Posology : מינונים

5     DOSAGE AND ADMINISTRATION
5.1   Patient Selection
Select patients for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer with PIQRAY, based on the presence of one or more PIK3CA mutations in tumor tissue or plasma specimens [see Clinical Studies (15)]. If no mutation is detected in a plasma specimen, test tumor tissue.

PIQ API FEB24 V6                                                                       USPI JAN24 5.2 Dosage and Administration
The recommended dose of PIQRAY is 300 mg (two 150 mg film-coated tablets) taken orally, once daily, with food [see Clinical Pharmacology (13.3)].
Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration (5.3)].

Patients should take their dose of PIQRAY at approximately the same time each day.
Swallow PIQRAY tablets whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
If a dose of PIQRAY is missed, it can be taken with food within 9 hours after the time it is usually taken. After more than 9 hours, skip the dose for that day. The next day, take PIQRAY at the usual time.
If the patient vomits after taking the dose, advise the patient not to take an additional dose on that day, and to resume the dosing schedule the next day at the usual time.
When given with PIQRAY, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter. Refer to the Full Prescribing Information for fulvestrant.
5.3 Dose Modifications for Adverse Reactions
The recommended dose modifications for adverse reactions are listed in Table 1.
Table 1: PIQRAY Dose Reduction Guidelines for Adverse Reactions1
PIQRAY dose level                          Dose and schedule                    Number and strength of tablets Starting dose                              300 mg once daily                    Two 150 mg tablets First-dose reduction                       250 mg once daily                    One 200 mg tablet and one 50 mg tablet Second-dose reduction                      200 mg once daily2                   One 200 mg tablet 1
Only one dose reduction is permitted for pancreatitis.
2
If further dose reduction below 200 mg once daily is required, discontinue PIQRAY.

Tables 2, 3, 4, and 5 summarize recommendations for dose interruption, reduction, or discontinuation of PIQRAY in the management of specific adverse reactions.


Cutaneous Adverse Reactions
If a severe cutaneous adverse reaction (SCAR) is confirmed, permanently discontinue PIQRAY. Do not reintroduce PIQRAY in patients who have experienced previous SCAR during PIQRAY treatment [see Warnings and
Precautions (7.2)].
Table 2: Dose Modification and Management for Rash and Severe Cutaneous Adverse Reactions (SCARs)
[see Warnings and Precautions (7.1, 7.2)]


PIQ API FEB24 V6                                                                                    USPI JAN24 Grade1,2                            Recommendation3
Grade 1                             No PIQRAY dose adjustment
(< 10% body surface                 required. Initiate topical area (BSA) with active corticosteroid treatment.
skin toxicity)
Consider adding oral antihistamine to manage symptoms.
If active rash is not improved within 28 days of appropriate treatment, add a low dose systemic corticosteroid.

If the etiology is SCAR, permanently discontinue PIQRAY.
Grade 2                             No PIQRAY dose adjustment required.
(10%-30% BSA with                   Initiate or intensify topical corticosteroid and oral antihistamine active skin toxicity) treatment. Consider low dose systemic corticosteroid treatment.

If rash improves to Grade ≤ 1 within 10 days, systemic corticosteroid may be discontinued.


If the etiology is SCAR, permanently discontinue PIQRAY.
Grade 3 (e.g., severe rash          Interrupt PIQRAY.
not responsive to medical
Initiate or intensify topical/systemic corticosteroid and oral antihistamine management) treatment. If the etiology is SCAR, permanently discontinue PIQRAY.
(> 30% BSA with active skin toxicity)                      If the etiology is not a SCAR, interrupt dose until improvement to Grade ≤ 1, then resume PIQRAY at next lower dose level.

Grade 4 (e.g., severe               Permanently discontinue PIQRAY.
bullous, blistering or exfoliating skin conditions)
(any % BSA associated with extensive superinfection, with
IV antibiotics indicated; life- threatening consequences)
1Grading  according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
2Forall grades of rash, consider consultation with a dermatologist.
3Antihistamines administered prior to rash onset may decrease incidence and severity of rash based on the SOLAR-1 trial.



Hyperglycemia
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. In patients with risk factors for hyperglycemia, monitor fasting glucose more closely and as clinically indicated [see Warnings and Precautions (7.3)].


PIQ API FEB24 V6                                                                                               USPI JAN24 Table 3: Dose Modification and Management for Hyperglycemia
[see Warnings and Precautions (7.3)]

Fasting plasma glucose       Recommendation
(FPG)/Fasting blood glucose values1
Dose modifications and management should only be based on fasting glucose values (FPG or fasting blood glucose).
Grade 1                       No PIQRAY dose adjustment
Fasting glucose > ULN -160    required. Initiate or intensify anti- mg/dL or > ULN -8.9 mmol/L                        hyperglycemic treatment2.

