Pivikto

Alpelisib.

Active substance: Film-coated tablets containing alpelisib.
Excipients/Inactive Ingredients: Film-coated tablet core: Microcrystalline cellulose, mannitol, sodium starch glycolate, hypromellose and magnesium stearate.
Coating material: Hypromellose, titanium dioxide, macrogol / polyethylene glycol (PEG), talc, iron oxide red, and iron oxide black.

Pharmacology: Mechanism of action: Alpelisib is an α specific class I phosphatidylinositol3kinase (PI3Kalpha) inhibitor.
Class I PI3K lipid kinases are key components of the PI3K/AKT/mTOR (mammalian target of rapamycin) signaling pathway.
Gain-of-function mutations in the gene encoding the catalytic alpha-subunit of PI3K (PIK3CA) lead to activation of PI3Kalpha manifested by increased lipid kinase activity, growth-factor independent activation of Akt-signaling, cellular transformation and the generation of tumors in a diverse array of preclinical models.
In vitro, alpelisib treatment potently inhibited the phosphorylation of PI3K downstream targets Akt as well as its various downstream effectors in breast cancer cells and showed selectivity towards cell lines harboring a PIK3CA mutation.
In vivo, alpelisib showed good tolerability as well as dose-and time-dependent inhibition of the PI3K/Akt pathway and dose-dependent tumor growth inhibition in relevant tumor xenograft models, including models of breast cancer.
PI3K inhibition by alpelisib treatment has been shown to induce an increase in ER transcription in breast cancer cells, therefore, sensitizing these cells to estrogen receptor (ER) inhibition by fulvestrant treatment. Combination of alpelisib and fulvestrant demonstrated increased anti-tumor activity than either treatment alone in xenograft models derived from ER+, PIK3CA mutated breast cancer cell lines (MCF-7 and KPL1).
Pharmacodynamics: In biochemical assays, alpelisib inhibited wild type PIK3alpha (IC₅₀=4.6 nmol/L) and its 2 most common somatic mutations (H1047R, E545K) (IC₅₀~4 nmol/L) more potently than the PI3Kdelta (IC₅₀=290 nmol/L) and PI3Kgamma (IC₅₀=250 nmol/L) isoforms and showed significantly reduced activity against PI3Kbeta (IC₅₀=1,156 nmol/L).
The potency and selectivity of alpelisib was confirmed at the cellular level in mechanistic and relevant tumor cell lines.
Cardiac electrophysiology: Serial, triplicate ECGs (electrocardiogram) were collected following a single dose and at steady-state to evaluate the effect of alpelisib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 134 patients treated with alpelisib at doses ranging from 30 to 450 mg.
The analysis demonstrates the absence of a clinically significant QTcF prolongation at the recommended 300 mg dose with or without fulvestrant. The estimated mean change from baseline in QTcF was <10 msecs (7.2 ms; 90% CI: 5.62, 8.83) at the observed geometric-mean Cmax at steady-state (2,900 ng/mL) following single agent administration at the recommended 300 mg dose.
Clinical Studies: Alpelisib (Pivikto) was evaluated in a pivotal phase III, randomized, double-blind, placebo controlled study of alpelisib (Pivikto) in combination with fulvestrant in men and postmenopausal women with HR+, HER2- locally advanced breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor based treatment (with or without CDK4/6 combination).
A total of 572 patients were enrolled into two cohorts, cohort with PIK3CA mutation or cohort without PIK3CA mutation breast cancer. PIK3CA mutation status was determined by clinical trial assays. Patients were randomized to receive either alpelisib (Pivikto) 300 mg plus fulvestrant or placebo plus fulvestrant in a 1:1 ratio. Randomization was stratified by presence of lung and/or liver metastasis and previous treatment with CDK4/6 inhibitor(s).
Within the cohort with a PIK3CA mutation, 169 patients were randomized to receive alpelisib (Pivikto) in combination with fulvestrant and 172 patients were randomized to placebo in combination with fulvestrant. Within this cohort, 170 (49.9%) patients had liver/lung metastases and 20 (5.9%) patients had received prior CDK4/6 inhibitor treatment.
Within the cohort without PIK3CA mutation, 115 patients were randomized to receive alpelisib (Pivikto) in combination with fulvestrant and 116 were randomized to receive placebo in combination with fulvestrant. 112 (48.5%) patients had liver/lung metastases and 15 (6.5%) patients had prior CDK4/6 inhibitor treatment.
In the cohort with PIK3CA mutation, 97.7% of patients received prior hormonal therapy and 47.8% of patients had the last setting as metastatic and 51.9% of patients whose last setting was adjuvant therapy. Overall, 85.6% of the patients were considered to have endocrine resistant disease; primary endocrine resistance was observed in 13.2% and secondary endocrine resistance in 72.4% of patients.
In both cohorts with or without PIK3CA mutation, demographics and baseline disease characteristics, ECOG ( Eastern Cooperative Oncology Group) performance status, tumor burden, and prior antineoplastic therapy were well balanced between the study arms.
During the randomized treatment phase, alpelisib (Pivikto) 300 mg or alpelisib (Pivikto) matching placebo was administered orally once daily on a continuous basis. Fulvestrant 500 mg was administered intramuscularly on Cycle 1 Day 1 and 15 and then at Day 1 of a 28-day cycle during treatment phase (administration +/- 3 days).
Patients were not allowed to cross over from placebo to alpelisib (Pivikto) during the study or after disease progression.
The primary endpoint for the study was progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), based on the investigator assessment in patients with a PIK3CA mutation. The key secondary endpoint was overall survival (OS) for patients with a PIK3CA mutation.
Other secondary endpoints included PFS for patients without a PIK3CA mutation, OS for patients without a PIK3CA mutation, as well as overall response rate (ORR) and clinical benefit rate (CBR) by PIK3CA mutation cohort.
Cohort with PIK3CA mutation: Patients enrolled with a PIK3CA mutation had a median age of 63 years (range 25 to 92). 44.9% patients were 65 years of age or older and <85 years. The patients included were White (66.3%), Asian (21.7%), Black or African American (1.2%).
Primary analysis: The study met its primary objective at the final PFS analysis (data cut-off date 12-June-2018) demonstrating statistically significant improvement in PFS by investigator assessment in the PIK3CA mutant cohort for patients receiving alpelisib (Pivikto) plus fulvestrant, compared to patients receiving placebo plus fulvestrant (HR = 0.65 with 95% CI: 0.50, 0.85; one sided stratified log-rank test p= 0.00065), with an estimated 35% risk reduction of disease progression or death in favor of treatment with alpelisib (Pivikto) plus fulvestrant. The median PFS was prolonged by 5.3 months, from 5.7 months (95% CI: 3.7, 7.4) in the placebo plus fulvestrant arm to 11 months (95% CI: 7.5, 14.5) in the alpelisib (Pivikto) plus fulvestrant arm.
Primary PFS results were supported by consistent results from a blinded independent review committee (BIRC) assessment in this cohort, which included a randomly selected subset of 50% of randomized patients (HR= 0.48 with 95% CI: 0.32, 0.71).
PFS results are summarized in Table 1, Figure 1 and 2. (See Table 1 and Figures 1 and 2.)

