Piqray^® (Tablets) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Pharma Stein AG (Switzerland)

Labeled By

NOVARTIS PHARMACEUTICAL MANUFACTURING, LLC (Slovenia)

Packaging and Quality Control Release

NOVARTIS PHARMACEUTICAL MANUFACTURING, LLC (Slovenia)

Or

SCOPINFARM, LLC (Russia)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

L01EM03 (Alpelisib)

Active Substance

Alpelisib (Rec.INN registered by WHO)

Dosage Forms

	Piqray®	Film-coated tablets, 50 mg (in a set of 50 mg and 200 mg): 28 or 56 pcs.
		Film-coated tablets, 150 mg: 28 or 56 pcs.
		Film-coated tablets, 200 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light pink in color, round, biconvex, with beveled edges, without a score, with an engraving “L7” on one side and “NVR” on the other side.

Excipients: microcrystalline cellulose (PH102, PH101), mannitol, sodium starch glycolate (type A), hypromellose, magnesium stearate.

Film coating composition white coating premix: hypromellose, titanium dioxide (E171), macrogol 4000, talc; black coating premix: hypromellose, iron oxide black (E172), macrogol 4000, talc; red coating premix: hypromellose, iron oxide red (E172), macrogol 4000, talc.

Packaging for a daily dose of 250 mg
7 pcs.* – blisters (2*) – cardboard cartridges (2) – cardboard packs^×.
7 pcs.* – blisters (2*) – cardboard cartridges (4) – cardboard packs^×.

Film-coated tablets pale red in color, oval, biconvex, with beveled edges, without a score, with an engraving “UL7” on one side and “NVR” on the other side.

Excipients: microcrystalline cellulose (PH102, PH101), mannitol, sodium starch glycolate (type A), hypromellose, magnesium stearate.

Film coating composition white coating premix: hypromellose, titanium dioxide (E171), macrogol 4000, talc; black coating premix: hypromellose, iron oxide black (E172), macrogol 4000, talc; red coating premix: hypromellose, iron oxide red (E172), macrogol 4000, talc.
Packaging for a daily dose of 300 mg
7 pcs. – blisters (2**) – cardboard cartridges (2) – cardboard packs^×.
7 pcs. – blisters (2**) – cardboard cartridges (4) – cardboard packs^×.

Film-coated tablets light red in color, oval, biconvex, with beveled edges, without a score, with an engraving “YL7” on one side and “NVR” on the other side.

Excipients: microcrystalline cellulose (PH102, PH101), mannitol, sodium starch glycolate (type A), hypromellose, magnesium stearate.

Film coating composition white coating premix: hypromellose, titanium dioxide (E171), macrogol 4000, talc; black coating premix: hypromellose, iron oxide black (E172), macrogol 4000, talc; red coating premix: hypromellose, iron oxide red (E172), macrogol 4000, talc.

Packaging for a daily dose of 200 mg
7 pcs. – blisters (2**) – cardboard cartridges (1) – cardboard packs^×.
7 pcs. – blisters (2**) – cardboard cartridges (2) – cardboard packs^×.

* 1 blister (tab. 50 mg 7 pcs.) and 1 blister (tab. 200 mg 7 pcs.) are affixed in a cardboard cartridge.
** 2 blisters are affixed in a cardboard cartridge.
^× the presence of a first-opening control on the cardboard pack is allowed.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors

Pharmacological Action

Mechanism of action

Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor that specifically inhibits PI3K alpha. According to in vitro and in vivo studies, activating mutations in the PIK3CA gene, which encodes the catalytic alpha subunit of PI3K, lead to activation of PI3K alpha and Akt-dependent signal transduction, cell transformation, and tumor development.

In breast cancer cell lines, Alpelisib suppressed phosphorylation of PI3K targets, including Akt, and demonstrated activity in cell lines carrying a PIK3CA mutation. In vivo, Alpelisib inhibited PI3K/Akt-dependent signal transduction and suppressed tumor growth in animals with tumor xenografts, including breast cancer xenografts.

Inhibition of PI3K during therapy with alpelisib has been shown to enhance transcription of the estrogen receptor (ER) in breast cancer cells. In studies on animals with xenografts of tumors consisting of ER-positive breast cancer cells carrying a PIK3CA mutation, the combination of alpelisib and fulvestrant demonstrated a more pronounced antitumor effect compared to each drug separately.

Cardiac electrophysiology

To assess the effect of alpelisib on the QTcF interval in patients with advanced malignant neoplasm, serial electrocardiograms (ECGs) were obtained both after a single dose and after reaching steady-state concentration. The analysis showed no clinically significant prolongation of the QTcF interval (> 20 msec) when using alpelisib at the recommended dose of 300 mg, both in combination with fulvestrant and alone.

Clinical efficacy and safety

SOLAR-1 study

The drug Piqray^® was evaluated in a pivotal randomized double-blind placebo-controlled phase III study investigating alpelisib in combination with fulvestrant in postmenopausal women and men with HR-positive HER2-negative advanced (locoregionally recurrent or metastatic) breast cancer, whose disease had progressed on or after aromatase inhibitor-based therapy (with or without CDK4/6 inhibitors).

A total of 572 patients were enrolled into two cohorts: a cohort of patients with breast cancer and a PIK3CA gene mutation and a cohort of patients with breast cancer without a PIK3CA gene mutation. Patients were randomized in a 1:1 ratio to receive alpelisib 300 mg in combination with fulvestrant or placebo in combination with fulvestrant. Randomization was stratified by the presence of lung and/or liver metastases and prior treatment with CDK4/6 inhibitors.