Grade 2                       No PIQRAY dose adjustment required.
Fasting glucose > 160-250     Initiate or intensify anti- hyperglycemic treatment2.
mg/dL or > 8.9-13.9 mmol/L                        If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days under appropriate anti-hyperglycemic treatment2,3, reduce PIQRAY dose by 1 dose level and follow fasting glucose value specific recommendations.
Grade 3                       Interrupt PIQRAY.
> 250-500 mg/dL               Initiate or intensify oral anti- hyperglycemic treatment2 and consider additional anti- or > 13.9-27.8 mmol/L         hyperglycemic medications3 for 1-2 days until hyperglycemia improves, as clinically indicated.
Administer intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances).
If fasting glucose decreases to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate anti- hyperglycemic treatment, resume PIQRAY at 1 lower dose level.
If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 3 to 5 days under appropriate anti- hyperglycemic treatment, consultation with a physician with expertise in the treatment of hyperglycemia is recommended.
If fasting glucose does not decrease to ≤ 160 mg/dL or 8.9 mmol/L within 21 days following appropriate anti- hyperglycemic treatment2,3, permanently discontinue PIQRAY treatment.
Grade 4                       Interrupt PIQRAY.
> 500 mg/dL                   Initiate or intensify appropriate anti- hyperglycemic treatment2,3 (administer or > 27.8 mmol/L              intravenous hydration and consider appropriate treatment (e.g., intervention for electrolyte/ketoacidosis/hyperosmolar disturbances)), re-check fasting glucose within 24 hours and as clinically indicated.
If fasting glucose decreases to ≤ 500 mg/dL or 27.8 mmol/L, follow fasting glucose value specific recommendations for Grade 3.
If fasting glucose is confirmed at > 500 mg/dL or 27.8 mmol/L, permanently discontinue PIQRAY treatment.


PIQ API FEB24 V6                                                                                   USPI JAN24 Abbreviation: ULN, upper limit of normal.
1FPG/Fasting Blood Glucose/Grade levels reflect hyperglycemia grading according to Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03.
2Initiate applicable anti- hyperglycemic medications, including metformin, SGLT2 inhibitors or insulin sensitizers (such as
 thiazolidinediones or dipeptidyl peptidase-4 inhibitors), and review respective prescribing information for dosing and dose titration recommendations, including local hyperglycemic treatment guidelines. Metformin was recommended in the SOLAR-1 trial with the following guidance: Initiate metformin 500 mg once daily. Based on tolerability, metformin dose may be increased to 500 mg twice daily, followed by 500 mg with breakfast, and 1,000 mg with dinner, followed by further increase to 1,000 mg twice daily if needed [see Warnings and Precautions (7.3)].
3As recommended in the SOLAR-1 trial, insulin may be used for 1-2 days until hyperglycemia resolves. However, this may not be  necessary in the majority of PIQRAY-induced hyperglycemia, given the short half-life of PIQRAY and the expectation of glucose levels normalizing after interruption of PIQRAY.



Diarrhea or Colitis

Table 4: Dose Modification and Management for Diarrhea or Colitis
[see Warnings and Precautions (7.5)]
Grade1                    Recommendation
No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as Grade 1                   clinically indicated.

Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the same dose level.
Grade 2
For recurrent Grade ≥ 2, interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose level.
Initiate or intensify appropriate medical therapy and monitor as clinically indicated2.
Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose Grade 33                level.
Initiate or intensify appropriate medical therapy and monitor as clinically indicated2.
3
Grade 4
Permanently discontinue PIQRAY.

1Grading    according to CTCAE Version 5.0.
2For   Grade 2 and 3, colitis consider additional treatment, such as enteric-acting and/or systemic steroids.
3Patientsshould additionally be managed according to local standard of care, including electrolyte monitoring, administration of antiemetics and antidiarrhoeal medicinal products and/or fluid replacement and electrolyte supplements, as clinically indicated 

Other Toxicities
Table 5: Dose Modification and Management for Other Toxicities (Excluding Hyperglycemia, Rash and Severe Cutaneous Adverse Reactions, and Diarrhea or Colitis)
Grade1                    Recommendation
Grade 1 or 2              No PIQRAY dose adjustment is required. Initiate appropriate medical therapy and monitor as clinically indicated2,3.
Grade 3                   Interrupt PIQRAY dose until improvement to Grade ≤ 1, then resume PIQRAY at the next lower dose level.
PIQ API FEB24 V6                                                                                                  USPI JAN24 Grade 4               Permanently discontinue PIQRAY.
1Grading  according to CTCAE Version 5.0.
2For Grade 2 and 3 pancreatitis, interrupt PIQRAY dose until improvement to Grade < 2 and resume at next lower-dose level.

Only one dose reduction is permitted. If toxicity reoccurs, permanently discontinue PIQRAY treatment.
3For Grade 2 total bilirubin elevation, interrupt PIQRAY dose until improvement to Grade ≤ 1 and resume at the same dose if  resolved in ≤ 14 days or resume at the next lower dose level if improved in > 14 days.

Refer to the Full Prescribing Information of fulvestrant for dose modification guidelines in the event of toxicity and for other relevant safety information.