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PFS subgroup analyses by randomization stratification factors demonstrated a homogeneous and generally consistent treatment effect per investigator assessment across major demographic and prognostic subgroups irrespective of CDK4/6i prior treatment and presence or absence of lung/liver metastases.
Although limited in patient numbers, for the analysis of prior CDK4/6i treatment sub-group, the HR (95% CI) for PFS was 0.48 (0.17, 1.36).
In the subgroup of patients with presence of lung/liver metastases, the HR (95% CI) was 0.62 (0.44, 0.89). See Figure 3.

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Treatment with the combination of alpelisib (Pivikto) plus fulvestrant was associated with marked improvements in ORR and CBR relative to placebo + fulvestrant. See Table 2 for details. (See Table 2.)

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The global health status/Quality of Life (QoL) outcomes were similar between the alpelisib (Pivikto) plus fulvestrant arm and the placebo plus fulvestrant arm. Time-to-Deterioration (TTD) in global health status EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30) was defined as time between baseline and first occurrence of ≥10 point worsening of global health status (EORTC QLQ-C30 global health scale score) compared to baseline with no later improvement above this threshold observed during the treatment period or death due to any cause. The addition of alpelisib (Pivikto) to fulvestrant showed no relevant difference in TTD in EORTC QLQ-C30 global health scale score compared with placebo plus fulvestrant, (HR=1.03; 95% CI:0.72, 1.48).
Final OS Analysis: The final OS analysis was conducted using a data cut-off date of 23-Apr-2020 and PFS was re-run using this data cut. With a median duration from randomization to data cut-off of approximately 42 months, the PFS benefit was sustained and consistent with results from the final PFS analysis. There was an estimated 36% risk reduction of progression or death in favor of treatment with alpelisib (Pivikto) plus fulvestrant (HR = 0.64; 95% CI: 0.50, 0.81). See Figure 4 for details. (See Figure 4.)

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At the final OS analysis, the study did not meet its key secondary objective. As of the data cut-off date of 23-Apr-2020, a total of 87 (51.5%) deaths were reported in the alpelisib (Pivikto) plus fulvestrant arm and 94 (54.7%) in the placebo plus fulvestrant arm. The HR was 0.86 (95% CI: 0.64, 1.15; p = 0.15, one-sided) and the pre-specified O'Brien-Fleming efficacy boundary of p ≤ 0.0161 was not crossed. Median OS was prolonged by a clinically relevant 7.9 months, from 31.4 months (95% CI: 26.8, 41.3) in the placebo plus fulvestrant arm to 39.3 months (95% CI: 34.1, 44.9) in the alpelisib (Pivikto) plus fulvestrant arm. See Figure 5 for details. (See Figure 5.)

