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    Alpelisib

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    Sep.11.2024

    Alpelisib

    Indications/Dosage

    Labeled

    • breast cancer
    • PIK3CA-related overgrowth spectrum

    Off-Label

      † Off-label indication

      For the treatment of breast cancer

      NOTE: Patients should be selected 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 FDA-approved tests for the detection of PIK3CA mutations in breast cancer is available at www.fda.gov/CompanionDiagnostics.[64248]

      for the treatment of hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer in adults following progression on or after an endocrine-based regimen, in combination with fulvestrant

      Oral dosage

      Adults

      300 mg PO once daily with food, in combination with fulvestrant (500 mg IM on days 1, 15, 29 and once monthly thereafter) until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a randomized, double-blind clinical trial (SOLAR-1), treatment with fulvestrant plus alpelisib significantly improved progression-free survival (PFS) compared with fulvestrant plus placebo in patients with HR-positive, HER2-negative, advanced or metastatic breast cancer in patients with a PIK3CA mutation in tumor tissue, whose disease had progressed or recurred on or after aromatase inhibitor-based treatment (11 months vs. 5.7 months); similar results were seen in patients with tissue or plasma PIK3CA mutations. No PFS benefit was observed in patients whose tumors did not have a PIK3CA tissue mutation. The overall response rate was 35.7% in patients who were treated with fulvestrant plus alpelisib compared with 16.2% in those who received fulvestrant plus placebo. There was no significant difference in overall survival between treatment groups.[64248]

      Oral dosage

      Adults

      250 mg PO once daily with food until disease progression or unacceptable toxicity.[67501]

      Children and Adolescents 6 to 17 years

      50 mg PO once daily, initially. After 24 weeks, consider increasing dose to 125 mg PO once daily for response optimization (clinical/radiological). Administer with food. Continue until disease progression or unacceptable toxicity.[67501]

      Children 2 to 5 years

      50 mg PO once daily with food until disease progression or unacceptable toxicity.[67501]

      Therapeutic Drug Monitoring

      Dosage Adjustments for Treatment-Related Toxicity:

      Interrupt alpelisib therapy per specific instructions below. Restart alpelisib as appropriate at the following reduced doses:

      Adults with Breast Cancer

      • Starting dose: 300 mg PO once daily with food.
      • First dose reduction: 250 mg PO once daily with food.
      • Second dose reduction: 200 mg PO once daily with food.[64248]

      Adults with PIK3CA-Related Overgrowth Spectrum (PROS)

      • Starting dose: 250 mg PO once daily with food.
      • First dose reduction: 125 mg PO once daily with food.
      • Second dose reduction: 50 mg PO once daily with food. Discontinue dose in patients who cannot tolerate 50 mg PO once daily.[67501]

      Pediatric Patients with PROS

      • Starting dose: 125 mg PO once daily with food. Reduce to 50 mg once daily with food. Discontinue dose in patients who cannot tolerate 50 mg PO once daily.
      • Starting dose: 50 mg once daily with food. Discontinue dose in patients who cannot tolerate 50 mg PO once daily.[67501]

       

      Diarrhea or Colitis

      NOTE: In pediatric patients, consider consultation with a physician with experience in the treatment of gastrointestinal conditions.

      • Grade 1: Initiate appropriate medical therapy and monitor as clinically indicated. No dose adjustment of alpelisib is required.
      • Grade 2: Interrupt alpelisib treatment and initiate or intensify appropriate medical therapy, including enteric-acting and/or systemic corticosteroids; monitor as clinically indicated. When diarrhea improves to grade 1 or less, resume alpelisib therapy at the same dose level for the first occurrence.
        • For the recurrence of grade 2 diarrhea in adults with breast cancer, resume treatment at the next lower dose level upon improvement to grade 1 or less. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • For the second occurrence of grade 2 diarrhea in adults with PROS, interrupt alpelisib dose until improvement to grade 1 or less, then resume treatment at the next lower dose level.
        • For the second occurrence of grade 2 diarrhea in pediatric patients with PROS, interrupt alpelisib dose until improvement to grade 1 or less, then resume alpelisib 50 mg PO once daily.
      • Grade 3: Interrupt alpelisib treatment and initiate or intensify appropriate medical therapy, including enteric-acting and/or systemic corticosteroids; monitor as clinically indicated.
        • When diarrhea improves to grade 1 or less in adults with breast cancer, resume alpelisib therapy at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • When diarrhea improves to grade 1 or less in adults with PROS, resume alpelisib therapy at the next lower dose level.
        • When diarrhea improves to grade 1 or less in pediatric patients with PROS, either resume alpelisib 50 mg PO once daily or permanently discontinue alpelisib. If diarrhea recurs at grade 3 or higher, consider permanent discontinuation.
      • Grade 4: Permanently discontinue alpelisib.[64248][67501]

       

      Hyperglycemia

      NOTE: When initiating or intensifying antihyperglycemic treatment (as age appropriate) consult local guidelines for medications, including metformin, SGLT2 inhibitors, and insulin sensitizers (e.g., thiazolidinediones or dipeptidyl peptidase-4 inhibitors). In the randomized clinical trial evaluating alpelisib for breast cancer (SOLAR-1), metformin was recommended at an initial dose of 500 mg once daily with gradual increases to 1,000 mg twice daily if needed. A single-arm, two-cohort study (METALLICA; n = 68) in adult patients with HR-positive, HER2-negative breast cancer with PIK3CA mutation showed starting metformin 500 mg twice daily with gradual increase to 1,000 mg twice daily as tolerated 7 days prior to initiating alpelisib decreased incidence and severity of hyperglycemia events; however, there was an increase in incidences and severity of diarrhea, nausea, and vomiting.