In the cohort of patients with a PIK3CA gene mutation, 169 patients with one or more PIK3CA gene mutations (C420R, E542K, E545A, E545D (only 1635G>T), E545G, E545K, Q546E, Q546R, H1047L, H1047R or H1047Y) were randomized to receive alpelisib in combination with fulvestrant, and 172 patients were randomized to receive placebo in combination with fulvestrant. In this cohort, 170 (49.9%) patients had liver/lung metastases, and 20 (5.9%) patients had previously received treatment with CDK4/6 inhibitors.

The median age of patients was 63 years (range: from 25 to 92 years). 44.9% of patients were aged 65 to 85 years inclusive. 66.3% of patients were Caucasian, 21.7% were Asian, 1.2% were Black or African American. The study population included one male patient who was in the cohort of patients with a PIK3CA gene mutation and received treatment with alpelisib in combination with fulvestrant. 66.0% and 33.4% had an ECOG performance status of 0 or 1, respectively.

97.7% of patients had previously received endocrine therapy. 67.7% of patients had endocrine therapy as the last therapy they received prior to study entry. The most commonly used endocrine drugs were letrozole and anastrozole. The last therapy prior to study entry was endocrine therapy for the metastatic stage in 47.8% of patients and adjuvant therapy in 51.9% of patients. Overall, 85.6% of patients were considered endocrine-resistant; primary endocrine resistance was observed in 13.2% of patients, and secondary endocrine resistance in 72.4% of patients.

Patient demographics and baseline disease characteristics, ECOG (Eastern Cooperative Oncology Group) performance status, tumor burden, and prior antineoplastic therapy were well balanced between the treatment groups.

In the randomized treatment phase, patients took Alpelisib 300 mg or placebo orally once daily continuously. Fulvestrant at a dose of 500 mg was administered intramuscularly on days 1 and 15 of cycle 1, then on day 1 of the 28-day cycle during the treatment phase (dose administration ±3 days).

Patients were not allowed to cross over from the placebo group to the alpelisib group during the study and after disease progression.

The primary endpoint of the study was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) as assessed by the investigator in patients with a PIK3CA gene mutation. The key secondary endpoint was overall survival (OS) in patients with a PIK3CA gene mutation.

Other secondary endpoints were PFS and OS in patients without a PIK3CA gene mutation.

Cohort of patients with a PIK3CA gene mutation

• Primary analysis

The study met its primary objective at the final PFS analysis (data cut-off date: June 12, 2018), demonstrating a statistically significant improvement in PFS in the cohort of patients with a PIK3CA gene mutation receiving Alpelisib in combination with fulvestrant compared to patients receiving placebo in combination with fulvestrant, with a 35% reduction in the risk of disease progression or death in the group of patients receiving Alpelisib in combination with fulvestrant. The median PFS was increased by 5.3 months from 5.7 months in the group of patients receiving placebo in combination with fulvestrant (95% CI: 3.7; 7.4) to 11 months in the group of patients receiving Alpelisib in combination with fulvestrant (95% CI: 7.5; 14.5).

Table 1. SOLAR-1 study. Overview of efficacy results according to RECIST response criteria (PFS, cohort of patients with a PIK3CA gene mutation)

CI — confidence interval; N — number of patients; N/A — not applicable

^a p-value obtained from a one-sided stratified log-rank test.

* Audit approach based on a sample of 50% of randomized patients

In the cohort of patients with a PIK3CA gene mutation, the results of the subgroup analysis of PFS, conducted according to the investigator’s assessment by randomization stratification factors, demonstrated a generally consistent treatment effect in favor of the alpelisib group, regardless of the presence or absence of lung/liver metastases.

In the 20 patients previously treated with CDK4/6i, the hazard ratio (HR) for PFS was 0.48 (95% CI: 0.17; 1.36); the median PFS was 1.8 months (95% CI: 1.7; 3.6) in the placebo plus fulvestrant group and 5.5 months (95% CI: 1.6; 16.8) in the alpelisib plus fulvestrant group.

At the data cut-off (June 12, 2018), the PFS results in the subgroup of patients resistant to endocrine therapy (HR = 0.64; 95% CI: 0.49; 0.85, n = 292) were in favor of the alpelisib plus fulvestrant group. The number of patients with a PIK3CA gene mutation who were sensitive to endocrine therapy was limited (n = 39), so the results should be interpreted with caution.

At the data cut-off (June 12, 2018), the overall response rate in patients with a PIK3CA gene mutation with measurable disease at baseline was 35.7% (95% CI: 27.4; 44.7) in the alpelisib plus fulvestrant group and 16.2% (95% CI: 10.4; 23.5) in the placebo plus fulvestrant group.

Figure 1. SOLAR-1 study – Analysis of the primary efficacy endpoint – Kaplan-Meier plot for progression-free survival as assessed by the local investigator in the cohort of patients with a PIK3CA gene mutation (data cut-off date: June 12, 2018)

• Final overall survival (OS) analysis

The final OS analysis was performed using data as of the data cut-off date (April 23, 2020), and a descriptive analysis of PFS was performed using this data. The median time from randomization to the data cut-off date was 42 months, the PFS benefit was sustained and consistent with the results of the final PFS analysis. The estimated reduction in the risk of disease progression or death in the group of patients receiving Alpelisib in combination with fulvestrant was 36% (HR =0.64; 95% CI: 0.50, 0.81).

At the final OS analysis, the study did not meet its key secondary objective. As of the data cut-off date (April 23, 2020), a total of 87 (51.5%) deaths were recorded in the group of patients receiving Alpelisib in combination with fulvestrant, and 94 (54.7%) in the group of patients receiving placebo in combination with fulvestrant. The median OS was increased by 7.9 months from 31.4 months (95% CI: 26.8, 41.3) in the group of patients receiving placebo in combination with fulvestrant to 39.3 months (95% CI: 34.1, 44.9) in the group of patients receiving Alpelisib in combination with fulvestrant.

