Source: FDA, National Drug Code (US) Revision Year: 2020
PIQRAY is contraindicated in patients with severe hypersensitivity to it or any of its components [see Warnings and Precautions (5.1)].
Severe hypersensitivity reactions, including anaphylaxis and anaphylactic shock, can occur in patients treated with PIQRAY. Severe hypersensitivity reactions were manifested by symptoms including, but not limited to, dyspnea, flushing, rash, fever, or tachycardia.
The incidence of Grade 3 and 4 hypersensitivity reactions was 0.7% [see Adverse Reactions (6)].
Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) can occur in patients treated with PIQRAY.
In the SOLAR-1 study, SJS and EM were reported in 0.4% and 1.1% of the patients, respectively [see Adverse Reactions (6.1)]. Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with PIQRAY in the postmarketing setting [see Adverse Reactions (6.2)].
If signs or symptoms of SCARs occur, interrupt PIQRAY until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended.
If a SCAR is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous severe cutaneous adverse reactions during PIQRAY treatment.
If a SCAR is not confirmed, PIQRAY may require dose modifications, topical corticosteroids, or oral antihistamine treatment as described in Table 2 [see Dosage and Administration (2.3)].
Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).
Severe hyperglycemia, including ketoacidosis, can occur in patients treated with PIQRAY. Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG > 250 to 500 mg/dL) and Grade 4 (FPG > 500 mg/dL) hyperglycemia was reported in 33% and 3.9% of patients, respectively. Ketoacidosis was reported in 0.7% of patients (n = 2) treated with PIQRAY.
Among the patients who experienced Grade ≥ 2 (FPG 160 to 250 mg/dL) hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range, 5 to 517 days).
In the 187 patients with hyperglycemia, 87% (163/187) were managed with anti-diabetic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-diabetic medication [i.e., insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas]. In patients with Grade ≥ 2 hyperglycemia with at least 1 grade improvement (n = 153), median time to improvement from the first event was 8 days (range, 2 to 65 days).
In all patients with elevated FPG who continued fulvestrant treatment after discontinuing PIQRAY (n = 54), 96% (n = 52) of patients had FPG levels that returned to baseline.
Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with PIQRAY, monitor fasting glucose (FPG or fasting blood glucose) at least once every week for the first 2 weeks, then at least once every 4 weeks, and as clinically indicated. Monitor HbA1c every 3 months and as clinically indicated.
If a patient experiences hyperglycemia after initiating treatment with PIQRAY, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-diabetic medication, continue monitoring fasting glucose at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated. Consider consultation with a healthcare practitioner with expertise in the treatment of hyperglycemia and counsel patients on lifestyle changes.
The safety of PIQRAY in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the SOLAR-1 trial. Patients with a medical history of Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified diabetic treatment. Closely monitor patients with diabetes.
Based on the severity of the hyperglycemia, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 3 [see Dosage and Administration (2.3)].
Advise patients of the signs and symptoms of hyperglycemia (e.g., excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss).
Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, can occur in patients treated with PIQRAY.
Pneumonitis was reported in 1.8% of patients treated with PIQRAY.
In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt PIQRAY immediately and evaluate the patient for pneumonitis. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations.
Permanently discontinue PIQRAY in all patients with confirmed pneumonitis.
Advise patients to immediately report new or worsening respiratory symptoms.
Severe diarrhea, including dehydration and acute kidney injury, can occur in patients treated with PIQRAY. Most patients (58%) experienced diarrhea during treatment with PIQRAY. Grade 3 diarrhea occurred in 7% (n = 19) of patients. Among patients with Grade 2 or 3 diarrhea (n = 71), the median time to onset was 46 days (range, 1 to 442 days).
Dose reductions of PIQRAY were required in 6% of patients and 2.8% of patients permanently discontinued PIQRAY due to diarrhea. In the 164 patients that experienced diarrhea, anti-diarrheal medications (e.g., loperamide) were required to manage symptoms in 63% (104/164) of these patients.
Based on the severity of the diarrhea, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 4 [see Dosage and Administration (2.3)].
Advise patients to start anti-diarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY.
Based on findings in animals and its mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures based on area under the curve (AUC) that were ≥ 0.8 times the exposure in humans at the recommended dose of 300 mg/day. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of PIQRAY was evaluated in a randomized, double-blind, placebo-controlled trial (SOLAR-1) in 571 patients with HR-positive, HER2-negative, advanced or metastatic breast cancer enrolled into two cohorts, with or without a PIK3CA mutation [see Clinical Studies (14)].
Patients received either PIQRAY 300 mg plus fulvestrant (n = 284) or placebo plus fulvestrant (n = 287). Fulvestrant 500 mg was administered intramuscularly on Cycle 1, Day 1 and 15, and then at Day 1 of each 28-day cycle during treatment phase.