      • Grade 1 (fasting plasma glucose (FPG) greater than the upper limit of normal (ULN) to 160 mg/dL or FPG greater than ULN to 8.9 mmol/L): Initiate or intensify antihyperglycemic treatment. No dose adjustment of alpelisib is required. Continue to monitor blood glucose at least once weekly for 8 weeks, followed by once every 2 weeks and as clinically indicated.
      • Grade 2 (FPG 161 mg/dL to 250 mg/dL or FPG 9 mmol/L to 13.9 mmol/L): Initially, no dose adjustment of alpelisib is required. Initiate or intensify antihyperglycemic treatment. During treatment with antihyperglycemic medication, continue to monitor blood glucose at least once weekly for 8 weeks, followed by once every 2 weeks and as clinically indicated.
        • In adults with breast cancer, consider additional antihyperglycemic medications (e.g., insulin) for 1 to 2 days if necessary until hyperglycemia improves; however, this may not be necessary due to the short half-life of alpelisib. If FPG does not decrease to grade 1 or less within 21 days of appropriate antihyperglycemic treatment, reduce the dose of alpelisib by 1 dose level, and follow FPG value-specific recommendations. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • In adults with PROS, if FPG does not decrease to grade 1 or less within 21 days of appropriate antihyperglycemic treatment, reduce the dose of alpelisib by 1 dose level, and follow FPG value-specific recommendations.
        • In pediatric patients with PROS, if FPG does not decrease to grade 1 or less within 21 days of appropriate antihyperglycemic treatment, interrupt alpelisib until improvement to grade 1 or less, then resume alpelisib 50 mg PO once daily, and follow FPG value-specific recommendations.
      • Grade 3 (FPG 251 mg/dL to 500 mg/dL or FPG 14 mmol/L to 27.8 mmol/L): Interrupt alpelisib treatment and initiate or intensify antihyperglycemic treatment. Consider additional antihyperglycemic medications (e.g., insulin) for 1 to 2 days until hyperglycemia improves; however, this may not be necessary due to the short half-life of alpelisib. Administer IV hydration; consider interventions for ketoacidosis and electrolyte disturbances as clinically appropriate. During treatment with antihyperglycemic medication, continue to monitor blood glucose at least once weekly for 8 weeks, followed by once every 2 weeks and as clinically indicated.
        • In adults with breast cancer, if FPG decreases to grade 1 or less within 3 to 5 days under appropriate antihyperglycemic treatment, resume alpelisib therapy at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib. If FPG does not decrease to grade 1 or less within 3 to 5 days of appropriate antihyperglycemic treatment, consult with a physician with expertise in the treatment of hyperglycemia. If FPG does not decrease to grade 1 or less within 21 days after appropriate antihyperglycemic treatment, permanently discontinue alpelisib treatment.
        • In adults with PROS, if FPG decreases to grade 1 or less within 3 to 5 days under appropriate antihyperglycemic treatment, resume alpelisib therapy at the next lower dose level. If FPG does not decrease to grade 1 or less within 3 to 5 days of appropriate antihyperglycemic treatment, consult with a physician with expertise in the treatment of hyperglycemia. If FPG does not decrease to grade 1 or less within 21 days after appropriate antihyperglycemic treatment, permanently discontinue alpelisib treatment.
        • In pediatric patients with PROS, if FPG decreases to grade 1 or less within 3 to 5 days under appropriate antihyperglycemic treatment, resume alpelisib 50 mg PO once daily. If FPG does not decrease to grade 1 or less within 3 to 5 days of appropriate antihyperglycemic treatment, consult with a physician with expertise in the treatment of hyperglycemia. If FPG does not decrease to grade 1 or less within 21 days after appropriate antihyperglycemic treatment, permanently discontinue alpelisib treatment.
      • Grade 4 (FPG greater than 500 mg/dL or FPG greater than 27.8 mmol/L): Interrupt alpelisib treatment and initiate or intensify antihyperglycemic treatment. Consider additional antihyperglycemic medications (e.g., insulin) for 1 to 2 days until hyperglycemia improves; however, this may not be necessary due to the short half-life of alpelisib. Administer IV hydration; consider interventions for ketoacidosis and electrolyte disturbances as clinically appropriate. Recheck FPG within 24 hours and as clinically indicated. If FPG decreases to grade 3 or less after 24 hours, follow FPG value-specific recommendations for grade 3 hyperglycemia. If FPG is confirmed to be grade 4 at 24 hours, permanently discontinue alpelisib treatment.[64248][67501]

       

      Pancreatitis

      • Grade 1: Initiate appropriate medical therapy and monitor as clinically indicated. No dose adjustment of alpelisib is required.
      • Grade 2: Interrupt alpelisib therapy and initiate appropriate medical therapy; monitor as clinically indicated.
        • For the first occurrence of pancreatitis in adults with breast cancer, resume therapy at the next lower dose level when pancreatitis recovers to grade 1 or less. If dose reduction below 200 mg once daily is required, discontinue alpelisib. For the second occurrence of pancreatitis, permanently discontinue alpelisib treatment.
        • For the first occurrence of pancreatitis in adults with PROS, resume therapy at the next lower dose level when pancreatitis recovers to less than grade 2. For the second occurrence of pancreatitis, permanently discontinue alpelisib treatment.
        • For the first occurrence of pancreatitis in pediatric patients with PROS, resume alpelisib 50 mg PO once daily. For the second occurrence of pancreatitis, permanently discontinue alpelisib treatment.
      • Grade 3: Interrupt alpelisib therapy and initiate appropriate medical therapy; monitor as clinically indicated.
        • For the first occurrence of pancreatitis in adults with breast cancer, resume therapy at the next lower dose level when pancreatitis recovers to grade 1 or less. If dose reduction below 200 mg once daily is required, discontinue alpelisib. For the second occurrence of pancreatitis, permanently discontinue alpelisib treatment.
        • For the first occurrence of pancreatitis in adults with PROS, resume therapy at the next lower dose level when pancreatitis recovers to less than grade 2. For the second occurrence of pancreatitis, permanently discontinue alpelisib treatment.
        • For the first occurrence of pancreatitis in pediatric patients with PROS, permanently discontinue alpelisib treatment.
      • Grade 4: Permanently discontinue alpelisib treatment.[64248][67501]

       

      Pneumonitis

      • Interrupt alpelisib therapy if pneumonitis is suspected. Permanently discontinue therapy if pneumonitis is confirmed.[64248][67501]

       

      Rash and Severe Cutaneous Adverse Reactions (SCARs)

      • Grade 1 (less than 10% body surface area (BSA) with active skin toxicity): Initiate topical corticosteroid treatment and consider adding an oral antihistamine to manage symptoms; add a low-dose systemic corticosteroid if active rash is not improved within 28 days of appropriate treatment. Consultation with a dermatologist is recommended. No dose adjustment of alpelisib is required. If the etiology is a SCAR such as Stevens-Johnson Syndrome, erythema multiforme, toxic epidermal necrolysis, or drug reaction with eosinophilia syndrome (DRESS), permanently discontinue alpelisib therapy.
      • Grade 2 (10% to 30% BSA with active skin toxicity): Initiate or intensify topical corticosteroid and oral antihistamine treatment. Consider low-dose systemic corticosteroid treatment; if the rash improves to grade 1 or less within 10 days, the systemic corticosteroid may be discontinued. Consultation with a dermatologist is recommended. No dose adjustment of alpelisib is required. If the etiology is a SCAR, permanently discontinue alpelisib therapy.
      • Grade 3 (severe rash not responsive to medical treatment; greater than 30% BSA with active skin toxicity): Interrupt alpelisib treatment and initiate or intensify topical/systemic corticosteroid and oral antihistamine treatment. Consultation with a dermatologist is recommended. If the etiology is a SCAR, permanently discontinue alpelisib therapy.
        • If the etiology is not a SCAR in adults with breast cancer, when rash improves to grade 1 or less, resume alpelisib at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • If the etiology is not a SCAR in adults with PROS, when rash improves to grade 1 or less, resume alpelisib at the next lower dose level.
        • If the etiology is not a SCAR in pediatric patients with PROS, when rash improves to grade 1 or less, resume alpelisib 50 mg PO once daily while continuing oral antihistamine treatment or permanently discontinue alpelisib. Permanently discontinue alpelisib if patient was receiving antihistamines at the time of rash onset and antihistamine dose cannot be increased or if grade 3 or higher rash recurs.
      • Grade 4 (severe bullous, blistering, or exfoliating skin conditions; any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences): Permanently discontinue alpelisib therapy. Consultation with a dermatologist is recommended.[64248][67501]

       

      Other Toxicities

      • Grade 1 or 2: Initiate appropriate medical therapy and monitor as clinically indicated. No dose adjustment of alpelisib is required.
      • Grade 3: Interrupt alpelisib therapy and initiate or intensify appropriate medical therapy; monitor as clinically indicated.
        • When toxicity recovers to grade 1 or less in adults with breast cancer, resume alpelisib therapy at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • When toxicity recovers to grade 1 or less in adults with PROS, resume alpelisib therapy at the next lower dose level.
        • When toxicity recovers to grade 1 or less in pediatric patients with PROS, either resume alpelisib 50 mg PO once daily or permanently discontinue alpelisib. For the second occurrence, consider permanently discontinuing alpelisib treatment. Consultation with a physician with expertise in the treatment of the specific adverse reaction is recommended.
      • Grade 4: Permanently discontinue alpelisib.[64248][67501]

      Maximum Dosage Limits

      • Adults

        250 mg PO once daily for PROS; 300 mg PO once daily for breast cancer.

      • Geriatric

        300 mg PO once daily for breast cancer; safety and efficacy have not been established for treatment of PROS.

      • Adolescents

        125 mg PO once daily for PROS; safety and efficacy have not been established for treatment of breast cancer.

      • Children

        6 to 12 years: 125 mg PO once daily for PROS; safety and efficacy have not been established for treatment of breast cancer.