The subgroup analysis of OS, conducted according to the investigator’s assessment by randomization stratification factors, demonstrated a generally consistent treatment effect. Despite the limited number of patients, for the analysis of the subgroup that received prior CDK4/6i treatment, the median OS in the group of patients receiving Alpelisib in combination with fulvestrant was 29.8 months (95% CI: 6.7, 38.2) compared to 12.9 months (95% CI: 2.5, 34.6) in the group of patients receiving placebo in combination with fulvestrant. In the subgroup of patients with lung/liver metastases, the median OS in the group of patients receiving Alpelisib in combination with fulvestrant was 37.2 months (95% CI: 28.7, 43.6) compared to 22.8 months (95% CI: 19.0, 26.8) in the group of patients receiving placebo in combination with fulvestrant.

Cohort of patients without a PIK3CA gene mutation

No improvement in PFS was observed in patients without a PIK3CA gene mutation in the tumor tissue.

Prior fulvestrant use in study CBYL719X2102

Patients previously treated with fulvestrant were not included in the SOLAR-1 study. In the phase I study CBYL719X2101, 39 patients previously treated with fulvestrant participated. The best overall response to treatment with alpelisib in combination with fulvestrant, noted in 21 patients with PIK3CA gene mutations and measurable disease at baseline, was a partial response in 7 patients, stable disease in 11 patients, and disease progression in 2 patients.

Consequently, the efficacy of this treatment in patients previously treated with fulvestrant has not been established due to the limited data currently available.

Preclinical safety data

Pharmacological safety and repeat-dose toxicity

Most of the observed effects of alpelisib were related to the pharmacological action of alpelisib as a p110alpha-specific inhibitor of the PI3K signaling pathway, for example, the effect on glucose homeostasis leading to the development of hyperglycemia and the risk of increased blood pressure. The main target organs of adverse reactions were bone marrow and lymphoid tissue, pancreas, and some reproductive organs in both sexes. Adverse reactions in the bone marrow and lymphoid tissue were generally reversible after discontinuation of treatment. Adverse reactions in the pancreas and reproductive organs did not completely resolve, but a trend towards reversibility was noted.

Cardiovascular safety pharmacology

At concentrations approximately 13 times the human exposure at the recommended dose of 300 mg/day, inhibition of hERG channels (human ether-à-go-go-related gene) was observed in vitro (IC₅₀ = 9.4 µM). No significant electrophysiological effect was observed in studies on dogs.

Carcinogenicity and mutagenicity

Carcinogenicity studies have not been conducted.

Standard genotoxicity studies of alpelisib yielded negative results. In a repeat-dose toxicity study in rats using the micronucleus test, it was noted that the exposure to alpelisib was 1.4 times higher in males and 2 times higher in females compared to the therapeutic exposure in adult humans receiving Alpelisib at the recommended dose. Therefore, the genotoxic potential of alpelisib in humans cannot be ruled out.

Reproductive toxicity

Studies of embryo-fetal development in rats and rabbits showed that oral administration of alpelisib during organogenesis caused embryotoxicity, fetotoxicity, and teratogenicity.

Following prenatal exposure in rats and rabbits, there was an increase in the frequency of pre- and post-implantation embryo loss, a decrease in fetal weight, and an increase in fetal abnormalities (enlarged brain ventricles, low degree of bone ossification, and skeletal development disorders), starting at exposure levels observed in humans at the maximum recommended dose of 300 mg, indicating potential clinical significance.

A study of reproductive function in rats was not conducted.

However, in a multiple-dose toxicity study, adverse reactions of the reproductive organs were observed (e.g., vaginal or uterine atrophy and changes in the estrous cycle in rats, decreased prostate and testicular weight in rats and dogs, prostate atrophy in dogs) when the drug was administered at clinically significant doses established based on AUC.

Phototoxicity

A phototoxicity study conducted in vitro on fibroblasts of the Balb/c mouse 3T3 cell line did not reveal significant phototoxicity potential for alpelisib.

Pharmacokinetics

The pharmacokinetics of alpelisib were studied in healthy volunteers and adult patients with solid tumors.

When alpelisib was administered with food, its C_max and AUC increased proportionally to the dose in the dose range from 30 to 450 mg (0.1-1.5 times the approved recommended dose).

The mean accumulation ratio of alpelisib is 1.3-1.5, and its C_ss in plasma is reached within 3 days with daily administration.

In adult patients receiving Alpelisib at a dose of 300 mg in the SOLAR-1 study, the mean C_max and AUC_{0-24 h} values of alpelisib according to population analysis were 2480 ng/ml (coefficient of variation (CV%): 23%) and 33224 ng×h/ml (CV%: 21%), respectively.

Absorption

After oral administration of alpelisib, the median time to reach T_max in plasma was from 2.0 to 4.0 hours, regardless of dose, time, or treatment regimen.

Effect of food. When a single dose of alpelisib was taken with a high-calorie, high-fat meal (985 calories, 58.1 g fat), the AUC of alpelisib increased by 73%, and C_max by 84%; when taken with a low-calorie, low-fat meal (334 calories, 8.7 g fat), the AUC of alpelisib increased by 77%, and C_max by 145%.

No clinically significant differences in alpelisib AUC values were observed between intake with a low-calorie, low-fat meal and a high-calorie, high-fat meal.

Distribution

The apparent volume of distribution of alpelisib at steady state (Vss/F) is calculated to be 114 L (with an inter-subject CV% of 46%).

The degree of binding of alpelisib to plasma proteins is 89% and is concentration-independent.

Metabolism

In vitro studies have shown that the main metabolic pathway of the drug is amide hydrolysis under the action of chemicals and enzymes to form the metabolite BZG791, with a minor contribution from the CYP3A4 isoenzyme.

Elimination

The T_1/2 of alpelisib is 8-9 h. The mean predicted value (CV%) of alpelisib clearance when taken with food is 9.2 L/h (21%).