Two patients (0.7%) died while on treatment with PIQRAY plus fulvestrant due to causes other than the underlying malignancy. Causes of death included one cardio-respiratory arrest and one second primary malignancy. Neither was suspected to be related to study treatment.
Serious adverse reactions occurred in 35% of patients receiving PIQRAY plus fulvestrant. Serious adverse reactions in > 2% of patients receiving PIQRAY plus fulvestrant included hyperglycemia (10%), rash (3.5%), diarrhea (2.8%), acute kidney injury (2.5%), abdominal pain (2.1%), and anemia (2.1%).
Osteonecrosis of the jaw (ONJ) was reported in 4.2% of patients (12/284) in the PIQRAY plus fulvestrant arm compared to 1.4% of patients (4/287) in the placebo arm. All patients experiencing ONJ had prior or concomitant bisphosphonates or RANK-ligand inhibitor administration.
Among patients receiving PIQRAY plus fulvestrant, 4.6% permanently discontinued both PIQRAY and fulvestrant and 21% permanently discontinued PIQRAY alone, due to ARs. The most frequent ARs leading to treatment discontinuation of PIQRAY in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (6%), rash (4.2%), diarrhea (2.8%), and fatigue (2.5%).
Dose reductions due to ARs occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent ARs leading to dose reduction in > 2% patients receiving PIQRAY plus fulvestrant were hyperglycemia (29%), rash (9%), diarrhea (6%), stomatitis (3.5%), and mucosal inflammation (2.1%).
The most common adverse reactions, including laboratory abnormalities (all grades, incidence ≥ 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, gamma glutamyl transferase (GGT) increased, nausea, alanine aminotransferase (ALT) increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, activated partial thromboplastin time (aPTT) prolonged, and alopecia.
Adverse reactions and laboratory abnormalities are listed in Table 6 and Table 7, respectively.
Table 6. Adverse Reactions Occurring in ≥ 10% and ≥ 2% Higher than Placebo Arm in SOLAR-1 (All Grades):
| Adverse reactions | PIQRAY plus fulvestrant N = 284 | Placebo plus fulvestrant N = 287 | ||
|---|---|---|---|---|
| All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Gastrointestinal disorders | ||||
| Diarrhea | 58 | 7* | 16 | 0.3* |
| Nausea | 45 | 2.5* | 22 | 0.3* |
| Stomatitis 1 | 30 | 2.5* | 6 | 0* |
| Vomiting | 27 | 0.7* | 10 | 0.3* |
| Abdominal pain2 | 17 | 1.4* | 11 | 1* |
| Dyspepsia | 11 | 0* | 6 | 0* |
| General disorders and administration site conditions | ||||
| Fatigue3 | 42 | 5* | 29 | 1* |
| Mucosal inflammation | 19 | 2.1* | 1 | 0* |
| Edema peripheral | 15 | 0* | 5 | 0.3* |
| Pyrexia | 14 | 0.7 | 4.9 | 0.3* |
| Mucosal dryness4 | 12 | 0.4* | 4.2 | 0* |
| Infections and infestations | ||||
| Urinary tract infection5 | 10 | 0.7* | 5 | 1* |
| Investigations | ||||
| Weight decreased | 27 | 3.9* | 2.1 | 0* |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 36 | 0.7* | 10 | 0.3* |
| Nervous system disorders | ||||
| Dysgeusia 6 | 18 | 0.4* | 3.5 | 0* |
| Headache | 18 | 0.7* | 13 | 0* |
| Skin and subcutaneous tissue disorders | ||||
| Rash 7 | 52 | 20* | 7 | 0.3* |
| Alopecia | 20 | 0* | 2.4 | 0* |
| Pruritus | 18 | 0.7* | 6 | 0* |
| Dry skin 8 | 18 | 0.4* | 3.8 | 0* |
Grading according to CTCAE Version 4.03
1 Stomatitis: including stomatitis, aphthous ulcer and mouth ulceration
2 Abdominal pain: abdominal pain, abdominal pain upper, abdominal pain lower
3 Fatigue: including fatigue, asthenia
4 Mucosal dryness: including dry mouth, mucosal dryness, vulvovaginal dryness
5 Urinary tract infection: including UTI and single case of urosepsis
6 Dysgeusia: including dysgeusia, ageusia, hypogeusia 7Rash: including rash, rash maculo-papular, rash macular, rash generalized, rash papular, rash pruritic
8 Dry skin: including dry skin, skin fissures, xerosis, xeroderma
* No Grade 4 adverse reactions were 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. A subgroup of 86 patients received prophylaxis, including antihistamines, prior to onset of rash. In these patients, rash was reported less frequently than in the overall population, for all grades rash (27% vs 54%), Grade 3 rash (12% vs 20%) and rash leading to permanent discontinuation of PIQRAY (3.5% vs 4.2%). Of the 153 patients who experienced rash, 141 had resolution of the rash.