        2 to 5 years: 50 mg PO once daily for PROS; safety and efficacy have not been established for treatment of breast cancer.

        1 year: Safety and efficacy have not been established.

      • Infants

        Safety and efficacy have not been established.

      • Neonates

        Safety and efficacy have not been established.

      Patients with Hepatic Impairment Dosing

      Baseline Hepatic Impairment

      • Dose adjustments are not necessary.[64248][67501]

       

      Treatment-Related Hyperbilirubinemia

      • Grade 1: Initiate appropriate medical therapy and monitor as clinically indicated. No dose adjustment of alpelisib is required.
      • Grade 2: Interrupt alpelisib therapy and initiate appropriate medical therapy; monitor as clinically indicated.
        • In adults with breast cancer, if the bilirubin level recovers to grade 1 or less within 14 days, resume alpelisib therapy at the same dose level. If the bilirubin level recovers to grade 1 or less in more than 14 days, resume therapy at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • In adults with PROS, if the bilirubin level recovers to grade 1 or less within 14 days, resume alpelisib therapy at the same dose level. If the bilirubin level recovers to grade 1 or less in more than 14 days, resume therapy at the next lower dose level.
        • In pediatric patients with PROS, if the bilirubin level recovers to grade 1 or less within 14 days, resume alpelisib therapy at the same dose level. If the bilirubin level recovers to grade 1 or less in more than 14 days, resume alpelisib 50 mg PO once daily.
      • Grade 3: Interrupt alpelisib therapy and initiate appropriate medical therapy; monitor as clinically indicated.
        • In adults with breast cancer, if the bilirubin level recovers to grade 1 or less, resume alpelisib therapy at the next lower dose level. If dose reduction below 200 mg once daily is required, discontinue alpelisib.
        • In adults with PROS, if the bilirubin level recovers to grade 1 or less, resume alpelisib therapy at the next lower dose level.
        • In pediatric patients with PROS, if the bilirubin level recovers to grade 1 or less either resume alpelisib 50 mg PO once daily or permanently discontinue alpelisib. For the second occurrence, consider permanently discontinuing alpelisib treatment. Consultation with a physician with expertise in the treatment of the specific adverse reaction is recommended.
      • Grade 4: Permanently discontinue alpelisib.[64248][67501]

      Patients with Renal Impairment Dosing

      Baseline Renal Impairment

      • Dose adjustments are not necessary.[64248][67501]
      † Off-label indication
      Revision Date: 09/11/2024, 01:56:00 AM

      References

      64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

      How Supplied

      Vijoice 50mg Daily Dose Granules (00078-1175) (Novartis Pharmaceuticals Corporation) nullVijoice 50mg Daily Dose Granules package photo

      Alpelisib Oral tablet

      PIQRAY 300mg Daily Dose Tablet (00078-0708) (Novartis Pharmaceuticals Corporation) null

      Alpelisib Oral tablet

      PIQRAY 200mg Daily Dose Tablet (00078-0701) (Novartis Pharmaceuticals Corporation) null
      Vijoice 50mg Daily Dose Tablet (00078-1021) (Novartis Pharmaceuticals Corporation) null
      Vijoice 125mg Daily Dose Tablet (00078-1028) (Novartis Pharmaceuticals Corporation) null
      Vijoice 250mg Daily Dose Tablet (00078-1035) (Novartis Pharmaceuticals Corporation) null

      Alpelisib Oral tablet, Alpelisib Oral tablet

      PIQRAY 250mg Daily Dose Tablet (00078-0715) (Novartis Pharmaceuticals Corporation) null

      Description/Classification

      Description

      Alpelisib is an oral phosphatidylinositol 3-kinase (PI3K) inhibitor. It is indicated in combination with fulvestrant for the treatment of adults with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen. It is also indicated in adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. 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. Efficacy for PROS was evaluated in a single-arm clinical study in 37 patients who received alpelisib as part of an expanded access program for compassionate use. Patients had severe or life-threatening clinical manifestations and had documented mutation of the PIK3CA gene. Of the 37 patients included in the efficacy population, 27% (95% CI: 14, 44) had a radiological response (defined as a 20% or greater reduction from baseline in the sum of measurable target lesion volume in up to 3 lesions) at week 24. Of the patients with a radiological response, 60% had a response that lasted 12 months or longer. Hyperglycemia is an expected laboratory abnormality related to PI3K inhibition; the safety of alpelisib in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from clinical trials. Alpelisib was initially FDA-approved in 2019.[64248][67501]

      Classifications

      • Alimentary Tract and Metabolism
        • Metabolic Disorder Agents
          • Metabolic Agents, Phosphatidylinositol-3-Kinase (PI3K) Inhibitors
      • Antineoplastic and Immunomodulating Agents
        • Antineoplastics
          • Small Molecule Antineoplastic Phosphatidylinositol-3-Kinase (PI3K) Inhibitors
      Revision Date: 09/11/2024, 01:56:00 AM

      References

      64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

      Administration Information

      General Administration Information

      For storage information, see the specific product information within the How Supplied section.

      Emetic Risk

      • Minimal/Low
      • Administer prn antiemetics as necessary.[67389]

      Route-Specific Administration

      Oral Administration

      General information

      • Administer with food at approximately the same time each day.
      • If vomiting occurs, do not administer an additional dose on that day. Resume dosing the following day at the usual time.
      • Missed Dose: If a dose 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 and resume dosing on the following day at the usual time.[64248][67501]

      Oral Solid Formulations

      Tablets

      • Do not crush, chew, or split alpelisib tablets; administer alpelisib tablets whole. Do not administer any tablet that is broken, cracked, or otherwise not intact.[64248][67501]

       

      Preparation of oral suspension from tablets

      • For patients receiving alpelisib for PIK3CA-Related Overgrowth Spectrum (PROS) and not able to swallow tablets, administer as an oral suspension with food.
      • Place the tablet(s) in a glass containing 2 to 4 ounces of water and let stand for approximately 5 minutes; only use water to prepare the suspension.
      • Crush the tablets with a spoon and stir until an oral suspension is obtained. Administer immediately after preparation; discard if it is not administered within 60 minutes after preparation.
      • After administration, add approximately 2 to 3 tablespoons of water to the same glass, stir with the same soon to re-suspend remaining particles, and administer the entire contents of the glass. Repeat if particles remain.[67501]

      Other Oral Formulations

      Oral granules

      • Each oral granule packet is for single use only. Do not use if the packet seal is broken.
      • Do not attempt to use partial quantities of oral granules from the packets to prepare a dose. Do not combine the oral granules with tablets to achieve a prescribed dose. The oral granules are intended for individuals needing a 50 mg dose.
      • Administer a 50 mg dose of the oral granules in one of the following ways:
        • Pour the contents of 1 packet directly onto the tongue and swallow with approximately 60 to 120 mL (2 to 4 ounces) of water. If needed, rinse the mouth with additional water and swallow to ensure no particles remain in the mouth.
        • Pour the contents of 1 packet into a cup. Add 5 to 15 mL (1 to 3 teaspoons or about 0.5 ounces) of a beverage (water, milk, or apple juice) or soft food (applesauce or yogurt) and administer the mixture immediately. Rinse the cup with up to 60 mL (2 ounces) of a beverage (water, milk or apple juice) and administer the mixture immediately to ensure the entire dose is administered. If particles remain, repeat until the full dose is administered. Discard mixed oral granules if they are not administered within 2 hours after preparation.[67501]

      Clinical Pharmaceutics Information

      From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67389 - Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Adverse Reactions

        Mild

        • abdominal pain
        • acneiform rash
        • alopecia
        • anorexia
        • asthenia
        • diarrhea
        • dysgeusia
        • dyspepsia
        • fatigue
        • fever
        • flushing
        • headache
        • infection
        • maculopapular rash
        • nausea
        • pruritus
        • rash
        • vomiting
        • weight loss
        • xerosis
        • xerostomia