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OS subgroup analyses by randomization stratification factors demonstrated a homogeneous and generally consistent treatment effect per investigator assessment. Although limited in patient numbers, for the analysis of prior CDK4/6i treatment subgroup, median OS in the alpelisib (Pivikto) plus fulvestrant arm was 29.8 months (95% CI: 6.7, 38.2) compared to 12.9 months (95% CI: 2.5, 34.6) in the placebo plus fulvestrant arm. In the subgroup of patients with presence of lung/liver metastases, median OS in the alpelisib (Pivikto) plus fulvestrant arm was 37.2 months (95% CI: 28.7, 43.6) compared to 22.8 months (95% CI: 19, 26.8) in the placebo plus fulvestrant arm.
Cohort without PIK3CA mutation: The proof of concept criteria to conclude a treatment benefit with alpelisib (Pivikto) and fulvestrant with respect to PFS in patients in the PIK3CA non-mutant cohort were not met (HR = 0.85; 95% CI: 0.58, 1.25) (see DOSAGE & ADMINISTRATION).
Pharmacokinetics: The pharmacokinetics of alpelisib were investigated in patients under an oral dosing regimen ranging from 30 to 450 mg daily. Healthy subjects received single oral doses ranging from 300 mg to 400 mg. The PK was mostly comparable in both oncology patients and healthy subjects.
Absorption: Following oral administration of alpelisib, median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours, independent of dose, time or regimen. Based on absorption modelling bioavailability was estimated to be very high (>99%) under fed conditions but lower under fasted conditions (~68.7% at a 300 mg dose). Steady-state plasma levels of alpelisib after daily dosing can be expected to be reached on day 3, following onset of therapy in most patients.
Food effect: Alpelisib absorption is affected by food. In healthy volunteers after a single 300 mg oral dose of alpelisib, compared to the fasted state, a high-fat high-calorie (HFHC) meal (985 calories with 58.1 g of fat) increased AUCinf by 73% and Cmax by 84%, and a low-fat low-calorie (LFLC) meal (334 calories with 8.7 g of fat) increased AUCinf by 77% and Cmax by 145%. No significant difference was found for AUCinf between LFLC and HFHC with a geometric mean ratio of 0.978 [CI: 0.876, 1.09] showing that neither fat content nor overall caloric intake has a considerable impact on absorption. The increase in gastrointestinal solubility by bile, secreted in response to food intake, is considered to be the driver of the food effect. Hence, alpelisib (Pivikto) should be taken immediately after food, at approximately the same time each day.
Acid reducing agents: The co-administration of the H2 receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib slightly reduced the bioavailability of alpelisib and decreased overall exposure of alpelisib. In the presence of a LFLC meal, AUCinf was decreased on average by 21% and Cmax by 36% with ranitidine. In the absence of food, the effect was more pronounced with a 30% decrease in AUCinf and a 51% decrease in Cmax with ranitidine compared to the fasted state without co-administration of ranitidine. Alpelisib (Pivikto) can be co-administered with drugs that are acid-reducing agents, if alpelisib (Pivikto) is taken immediately after food. Population pharmacokinetic analysis showed no significant effect on the PK of alpelisib (Pivikto) by co-administration of acid reducing agents including proton pump inhibitors, H2 receptor antagonists and antacids.
Distribution: Alpelisib moderately binds to protein with a free fraction of 10.8% regardless of concentration. Alpelisib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.03. There was no evidence for distribution into red blood cells caused by metabolites. Alpelisib did not penetrate the blood-brain-barrier in rats. As alpelisib (Pivikto) is a substrate of human efflux transporters, penetration of the blood-brain-barrier is not expected to occur in human. The volume of distribution of alpelisib at steady-state (Vss/F) is estimated at 114 L (intersubject CV% 46%).
Biotransformation/metabolism: In vitro studies demonstrated that formation of the hydrolysis metabolite BZG791 by chemical and enzymatic amide hydrolysis was a major metabolic pathway, followed by CYP3A4 mediated hydroxylation. Alpelisib hydrolysis occurs systemically by both chemical decomposition and enzymatic hydrolysis via ubiquitously expressed, high-capacity enzymes (esterases, amidases, choline esterase) not limited to the liver. CYP3A4-mediated metabolites and glucuronides amounted to ~15% of the dose BZG791 accounted for ~40 to 45% of the dose. The rest of the dose, which was found as unchanged alpelisib in urine and feces, was either excreted as alpelisib or non-absorbed.
Elimination: Alpelisib exhibits low clearance with 9.2 L/hr (CV% 21%) based on population PK analysis under fed conditions. The population derived half-life, independent of dose and time, was 8 to 9 hours at steady state of 300 mg, once daily.
In human mass-balance study, after oral administration, alpelisib and its metabolites were primarily found in the feces (81.0%), as alpelisib or metabolized as BZG791. Excretion in the urine is minor (13.5%), with 2% of unchanged alpelisib. Following single oral dose of [14C]- alpelisib, 94.5% of the total administered radioactive dose was recovered within 8 days.
Linearity/non-linearity: The pharmacokinetics were found to be linear with respect to dose and time under fed conditions between 30 and 450 mg. After multiple doses, alpelisib exposure (AUC) at steady-state is only slightly higher than that of a single dose with an average accumulation of 1.3 to 1.5 with a daily dosing regimen.
Metabolic interaction: Based on the results of metabolic in vitro induction and inhibition studies, alpelisib may induce the metabolic clearance of co-medications metabolized by CYP2B6, CYP2C9 and CYP3A4 and may inhibit the metabolic clearance of co-medications metabolized CYP3A4 (time-dependent inhibition) if sufficiently high concentrations are achieved in vivo.
In a drug-drug interaction study, co-administration of alpelisib with everolimus, a sensitive CYP3A4 substrate, confirmed that there are no clinically significant pharmacokinetic interactions (increase in AUC by 11.2%) between alpelisib and CYP3A4 substrates. No change in everolimus exposure was observed at alpelisib doses ranging from 250 to 300 mg, also confirmed by PBPK modeling with everolimus and midazolam (≤ 15% increase in AUC). Due to the concurrent induction and time-dependent inhibition by alpelisib, PBPK simulations with substrates of CYP3A4 that also possess an additional time-dependent inhibition and induction potential on CYP3A4 that affects their own metabolism predict changes in exposure (decrease or increase) less than 2-fold, depending on the substrate.
In a drug-drug interaction study, co-administration of alpelisib with rifampin, a strong CYP3A4 inducer, confirmed that there is a clinically significant pharmacokinetic interaction between alpelisib and strong CYP3A4 inducers leading to a decrease in AUC by 57% and 74% for a single 300 mg dose and a repeated 300 mg dose of alpelisib, respectively (see INTERACTIONS).
CYP2C9 substrates: In lieu of a clinical study, PBPK modeling showed that AUC and Cmax ratios of warfarin (10 mg single dose) were estimated to be 0.91 and 0.99, respectively, after repeated co-administration of alpelisib (300 mg), indicating no or weak induction potential of alpelisib on CYP2C9.
Transporter-based interaction: Alpelisib showed only weak in vitro inhibition towards the ubiquitously expressed efflux transporters (P-gp, BCRP, MRP2, BSEP), solute carrier transporters at the liver inlet (OATP1B1, OATP1B3, OCT1) and solute carrier transporters in the kidney (OAT1, OAT3, OCT2, MATE1, MATE2K. As unbound systemic steady state concentrations (or concentrations at the liver inlet) at both the therapeutic dose and maximum tolerated dose are significantly lower than the experimentally determined unbound inhibition constants or IC50, the inhibition will not translate into clinical significance. A clinically relevant effect on P-gp substrates can be excluded.
Fulvestrant: Data from a clinical study in patients with breast cancer indicated no effect of fulvestrant on alpelisib exposure (and vice versa) following co-administration of the drugs.
Special populations: Effect of age, weight and gender: The population PK analysis showed that there are no clinically relevant effects of age, body weight, or gender on the systemic exposure of alpelisib that would require alpelisib (Pivikto) dose adjustment.
Pediatric patients (below 18 years): The pharmacokinetics of alpelisib (Pivikto) in pediatric patients have not been established.
Geriatric patients (65 years or above): Of 284 patients who received alpelisib (Pivikto) in the phase III study (in alpelisib (Pivikto) plus fulvestrant arm), 117 patients were ≥65 years of age and 34 patients were ≥75 years of age. No overall differences in safety or effectiveness of alpelisib (Pivikto) were observed between these patients and younger patients (see DOSAGE & ADMINISTRATION).
Race/Ethnicity: Population PK analyses and PK analysis from a single agent study in Japanese cancer patients showed that there are no clinically relevant effects of ethnicity on the systemic exposure of alpelisib (Pivikto).
Non-compartmental PK parameters after single and multiple daily doses of alpelisib (Pivikto) for Japanese patients were very similar to those reported in the Caucasian population.
Renal impairment: No dose adjustment is necessary in patients with mild or moderate renal impairment. Patients with severe renal impairment have not been studied and caution should be used. Based on a population pharmacokinetic analysis that included 117 patients with normal renal function (eGFR [estimated glomerular filtration rate] ≥90 mL/min/1.73 m²) / (CLcr ≥90 mL/min), 108 patients with mild renal impairment (eGFR 60 to <90 mL/min/1.73m²)/ (CLcr 60 to <90 mL/min), and 45 patients with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m²), mild and moderate renal impairment had no effect on the exposure of alpelisib (see DOSAGE & ADMINISTRATION).
Hepatic impairment: No dose adjustment is necessary in patients with mild, moderate or severe hepatic impairment (Child-Pugh A, B and C).
Based on a pharmacokinetic trial in patients with hepatic impairment, moderate and severe hepatic impairment had negligible effect on the exposure of alpelisib (see DOSAGE & ADMINISTRATION). The mean exposure for alpelisib was increased by 1.26-fold in patients with severe (GMR [geometric mean ratio]: 1.00 for C_max; 1.26 for AUC_last/AUC_inf) hepatic impairment.
Based on a population pharmacokinetic analysis that included 230 patients with normal hepatic function, 45 patients with mild hepatic impairment and no patients with moderate hepatic impairment, further supporting the findings from the dedicated hepatic impairment study, mild and moderate hepatic impairment had no effect on the exposure of alpelisib, (see DOSAGE & ADMINISTRATION).
Toxicology: Non-Clinical Safety Data: Alpelisib was evaluated in safety pharmacology, single- and repeated dose toxicity, genotoxicity and photo-toxicity studies.
Safety pharmacology and repeat dose toxicity: The majority of the observed alpelisib effects were related to the pharmacological activity of alpelisib as a p110alpha specific inhibitor of the PI3K pathway, such as the influence on the glucose homeostasis resulting in hyperglycemia and the risk of increased blood pressure.
The bone marrow and lymphoid tissue, pancreas, and some reproductive organs of both genders were the main target organs for adverse effects, which were generally reversible upon cessation of treatment. Alpelisib showed no effect on neuronal or pulmonary function. No evidence of skin irritation or corrosion was observed with alpelisib.
Cardiovascular safety pharmacology: In an in vitro hERG (human Ether-à-go-go-Related Gene) test, (where functionality of the human cardiac hERG channel heterologously expressed in HEK293 cells in vitro is assessed), an IC₅₀ of 9.4 microM (4.2 microgram/mL) was found. No relevant electrophysiological effect was seen in dogs in several studies, up to single doses of 180 mg/kg in-vivo. An in vivo telemetry study in dogs showed an elevated blood pressure, starting at exposure lower than the exposure in humans, at the highest recommended dose of 300 mg/day.
Carcinogenicity and mutagenicity: No carcinogenicity studies have been conducted.
Alpelisib was not mutagenic in a Salmonella reverse mutation test in five strains, or aneugenic or clastogenic in human cell micronucleus and chromosome aberration tests in vitro. Also, an in vivo micronucleus test in peripheral blood reticulocytes obtained in week 4 of a 13-week rat repeated-dose toxicity study at dose levels of up to 20 mg/kg/day, at plasma exposure levels of about 1.7 times the exposure in humans at the highest recommended dose of 300 mg/day based on AUC, was negative.
Fertility and Reproductive toxicity: Please see USE IN PREGNANCY & LACTATION.
In repeated-dose toxicity studies up to 13 weeks duration, adverse effects were observed in reproductive organs of females and males, such as vaginal atrophy and oestrus cycle variations in rats (at or above 6 mg/kg/day, a dose that provides plasma exposure levels below the exposure in humans, at the highest recommended dose of 300 mg/day based on AUC), or prostate atrophy in dogs (at 15 mg/kg/day, at plasma exposure levels about 2.8 times the exposure in humans, at the highest recommended dose of 300 mg/day based on AUC) (see USE IN PREGNANCY & LACTATION). In general, the observed effects were reversible upon treatment discontinuation.
In fertility studies conducted in male and female rats, similar effects on fertility were observed. In females at doses of 20 mg/kg/day (approximately 1.7 times the estimated exposure (AUC) in humans at the recommended dose of 300 mg), increased pre- and post-implantation losses led to reduced numbers of implantation sites and live embryos. The NOAEL (No-observed-adverse- effect-level) for female fertility was determined at 10 mg/kg/day (at exposure levels (AUC) at or below the recommended human dose of 300 mg). In males, at doses of ≥ 10 mg/kg/day, accessory glands weights (seminal vesicles, prostate) were reduced and correlated microscopically with atrophy and/or reduced secretion in prostate and seminal vesicles, respectively. Male fertility parameters were unaffected at doses up to 20 mg/kg/day.
Toxicokinetic endpoints were not included in either of the two fertility studies since the toxicokinetic parameters of alpelisib in rats had been sufficiently established earlier.
Phototoxicity: An in vitro phototoxicity test on the on the mouse Balb/c 3T3 fibroblast cell line did not identify a relevant phototoxicity potential for alpelisib.
Juvenile animal studies: Juvenile animal studies are not available.