Table 7: Laboratory Abnormalities Occurring in ≥ 10% of Patients in SOLAR-1
| Laboratory Abnormality | PIQRAY plus fulvestrant >N = 284 | Placebo plus fulvestrant N = 287 | ||||
|---|---|---|---|---|---|---|
| All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | |||
| Hematological parameters | ||||||
| Lymphocyte count decreased | 52 | 8 | 40 | 4.5* | ||
| Hemoglobin decreased | 42 | 4.2* | 29 | 1* | ||
| Activated Partial Thromboplastin Time (aPTT) prolonged | 21 | 0.7 * | 16 | 0.3 * | ||
| Platelet count decreased | 14 | 1.1 | 6 | 0* | ||
| Biochemical parameters | ||||||
| Glucose increased 1 | 79 | 39 | 34 | 1 | ||
| Creatinine increased | 67 | 2.8* | 25 | 0.7* | ||
| Gamma Glutamyl Transferase (GGT) increased | 52 | 11 | 44 | 10 | ||
| Alanine Aminotransferase (ALT) increased | 44 | 3.5 | 34 | 2.4 * | ||
| Lipase increased | 42 | 7 | 25 | 6 | ||
| Calcium (corrected) decreased | 27 | 2.1 | 20 | 1.4 | ||
| Glucose decreased | 26 | 0.4 | 14 | 0* | ||
| Potassium decreased | 14 | 6 | 2.8 | 0.7* | ||
| Albumin decreased | 14 | 0* | 8 | 0* | ||
| Magnesium decreased | 11 | 0.4* | 4.2 | 0* | ||
1 Glucose increase is an expected laboratory abnormality of PI3K inhibition.
* No Grade 4 laboratory abnormalities were reported.
The following adverse reactions have been identified during post-approval use of PIQRAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Skin and sub-cutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS).
Coadministration of PIQRAY with a strong CYP3A4 inducer may decrease alpelisib concentration [see Clinical Pharmacology (12.3)], which may decrease alpelisib activity. Avoid coadministration of PIQRAY with strong CYP3A4 inducers.
Coadministration of PIQRAY with a breast cancer resistance protein (BCRP) inhibitor may increase alpelisib concentration [see Clinical Pharmacology (12.3)], which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, when PIQRAY is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.
Coadministration of PIQRAY with CYP2C9 substrates (e.g., warfarin) may reduce plasma concentration of these drugs [see Clinical Pharmacology (12.3)]. Closely monitor when PIQRAY is used in combination with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.
PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.
Based on animal data and mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of alpelisib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at maternal exposures ≥ 0.8 times the exposure in humans based on AUC at the recommended dose of 300 mg/day (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.
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 resulted in maternal toxicity (body weight loss, low food consumption) and no viable fetuses (post-implantation loss) at 30 mg/kg/day (approximately 3 times the exposure in humans at the recommended dose of 300 mg/day based on AUC). At a dose of 10 mg/kg/day (approximately 0.8 times the exposure in humans at the recommended dose of 300 mg/day based on AUC), toxicities included reduced fetal weight and increased incidences of skeletal malformations (bent scapula and thickened or bent long bones) and fetal variations (enlarged brain ventricle, decreased bone ossification).
In a pilot embryo-fetal development study in rabbits, a dose of 30 mg/kg/day resulted in no viable fetuses (post-implantation loss). Doses ≥ 15 mg/kg/day resulted in increased embryo-fetal deaths, reduced fetal weights, and malformations, mostly related to the tail and head. At 15 mg/kg/day in rabbits, the maternal exposure was approximately 5 times the exposure achieved at the recommended human dose of 300 mg/day based on AUC.
PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.
There is no data on the presence of alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with PIQRAY and for 1 week after the last dose.
PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.
Verify the pregnancy status in females of reproductive potential prior to initiating PIQRAY.
PIQRAY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose.
Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose.
Based on findings from animal studies, PIQRAY may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].
The safety and efficacy of PIQRAY in pediatric patients have not been established.
Of 284 patients who received PIQRAY in the SOLAR-1 trial, 117 patients were ≥ 65 years of age and 34 patients were ≥ 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was a higher incidence of Grade 3-4 hyperglycemia in patients ≥ 65 years of age (44%) compared to patients < 65 years of age (32%). No overall differences in effectiveness of PIQRAY were observed between patients ≥ 65 years of age compared to younger patients. There are an insufficient number of patients ≥ 75 years of age to assess whether there are differences in safety or effectiveness.
The effect of severe renal impairment (CLcr < 30 mL/min) on alpelisib pharmacokinetics is unknown The effect of severe renal impairment (CLcr < 30 mL/min) on alpelisib pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].
No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 mL/min).
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