        Moderate

        • anemia
        • colitis
        • dehydration
        • dyspnea
        • elevated hepatic enzymes
        • hyperbilirubinemia
        • hyperglycemia
        • hypertriglyceridemia
        • hypoalbuminemia
        • hypocalcemia
        • hypoglycemia
        • hypokalemia
        • hypomagnesemia
        • hyponatremia
        • hypophosphatemia
        • interstitial lung disease
        • leukopenia
        • lymphopenia
        • peripheral edema
        • pneumonitis
        • prolonged bleeding time
        • stomatitis
        • thrombocytopenia

        Severe

        • abdominal pain
        • anaphylactic shock
        • anaphylactoid reactions
        • angioedema
        • anorexia
        • diabetic ketoacidosis
        • diarrhea
        • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
        • dysgeusia
        • elevated hepatic enzymes
        • erythema multiforme
        • fatigue
        • fever
        • headache
        • hyperbilirubinemia
        • hyperglycemia
        • hyperkalemia
        • hypoglycemia
        • infection
        • nausea
        • osteonecrosis
        • pancreatitis
        • prolonged bleeding time
        • pruritus
        • rash
        • renal failure (unspecified)
        • Stevens-Johnson syndrome
        • stomatitis
        • toxic epidermal necrolysis
        • uveitis
        • vomiting
        • weight loss
        • xerosis

        Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with alpelisib. In a randomized clinical trial, SJS and EM were reported in 0.4% and 1.1% of patients treated with alpelisib, respectively. DRESS was reported in postmarketing experience with alpelisib. If signs or symptoms of a SCAR occur, interrupt alpelisib therapy until the etiology has been determined; if a diagnosis of a SCAR is confirmed, permanently discontinue alpelisib. Rash (e.g., maculopapular rash and pruritic rash) was reported in 52% (grade 3 or 4, 20%) of patients who received alpelisib plus fulvestrant (n = 284) compared with 7% (grade 3 or 4, 0.3%) of those receiving placebo plus fulvestrant (n = 287) in a randomized clinical trial; the median time to onset of grade 2 or 3 rash was 12 days. Rash was reported less often in a subgroup of patients who received prophylaxis, including antihistamines, prior to the onset of rash compared to the overall population (27% vs. 54%; grade 3, 12% vs. 20%). Pruritus (18%; grade 3 or 4, 0.7%) and xerosis (18%; grade 3 or 4, 0.4%) were also reported in patients who received alpelisib in the randomized clinical trial.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, eczema (7%) and dry skin (7%) were reported. Pruritus, rash (including maculopapular rash, erythematous rash, papular rash, and pruritic rash), and acne (including acneiform rash) were also reported during postmarketing experience.[67501]

        Alopecia occurred in 20% of patients treated with alpelisib plus fulvestrant (n = 284) compared with 2.4% of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] Alopecia was reported in 5% of patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use.[67501].

        Fever (14% vs. 4.9%; grade 3 or 4, 0.7% vs. 0.3%) and urinary tract infection (10% vs. 5%; grade 3 or 4, 0.7% vs. 1%) were reported more often in patients treated with alpelisib plus fulvestrant (n = 284) compared with placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] Cellulitis (5%; grade 3 or 4, 3.5%) was reported in patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use.[67501]

        Severe hypersensitivity reactions including anaphylaxis, anaphylactoid reactions, and anaphylactic shock, were reported in patients treated with alpelisib in clinical trials; symptoms included dyspnea, flushing, rash, fever, and tachycardia. Grade 3 or 4 hypersensitivity reactions were reported in 0.7% of patients who received alpelisib. Angioedema was reported in postmarketing experience with alpelisib. Permanently discontinue alpelisib if a severe hypersensitivity reaction occurs.[64248] [67501]

        Hyperglycemia is an expected laboratory abnormality of PI3K inhibition. Hyperglycemia was reported in 65% (grade 3 or 4, 36.9%) of breast cancer patients treated with alpelisib; diabetic ketoacidosis was reported in 0.7% of patients. The median time to the first occurrence of grade 2 or higher hyperglycemia was 15 days; the median time to improvement of at least 1 grade was 8 days. Most patients (76%) who developed hyperglycemia used metformin monotherapy or in combination with other antihyperglycemic medication (i.e., insulin, dipeptidyl peptidase-4 inhibitors, and sulfonylureas); although insulin may be used for 1 to 2 days in patients with severe hyperglycemia, this may not be necessary for most patients as the half-life of alpelisib is short which should result in normalization of blood glucose concentrations after interruption of therapy. As expected, blood glucose was increased more often in patients treated with fulvestrant in combination with alpelisib (n = 284) compared with placebo (n = 287) in the randomized clinical trial (79% vs. 34%; grade 3 or 4, 39% vs. 1%); hyperglycemia was more common in patients age 75 years or older compared to those younger than 75 years (74% vs. 66%; grade 3 or 4, 56% vs. 36%). Decreased blood glucose/hypoglycemia was also reported more often in the alpelisib arm (26% vs. 14%; grade 3 or 4, 0.4% vs. 0%). Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS) and fatal cases of ketoacidosis have occurred in patients treated with alpelisib in postmarketing experience.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, hyperglycemia (12%), increased glucose (56%; grade 3 or 4, 11%), and increased glycosylated hemoglobin (HbA1c) (38%) were reported.[67501]

        Severe pneumonitis, including interstitial pneumonitis and interstitial lung disease, has been reported in patients treated with alpelisib; pneumonitis was reported in 1.8% of patients. Interrupt alpelisib therapy immediately in patients with new or worsening respiratory symptoms and evaluate for pneumonitis. Consider a diagnosis of noninfectious 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. Permanently discontinue therapy if pneumonitis is confirmed.[64248]

        Severe diarrhea, resulting in dehydration and acute kidney injury, occurred in patients treated with alpelisib; colitis has also been reported in postmarketing experience with alpelisib. Diarrhea was reported in 58% (grade 3, 7%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 16% (grade 3, 0.3%) of those receiving placebo plus fulvestrant (n = 287) in a randomized clinical trial. The median time to onset of grade 2 or higher diarrhea was 46 days. Treatment with antidiarrhea medication (e.g., loperamide) was required to manage symptoms in 63% of patients.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, diarrhea was reported in 16% of patients. Dehydration was reported in less than 5% of patients, including 2 patients who experienced severe dehydration.[67501] Monitor patients for diarrhea and additional symptoms of colitis (e.g., abdominal pain and mucus or blood in stool); an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity. Patients with colitis may require treatment with enteric-acting and/or systemic corticosteroids. Educate patients to begin antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs.[64248] [67501]

        An increase in creatinine occurred in 67% of patients treated with alpelisib plus fulvestrant (n = 284) compared with 25% of those who received placebo plus fulvestrant in a randomized clinical trial; grade 3 or 4 renal failure (unspecified) occurred in 2.8% versus 0.7% of patients, respectively. Acute kidney injury was reported in 2.5% of alpelisib-treated patients.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, increased creatinine was reported in 31% of patients.[67501]

        Gastrointestinal adverse reactions were more common in patients treated with alpelisib plus fulvestrant compared with placebo plus fulvestrant, including nausea (45% vs. 22%; grade 3 or 4, 2.5% vs. 0.3%), stomatitis (30% vs. 6%; grade 3 or 4, 2.5% vs. 0%), vomiting (27% vs. 10%; grade 3 or 4, 0.7% vs. 0.3%), mucosal inflammation (19% vs. 1%; grade 3 or 4, 2.1% vs. 0%), abdominal pain (17% vs. 11%; grade 3 or 4, 1.4% vs. 1%), and dyspepsia (11% vs. 6%).[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, stomatitis was reported in 16% of patients. Nausea and vomiting were both reported in less than 5% of patients.[67501]