After a single oral dose of radiolabeled alpelisib 400 mg on an empty stomach, 81% of the administered dose was found in feces (36% as unchanged substance, 32% as metabolite BZG791), and 14% in urine (2% as unchanged substance, 7.1% as metabolite BZG791).

Metabolites formed with the participation of the CYP3A4 isoenzyme and glucuronides accounted for approximately 12% and 15% of the dose, respectively.

Pharmacokinetics in special patient groups

Clinically significant differences in the pharmacokinetics of alpelisib are not expected in individuals differing in age (from 21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (from 37 to 181 kg), degree of renal impairment (from mild to moderate; CrCl from 30 to < 90 ml/min calculated by the Cockcroft-Gault formula) or degree of hepatic impairment (from mild to severe; Child-Pugh class A, B and C).

The effect of severe renal impairment (CrCl < 30 ml/min) on the pharmacokinetics of alpelisib is unknown.

Indications

In combination with fulvestrant

• For the treatment of postmenopausal women and men with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer with a PIK3CA gene mutation (PIK3CA+) with disease progression during/after endocrine therapy regimens.

ICD codes

Dosage Regimen

Orally, immediately after a meal.

Patients should take Piqray^® at approximately the same time every day.

Piqray^® tablets should be swallowed whole (not chewed, broken, or divided before swallowing). Do not take damaged tablets (broken, cracked, or with other signs of damage).

Treatment with Piqray^® should be carried out only under the supervision of a physician experienced in the use of anticancer drugs.

The recommended dose of Piqray^® is 300 mg once daily immediately after a meal.

If a dose of Piqray^® is missed, it should be taken immediately after a meal within 9 hours of the usual time of administration.

If a dose is missed by more than 9 hours, the dose should be skipped for that day. The next scheduled dose should be taken at the usual time.

If a patient vomits after taking Piqray^®, an additional dose of the drug should not be taken on that day; the standard dosing regimen should be resumed the next day at the usual time.

When used concomitantly with Piqray^®, the recommended dose of fulvestrant is 500 mg intramuscularly on days 1, 15, and 29, and then once a month. Please refer to the fulvestrant prescribing information.

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicities occur.

Dose adjustment

If severe or intolerable adverse drug reactions (ADRs) occur, temporary interruption of therapy, dose reduction, and/or complete discontinuation of Piqray^® therapy may be required.

If necessary, dose adjustment is performed according to the recommendations for dose reduction in case of ADRs in Table 2.

Dose reduction should be performed no more than twice; if further dose reduction is necessary, Piqray^® should be discontinued.

Table 2. Recommendations for dose reduction in case of ADRs with Piqray^®®1

¹ In case of pancreatitis, only a single dose reduction is possible.

² If further dose reduction below 200 mg once daily is required, Piqray^® should be permanently discontinued.

Tables 3, 4, 5, and 6 provide recommendations for temporary interruption of therapy, dose reduction, or complete discontinuation of Piqray^® therapy depending on the ADR.

Hyperglycemia

Consultation with a healthcare professional experienced in managing hyperglycemia should be considered, as well as lifestyle modifications according to local guidelines, including recommending/increasing physical activity and dietary changes (e.g., eating smaller, more frequent meals, consuming food low in simple carbohydrates and high in fiber, instead of one large meal, consuming a macronutrient-balanced diet in three meals and, if necessary, two small snacks).

Before starting treatment with Piqray^®, fasting blood glucose should be carefully monitored in patients at high risk of developing hyperglycemia.

Table 3. Dose adjustment and management of patients with hyperglycemia¹

¹ Fasting glucose levels correspond to the assessment of hyperglycemia according to CTCAE version 4.03. CTCAE = Common Terminology Criteria for Adverse Events.

² Antihyperglycemic medication therapy should be initiated, e.g., metformin, sodium-glucose cotransporter-2 inhibitors, or insulin sensitizers (e.g., thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and relevant prescribing information for these medications should be considered. Metformin is used based on Phase III clinical trial data according to the following recommendations: therapy should be initiated only at a dose of 500 mg once daily. Based on tolerability assessment, the metformin dose can be increased to 500 mg twice daily, then 500 mg with breakfast and 1000 mg with dinner, and further, if necessary, the dose can be increased to 1000 mg twice daily.

³ According to recommendations based on Phase III clinical trial data, insulin may be used for 1-2 days until hyperglycemia resolves. Given the short T_1/2 of alpelisib and the expected normalization of serum glucose levels after discontinuation of Piqray^® therapy, long-term therapy for this type of hyperglycemia is not required.

Risk factors for developing hyperglycemia during Piqray^® therapy include the presence of prediabetes or diabetes at baseline, body mass index ≥30, age ≥75 years. 74.7% of patients with hyperglycemia of any grade, and 86.2% of patients with grade 3 and 4 hyperglycemia, had the above risk factors.

Rash

At the start of Piqray^® treatment, consideration should be given to prescribing oral H1-histamine blockers for rash prophylaxis.

H₁-histamine receptor blockers are also recommended for relieving rash symptoms.

At the first symptoms of a rash, topical corticosteroids should be initiated. Systemic corticosteroids should be used for moderate to severe rash.

Depending on the severity of the rash, temporary interruption of therapy, dose reduction, or complete discontinuation of Piqray^® therapy may be required, as described in Table 4.

Table 4. Dose adjustment and management of patients with rash¹

Diarrhea or colitis

Table 5. Dose adjustment and management of patients with diarrhea or colitis¹

¹ Severity assessment according to CTCAE version 5.0.

² For grade 2 and 3 colitis, consider additional therapy, e.g., corticosteroids.

³ For grade 3 and 4 diarrhea, patient management should be in accordance with local standards of care, including monitoring of electrolytes, administration of antiemetic and antidiarrheal medications and/or fluid therapy and electrolyte replacement infusion, as clinically indicated.

