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  • CLASSES

    Small Molecule Antineoplastic Phosphatidylinositol-3-Kinase (PI3K) Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Phosphatidylinositol 3-kinase inhibitor
    Used in combination with fulvestrant for certain types of breast cancer
    Safety in patients with Type 1 and uncontrolled Type 2 diabetes has not been established

    COMMON BRAND NAMES

    PIQRAY

    HOW SUPPLIED

    Alpelisib/PIQRAY Oral Tab: 150mg, 200mg, 50-200mg

    DOSAGE & INDICATIONS

    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.
    For the treatment of hormone receptor (HR)-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer in men and postmenopausal women following progression on or after an endocrine-based regimen, in combination with fulvestrant.
    Oral dosage
    Males and postmenopausal females

    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 whose disease had progressed or recurred on or after aromatase inhibitor-based treatment (11 months vs. 5.7 months); one or more PIK3CA mutations were present in the tissue of 60% of enrolled patients. No PFS benefit was observed in patients whose tumors did not have a PIK3CA tissue mutation. Overall survival data were immature. 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.

    MAXIMUM DOSAGE

    Adults

    300 mg PO once daily.

    Geriatric

    300 mg PO once daily.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment
    Dose adjustments are not necessary.
     
    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. 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.
    Grade 3: Interrupt alpelisib therapy and initiate appropriate medical therapy; monitor as clinically indicated. When 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.
    Grade 4: Permanently discontinue alpelisib.

    Renal Impairment

    Baseline Renal Impairment
    Dose adjustments are not necessary.

    ADMINISTRATION

    Oral Administration

    Administer alpelisib with food at approximately the same time each day.
    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.
    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.
    If vomiting occurs, do not administer an additional dose on that day. Resume dosing the following day at the usual time.[64248]

    STORAGE

    PIQRAY:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    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.

    Serious rash

    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.
     

    Diabetes mellitus, hyperglycemia, type 1 diabetes mellitus

    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. Fasting blood glucose and hemoglobin A1c (HbA1c) should be monitored prior to starting treatment and any anti-diabetic treatment optimized. 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 levels 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]

    Chronic lung disease (CLD), interstitial lung disease, pneumonitis

    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]

    Diarrhea

    Severe diarrhea, including dehydration and acute kidney injury, occurred in patients treated with alpelisib. Diarrhea was reported in 58% (grade 3 or 4, 7%) of patients treated with alpelisib plus fulvestrant (n = 284) compared with 16% (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 higher diarrhea was 46 days. Treatment with anti-diarrheal medication (e.g., loperamide) was required to manage symptoms in 63% of patients. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of diarrhea. Educate patients to begin antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs.[64248]

    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]

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    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.

    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.

    ADVERSE REACTIONS

    Severe

    hyperglycemia / Delayed / 36.9-56.0
    rash / Early / 12.0-20.0
    elevated hepatic enzymes / Delayed / 3.5-11.0
    diarrhea / Early / 7.0-7.0
    fatigue / Early / 5.0-5.0
    weight loss / Delayed / 3.9-3.9
    renal failure (unspecified) / Delayed / 2.8-2.8
    stomatitis / Delayed / 2.5-2.5
    nausea / Early / 2.5-2.5
    abdominal pain / Early / 1.4-1.4
    erythema multiforme / Delayed / 1.1-1.1
    pruritus / Rapid / 0.7-0.7
    infection / Delayed / 0.7-0.7
    fever / Early / 0.7-0.7
    diabetic ketoacidosis / Delayed / 0.7-0.7
    vomiting / Early / 0.7-0.7
    anorexia / Delayed / 0.7-0.7
    headache / Early / 0.7-0.7
    prolonged bleeding time / Delayed / 0.7-0.7
    xerosis / Delayed / 0.4-0.4
    Stevens-Johnson syndrome / Delayed / 0.4-0.4
    hypoglycemia / Early / 0.4-0.4
    dysgeusia / Early / 0.4-0.4
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    osteonecrosis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    peripheral edema / Delayed / 15.0-15.0
    pneumonitis / Delayed / 1.8-1.8
    dyspnea / Early / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    hypomagnesemia / Delayed / Incidence not known
    hypocalcemia / Delayed / Incidence not known
    hypoalbuminemia / Delayed / Incidence not known

