ALPELISIB Drug Interactions: What You Need to Know

INTERACTIONS CYP3A4 Inducers : Avoid coadministration of VIJOICE with a strong CYP3A4 inducer. Consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. ( 7.1 )

Breast Cancer Resistance

Protein (BCRP) Inhibitors : Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, closely monitor for increased adverse reactions. ( 7.1 )

7.1 Effect of Other Drugs on VIJOICE CYP3A4 Inducers Avoid coadministration of VIJOICE with strong CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4. Alpelisib is metabolized by CYP3A4. Concomitant use of VIJOICE with a strong CYP3A4 inducer may decrease alpelisib concentration <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> , which may decrease alpelisib activity.

Breast Cancer Resistance Protein

Inhibitors (BCRP) Avoid the use of BCRP inhibitors in patients treated with VIJOICE. If unable to use alternative drugs, when VIJOICE is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions. Alpelisib is transported by BCRP. Concomitant use of VIJOICE with a BCRP inhibitor may increase alpelisib exposure [see Clinical Pharmacology (12.3)] , which may increase the risk of adverse reactions.

VIJOICE is contraindicated in patients with severe hypersensitivity to alpelisib or any of its ingredients [see Warnings and Precautions (5.1)] . Severe hypersensitivity to VIJOICE or to any of its ingredients. ( 4 )

AND PRECAUTIONS Severe Hypersensitivity : Permanently discontinue PIQRAY. Promptly initiate appropriate treatment. ( 5.1 )

Severe Cutaneous Adverse

Reactions (SCARs) : PIQRAY 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 PIQRAY for signs or symptoms of SCARs. Permanently discontinue PIQRAY if SCARs are confirmed. ( 5.2 ) Hyperglycemia : PIQRAY can cause severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose. Consider premedication with metformin prior to the initiation of PIQRAY based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation. Use of metformin premedication prior to the initiation of PIQRAY decreases the incidence and severity of hyperglycemia, but increases the incidence and severity of nausea, vomiting, and diarrhea adverse reactions. After initiating treatment, monitor FPG and HbA1c periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated. Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia occurs. ( 2.3 , 5.3 , 6.1 ) Pneumonitis : PIQRAY can cause severe pneumonitis and interstitial lung disease. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs. ( 2.3 , 5.4 ) Diarrhea or Colitis : PIQRAY causes diarrhea in most patients and may be severe, resulting in dehydration and acute kidney injury. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs. Colitis has been reported in patients treated with PIQRAY. Monitor for diarrhea and additional symptoms of colitis, including abdominal pain and mucus or blood in stool. Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea or colitis occurs. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids. ( 2.3 , 5.5 , 6.2 ) Embryo-Fetal Toxicity : PIQRAY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

5.1 Severe Hypersensitivity 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% <span class="opacity-50 text-xs">[see Adverse Reactions (6)]</span> . Angioedema has been reported in the postmarketing setting in patients treated with PIQRAY <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue PIQRAY in the event of severe hypersensitivity.

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) 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Drug reaction with eosinophilia and systemic symptoms (DRESS) was reported in patients treated with PIQRAY in the postmarketing setting <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3)]</span> . 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).

5.3 Hyperglycemia Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Fatal cases of ketoacidosis have occurred in the postmarketing setting. 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-hyperglycemic medication, and 76% (142/187) reported use of metformin as single agent or in combination with other anti-hyperglycemic 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. Monitor fasting glucose more frequently for the first few weeks during treatment with PIQRAY 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 PIQRAY, 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 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 controlled Type 2 diabetes were included. Patients with a history of diabetes mellitus may require intensified hyperglycemic treatment. Closely monitor patients with diabetes. Consider premedication with metformin prior to the initiation of PIQRAY in combination with fulvestrant based on patient risk factors for hyperglycemia, gastrointestinal tolerability, and clinical situation. In the METALLICA study, use of metformin starting 7 days prior to the initiation of PIQRAY appeared to decrease the incidence and severity of hyperglycemia events, but increased the incidence and severity of nausea, vomiting, and diarrhea adverse reactions [see Adverse Reactions (6.1)] . 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).

5.4 Pneumonitis 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.

5.5 Diarrhea or Colitis Severe diarrhea, resulting in dehydration and in some cases in 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). In clinical trials, 63% of patients who experienced diarrhea required antidiarrheal medications (e.g., loperamide) to manage symptoms. Dose reductions of PIQRAY were required in 6% of patients, and 2.8% of patients permanently discontinued PIQRAY due to diarrhea. Colitis has been reported in the postmarketing setting in patients treated with PIQRAY [see Adverse Reactions (6.2)] . Monitor patients 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, PIQRAY may require dose interruption, reduction, or discontinuation as described in Table 4 [see Dosage and Administration (2.3)] . Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY. Patients with colitis may require additional treatment, such as enteric-acting and/or systemic steroids.

5.6 Embryo-Fetal Toxicity 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]</span> . Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.