        Decreased appetite/anorexia (36% vs. 10%; grade 3 or 4, 0.7% vs. 0.3%) and dysgeusia including ageusia and hypogeusia (18% vs. 3.5%; grade 3 or 4, 0.4% vs. 0%) were reported more often in patients treated with alpelisib plus fulvestrant (n = 284) compared with placebo plus fulvestrant (n = 287) in a randomized clinical trial. Weight loss occurred in 27% of alpelisib-treated patients compared with 2.1% of those in the placebo arm (grade 3 or 4, 3.9% vs. 0%).[64248] Decreased appetite was reported during postmarketing experience in patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use.[67501]

        Mucosal dryness, including xerostomia and vulvovaginal dryness, occurred more often in patients treated with alpelisib plus fulvestrant (n = 284) compared with placebo plus fulvestrant (n = 287) in a randomized clinical trial (12% vs. 4.2%; grade 3 or 4, 0.4% vs. 0%).[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, xerostomia/mucosal dryness (less than 5%) was reported.[67501]

        Osteonecrosis of the jaw (ONJ) occurred in 4.2% of patients treated with alpelisib plus fulvestrant (n = 284) compared with 1.4% of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial. All patients experiencing ONJ had prior or concomitant bisphosphonate or RANK-ligand inhibitor administration.[64248]

        Fatigue including asthenia was reported in 42% (grade 3, 5%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 29% (grade 3, 1%) of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] Asthenia has been reported with alpelisib use for PIK3CA-Related Overgrowth Spectrum (PROS).[67501]

        Headache was reported in 18% (grade 3 or 4, 0.7%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 13% of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] Headache was also reported in 5% of patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use.[67501]

        Peripheral edema occurred more often in patients treated with alpelisib plus fulvestrant (n = 284) compared with placebo plus fulvestrant (n = 287) in a randomized clinical trial (15% vs. 5%; grade 3, 0% vs. 0.3%).[64248]

        Increased lipase occurred in 42% (grade 3 or 4, 7%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 25% (grade 3 or 4, 6%) of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial. An interruption of therapy, dose adjustment, or discontinuation of therapy may be necessary for patients who develop pancreatitis.[64248] [67501]

        Elevated hepatic enzymes including increased GGT (52% vs. 44%; grade 3 or 4, 11% vs. 10%) and increased ALT (44% vs. 34%; grade 3 or 4, 3.5% vs. 2.4%) have been reported more often in patients treated with alpelisib plus fulvestrant (n = 284) compared with placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, increased AST (17%), increased GGT (11%), and increased ALT (10%) were reported.[67501]

        Uveitis has been reported in postmarketing experience with alpelisib use in patients with breast cancer.[64248]

        Hematologic abnormalities including leukopenia, lymphopenia, anemia, and thrombocytopenia have been reported in patients treated with alpelisib.[64248] [67501] In a randomized clinical trial comparing patients with advanced breast cancer treated with fulvestrant plus alpelisib (n = 284) or placebo (n = 287), decreased lymphocyte count (52% vs. 40%; grade 3 or 4, 8% vs. 4.5%), decreased hemoglobin (42% vs. 29%; grade 3, 4.2% vs. 1%), and decreased platelet count (14% vs. 6%; grade 3 or 4, 1.1% vs. 0%) were reported more often in the alpelisib arm.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, decreased leukocyte count (22%), decreased hemoglobin (20%; grade 3, 6%), decreased lymphocyte count (20%), decreased neutrophil count (19%), increased lymphocyte count (17%), and decreased platelet count (14%; grade 3, 2%) were reported.[67501]

        Electrolyte abnormalities including hypocalcemia, hypokalemia, hyperkalemia, hypomagnesemia, hyponatremia, hypophosphatemia, and hypertriglyceridemia have been reported in patients treated with alpelisib.[64248] [67501] In a randomized clinical trial of patients with advanced breast cancer treated with fulvestrant plus alpelisib (n = 284) or placebo (n = 287), decreased corrected calcium (27% vs. 20%; grade 3 or 4, 2.1% vs. 1.4%), decreased potassium (14% vs. 2.8%; grade 3 or 4, 6% vs. 0.7%), and decreased magnesium (11% vs. 4.2%; grade 3 or 4, 0.4% vs. 0%) occurred more often in the alpelisib arm.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, decreased corrected calcium (60%), decreased phosphate (59%; grade 3, 5%), increased potassium (24%), increased triglycerides (19%), decreased magnesium (18%), increased cholesterol (13%), decreased sodium (12%; grade 3, 2%), and decreased potassium (12%) were reported.[67501]

        Mild hypoalbuminemia has been reported in patients treated with alpelisib. Grade 1 or 2 decreases in albumin were reported in 14% of patients treated with alpelisib plus fulvestrant (n = 284) compared with 8% of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248] In patients with PIK3CA-related overgrowth spectrum (PROS) receiving alpelisib as part of an expanded access program for compassionate use, hypoalbuminemia (13%) and hyperbilirubinemia (29%; grade 3, 2%) were reported.[67501]

        A prolonged bleeding time manifested as an increased activated partial thromboplastin time (aPTT) was reported in 21% (grade 3, 0.7%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 16% (grade 3, 0.3%) of those who received placebo plus fulvestrant (n = 287) in a randomized clinical trial.[64248]

        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Contraindications/Precautions

        Absolute contraindications are italicized.

        • breast-feeding
        • chronic lung disease (CLD)
        • contraception requirements
        • diabetes mellitus
        • diarrhea
        • hyperglycemia
        • infertility
        • interstitial lung disease
        • male-mediated teratogenicity
        • pneumonitis
        • pregnancy
        • pregnancy testing
        • reproductive risk
        • serious rash
        • type 1 diabetes mellitus

        Alpelisib is contraindicated in patients with severe hypersensitivity to it or any of its components. Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, have been reported in patients treated with alpelisib. Monitor patients for severe hypersensitivity reactions and educate patients on the signs and symptoms including dyspnea, flushing, rash, fever, or tachycardia. Permanently discontinue alpelisib if severe hypersensitivity occurs.[64248][67501]

        Serious rash including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) has occurred in patients treated with alpelisib. Advise patients of the signs and symptoms of severe cutaneous adverse reactions (SCARs) such as a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy. If signs or symptoms of a SCAR occur, interrupt alpelisib therapy until the etiology of the reaction has been determined; consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue therapy; if a SCAR is not confirmed, a dose reduction may be necessary as well as treatment with topical corticosteroids or oral antihistamines. Do not initiate therapy in patients with a history of a SCAR during alpelisib treatment.[64248] [67501]

        Patients with a history of diabetes mellitus may require intensified antihyperglycemic treatment; closely monitor these patients. The safety of alpelisib in patients with type 1 diabetes mellitus and uncontrolled type 2 diabetes has not been established as these patients were excluded from the randomized clinical trial; patients with a history of type 2 diabetes whose blood sugars were controlled were included in the trial. An increase in blood glucose is an expected laboratory abnormality of PI3K inhibition. Monitor fasting blood glucose and hemoglobin A1c (HbA1c) prior to starting treatment and optimize any anti-diabetic treatment. Consider premedication with metformin for adult patients based on clinical situation, risk factors for hyperglycemia, and gastrointestinal tolerability. Continue to monitor fasting blood glucose at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated; monitor more closely in patients with risk factors for hyperglycemia such as obesity (BMI 30 or higher), elevated fasting plasma glucose, HbA1c at or above the upper limit of normal, concomitant use of systemic corticosteroid therapy, or geriatric patients (age 75 or older). Monitor HbA1c every 3 months and as clinically indicated. If a patient develops hyperglycemia after beginning treatment with alpelisib, an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary; monitor blood glucose at least twice weekly or as clinically indicated until concentrations decrease to normal. If antihyperglycemic treatment is initiated, continue monitoring blood glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Educate patients on the signs and symptoms of hyperglycemia.[64248] [67501]

