5.3 Hyperglycemia

(Additions and/or revisions underlined)

…

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).

6.1 Clinical Trial Experience

(Extensive changes; please refer to label for complete information)

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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.

Eye disorders: Uveitis

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Uveitis

Advise patients to contact their healthcare provider immediately for signs and symptoms of uveitis [see Adverse Reactions (6.2)].

…

Drug Interactions

Advise patients to avoid the use of strong CYP3A4 inducers in patients treated with PIQRAY. Advise patients to avoid the use of BCRP inhibitors while taking PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions. No dose adjustment is required when coadministering PIQRAY with CYP3A4, CYP2C8, CYP2C9, CYP2C19 and CYP2B6 substrates [see Drug Interactions (7.1, 7.2)].

CYP3A4 Inducer

Additions and/or revisions underlined:

Coadministration of PIQRAY with a strong CYP3A4 inducer decreases alpelisib concentration [see Clinical Pharmacology (12.3)], which may reduce alpelisib efficacy. Avoid concomitant use of strong CYP3A4 inducers and consider an alternative concomitant drug with no or minimal potential to induce CYP3A4.

Newly added information:

Angioedema has been reported in the postmarketing setting in patients treated with PIQRAY [see Adverse Reactions (6.2)].

Additions and revisions underlined:

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.

For patients with colitis, additional treatment, such as enteric-acting and/or systemic steroids, may be required.

Additions and revisions underlined:

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)]

Additions and revisions underlined:

The following adverse reactions have been identified during postapproval 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.

Gastrointestinal disorders: Colitis

Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).

Skin and subcutaneous tissue disorders: Angioedema, Drug reaction with eosinophilia and systemic symptoms (DRESS).

Additions and revisions underlined:

Hyperglycemia

Advise patients that PIQRAY may cause hyperglycemia and requires monitoring of fasting blood glucose periodically during therapy. Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia [see Warnings and Precautions (5.3)].

Pneumonitis

Inform patients that PIQRAY may cause pneumonitis and to immediately contact their healthcare provider if they experience respiratory problems [see Warnings and Precautions (5.4)].

Diarrhea or Colitis

Advise patients that PIQRAY may cause diarrhea, which may be severe, and to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY [see Warnings and Precautions (5.5)].

Advise patients that PIQRAY may cause colitis and to notify their healthcare provider immediately of any symptoms of colitis, such as abdominal pain and mucus or blood in stool, while taking PIQRAY [see Warnings and Precautions (5.5)].

Additions and revisions underlined:

PIQRAY may cause serious side effects, including:

• Severe allergic reactions. Tell your healthcare provider or get medical help right away if you have trouble

breathing, swelling of the face or throat, flushing, rash, fever, or fast heart rate during treatment with

PIQRAY.

• Diarrhea or colitis (inflammation of your intestines). Diarrhea is common with PIQRAY and may be

severe. Severe diarrhea can lead to the loss of too much body water (dehydration) and kidney injury. Tell

your healthcare provider right away if you develop diarrhea, stomach-area (abdominal) pain, or see mucus or

blood in your stool during treatment with PIQRAY. Your healthcare provider may tell you to drink more fluids

or take medicines to treat diarrhea or colitis.

Additions and/or revisions underlined:

‘hyperglycemic’ replaces ‘diabetic’ throughout subsection.

Severe hyperglycemia, in some cases associated with hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) or ketoacidosis has occurred in patients treated with PIQRAY. Some fatal cases of ketoacidosis have occurred in the post marketing setting …

… 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 greater than or equal to 30), elevated FPG, HbA1c at the upper limit of normal or above, use of concomitant systemic corticosteroids, or age greater than or equal to 75 [see Use in Specific Populations (8.5)] …

… 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 …

Additions and/or revisions underlined:

Metabolism and nutrition disorders: Hyperglycemic hyperosmolar nonketotic syndrome (HHNKS).

Skin and sub-cutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS).

Additions and/or revisions underlined:

… There are an insufficient number of patients greater than or equal to 75 years of age to assess whether there are differences in safety or effectiveness. However, in the SOLAR-1 trial, an increase in the hyperglycemia adverse reactions (74% vs 66%) and Grade 3-4 (56% vs 36%) hyperglycemia were observed in patients > 75 years of age compared to patients < 75 years of age, respectively [see Warnings and Precautions (5.3)].

What are the possible side effects of PIQRAY?

PIQRAY may cause serious side effects, including:

High blood sugar levels (hyperglycemia) …

Addition of the following under the bulleted line listing:

• Confusion

• Nausea

• Vomiting

• Fruity odor on breath

• Difficulty breathing

• Dry or flushed skin

Additions and/or revisions underlined:

Severe Cutaneous Adverse Reactions

Inform patients of the signs and symptoms of severe cutaneous adverse reactions (SCARs) …

(Additions and/or revisions underlined)

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.

(Subsection title revised; Additions and/or revisions underlined)

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 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).

(Additions and/or revisions underlined)

Severe hyperglycemia, including ketoacidosis, can occur in patients treated with PIQRAY. Hyperglycemia was reported in 65% of patients treated with PIQRAY. Grade 3 (FPG > 250-500 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 160-250 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).

(Additions and/or revisions underlined)

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.

(Additions and/or revisions underlined)

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 antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY.

(Additions and/or revisions underlined)

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 [see Warnings and Precautions (5.5)]

(Newly added subsection)

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).