4 hyperglycemia in patients ≥65 years of age (44%) compared to patients <65 years of age (32%). No overall differences in effectiveness of alpelisib were observed between patients ≥65 years of age compared to younger patients. There are an insufficient number of patients ≥75 years of age to assess whether there are differences in safety or effectiveness.1

Renal Impairment

The effect of severe renal impairment (Clcr <30 mL/min) on alpelisib pharmacokinetics is unknown.1

No dose adjustment is recommended for patients with mild to moderate renal impairment (Clcr 30 to <90 mL/min).1

Common Adverse Effects

Most common adverse reactions including laboratory abnormalities (all grades, incidence ≥20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, GGT increased, nausea, ALT increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, aPTT prolonged, and alopecia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A4 Inducers: Avoid coadministration of alpelisib with a strong CYP3A4 inducer.1

  • BCRP Inhibitors: Avoid the use of BCRP inhibitors in patients treated with alpelisib. If unable to use alternative drugs, closely monitor for increased adverse reactions.1

  • CYP2C9 Substrates: Closely monitor when alpelisib is coadministered with CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce activity.1

Actions

Mechanism of Action

Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.1

In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.1

PI3K inhibition by alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of alpelisib and fulvestrant demonstrated increased anti-tumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Inform patients of the signs and symptoms of hypersensitivity. Advise patients to contact their healthcare provider immediately for signs and symptoms of hypersensitivity.1

Inform patients of the signs and symptoms of severe cutaneous reactions. Advise patients to contact their healthcare provider immediately for signs and symptoms of severe cutaneous reactions.1

Advise patients of the possibility of developing hyperglycemia and the need to monitor blood glucose periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia.1

Inform patients of the possibility of developing pneumonitis and to immediately contact their healthcare provider if they experience respiratory problems.1

Advise patients that alpelisib may cause diarrhea, which may be severe in some cases. Inform patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking alpelisib.1

Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.1

Advise females of reproductive potential to use effective contraception during treatment with alpelisib and for 1 week after the last dose.1

Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with alpelisib and for 1 week after the last dose.1

Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.1

Advise women not to breastfeed during treatment with alpelisib and for 1 week after the last dose. Refer to the Full Prescribing Information of fulvestrant for lactation information.1

Advise males and females of reproductive potential that alpelisib may impair fertility. Refer to the Full Prescribing Information of fulvestrant for infertility information.1

Advise patients to avoid the use of strong CYP3A4 inducers in patients treated with alpelisib. Advise patients to avoid the use of BCRP inhibitors in patients treated with alpelisib. If unable to use alternative drugs, closely monitor for increased adverse reactions. Advise patients that close monitoring may be required when alpelisib is coadministered with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.1

Instruct patients to take alpelisib at approximately the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split prior to swallowing).1

Advise patients to take alpelisib with food.1

Instruct patients that if a dose of alpelisib is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take alpelisib at the usual time. Instruct patients not to take 2 doses to make up for a missed dose.1

Instruct patients that if they vomit after taking the dose of alpelisib, they should not take an additional dose on that day, and to resume the usual dosing schedule the next day at the usual time.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Kit

50 mg (film-coated tablets)

200 mg (film-coated tablets)

Piqray (available as blister packs containing 50-mg tablets and 200-mg tablets)

Novartis Pharmaceuticals Corporation

Tablets, film-coated

150 mg

Piqray

Novartis Pharmaceuticals Corporation

200 mg

Piqray

Novartis Pharmaceuticals Corporation

AHFS Drug Information. © Copyright 2020, Selected Revisions June 10, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Corporation. PIQRAY (alpelisib) tablets prescribing information. 2019 May. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b20b4e18-7a4b-4500-a08f-06c6dab0ee5b