    Mild

    alopecia / Delayed / 20.0-20.0
    dyspepsia / Early / 11.0-11.0
    maculopapular rash / Early / Incidence not known
    flushing / Rapid / Incidence not known
    xerostomia / Early / Incidence not known
    asthenia / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    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.
    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.
    Belladonna Alkaloids; Ergotamine; 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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Daclatasvir: (Major) Avoid coadministration of alpelisib with daclatasvir 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 daclatasvir is a BCRP inhibitor.
    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.
    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.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of alpelisib with dasabuvir 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 dasabuvir is a BCRP inhibitor. (Major) Avoid coadministration of alpelisib with paritaprevir 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 paritaprevir is a BCRP inhibitor.
    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. (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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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. (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.
    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.
    Glimepiride; Rosiglitazone: (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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of alpelisib with paritaprevir 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 paritaprevir is a BCRP inhibitor.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    Simeprevir: (Major) Avoid coadministration of alpelisib with simeprevir 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 simeprevir is a BCRP inhibitor.
    Sirolimus: (Major) Avoid coadministration of alpelisib with sirolimus 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 sirolimus is a BCRP inhibitor.
    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.
    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. (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.
    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.
    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.
    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.
    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.
    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.
    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.
    Tolbutamide: (Moderate) Monitor for decreased efficacy of tolbutamide during coadministration of alpelisib as plasma concentrations of tolbutamide may be decreased. Tolbutamide is a sensitive CYP2C9 substrate; in vitro data suggest alpelisib is a CYP2C9 inducer.
    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.
    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.

    PREGNANCY AND LACTATION

    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]

    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.

    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. 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.[64248]
     
    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]

    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 following daily dosage. Following 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]
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP2C9, CYP3A4, BCRP
    Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to a lesser extent by CYP3A4, in vitro. It is also an in vitro substrate of BCRP. Alpelisib inhibits CYP3A4 in a time-dependent manner and induces CYP2B6, CYP2C9, and CYP3A4 in vitro. 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, OCT2, MATE1, and MATE2K at clinically relevant concentrations. No clinically significant differences in the pharmacokinetics of everolimus (a CYP3A4 and P-gp substrate) were observed when coadministered with alpelisib.[64248]

    Oral Route

    In adult breast cancer patients who received alpelisib at the recommended dosing in the SOLAR-1 trial, population approach derived mean steady-state alpelisib Cmax was 2,480 ng/mL (CV, 23%) and AUC was 33,224 ng x hour/mL (CV, 21%). The median time to reach peak plasma concentration (Tmax) ranged from 2 to 4 hours. Steady-state alpelisib Cmax and AUC increased proportionally over the dose range of 30 mg to 450 mg (0.1 to 1.5 times the approved recommended dosage) under fed conditions. The mean accumulation of alpelisib is 1.3 to 1.5. [64248]
     
    A high-fat, high-calorie meal (985 calories, 58.1 g fat) increased the AUC of alpelisib by 73% and the Cmax by 84% after a single dose. A low-fat, low-calorie meal (334 calories, 8.7 g fat) increased the AUC of alpelisib by 77% and the Cmax by 145% after a single dose. No clinically significant differences in the AUC of alpelisib were observed between low-fat, low-calorie and high-fat, high-calorie meals. Alpelisib can be administered with acid-reducing agents since it should be taken with food. Food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH value. Coadministration with ranitidine decreased the AUC and Cmax of alpelisib by 21% and 36%, respectively, with a low-fat, low-calorie meal. Under the fasted state, the AUC and Cmax of alpelisib decreased on average by 30% and 51% with ranitidine.[64248]