        Use alpelisib with caution in patients who have a history of pre-existing chronic lung disease (CLD); severe pneumonitis/interstitial lung disease has been reported in patients treated with alpelisib. Advise patients to immediately report any new or worsening respiratory symptoms including hypoxia, cough, dyspnea. Immediately interrupt alpelisib therapy for new or worsening respiratory symptoms and evaluate for pneumonitis. Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific respiratory signs and symptoms, or in patients who have interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded using appropriate investigations. Permanently discontinue alpelisib in patients with confirmed pneumonitis.[64248] [67501]

        Severe diarrhea, resulting in dehydration and acute kidney injury, occurred in breast cancer patients treated with alpelisib; colitis has also been reported in postmarketing experience with alpelisib. Mild cases of diarrhea were reported in patients with PIK3Ca-related overgrowth spectrum (PROS). Monitor patients for diarrhea and additional symptoms of colitis (e.g., abdominal pain and mucus or blood in stool); an interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity. Patients with colitis may require treatment with enteric-acting and/or systemic corticosteroids. Educate patients to begin antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs.[64248] [67501]

        Pregnancy should be avoided by females of reproductive potential during alpelisib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, alpelisib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving alpelisib should be apprised of the potential hazard to the fetus. Oral administration of alpelisib to pregnant rats caused maternal toxicity (weight loss, decreased food consumption) and no viable fetuses (postimplantation loss) at doses approximately 3 times the exposure in humans at the recommended dose based on AUC. At approximately 0.8 times the exposure in humans at the recommended dose, 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). In a pilot embryofetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (postimplantation loss). Administering half of this dose increased embryofetal deaths, reduced fetal weights, and caused malformations mostly related to the tail and head; at this dose, the maternal exposure was approximately 5 times that achieved at the recommended human dose based on AUC.[64248]

        Counsel patients about the reproductive risk and contraception requirements during alpelisib treatment. Alpelisib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with alpelisib. Females of reproductive potential should undergo pregnancy testing prior to initiation of alpelisib. Women who become pregnant while receiving alpelisib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during and for at least 1 week after treatment with alpelisib. Although there are no data regarding the effect of alpelisib on human fertility, male and female infertility has been observed in animal studies.[64248]

        Due to the potential for serious adverse reactions in nursing infants from alpelisib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether alpelisib is present in human milk, although many drugs are excreted in human milk.[64248]

        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Mechanism of Action

        Alpelisib is a kinase inhibitor targeting phosphatidylinositol-3-kinase (PI3K); its inhibitory activity primarily targets PI3K-alpha. Gain-of-function mutations in the gene encoding the catalytic alpha-subunit of PI3K (PIK3CA) lead to activation of PI3K-alpha and Akt-signaling, cellular transformation, and the generation of tumors in in vitro and in vivo models.[64248][67501]

         

        In breast cancer cell lines, alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt, and showed activity in cell lines harboring a PI3KCA mutation. In vivo, alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer. 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.[64248]

         

        Activating mutations in PIK3CA have been found to induce a spectrum of overgrowths and malformations comprising a wide group of clinically recognizable disorders commonly known as PIK3CA-related overgrowth spectrum (PROS). In an inducible mouse model of congential lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES), a phenotype of PROS, alpelisib inhibition of the PI3K pathway resulted in the prevention or improvement of organ abnormalities associated with the disease, depending on when alpelisib treatment was started. These findings were reversed after alpelisib withdrawal.[67501]

        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Pharmacokinetics

        Alpelisib is administered orally. It is 89% protein bound, independent of concentration. The mean apparent volume of distribution (Vd) at steady state is predicted to be 114 liters (CV, 46%). The half-life of alpelisib is predicted to be 8 to 9 hours, with a mean clearance of 9.2 liters/hour (CV, 21%) under fed conditions; steady-state plasma concentrations are reached within 3 days after daily dosage. After a single radiolabeled dose under fasted conditions, 81% of the administered dose was recovered in feces (36% unchanged, 32% as metabolite BZG791) and 14% was recovered in urine (2% unchanged, 7.1% BZG791). CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.[64248][67501]

         

        Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, BCRP

        Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 followed by CYP3A4 mediated hydroxylation. It is also an in vitro substrate of BCRP. Alpelisib is an in vitro inhibitor of P-glycoprotein (P-gp), and has a low potential to inhibit BCRP, MRP2, BSEP, OATP1B1, OATP1B3, OCT1, OAT1, OAT3, OCT2, MATE1, and MATE2K at clinically relevant concentrations. No clinically significant differences in the pharmacokinetics of everolimus (a CYP3A4 and P-gp substrate), midazolam (substrate of CYP3A4), repaglinide (substrate of CYP2C8), warfarin (substrate of CYP2C9), omeprazole (substrate of CYP2C19), and bupropion (substrate of CYP2B6) were observed when coadministered with alpelisib.[64248][67501]

        Route-Specific Pharmacokinetics

        Oral Route

        The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors and are presented as mean (% CV) under fed conditions unless otherwise specified. Alpelisib Cmax was 277 ng/mL (24%) and AUC was 2,090 hr x ng/mL (24%) following a single 50 mg oral dose. Steady-state alpelisib Cmax and AUC increased proportionally over the dose range of 30 mg (0.6 times the lowest approved recommended dosage) to 450 mg (1.8 times the highest approved recommended dosage) under fed conditions. The mean accumulation of alpelisib was 1.3 to 1.5 and steady state plasma concentrations were reached within 3 days of daily dosing.[64248][67501]

         

        A high-fat high-calorie (HFHC) meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and Cmax by 84%, and a low-fat low-calorie (LFLC) meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and Cmax by 145% following administration of a single 300 mg dose of alpelisib as tablets. No clinically relevant food effect on alpelisib pharmacokinetics was observed after a single 50 mg dose as oral granules taken with a LFLC meal as compared to that taken under fasted conditions. No clinically relevant differences in alpelisib Cmax and AUC were observed following a single 50 mg dose as oral granules or tablets taken with a LFLC meal. No clinically significant differences in the pharmacokinetics of alpelisib were observed when used concomitantly with ranitidine (H2 receptor antagonist) and administered with food as directed.[64248][67501]

        Special Populations

        Hepatic Impairment

        Hepatic impairment (Child-Pugh A, B, and C) is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib.[64248][67501]

        Renal Impairment

        Mild to moderate renal impairment (CrCl 30 to 89 mL/minute) is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib. The effect of severe renal impairment (CrCl less than 30 mL/minute) on the pharmacokinetics of alpelisib is unknown.[64248][67501]

        Pediatrics

        The pharmacokinetics of alpelisib have not been evaluated in pediatric patients.[67501]

        Geriatric

        Age (range, 21 to 87 years) is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib.[64248][67501]

        Gender Differences

        Gender is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib.[64248][67501]

        Ethnic Differences

        Race/ethnicity (Japanese or Caucasian) is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib.[64248][67501]

        Obesity

        Body weight (37 kg to 181 kg) is not predicted to have a clinically significant effect on the pharmacokinetics of alpelisib.[64248][67501]

        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Pregnancy/Breast-feeding

        pregnancy

        Pregnancy should be avoided by females of reproductive potential during alpelisib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, alpelisib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. Women who are pregnant or who become pregnant while receiving alpelisib should be apprised of the potential hazard to the fetus. Oral administration of alpelisib to pregnant rats caused maternal toxicity (weight loss, decreased food consumption) and no viable fetuses (postimplantation loss) at doses approximately 3 times the exposure in humans at the recommended dose based on AUC. At approximately 0.8 times the exposure in humans at the recommended dose, 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). In a pilot embryofetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (postimplantation loss). Administering half of this dose increased embryofetal deaths, reduced fetal weights, and caused malformations mostly related to the tail and head; at this dose, the maternal exposure was approximately 5 times that achieved at the recommended human dose based on AUC.[64248]

        breast-feeding

        Due to the potential for serious adverse reactions in nursing infants from alpelisib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether alpelisib is present in human milk, although many drugs are excreted in human milk.[64248]

        Revision Date: 09/11/2024, 01:56:00 AM

        References

        64248 - Piqray (alpelisib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2024 Jan.67501 - Vijoice (alpelisib) tablets and oral granules package insert. East Hanover NJ. Novartis Pharmaceuticals Corporation; 2024 April.