Other toxicities

Table 6. Dose adjustment and management of patients with other toxicities (excluding hyperglycemia, rash, diarrhea, or colitis)¹

¹ Assessment based on CTCAE version 5.0.

² In case of Grade 2 and 3 pancreatitis, discontinue Piqray^® therapy until the severity of the reaction decreases to Grade ≤ 1 and resume therapy at one dose level lower. Only one dose reduction is allowed. If toxic reactions recur, Piqray^® therapy should be permanently discontinued.

³ In case of total bilirubin elevation to Grade 2, temporarily interrupt Piqray^® therapy until the severity decreases to Grade ≤ 1, and then resume therapy at the same dose provided the symptom resolved within ≤ 14 days, or resume therapy at a dose corresponding to one level lower if the symptom resolved in >14 days.

For recommendations on dose adjustment of fulvestrant in case of toxic reactions, as well as other significant safety information, refer to the full prescribing information for fulvestrant.

Special Patient Populations

No dose adjustment is required when using the drug in patients with mild or moderate renal impairment based on a population pharmacokinetic analysis. Due to the lack of experience with the drug in patients with severe renal impairment, caution should be exercised when using Piqray^® in patients of this category.

Based on studies of hepatic impairment in patients without malignant disease with impaired hepatic function, it was determined that no dose adjustment is required for patients with mild, moderate, and severe hepatic impairment (Child-Pugh classes A, B, and C). For recommendations on dose adjustment of fulvestrant in hepatic impairment, refer to the full prescribing information for fulvestrant.

No dose adjustment is required for patients aged 65 years and older.

The efficacy and safety of Piqray^® in children under 18 years of age have not been established. No data are available.

Adverse Reactions

Safety information from the SOLAR-1 study

The overall safety profile of Piqray^® is based on data from a Phase III clinical study involving 571 female patients with HR-positive, HER2-negative advanced or metastatic breast cancer with or without a PIK3CA mutation.

Patients received either Piqray^® in combination with fulvestrant (n = 284) or placebo in combination with fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on days 1 and 15 of cycle 1, and then on day 1 of each 28-day cycle.

Two patients (0.7%) died while receiving Piqray^® in combination with fulvestrant due to reasons other than the primary malignancy. Causes of death included cardiorespiratory arrest in one patient and a second primary malignancy in the other patient. In no case was a relationship to the investigational therapy suspected.

Serious adverse reactions occurred in 35% of patients receiving Piqray^® in combination with fulvestrant. Serious adverse reactions occurring in > 2% of patients receiving Piqray^® in combination with fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).

In 4.6% of all patients receiving Piqray^® in combination with fulvestrant, both Piqray^® and fulvestrant were permanently discontinued due to adverse drug reactions (ADRs), and in 21% of patients, only Piqray^® was permanently discontinued. The most common ADRs leading to permanent discontinuation of Piqray^® therapy (> 2% of patients receiving Piqray^® in combination with fulvestrant) were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).

Dose reduction due to ADRs occurred in 55% of patients receiving Piqray^® in combination with fulvestrant. The most common ADRs requiring dose reduction of Piqray^® (> 2% of patients receiving Piqray^® and fulvestrant) were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%). The most common adverse reactions, including laboratory abnormalities (any grade, frequency ≥ 20%), were increased serum glucose, increased serum creatinine, diarrhea, rash, lymphopenia, increased GGT, nausea, increased ALT, fatigue, decreased hemoglobin, increased lipase, decreased appetite, stomatitis, vomiting, weight loss, hypocalcemia, hypoglycemia, prolonged aPTT, and alopecia.

ADRs in the Phase III clinical studies (Table 7) are grouped according to the MedDRA system organ class, listed in order of decreasing frequency.
Frequency was assessed as follows: 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), frequency not known (cannot be estimated from the available data). Within each category, ADRs are listed in order of decreasing frequency.

Table 7. ADRs reported in the Phase III clinical study and post-marketing period

* No Grade 4 ADRs were reported.

¹ Urinary tract infection: also includes a single case of urosepsis.

² Hypersensitivity: also includes allergic dermatitis.

³ Ketoacidosis: also includes diabetic ketoacidosis.

⁴ Dysgeusia: also includes ageusia and hypogeusia.

⁵ Pneumonitis: also includes interstitial lung disease.

⁶ Stomatitis: also includes aphthous ulcers and ulcerative stomatitis.

⁷ Rash: also includes maculo-papular rash, macular rash, generalized rash, papular rash, and pruritic rash.

⁸ Dry skin: also includes skin fissures, xerosis, and xeroderma.

⁹ Erythema: also includes generalized erythema.

¹⁰ Dermatitis: also includes acneiform dermatitis.

¹¹ Fatigue: also includes asthenia.

¹² Dry mucous membranes: also includes dry mouth and vulvovaginal dryness.

¹³ Edema: also includes face swelling, facial edema, and periorbital edema.

ADRs from spontaneous reports and literature sources (frequency not known)

The following ADRs were received during the post-marketing period for Piqray^® from spontaneous reports and literature sources. Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency, hence the frequency category is unknown.

Table 8. ADRs from spontaneous reports and literature sources (frequency not known)

Description of Selected ADRs

Hyperglycemia

Hyperglycemia (FPG >160 mg/dL) was reported in 190 (66.9%) patients; hyperglycemia of Grade 2 (FPG 160-250 mg/dL), Grade 3 (FPG >250-500 mg/dL), and Grade 4 (FPG >500 mg/dL) was reported in 16.2%, 33.8%, and 4.6% of patients, respectively.

Based on baseline FPG and HbA1c values, 56% of patients had prediabetes (FPG >100-126 mg/dL (5.6-6.9 mmol/L) and/or HbA1c 5.7-6.4%), and 4.2% of patients had diabetes (FPG ≥126 mg/dL (≥7.0 mmol/L) and/or HbA1c ≥6.5%).