Alpelisib (Pivikto) is an alpha-specific class I phosphatidylinositol-3-kinase (PIK3CA) inhibitor indicated for the treatment of postmenopausal women, and men, with hormone receptor positive, HER2-negative, advanced breast cancer with a PIK3CA mutation in combination with fulvestrant after disease progression following an endocrine-based regimen.

Treatment with alpelisib (Pivikto) should be initiated by a physician experienced in the use of anticancer therapies.
Dosage regimen: General target population: Patients with HR (hormone receptor) positive, HER2 negative advanced breast cancer should be selected for treatment with alpelisib (Pivikto), based on the presence of a PIK3CA mutation in tumor or plasma specimens, using a validated test. If a mutation is not detected in a plasma specimen, test tumor tissue if available.
There was no treatment benefit demonstrated in patients without PIK3CA mutations in the phase III clinical study (see PHARMACOLOGY: PHARMACODYNAMICS: CLINICAL STUDIES under ACTIONS).
The recommended dose of alpelisib (Pivikto) is 300 mg (2×150 mg film-coated tablets) taken orally, once daily on a continuous basis. Alpelisib (Pivikto) should be taken immediately following food, at approximately the same time each day (see PHARMACOLOGY under ACTIONS and INTERACTIONS). The maximum recommended daily dose of alpelisib (Pivikto) is 300 mg. If a dose of alpelisib (Pivikto) is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day. On the next day, alpelisib (Pivikto) should be taken at its usual time. If the patient vomits after taking the alpelisib (Pivikto) dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day, at the usual time.
When co-administered with alpelisib (Pivikto), the recommended dose of fulvestrant is 500 mg administered intramuscularly on days 1, 15 and, 29, and once monthly thereafter. Please refer to the full prescribing information of fulvestrant.
Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. Dosing modifications may be necessary to improve tolerability.
Dosing modifications: The recommended daily dose of alpelisib (Pivikto) is 300 mg. Management of severe or intolerable adverse drug reactions (ADRs) may require temporary dosing interruption, reduction, and/or discontinuation of alpelisib (Pivikto). If dosing reduction is required, the dosing reduction guidelines for ADRs are listed in Table 3. A maximum of 2 dosing reductions are recommended, after which the patient should be discontinued from treatment with alpelisib (Pivikto). Dosing reduction should be based on worst preceding toxicity. (See Table 3.)

