Can Alpelisib cause hyperglycaemia?

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Severe Hypersensitivity [see Warnings and Precautions (5.1)] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.2)] Hyperglycemia [see Warnings and Precautions (5.3)] Pneumonitis [see Warnings and Precautions (5.4)] Diarrhea or Colitis [see Warnings and Precautions (5.5)] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience 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 adverse reactions. The most frequent adverse reactions 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 adverse reactions occurred in 55% of patients receiving PIQRAY plus fulvestrant. The most frequent adverse reactions 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) 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. 7 Rash: 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. PIQRAY plus fulvestrant N = 284 Placebo plus fulvestrant N = 287 Adverse reactions 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 pain 2 17 1.4 * 11 1 * Dyspepsia 11 0 * 6 0 * General disorders and administration site conditions Fatigue 3 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 dryness 4 12 0.4 * 4.2 0 * Infections and infestations Urinary tract infection 5 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 * 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 premedication, 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 1 Glucose increase is an expected laboratory abnormality of PI3K inhibition. * No Grade 4 laboratory abnormalities were reported. PIQRAY plus fulvestrant N = 284 Placebo plus fulvestrant N = 287 Laboratory abnormality 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 * Metformin Premedication for Hyperglycemia Adverse Reactions The safety of PIQRAY and endocrine therapy with metformin premedication was evaluated in METALLICA (NCT04300790), a single-arm, two-cohort study in 68 patients with HR-positive, HER2-negative advanced breast cancer harboring PIK3CA mutation(s). The majority of patients (93%) received fulvestrant as endocrine therapy during the study. Cohort A enrolled patients with normal glycemic status (FPG < 100 mg/dl [< 5.6 mmol/L] and HbA1c < 5.7%) and Cohort B enrolled patients with impaired glycemic status (FPG 100–140 mg/dL [5.6–7.8 mmol/L] or HbA1c 5.7%–6.4%). Metformin was administered beginning 7 days prior to treatment with PIQRAY. On Day 1 to Day 3, metformin 500 mg twice daily was administered orally and then increased up to 1,000 mg t

WARNINGS AND PRECAUTIONS Severe Hypersensitivity : Permanently discontinue VIJOICE. Promptly initiate appropriate treatment. ( 5.1 ) Severe Cutaneous Adverse Reactions (SCARs) : VIJOICE can cause SCARs, including Stevens-Johnson syndrome (SJS), erythema multiforme (EM), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS). Interrupt VIJOICE for signs or symptoms of SCARs. Permanently discontinue VIJOICE if SCARs are confirmed. ( 2.5 , 5.2 ) Hyperglycemia : VIJOICE can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. The safety of VIJOICE in patients with Type 1 or uncontrolled Type 2 diabetes has not been established. Before initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment, monitor periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue VIJOICE if severe hyperglycemia occurs. ( 2.5 , 5.3 ) Pneumonitis : VIJOICE can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Permanently discontinue VIJOICE if pneumonitis occurs. ( 2.5 , 5.4 ) Diarrhea or Colitis : VIJOICE can cause severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, as well as colitis. Monitor for diarrhea and additional symptoms of colitis, including abdominal pain and mucus or blood in stool. Interrupt, reduce dose, or permanently discontinue VIJOICE based on severity of diarrhea or colitis. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids. ( 2.5 , 5.5 ) Embryo-Fetal Toxicity : VIJOICE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Severe Hypersensitivity Severe hypersensitivity reactions, including anaphylaxis, anaphylactic shock, and angioedema, have occurred in adult patients treated with alpelisib in the oncology setting and in patients treated with VIJOICE [see Adverse Reactions (6.1)] . VIJOICE is not approved for use in the oncology setting. Permanently discontinue VIJOICE in the event of severe hypersensitivity [see Contraindications (4)] . 5.2 Severe Cutaneous Adverse Reactions 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), have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting. If signs or symptoms of SCARs occur, interrupt VIJOICE until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue VIJOICE. If a SCAR is not confirmed, VIJOICE may require dose modifications, topical or systemic corticosteroids, or oral antihistamine treatment as described in Table 4 [see Dosage and Administration (2.5)] . 5.3 Hyperglycemia Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or fatal cases of ketoacidosis, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting. In the EPIK-P1 study, Grade 1 or 2 hyperglycemia was reported in 12% of patients treated with VIJOICE [see Adverse Reactions (6.1)] . Before initiating treatment with VIJOICE, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. After initiating treatment with VIJOICE, 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. Monitor fasting glucose more frequently for the first few weeks during treatment with VIJOICE in patients with risk factors for hyperglycemia, such as obesity (BMI ≥ 30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age ≥ 75 [see Use in Specific Populations (8.5)] . If a patient experiences hyperglycemia after initiating treatment with VIJOICE, monitor fasting glucose as clinically indicated, and at least twice weekly until fasting glucose decreases to normal levels. During treatment with anti-hyperglycemic 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 VIJOICE in patients with Type 1 and uncontrolled Type 2 diabetes has not been established. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes. Interrupt, reduce the dose, or permanently discontinue VIJOICE based on the severity as described in Table 5 [see Dosage and Administration (2.5)] . 5.4 Pneumonitis Severe pneumonitis, including acute interstitial pneumonitis and interstitial lung disease, has occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting. In patients who have new or worsening respiratory symptoms or are suspected to have developed pneumonitis, interrupt VIJOICE 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 VIJOICE in all patients with confirmed pneumonitis [see Dosage and Administration (2.5)] . 5.5 Diarrhea or Colitis Severe diarrhea, resulting in dehydration and in some cases in acute kidney injury, as well as colitis, have occurred in adult patients treated with alpelisib in the oncology setting and may occur in patients treated with VIJOICE. VIJOICE is not approved for use in the oncology setting. In the EPIK-P1 study, 16% of patients experienced Grade 1 diarrhea during treatment with VIJOICE [see Adverse Reactions (6.1)] . Monitor patients for diarrhea and additional symptoms of colitis, such as abdominal pain and mucus or blood in stool. Interrupt, reduce the dose or permanently discontinue VIJOICE based on the severity of diarrhea or colitis [see Dosage and Administration (2.5)] . Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids [see Dosage and Administration (2.5)] . 5.6 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, VIJOICE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of alpelisib to pregnant animals during organogenesis caused adverse developmental outcomes, including embryo-fetal mortality (post-implantation loss), reduced fetal weights, and increased incidences of fetal malformations at doses that were approximately equivalent to the recommended pediatric and adult doses. 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 VIJOICE 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 VIJOICE and for 1 week after the last dose [see Use in Sp