Among patients with baseline prediabetes, 78.4% developed hyperglycemia (any grade) during alpelisib treatment. Among all patients with hyperglycemia ≥ Grade 2 (FPG ≥ 160 mg/dL), the median time to first onset was 15 days (range: 5 to 900 days) (based on laboratory data). The median duration of hyperglycemia ≥ Grade 2 was 10 days (95% CI: 8-13 days). The median time to improvement (by at least one grade relative to the first episode) in patients with hyperglycemia ≥ Grade 2 was 8 days (95% CI: 8-10 days). In all patients who continued fulvestrant treatment after permanent discontinuation of Piqray^®, FPG returned to baseline (to normal).

Hypoglycemic agents were used to manage hyperglycemia (see section “Special Instructions”).

Rash

ADRs of rash (including maculo-papular, macular, generalized, papular, and pruritic rash, dermatitis, and acneiform dermatitis) were reported in 153 (53.9%) patients. The rash was predominantly mild or moderate (Grade 1 or 2) and responsive to treatment; in some cases, the rash was accompanied by itching and dry skin. Rash of Grade 2 and 3 was reported in 13.7% and 20.1% of patients, respectively, with a median time to first onset of 12 days (range: 2 to 220 days).

In patients who received prophylactic treatment for rash, rash developed less frequently than in the overall population: rash of any grade – in 26.1% vs. 53.9% of patients, Grade 3 rash – in 11.4% vs. 20.1% of patients, rash leading to permanent discontinuation of Piqray^® therapy – in 3.4% vs. 4.2% of patients. Therefore, oral antihistamines may be prescribed prophylactically at the start of Piqray^® treatment.

Gastrointestinal Toxicity (nausea, diarrhea, vomiting)

Diarrhea, nausea, and vomiting were reported in 59.5%, 46.8%, and 28.5% of women, respectively (see Table 7).

Diarrhea of Grade 2 and 3 was reported in 19.7% and 7.0% of patients, respectively; the median time to onset of diarrhea ≥ Grade 2 was 50 days (range: 1 to 954 days).

Cases of severe diarrhea and its clinical consequences, such as dehydration and acute kidney injury, were reported during Piqray^® treatment; these adverse events were managed with appropriate treatment (see Table 4). Antiemetics (e.g., ondansetron) and antidiarrheals (e.g., loperamide) were used to manage symptoms in 28/133 (21.1%) and 109/169 (64.5%) of patients, respectively.

Osteonecrosis of the Jaw (ONJ)

ONJ was reported in 5.6% of patients (16/284) in the Piqray^® in combination with fulvestrant group. Fifteen patients who developed ONJ were receiving concomitant therapy with bisphosphonates (e.g., zoledronic acid) or RANK ligand inhibitors (e.g., denosumab). Therefore, an increased risk of ONJ cannot be excluded in patients receiving Piqray^® therapy and bisphosphonates or RANK ligand inhibitors.

Elderly Patients

In patients aged ≥ 65 years receiving alpelisib in combination with fulvestrant, a higher incidence of Grade 3-4 hyperglycemia (45.3%) was observed compared to patients aged < 65 years (33.5%), and in patients aged ≥ 75 years, the incidence of this ADR was 55.9% compared to 36% in patients aged < 75 years.

Contraindications

• Hypersensitivity to alpelisib or to any of the excipients of the drug;

• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Piqray^® is used in combination with fulvestrant. Refer to the full prescribing information for fulvestrant regarding use during pregnancy.

Women of childbearing potential (contraception in men and women)

In women of childbearing potential, a pregnancy test must be performed before starting Piqray^® therapy.

Women of childbearing potential should be informed that animal studies and the mechanism of action have shown that Alpelisib may be harmful to the developing fetus. Embryo-fetal development studies in rats and rabbits showed that oral administration of alpelisib during organogenesis caused embryotoxicity, fetotoxicity, and teratogenicity.

If Piqray^® is taken by women of childbearing potential, they must use effective contraceptive methods (e.g., double barrier method) while taking Piqray^® and for at least 1 week after completion of Piqray^® therapy.

Male patients whose partners are pregnant, possibly pregnant, or may become pregnant must use condoms during sexual intercourse and other effective methods of contraception while taking Piqray^® and for at least 1 week after completion of Piqray^® therapy.

Pregnancy

Piqray^® is contraindicated in established or suspected pregnancy, and in women of childbearing potential not using contraception.

There are no data on the use of alpelisib in pregnant women. Animal studies have shown reproductive toxicity.

Pregnancy status must be confirmed in women of childbearing potential prior to initiating Piqray^®.

Lactation

It is unknown whether Alpelisib is excreted in human or animal breast milk. Due to the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with Piqray^® and for at least 1 week after completion of Piqray^® therapy.

Fertility

There are no data on the effect of alpelisib on fertility. Data from repeated-dose toxicity studies in animals indicate that Alpelisib may impair fertility in men and women of reproductive potential.

Use in Hepatic Impairment

Dose adjustment is not required in patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C).

Use in Renal Impairment

No dose adjustment is required for patients with mild or moderate renal impairment based on a population pharmacokinetic analysis. Due to the lack of experience with the drug in patients with severe renal impairment, caution should be exercised when using Piqray^® in patients of this category.

Pediatric Use

The efficacy and safety of Piqray^® in children under 18 years of age have not been established. No data are available.

Geriatric Use

Dose adjustment is not required in patients aged 65 years and older.

Special Precautions

Hypersensitivity (including anaphylactic reactions)

Severe hypersensitivity reactions (including anaphylactic reactions and anaphylactic shock), presenting with symptoms such as dyspnea, flushing, rash, fever, or tachycardia, were observed in patients receiving Piqray^® in clinical studies. The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7%. In patients with severe hypersensitivity reactions, Piqray^® therapy should be permanently discontinued. Appropriate therapy should be initiated immediately.