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Tables 4, 5, 6 and 7 summarize recommendations for dosing interruption, reduction or discontinuation of alpelisib (Pivikto) in the management of specific ADRs. Clinical judgment of the treating physician, including confirmation of laboratory values if deemed necessary, should guide the management plan of each patient based on the individual benefit/risk assessment for treatment with alpelisib (Pivikto).
Hyperglycemia: Consultation with a Healthcare Professional (HCP) with experience in the management of hyperglycemia should be considered and lifestyle changes as per local guidelines (e.g. American Diabetes Association (ADA)), including exercise and dietary advice should be recommended/reinforced (e.g. small frequent meals, low carbohydrate, high fiber, low processed food intake, three macronutrient balanced meals and 2 optional small snacks rather than one large meal).
In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated (see PRECAUTIONS). (See Table 4.)

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Rash: Oral antihistamine administration may be considered prophylactically, at the time of initiation of treatment with alpelisib (Pivikto). Based on the severity of rash, alpelisib (Pivikto) may require dose interruption, reduction, or discontinuation as described in Table 5 (see ADVERSE REACTIONS). (See Tables 5 and 6.)

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Other toxicities: (See Table 7.)

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Refer to the full prescribing information for fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information.
Special populations: Renal impairment: Based on population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild or moderate renal impairment (see PHARMACOLOGY under ACTIONS). Caution should be used in patients with severe renal impairment as there is no experience with alpelisib (Pivikto) in this population (see PHARMACOLOGY under ACTIONS).
Hepatic impairment: Based on a hepatic impairment study in non-cancer subjects with impaired hepatic function, no dose adjustment is necessary in patients with mild, moderate and severe hepatic impairment (Child-Pugh class A, B or C, respectively) (see PHARMACOLOGY under ACTIONS).
Refer to the full prescribing information of fulvestrant for dose modifications related to hepatic impairment.
Pediatric patients (below 18 years): The safety and efficacy of alpelisib (Pivikto) in pediatric patients have not been established.
Geriatric patients (65 years or above): No dosage regimen adjustment is required in patients 65 years or above (see PHARMACOLOGY: PHARMACODYNAMICS: CLINICAL STUDIES under ACTIONS).
Method of administration: Alpelisib (Pivikto) tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should not be ingested.

There is limited experience of overdose with alpelisib (Pivikto) in clinical studies. In the clinical studies, alpelisib (Pivikto) was administered at doses up to 450 mg once daily.
In cases where accidental overdosage of alpelisib (Pivikto) was reported in the clinical studies, the adverse events associated with the overdose were consistent with the known safety profile of alpelisib (Pivikto) and included hyperglycemia, nausea, asthenia and rash.
General symptomatic and supportive measures should be initiated in all cases of overdosage where necessary. There is no known antidote for alpelisib (Pivikto).

Alpelisib (Pivikto) is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.

Hypersensitivity (including anaphylactic reaction): Serious hypersensitivity reactions (including anaphylactic reaction and anaphylactic shock), manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever or tachycardia were reported in patients treated with alpelisib (Pivikto) in clinical studies (see ADVERSE REACTIONS). Angioedema has been reported in the post marketing setting in patients treated with Alpelisib (Pivikto) (see ADVERSE REACTIONS). Alpelisib (Pivikto) should be permanently discontinued and should not be re-introduced in patients with serious hypersensitivity reactions. Appropriate treatment should be promptly initiated.
Severe cutaneous reactions: Severe cutaneous reactions have been reported with alpelisib (Pivikto). In the Phase III clinical study, Stevens-Johnson syndrome (SJS) and erythema multiforme (EM) were reported in 1 (0.4%) and 3 (1.1%) patients, respectively. Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in the post marketing setting (see ADVERSE REACTIONS).
Alpelisib (Pivikto) treatment should not be initiated in patients with history of severe cutaneous reactions.
Patients should be advised of the signs and symptoms of severe cutaneous reactions (e.g. a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash). If signs or symptoms of severe cutaneous reactions are present, alpelisib (Pivikto) should be interrupted until the etiology of the reaction has been determined. A consultation with a dermatologist is recommended. If a severe cutaneous reaction is confirmed, alpelisib (Pivikto) should be permanently discontinued. Alpelisib (Pivikto) should not be reintroduced in patients who have experienced previous severe cutaneous reactions. If a severe cutaneous reaction is not confirmed, alpelisib (Pivikto) may require treatment interruption, dose reduction, or treatment discontinuation as described in Table 5 Dose modification and management for rash (see DOSAGE & ADMINISTRATION).
Hyperglycemia: Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar nonketotic syndrome (HHNKS) or ketoacidosis, has been observed in patients treated with alpelisib (Pivikto). Some cases of ketoacidosis with fatal outcome have been reported in the post marketing setting.
Hyperglycemia was reported in 64.8% of patients treated with alpelisib (Pivikto) in the phase III clinical study. Grade 2 (FPG 160 to 250 mg/dL), 3 (FPG >250 to 500 mg/dL) or 4 (FPG > 500 mg/dL) hyperglycemia were reported in 15.8%, 33.1% and 3.9% of patients, respectively, in phase III clinical study.
In the phase III clinical study, patients with a history of diabetes mellitus intensified anti-diabetic medication(s) while on treatment with alpelisib (Pivikto); therefore, these patients require monitoring and possibly intensified anti-diabetic treatment. Patients with poor glycemic control may be at a higher risk of developing severe hyperglycemia and associated complications. Patients with risk factors for hyperglycemia such as obesity (BMI ≥30), elevated FPG or HbA1c at or above the upper limit of normal, or age ≥75 are at a higher risk of developing severe hyperglycemia. Schedule for monitoring fasting glucose is presented in Table 8.
Patients should be advised of the signs and symptoms of hyperglycemia (e.g. excessive thirst, urinating more often than usual or higher amount of urine than usual, increased appetite with weight loss). (See Table 8.)