        Interactions

        Level 1 (Severe)

        • Dengue Tetravalent Vaccine, Live

        Level 2 (Major)

        • Acalabrutinib
        • Apalutamide
        • Asciminib
        • Atazanavir; Cobicistat
        • Belumosudil
        • Brigatinib
        • Capmatinib
        • Carbamazepine
        • Cobicistat
        • Cyclosporine
        • Danicopan
        • Darolutamide
        • Darunavir; Cobicistat
        • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
        • Elacestrant
        • Elbasvir; Grazoprevir
        • Eltrombopag
        • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
        • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
        • Enasidenib
        • Encorafenib
        • Enzalutamide
        • Fosphenytoin
        • Fostamatinib
        • Fostemsavir
        • Futibatinib
        • Gilteritinib
        • Glecaprevir; Pibrentasvir
        • Ibrutinib
        • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
        • Isoniazid, INH; Rifampin
        • Itraconazole
        • Lazertinib
        • Ledipasvir; Sofosbuvir
        • Leflunomide
        • Lenacapavir
        • Leniolisib
        • Lumacaftor; Ivacaftor
        • Lumacaftor; Ivacaftor
        • Maribavir
        • Midostaurin
        • Mitotane
        • Momelotinib
        • Osimertinib
        • Oteseconazole
        • Pacritinib
        • Phenobarbital
        • Phenobarbital; Hyoscyamine; Atropine; Scopolamine
        • Phenytoin
        • Pirtobrutinib
        • Pretomanid
        • Primidone
        • Regorafenib
        • Rifampin
        • Rifapentine
        • Rolapitant
        • Safinamide
        • Sodium Phenylbutyrate; Taurursodiol
        • Sofosbuvir; Velpatasvir
        • Sofosbuvir; Velpatasvir; Voxilaprevir
        • Sotorasib
        • Sparsentan
        • St. John's Wort, Hypericum perforatum
        • Stiripentol
        • Sulfasalazine
        • Tacrolimus
        • Tafamidis
        • Tedizolid
        • Teriflunomide
        • Vemurafenib

        Level 3 (Moderate)