Severe Cutaneous Reactions

Severe cutaneous reactions have been reported in patients receiving Piqray^®. In a Phase III clinical study, Stevens-Johnson syndrome and erythema multiforme were described in 0.4% and 1.1% of cases, respectively. Post-marketing reports have included drug reactions with eosinophilia and systemic symptoms (DRESS syndrome).

Therapy with Piqray^® should not be initiated in patients with a history of severe cutaneous reactions.

Patients should be informed about the characteristic manifestations of severe cutaneous reactions (e.g., prodromal symptoms including fever, flu-like symptoms, mucosal lesions, or progressive skin rash). If signs of severe cutaneous reactions occur, Piqray^® therapy should be interrupted until the cause is identified, and dermatology consultation is recommended. If severe cutaneous reactions are confirmed, Piqray^® therapy should be permanently discontinued.

Piqray^® therapy should not be resumed in patients who experienced severe cutaneous reactions due to Piqray^®. If the aforementioned severe cutaneous reactions were not confirmed, therapy interruption, dose reduction, or therapy discontinuation may be considered.

Hyperglycemia

Severe hyperglycemia, sometimes accompanied by hyperglycemic hyperosmolar non-ketotic syndrome (HHNS) or ketoacidosis, was observed in patients treated with Piqray^®. Some fatal cases of ketoacidosis have been reported post-marketing.

Hyperglycemia was described in 64.8% of patients receiving Piqray^®. Data from a Phase III clinical study showed the development of Grade 2 (FPG 160-250 mg/dL), Grade 3 (FPG >250-500 mg/dL), or Grade 4 (FPG >500 mg/dL) hyperglycemia in 15.8%, 33.1%, and 3.9% of patients, respectively.

In the Phase III clinical study, patients with a history of diabetes required more intensive hypoglycemic therapy during treatment with Piqray^®; therefore, these patients require monitoring and possibly intensified hypoglycemic therapy.

Patients with inadequate glycemic control may be at higher risk of developing severe hyperglycemia and related complications. Patients with risk factors for hyperglycemia, such as obesity (BMI ≥30), elevated FPG or HbA1c (glycated hemoglobin) at or above the upper limit of normal (ULN), or patients aged ≥75 years, are at higher risk of developing severe hyperglycemia. The recommended schedule for monitoring fasting plasma glucose is provided in Table 9.

Patients should be informed about the characteristic manifestations of hyperglycemia (e.g., excessive thirst, frequent urination or increased urine volume, and increased appetite with weight loss).

Table 9. Fasting Plasma Glucose Monitoring Schedule

* Glucose monitoring should always be performed according to the physician’s recommendations and based on clinical indications.

Patients should be informed about the characteristic manifestations of hyperglycemia (e.g., excessive thirst, frequent urination or increased urine volume, and increased appetite with weight loss).

Of 190 patients with hyperglycemia, 87.4% (166/190) received hypoglycemic therapy and 75.8% (144/190) received metformin as monotherapy or in combination with other hypoglycemic drugs (e.g., insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, and sulfonylureas).

Oral hypoglycemic therapy was administered to 154 patients, of whom 17 (11%) discontinued treatment due to hyperglycemia. Concomitant insulin therapy was administered to 54 patients, of whom 13 (24.1%) discontinued treatment due to hyperglycemia.

Of 162 patients with Grade ≥2 hyperglycemia, 155 patients had a reduction in symptom severity by at least 1 grade, with a median time to improvement from the date of the first episode of 8 days (95% CI: 8 to 10 days).

Among patients with elevated FPG who continued to receive fulvestrant after Piqray^® discontinuation (n=58), 98.3% (n=57) had FPG values return to baseline.

The safety of Piqray^® therapy in patients with type I diabetes and uncontrolled type II diabetes has not been established, as these patients were excluded from the Phase III clinical study. Patients with a history of type II diabetes were included. Patients with a history of diabetes require closer monitoring, as they may require more intensive hypoglycemic therapy.

Depending on the severity of hyperglycemia, interruption, dose reduction, or permanent discontinuation of Piqray^® may be required, as described in Table 2.

Pneumonitis

Pneumonitis, including cases of severe pneumonitis/acute interstitial lung disease, has been described in patients receiving Piqray^®. Pneumonitis was observed in 1.8% of patients receiving Piqray^®. Patients are advised to promptly report the occurrence of new or worsening respiratory symptoms; if they occur, Piqray^® treatment should be interrupted immediately and investigation for pneumonitis should be conducted. In patients with nonspecific respiratory manifestations, particularly hypoxia, cough, dyspnea, or interstitial infiltrates on radiographic imaging, and in patients in whom infectious, neoplastic, and other causes have been excluded during evaluation, the possibility of non-infectious pneumonitis should be considered. Piqray^® therapy should be discontinued in all patients with confirmed pneumonitis.

Diarrhea or Colitis

Cases of severe diarrhea and its clinical consequences, such as dehydration and acute kidney injury, were observed in clinical studies during therapy with Piqray^®. In a Phase III clinical study, Grade 2 and 3 diarrhea were observed in 18.3% and 6.7% of patients, respectively. No Grade 4 diarrhea was observed. For patients with Grade 2 or 3 diarrhea, the median time to onset of diarrhea was 46 days (range: 1 to 442 days).

Post-marketing cases of colitis have been reported in patients receiving Piqray^®.

In the Phase III clinical study, dose reduction of Piqray^® was required in 6% of patients, and the drug was permanently discontinued due to diarrhea in 2.8% of patients.

Patients should be monitored for diarrhea and additional symptoms of colitis, such as abdominal pain, mucus or blood in stool. Depending on the severity of diarrhea or colitis, temporary discontinuation of Piqray^®, dose reduction, or permanent discontinuation may be required.