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In patients with hyperglycemia, 163/187 (87.2%) were managed with anti-diabetic medication and 142/187 (75.9%) reported use of metformin as single agent or in combination with other anti-diabetic medication. The maximum dose of metformin recommended in phase III clinical study was 2,000 mg per day.
In patients with hyperglycemia of at least Grade 2 (FPG 160 to 250 mg/dL), median time to improvement by at least 1 Grade of the first event was 8 days (95% CI of 8 to 10 days). In all patients with elevated FPG, who continued fulvestrant treatment after discontinuing alpelisib (Pivikto), all FPG levels returned to baseline (normal).
Based on the severity of the hyperglycemia, alpelisib (Pivikto) may require dose interruption, reduction, or discontinuation as described in Table 4 Dose modification and management for hyperglycemia. (see DOSAGE & ADMINISTRATION).
Pneumonitis: Pneumonitis including serious cases of pneumonitis/acute interstitial lung disease have been reported in alpelisib (Pivikto) treated patients in clinical studies. Patients should be advised to promptly report any new or worsening respiratory symptoms. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, alpelisib (Pivikto) treatment should be interrupted immediately and the patient should be evaluated for pneumonitis. A diagnosis of non-infectious pneumonitis should be considered 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. Alpelisib (Pivikto) should be permanently discontinued in all patients with confirmed pneumonitis.
Diarrhea or colitis: Severe diarrhea and clinical consequences, such as dehydration and acute kidney injury have been reported during treatment with alpelisib (Pivikto) in clinical studies(see Table 9 ADVERSE REACTIONS). In the phase III clinical study, Grade 2 and 3 diarrhea were reported in 18.3% and 6.7% of patients, respectively. There were no reported cases of Grade 4 diarrhea. Among patients with Grade 2 or 3 diarrhea, median time to onset was 46 days (range: 1 to 442 days).
Colitis has been reported in the post marketing setting in patients treated with alpelisib (Pivikto) (see ADVERSE REACTIONS).
In the phase III clinical study, dose reductions of alpelisib (Pivikto) were required in 6% of patients and 2.8% of patients permanently discontinued alpelisib (Pivikto) due to diarrhea.
Patients should be monitored for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Based on the severity of the diarrhea or colitis, Alpelisib (Pivikto) may require dose interruption, reduction, or discontinuation as described in Table 6 (see DOSAGE & ADMINISTRATION).
Patients should be advised to notify the healthcare provider if diarrhea or additional symptoms of colitis occur while taking alpelisib (Pivikto). Patients should be managed according to local standard of care medical management, including electrolyte monitoring, administration of anti-emetics and antidiarrheal medications and/or fluid replacement and electrolyte supplements, as clinically indicated. In case of colitis, additional treatment, such as steroids, may be considered as clinically indicated.
Osteonecrosis of the jaw: Caution should be exercised when alpelisib (Pivikto) and bisphosphonates or denosumab are used either simultaneously or sequentially. Alpelisib (Pivikto) treatment should not be initiated in patients with ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates/denosumab. Patients should be advised to promptly report any new or worsening oral symptoms (such as dental mobility, pain or swelling, non-healing of mouth sores, or discharge) during treatment with alpelisib (Pivikto).
In patients who develop osteonecrosis of the jaw, standard medical management should be initiated.

Pregnancy: Risk summary: Based on animal data and its mechanism of action, alpelisib (Pivikto) can cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies in pregnant women. Embryo-fetal development studies in rats and rabbits have demonstrated that oral administration of alpelisib during organogenesis induced embryo-toxicity, feto-toxicity, and teratogenicity. In rats and rabbits, following prenatal exposure to alpelisib, increased incidences of post-implantation loss, reduced fetal weights, and increased incidences of fetal abnormalities were observed starting at doses below (see animal data) the exposure in humans at the highest recommended dose of 300 mg.
Alpelisib should not be used during pregnancy unless the benefits to the mother outweigh the risk to the fetus. If alpelisib (Pivikto) is used during pregnancy, the patient should be advised of the potential risk to the fetus.
Data: Animal Data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of alpelisib up to 30 mg/kg/day, during the period of organogenesis.
In rats, oral administration of alpelisib was associated with maternal body weight loss or stagnation, low food consumption and embryonal death at 30 mg/kg/day, approximately 3.2 times (based on AUC) the exposure in humans at the highest recommended dose of 300 mg. Low maternal body weight gain, increased incidences of enlarged brain ventricle in the fetuses, reduced fetal weight, decreased bone ossification and skeletal malformations were seen at 10 mg/kg/day, that is equal to approximately 0.9 times below the exposure in humans at the highest recommended dose.
In rabbits, at doses of ≥25 mg/kg/day, maternal body weight loss with reduced food intake was observed. At 15mg/kg/day, slight transient body weight loss was observed. At ≥ 15 mg/kg/day increased embryo-fetal deaths and malformations were observed, mostly related to the tail and head, and were associated with increased serum glucose levels in dams. At 25 mg/kg/day, reduced mean fetal weight was observed. The dose of 15 mg/kg/day dose in rabbits is equivalent to approximately 5.5 times (based on AUC) the exposure achieved at the highest recommended human dose.
In rats and rabbits, no fetal effects were observed at 3 mg/kg/day, and considered to be the no-observable-adverse-effect-level (NOAEL) for fetal abnormalities. The maternal systemic exposures (AUC) at the NOAEL were 0.12 (rats) or 0.86 (rabbits) times the exposure in humans at the highest recommended dose of 300 mg.
Lactation: Risk summary: It is not known if alpelisib is transferred into human or animal milk after administration of alpelisib (Pivikto). There are no data on the effects of alpelisib on the breastfed child or the effects of alpelisib on milk production.
Because of the potential for serious adverse drug reactions in the breastfed child from alpelisib (Pivikto), it is recommended that women should not breastfeed during treatment and for at least 4 days after the last dose of alpelisib (Pivikto).
Females and males of reproductive potential: Pregnancy testing: The pregnancy status for females of reproductive potential should be verified prior to starting treatment with alpelisib (Pivikto).
Contraception: Females of reproductive potential should be advised that animal studies and the mechanism of action have shown that alpelisib can be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using alpelisib (Pivikto) during treatment and for at least 4 days after stopping treatment with alpelisib. It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.
Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant should use condoms during sexual intercourse while taking alpelisib (Pivikto) and for at least 4 days after stopping treatment with alpelisib (Pivikto).
Infertility: There are no clinical data available on the effect of alpelisib on fertility. Based on repeat dose toxicity studies in animals, alpelisib (Pivikto) may impair fertility in males and females of reproductive potential (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS). In fertility studies conducted in male and female rats, similar effects were observed (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).