        • Amlodipine; Celecoxib
        • Celecoxib
        • Celecoxib; Tramadol
        • Cholera Vaccine
        • Glimepiride
        • Pioglitazone; Glimepiride
        • SARS-CoV-2 (COVID-19) vaccines
        • SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine
        • SARS-CoV-2 Virus (COVID-19) mRNA Vaccine
        • SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine
        • Warfarin
        Acalabrutinib: (Major) Avoid coadministration of alpelisib with acalabrutinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and acalabrutinib is a BCRP inhibitor. [62578] [64248] amLODIPine; Celecoxib: (Moderate) Monitor for decreased efficacy of celecoxib during coadministration of alpelisib as plasma concentrations of celecoxib may be decreased. Celecoxib is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer. [28317] [64248] Apalutamide: (Major) Avoid coadministration of alpelisib with apalutamide due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; apalutamide is a strong CYP3A4 inducer. [62874] [64248] Asciminib: (Major) Avoid coadministration of alpelisib with asciminib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and asciminib is a BCRP inhibitor. [64248] [67087] Atazanavir; Cobicistat: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] Belumosudil: (Major) Avoid coadministration of alpelisib with belumosudil due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and belumosudil is a BCRP inhibitor. [64248] [66808] Brigatinib: (Major) Avoid coadministration of alpelisib with brigatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and brigatinib is a BCRP inhibitor. [61909] [64248] Capmatinib: (Major) Avoid coadministration of alpelisib with capmatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and capmatinib is a BCRP inhibitor. [64248] [65377] carBAMazepine: (Major) Avoid coadministration of alpelisib with carbamazepine due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; carbamazepine is a strong CYP3A4 inducer. [41237] [64248] Celecoxib: (Moderate) Monitor for decreased efficacy of celecoxib during coadministration of alpelisib as plasma concentrations of celecoxib may be decreased. Celecoxib is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer. [28317] [64248] Celecoxib; Tramadol: (Moderate) Monitor for decreased efficacy of celecoxib during coadministration of alpelisib as plasma concentrations of celecoxib may be decreased. Celecoxib is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer. [28317] [64248] Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine. [60871] Cobicistat: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] cycloSPORINE: (Major) Avoid coadministration of alpelisib with cyclosporine due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cyclosporine is a BCRP inhibitor. [28404] [64248] Danicopan: (Major) Avoid coadministration of alpelisib with danicopan due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and danicopan is a BCRP inhibitor. [64248] [70492] Darolutamide: (Major) Avoid coadministration of alpelisib with darolutamide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and darolutamide is a BCRP inhibitor. [64248] [64525] Darunavir; Cobicistat: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] Dengue Tetravalent Vaccine, Live: (Contraindicated) Avoid administration of the live dengue virus vaccine with immunosuppressive drug therapy and prior to immune recovery following treatment with immunosuppressive drug therapy. When feasible, administer indicated live virus vaccines at least 4 weeks before planned immunosuppression or wait until at least 3 months after discontinuation. The time to restoration of immune competence may be longer in some patients. Patients with altered immunocompetence may be at increased risk for severe adverse reactions due to uninhibited growth of the attenuated live virus. Additionally, vaccines may be less effective if administered during a period of altered immunocompetence. [60092] [64100] [65107] Elacestrant: (Major) Avoid coadministration of alpelisib with elacestrant due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and elacestrant is a BCRP inhibitor. [64248] [68530] Elbasvir; Grazoprevir: (Major) Avoid coadministration of alpelisib with elbasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and elbasvir is a BCRP inhibitor. [60523] [64248] (Major) Avoid coadministration of alpelisib with grazoprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and grazoprevir is a BCRP inhibitor. [60523] [64248] Eltrombopag: (Major) Avoid coadministration of alpelisib with eltrombopag due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and eltrombopag is a BCRP inhibitor. [40392] [64248] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor. [58000] [64248] Enasidenib: (Major) Avoid coadministration of alpelisib with enasidenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and enasidenib is a BCRP inhibitor. [62181] [64248] Encorafenib: (Major) Avoid coadministration of alpelisib with encorafenib due to altered exposure to alpelisib, which may decrease its efficacy and/or increase the risk of alpelisib-related toxicity. Alpelisib is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on alpelisib exposure is unknown. [63317] [64248] Enzalutamide: (Major) Avoid coadministration of alpelisib with enzalutamide due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; enzalutamide is a strong CYP3A4 inducer. [51727] [64248] Fosphenytoin: (Major) Avoid coadministration of alpelisib with fosphenytoin due to decreased exposure to alpelisib which could decrease efficacy; fosphenytoin exposure may also decrease. Alpelisib is a CYP3A4 substrate and may induce CYP2C9; fosphenytoin is a strong CYP3A4 inducer and a CYP2C9 substrate. [28001] [56579] [64248] Fostamatinib: (Major) Avoid coadministration of alpelisib with fostamatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and fostamatinib is a BCRP inhibitor. [63084] [64248] Fostemsavir: (Major) Avoid concomitant use of alpelisib with fostemsavir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and fostemsavir is a BCRP inhibitor. [64248] [65666] Futibatinib: (Major) Avoid coadministration of alpelisib with futibatinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and futibatinib is a BCRP inhibitor. [64248] [68013] Gilteritinib: (Major) Avoid coadministration of alpelisib with gilteritinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and gilteritinib is a BCRP inhibitor. [63787] [64248] Glecaprevir; Pibrentasvir: (Major) Avoid coadministration of alpelisib with glecaprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and glecaprevir is a BCRP inhibitor. [62201] [64248] (Major) Avoid coadministration of alpelisib with pibrentasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and pibrentasvir is a BCRP inhibitor. [62201] [64248] Glimepiride: (Moderate) Monitor for decreased efficacy of glimepiride during coadministration of alpelisib as plasma concentrations of glimepiride may be decreased. Glimepiride is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer. [35040] [64248] Ibrutinib: (Major) Avoid coadministration of alpelisib with ibrutinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and ibrutinib is a BCRP inhibitor. [56410] [64248] Isoniazid, INH; Pyrazinamide, PZA; rifAMPin: (Major) Avoid coadministration of alpelisib with rifampin due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. [30314] [64248] Isoniazid, INH; rifAMPin: (Major) Avoid coadministration of alpelisib with rifampin due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. [30314] [64248] Itraconazole: (Major) Avoid coadministration of alpelisib with itraconazole due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and itraconazole is a BCRP inhibitor. [27983] [64248] Lazertinib: (Major) Avoid coadministration of alpelisib with lazertinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and lazertinib is a BCRP inhibitor. [64248] [71127] Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of alpelisib with ledipasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and ledipasvir is a BCRP inhibitor. [58167] [64248] Leflunomide: (Major) Avoid coadministration of alpelisib with leflunomide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and leflunomide is a BCRP inhibitor. [49634] [64248] Lenacapavir: (Major) Avoid coadministration of alpelisib with lenacapavir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and lenacapavir is a BCRP inhibitor. [64248] [68383] Leniolisib: (Major) Avoid coadministration of alpelisib with leniolisib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and leniolisib is a BCRP inhibitor. [64248] [68778] Lumacaftor; Ivacaftor: (Major) Avoid coadministration of alpelisib with lumacaftor; ivacaftor due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. [59891] [64248] Lumacaftor; Ivacaftor: (Major) Avoid coadministration of alpelisib with lumacaftor; ivacaftor due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; lumacaftor is a strong CYP3A4 inducer. [59891] [64248] Maribavir: (Major) Avoid coadministration of alpelisib with maribavir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and maribavir is a BCRP inhibitor. [64248] [67137] Midostaurin: (Major) Avoid concomitant use of alpelisib with midostaurin due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and midostaurin is a BCRP inhibitor. [61906] [64248] Mitotane: (Major) Avoid coadministration of alpelisib with mitotane due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; mitotane is a strong CYP3A4 inducer. [41934] [64248] Momelotinib: (Major) Avoid coadministration of alpelisib with momelotinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and momelotinib is a BCRP inhibitor. [64248] [69458] Osimertinib: (Major) Avoid coadministration of alpelisib with osimertinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and osimertinib is a BCRP inhibitor. [60297] [64248] Oteseconazole: (Major) Avoid coadministration of alpelisib with oteseconazole due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and oteseconazole is a BCRP inhibitor. [64248] [67532] Pacritinib: (Major) Avoid coadministration of alpelisib with pacritinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and pacritinib is a BCRP inhibitor. [64248] [67427] PHENobarbital: (Major) Avoid coadministration of alpelisib with phenobarbital due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. [57048] [64248] PHENobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of alpelisib with phenobarbital due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; phenobarbital is a strong CYP3A4 inducer. [57048] [64248] Phenytoin: (Major) Avoid coadministration of alpelisib with phenytoin due to decreased exposure to alpelisib which could decrease efficacy; phenytoin exposure may also decrease. Alpelisib is a CYP3A4 substrate and may induce CYP2C9; phenytoin is a strong CYP3A4 inducer and a CYP2C9 substrate. [28001] [56579] [64248] Pioglitazone; Glimepiride: (Moderate) Monitor for decreased efficacy of glimepiride during coadministration of alpelisib as plasma concentrations of glimepiride may be decreased. Glimepiride is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer. [35040] [64248] Pirtobrutinib: (Major) Avoid coadministration of alpelisib with pirtobrutinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and pirtobrutinib is a BCRP inhibitor. [64248] [68520] Pretomanid: (Major) Avoid coadministration of alpelisib with pretomanid due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and pretomanid is a BCRP inhibitor. [64248] [64561] Primidone: (Major) Avoid coadministration of alpelisib with primidone due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; primidone is a strong CYP3A4 inducer. [56579] [64248] Regorafenib: (Major) Avoid coadministration of alpelisib with regorafenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and regorafenib is a BCRP inhibitor. [51883] [64248] rifAMPin: (Major) Avoid coadministration of alpelisib with rifampin due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; rifampin is a strong CYP3A4 inducer. [30314] [64248] Rifapentine: (Major) Avoid coadministration of alpelisib with rifapentine due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; rifapentine is a strong CYP3A4 inducer. [64248] [65685] Rolapitant: (Major) Avoid coadministration of alpelisib with rolapitant due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and rolapitant is a BCRP inhibitor. [60142] [64248] Safinamide: (Major) Avoid coadministration of alpelisib with safinamide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and safinamide is a BCRP inhibitor. [61825] [64248] SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine. [65107] [66080] Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of alpelisib with taurursodiol due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and taurursodiol is a BCRP inhibitor. [64248] [68007] Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of alpelisib with velpatasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and velpatasvir is a BCRP inhibitor. [60911] [64248] Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of alpelisib with velpatasvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and velpatasvir is a BCRP inhibitor. [60911] [64248] (Major) Avoid coadministration of alpelisib with voxilaprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and voxilaprevir is a BCRP inhibitor. [62131] [64248] Sotorasib: (Major) Avoid coadministration of alpelisib with sotorasib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sotorasib is a BCRP inhibitor. [64248] [66700] Sparsentan: (Major) Avoid coadministration of alpelisib with sparsentan due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sparsentan is a BCRP inhibitor. [64248] [68641] St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of alpelisib with St. John's Wort due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. [57202] [57852] [64248] Stiripentol: (Major) Avoid coadministration of alpelisib with stiripentol due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and stiripentol is a BCRP inhibitor. [63456] [64248] sulfaSALAzine: (Major) Avoid coadministration of alpelisib with sulfasalazine due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sulfasalazine is a BCRP inhibitor. [56579] [64248] Tacrolimus: (Major) Avoid coadministration of alpelisib with tacrolimus due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and tacrolimus is a BCRP inhibitor. [28611] [33537] [64248] Tafamidis: (Major) Avoid coadministration of alpelisib with tafamidis due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and tafamidis is a BCRP inhibitor. [64127] [64248] Tedizolid: (Major) Avoid coadministration of alpelisib with tedizolid due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and tedizolid is a BCRP inhibitor. [57468] [64248] Teriflunomide: (Major) Avoid coadministration of alpelisib with teriflunomide due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and teriflunomide is a BCRP inhibitor. [51794] [64248] Vemurafenib: (Major) Avoid coadministration of alpelisib with vemurafenib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and vemurafenib is a BCRP inhibitor. [45335] [64248] Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with alpelisib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Alpelisib is a weak CYP2C9 inducer and the S-enantiomer, the active metabolite of warfarin, is a CYP2C9 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. [28549] [64248]
        Revision Date: 09/11/2024, 01:56:00 AM

        References

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        Monitoring Parameters

        • blood glucose
        • glycosylated hemoglobin A1c (HbA1c)
        • pregnancy testing

        US Drug Names

        • PIQRAY
        • Vijoice
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