Patients should be advised that if diarrhea or additional symptoms of colitis occur during Piqray^® therapy, they should inform their physician. Management should include monitoring of electrolytes, administration of antiemetic and antidiarrheal medications and/or intravenous fluid therapy and electrolyte replacement infusion. In case of colitis, consider additional therapy, e.g., corticosteroids.

Effect on Ability to Drive and Use Machines

Piqray^® has a minor influence on the ability to drive and use machines. Patients should exercise caution when driving or operating machinery if they experience fatigue or blurred vision during treatment.

Overdose

Symptoms adverse reactions observed in overdose were consistent with the Piqray^® safety profile and included hyperglycemia, nausea, asthenia, and rash.

Treatment in all cases of overdose, symptomatic treatment and general supportive measures should be administered as necessary. No specific antidote for Piqray^® is known.

Drug Interactions

Drugs that may increase plasma concentration of alpelisib

BCRP Inhibitors

Alpelisib is a substrate for BCRP (Breast Cancer Resistance Protein) in vitro. BCRP is involved in the hepatobiliary excretion and intestinal secretion of alpelisib; therefore, inhibition of BCRP in the liver and intestine during excretion may lead to increased systemic exposure to alpelisib. Consequently, caution should be exercised and patients should be monitored for toxic reactions when alpelisib is co-administered with BCRP inhibitors (e.g., eltrombopag, lapatinib, pantoprazole).

Drugs that may decrease plasma concentration of alpelisib

Acid-Reducing Agents

Co-administration of the H2-receptor antagonist ranitidine with a single 300 mg oral dose of alpelisib led to a slight decrease in alpelisib bioavailability and reduced overall exposure to alpelisib. In the presence of a low-fat, low-calorie meal and ranitidine, AUC_inf decreased by an average of 21%, and C_max in plasma decreased by 36%. Under fasting conditions, the effect was more pronounced: concomitant administration of ranitidine resulted in a 30% and 51% decrease in AUC_inf and C_max, respectively, compared to taking the drug fasting without ranitidine. A population pharmacokinetic analysis did not reveal a significant effect of co-administration of alpelisib with acid-reducing agents (including proton pump inhibitors, H₂ receptor blockers, and antacids) on the pharmacokinetics of alpelisib. Thus, Alpelisib can be taken concomitantly with acid-reducing agents, provided that Alpelisib is taken immediately after a meal.

CYP3A4 Enzyme Inducers

In healthy adult subjects (N = 25) who received a single oral dose of Alpelisib 300 mg on day 8 during administration of rifampicin (a strong CYP3A4 inducer) 600 mg once daily for 7 days, the C_max of alpelisib decreased by 38% and AUC by 57%. When alpelisib 300 mg/day was administered from day 8 to day 15 during administration of rifampicin 600 mg once daily for 15 days, the steady-state C_max of alpelisib decreased by 59% and AUC by 74%.

Concomitant use of a strong CYP3A4 inducer decreases the AUC of alpelisib, which may reduce the efficacy of alpelisib. Concomitant use of alpelisib with strong CYP3A4 inducers (e.g., apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin, St. John’s wort) should be avoided. Consider using alternative concomitant medications that have no or minimal potential to induce CYP3A4.

Drugs whose plasma concentration may be altered by alpelisib

Based on in vitro metabolism induction and inhibition studies, Alpelisib may induce the metabolic clearance of co-administered drugs metabolized by CYP2B6, CYP2C9, and CYP3A, and may inhibit the metabolic clearance of co-administered drugs metabolized by CYP2C8, CYP2C9, CYP2C19, and CYP3A4 (time-dependent inhibition) at sufficiently high in vivo concentrations.

CYP3A4 Substrates

No dose adjustment is required when alpelisib is co-administered with CYP3A4 substrates (e.g., everolimus, midazolam).

In a drug interaction study, co-administration of alpelisib with everolimus (a sensitive CYP3A4 substrate) confirmed the absence of a clinically significant pharmacokinetic interaction (11.2% increase in AUC) between alpelisib and CYP3A4 substrates. No changes in everolimus exposure were observed with alpelisib doses from 250 to 300 mg.

Caution is recommended when using alpelisib in combination with CYP3A4 substrates (such as rifampicin, ribociclib, encorafenib) that possess additional inhibitory potential and time-dependent induction of CYP3A4, affecting their own metabolism.

CYP2C9 Substrates with a Narrow Therapeutic Index

Due to the lack of clinical data on use with CYP2C9 substrates, caution is advised. In vitro assessments indicated that the pharmacological activity of CYP2C9 substrates with a narrow therapeutic index (e.g., warfarin) may be reduced due to the inductive effect of alpelisib on CYP2C9.

Sensitive CYP2B6 Substrates with a Narrow Therapeutic Index

Sensitive CYP2B6 substrates (e.g., bupropion) and CYP2B6 substrates with a narrow therapeutic index should be used with caution in combination with alpelisib, as Alpelisib may reduce the clinical efficacy of such drugs.

Drugs that are Substrates of Transporters

In vitro assessments indicated that Alpelisib (and/or its metabolite BZG791) has the potential to inhibit the activity of the drug transporters OAT3, as well as BCRP and P-glycoprotein in the intestine. Alpelisib should be used with caution in combination with sensitive substrates of these transporters that have a narrow therapeutic index, as Alpelisib may increase the systemic exposure of these substrates.

Hormonal Contraceptives

No clinical studies have been conducted to evaluate the potential drug interaction between alpelisib and hormonal contraceptives.

Piqray^® is used in combination with fulvestrant. Please refer to the full prescribing information for fulvestrant regarding use in pregnancy.

Storage Conditions

The drug should be stored at a temperature not exceeding 30°C (86°F) in a dry place.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is prescription-only.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.