Summary of the safety profile:The overall safety evaluation of alpelisib (Pivikto) is based on data from the phase III clinical study of 572 patients (571 post-menopausal women and 1 male) who were randomized in a 1:1 ratio to receive alpelisib (Pivikto) plus fulvestrant or placebo plus fulvestrant; 284 of whom received alpelisib (Pivikto) at the recommended starting dose of 300 mg dose in combination with fulvestrant, using the proposed treatment regimen.
The median duration of exposure to alpelisib (Pivikto) plus fulvestrant was 8.2 months with 59.2% patients exposed for >6 months.
Alpelisib (Pivikto) dose reductions due to adverse events (AEs), regardless of causality occurred in 57.7% of patients receiving alpelisib (Pivikto) plus fulvestrant and in 4.5% of patients receiving placebo plus fulvestrant. Permanent discontinuations due to AEs were reported in 25% of patients receiving alpelisib (Pivikto) plus fulvestrant and 4.5% of patients receiving placebo and/or fulvestrant. The most common AEs leading to treatment discontinuation of both alpelisib (Pivikto) and/or fulvestrant were hyperglycemia (6.3%), rash (3.2%), diarrhea (2.8%), and fatigue (2.1%).
On-treatment deaths, regardless of causality, were reported in 7 patients (2.5%) treated with alpelisib (Pivikto) plus fulvestrant vs. 12 patients (4.2%) treated with placebo plus fulvestrant. In alpelisib (Pivikto) plus fulvestrant treated patients, disease progression (5 patients, 1.8%) was the most frequent cause of death; the others were one each for cardio-respiratory arrest and second primary malignancy, neither of which were considered related to treatment with alpelisib (Pivikto).
The most common ADRs in alpelisib (Pivikto) plus fulvestrant treated patients (reported at a frequency ≥20% and for which the frequency for alpelisib (Pivikto) plus fulvestrant exceeds the frequency for placebo plus fulvestrant) were hyperglycemia, diarrhea, rash, nausea, fatigue and asthenia, decreased appetite, stomatitis, vomiting and weight decreased.
The most common Grade 3/4 ADRs (reported at a frequency ≥2% in the alpelisib (Pivikto) plus fulvestrant arm and for which the frequency for alpelisib (Pivikto) plus fulvestrant exceeds the frequency for placebo plus fulvestrant) were hyperglycemia, rash and maculo-papular rash, fatigue, diarrhea, lipase increased, hypertension, hypokalemia, anemia, weight decreased, gamma-glutamyltransferase increased, lymphopenia, nausea, stomatitis, alanine aminotransferase increased and mucosal inflammation.
Tabulated summary of adverse drug reactions from clinical studies: ADRs from the phase III clinical study (Table 9) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, ADRs are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each ADR is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Tables 9 and 10.)

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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with alpelisib (Pivikto) via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. (See Table 11.)

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Description of selected ADRs and treatment recommendations, where applicable: Hyperglycemia: In the phase III clinical study, hyperglycemia (FPG > 160 mg/dL) was reported in 184 (64.8%) of patients. An event of hyperglycemia resolved to ≤Grade 1 (FPG < 160 mg/dL) in 166 (88.8%) of the 187 patients. Dose interruptions and adjustments due to hyperglycemic events were reported in 26.8% and 28.9% of patients, respectively, in the alpelisib (Pivikto) plus fulvestrant arm. Hyperglycemic events leading to discontinuation of alpelisib (Pivikto) and/or fulvestrant were reported in 19 (6.7 %) patients.
Based on baseline FPG and HbA1c values, 56% of patients were considered pre-diabetic (FPG > 100 to 126 mg/dL (5.6 to 6.9 mmol/L) and/or HbA1c 5.7 to 6.4%) and 4.2% of patients were considered diabetic (FPG≥126 mg/dL (≥7.0 mmol/L) and/or HbA1c ≥ 6.5 %). There were no patients with type 1 diabetes mellitus based on reported medical history. Among those pre-diabetic patients at baseline, 74.2% experienced hyperglycemia (any Grade) when treated with alpelisib (Pivikto). Among the patients who had Grade ≥2 (FPG 160 to 250 mg/dL) hyperglycemia , the median time to first occurrence of Grade ≥2 (FPG > 160 to 250 mg/dL) hyperglycemia was 15 days (range: 5 days to 517 days) (based on laboratory findings). The median duration of Grade 2 (FPG >160 to 250 mg/dL) or higher hyperglycemia (based on laboratory findings) was 10 days (95% CI: 8 to 13 days).
Rash: In the phase III clinical study, rash events (including rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic, dermatitis and dermatitis acneiform) were reported in 153 (53.9%) patients. Rash may be accompanied by pruritus and dry skin in some cases. Rash was predominantly mild or moderate (Grade 1 or 2) and responsive to therapy. Maximum Grade 2 and 3 rash events were reported in 13.7% and 20.1% of patients, respectively. There were no Grade 4 cases of rash reported. Among the patients with Grade 2 or 3 rash, the median time to first onset of Grade 2 or 3 rash was 12 days (range: 2 days to 220 days). Dose interruptions and dose adjustments due to rash were reported in 21.8% and 9.2% of patients, respectively, in the alpelisib (Pivikto) plus fulvestrant arm.
Topical corticosteroid treatment should be initiated at the first signs of rash and oral corticosteroids should be considered for moderate to severe rashes. Additionally, antihistamines are recommended to manage symptoms of rash. In the Phase III study, among the patients who developed a rash, 73.9% (113/153) reported use of at least one topical corticosteroid and 67.3% (103/153) of at least one oral antihistamine. Systemic corticosteroid were administered for rash events in 23% (66/284) of patients. Of the patients who received systemic corticosteroids, 55% (36/66) received oral corticosteroids for rash. At least one event of rash resolved in the majority of the patients, 141 out of 153 patients (92%). Discontinuation of alpelisib (Pivikto) and/or fulvestrant treatment due to rash events occurred in 12 patients (4.2%).
A subgroup of 86 patients received anti rash treatment, including anti-histamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all Grades rash (26.7% vs 53.9%), Grade 3 rash (11.6% vs 20.1%) and rash leading to permanent discontinuation of alpelisib (Pivikto) (3.5% vs 4.2%). Accordingly, antihistamines may be initiated prophylactically, at the time of initiation of treatment with alpelisib (Pivikto). Based on the severity of rash, alpelisib (Pivikto) may require dose interruption, reduction, or discontinuation as described in Table 5 Dose modification and management for rash (see DOSAGE & ADMINISTRATION).
GI toxicity (nausea, diarrhea, vomiting): In the phase III study, diarrhea, nausea and vomiting were (see Table 9 as previously mentioned) reported in 57.7%, 44.7% and 27.1% of the patients, respectively, and led to discontinuation of alpelisib (Pivikto) and/or fulvestrant in 8 (2.8%), 5 (1.8%) and 3 (1.1%) of the patients, respectively.
Anti-emetics (e.g. ondansetron) and anti-diarrheal medications (e.g. loperamide) were used in 27/149 (18.1%) and 104/164 (63.4%) of patients to manage symptoms.
Osteonecrosis of the jaw (ONJ): In the phase III clinical study, ONJ was reported in 4.2% patients (12/284) in the alpelisib (Pivikto) plus fulvestrant arm compared to 1.4% patients (4/287) in the placebo plus fulvestrant arm. All patients experiencing ONJ were also exposed to prior or concomitant bisphosphonates (e.g. zoledronic acid) or RANK-ligand inhibitors (e.g. denosumab). Therefore, in patients receiving alpelisib (Pivikto) and bisphosphonates or RANK-ligand inhibitors, an increased risk of development of ONJ cannot be excluded.

The elimination of alpelisib is majorly driven by non-hepatic hydrolysis, mediated by multiple enzymes (esterases, amidases, choline esterase) and, to a lesser degree, CYP3A4 mediated metabolism (hydroxylation). The contribution of hepatobiliary export or intestinal secretion via BCRP in human is considered to be low.
Medicinal products that may increase alpelisib plasma concentrations: BCRP inhibitors: Alpelisib is a sensitive substrate for BCRP (breast cancer resistance protein) in vitro, predominantly expressed in the liver, intestine, and at blood-brain barrier. Absorption of alpelisib will not be affected by BCRP inhibition due to saturation of the transporter in the intestine. However, due to the involvement of BCRP in the hepatobiliary export and intestinal secretion of alpelisib, caution is advised when co-administering alpelisib (Pivikto) with a BCRP inhibitor (e.g. eltrombopag, lapatininb, pantoprazole), as inhibition of BCRP in the liver and in the intestine after absorption may lead to an increase in systemic exposure of alpelisib (Pivikto).
Medicinal products that may decrease alpelisib plasma concentrations: CYP3A4 inducers: Administration of 600 mg once daily rifampin, a strong CYP3A4 inducer, for 7 days, before co-administration with a single oral 300 mg alpelisib dose on Day 8, decreased alpelisib Cmax by 38% and AUC by 57% in healthy adults (N = 25). Administration of 600 mg once daily rifampin for 15 days, coadministered with daily 300 mg alpelisib starting from Day 8 to Day 15 decreased the steady state alpelisib Cmax by 59% and AUC by 74%.
Co-administration with a strong CYP3A4 inducer decreases alpelisib area under the curve (AUC) (see PHARMACOLOGY under ACTIONS), which may reduce alpelisib efficacy. Co-administration of alpelisib with strong CYP3A4 inducers (e.g., apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John's wort) should be avoided and selection of an alternative concomitant medicinal product, with no or minimal potential to induce CYP3A4, should be considered (see PHARMACOLOGY under ACTIONS).
Medicinal products whose plasma concentrations may be altered by alpelisib: CYP3A4 substrates: No dose adjustment is required when co-administering alpelisib (Pivikto) with CYP3A4 substrates (e.g. everolimus, midazolam).
Caution is recommended when alpelisib (Pivikto) is used in combination with CYP3A4 substrates that also possess an additional time-dependent inhibition and induction potential on CYP3A4 that affects their own metabolism (e.g. rifampicin, ribociclib, encorafenib). Systemic exposures of such CYP3A4 auto-inhibitors and auto-inducers may be decreased and increased, respectively, when alpelisib (Pivikto) is co-administered, based on PBPK (physiologically based pharmacokinetic) simulations.
CYP2C9 substrates with narrow therapeutic index: In vitro evaluations indicate that the pharmacological activity may be reduced by the CYP2C9 induction effects of alpelisib. Based on PBPK modeling data with sensitive CYP2C9 substrate warfarin, after co-administration of alpelisib (300 mg once daily for 20 days), AUC (area under curve) and Cmax (maximum concentration) ratios of warfarin were estimated to be 0.91 and 0.99, respectively, indicating no or weak induction potential of alpelisib on CYP2C9. No dose adjustment is required when alpelisib (Pivikto) is co-administered with CYP2C9 substrates with narrow therapeutic index (e.g. warfarin). However, in the absence of clinical data, caution is recommended.
CYP2B6 sensitive substrates with narrow therapeutic index: Static mechanistic assessment with sensitive CYP2B6 substrates such as bupropion, a reduction of exposure by up to 3-fold can be expected when co-administered with alpelisib based on in vitro assessment, no clinical study was performed. Sensitive CYP2B6 substrates (e.g. bupropion) or CYP2B6 substrates with a narrow therapeutic window should be used with caution in combination with alpelisib (Pivikto), as alpelisib (Pivikto) may reduce the clinical activity of such drugs.
Drug-food interactions: In healthy subjects, co-administration of alpelisib with food resulted in an increased AUC of alpelisib by 77% (see DOSAGE & ADMINISTRATION and PHARMACOLOGY under ACTIONS). Therefore, alpelisib (Pivikto) should be taken immediately after food, at approximately same time each day (see DOSAGE & ADMINISTRATION).
Hormonal contraceptives: It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.

Incompatibilities: Not applicable.

Store at temperatures not exceeding 30°C. Protect from moisture.

Targeted Cancer Therapy

L01EM03 - alpelisib ; Belongs to the class of phosphatidylinositol-3-kinase (Pi3K) inhibitors. Used in the treatment of cancer.

Rx