Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
ALPEFLVS
Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.
For treatment of PIK3CA-mutated hormone receptor positive, HER2-negative advanced breast cancer in patients who have had previous endocrine therapy.
fulvestrant
ODB - General Benefit
(fulvestrant)
(ODB Formulary
)
Cycle 1 (loading dose):
| fulvestrant | 500 mg | IM | Days 1, 15 |
| alpelisib | 300 mg | PO | Daily (Continuous) |
| (This drug is not currently publicly funded for this regimen and intent) | |||
|
Cycles 2+: |
|||
| fulvestrant | 500 mg | IM | Day 1 |
| alpelisib | 300 mg | PO | Daily (Continuous) |
| (This drug is not currently publicly funded for this regimen and intent) | |||
Minimal – No routine prophylaxis; PRN recommended
- Also refer to CCO Antiemetic Recommendations.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Other Supportive Care:
- Oral antihistamine administration may be considered prophylactically for rash and severe cutaneous reactions to decrease incidence and severity, at the time of treatment initiation.
Doses should be modified according to the protocol by which the patient is being treated.
Alpelisib is only for use in hormone receptor (HR) positive, HER2-negative advanced breast cancer patients with known a PIK3CA mutation confirmed using a validated test.
Fasting plasma glucose and/or HbA1c (hemoglobin A1c test) should be performed and glucose levels should be corrected in patients with abnormal fasting glucose levels in the range of prediabetic or diabetic before initiating treatment.
A dental examination with appropriate preventive dentistry is recommended prior to treatment in patients with risk factors for ONJ, such as invasive dental procedures, concomitant therapies, poor oral hygiene and comorbid disorders.
Dosage with toxicity
| Dose Level | Alpelisib Dose (mg/day) |
Fulvestrant Dose (after loading dose in cycle 1) |
| 0 | 300 | 500 mg IM q 4 weeks |
| -1 | 250 | |
| -2 | 200 | |
| -3 | Discontinue |
Fulvestrant Dose Modification for Toxicity
|
Toxicity |
Action (fulvestrant) |
|
Hypersensitivity |
Consider discontinuing if severe. |
|
Mild hepatotoxicity |
Hold until recovery and then restart. |
|
Moderate to severe hepatotoxicity |
Discontinue. |
Alpelisib Dose Modification for Toxicity
| Toxicity | Grade | Action |
| Fasting glucose |
Grade 1 |
No dosage adjustment required.† |
|
Grade 2 |
No dosage adjustment required.† If fasting glucose does not decrease to ≤ 8.9 mmol/L in ≤ 21 days, ↓ alpelisib by 1 dose level. |
|
|
Grade 3 |
Hold.† Consider additional antidiabetic medications* for 1-2 days until hyperglycemia improves. Administer intravenous hydration and consider appropriate treatment (e.g. intervention for electrolyte/ketoacidosis/hyperosmolar disturbances). If fasting glucose decreases to ≤ 8.9 mmol/L in ≤ 3-5 days, resume at 1 dose level ↓. If fasting glucose does not decrease to ≤8.9 mmol/L within:
|
|
|
Grade 4 |
Hold.† Administer 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 ≤ 27.8 mmol/L, follow specific recommendations for hyperglycemia above. If fasting glucose is confirmed at > 27.8 mmol/L, discontinue. |
|
| Rash and cutaneous reactions** (excluding severe cutaneous adverse reactions etiology) |
Grade 1 |
No dosage adjustment required; initiate topical corticosteroid treatment. Consider adding oral antihistamine treatment. If active rash does not improve within 28 days of appropriate treatment, add low dose oral corticosteroid. |
|
Grade 2 |
No dosage adjustment required; initiate/intensify topical corticosteroid and oral antihistamine treatment. Consider adding low dose systemic corticosteroid. If rash improves to ≤ grade 1 within 10 days, discontinue systemic corticosteroids. |
|
|
Grade 3 |
Hold and initiate or intensify topical/oral corticosteroid and antihistamine treatment. When resolved to ≤ grade 1, resume at 1 dose level ↓. |
|
| Grade 4 (e.g. severe bullous, blistering or exfoliating skin conditions; any % BSA associated with extensive superinfection, with IV antibiotics indicated; life-threatening consequences) | Discontinue | |
| Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome /Toxic Epidermal Necrolysis, DRESS or erythema multiforme | Any | Discontinue |
| Diarrhea or Colitis | Grade 1 | No dosage adjustment required.† |
| Grade 2 |
Hold until resolved to ≤ grade 1 then resume at same dose level.† If it recurs, hold until ≤ grade 1 then resume at 1 dose level ↓.† |
|
| Grade 3 |
Hold until resolution to ≤ grade 1 then resume at 1 dose level ↓.† |
|
| Grade 4 | Discontinue | |
| Pancreatitis | Grade 2 or 3 |
Hold until resolved to ≤ grade 1 then resume at 1 dose level ↓. If toxicity re-occurs, discontinue. |
| Grade 4 | Discontinue | |
| Symptoms of pneumonitis | Any | Hold and investigate; discontinue if confirmed |
| Bilirubin | Grade 2 | Hold until resolved to ≤ grade 1:
|
| Grade 3 | Hold until resolution to ≤ grade 1 then resume at 1 dose level ↓. | |
| Grade 4 | Discontinue | |
| Serious hypersensitivity reactions / Anaphylactic reactions | Any | Discontinue |
| All other toxicities | Grade 1 or 2 | No dosage adjustment required.† |
| Grade 3 | Hold until resolved to ≤ grade 1 then resume at 1 dose level ↓. | |
| Grade 4 | Discontinue. |
†Initiate or intensify appropriate medical therapy (e.g. oral anti-diabetic or anti-diarrhea treatment) and monitor as clinically indicated. For Grade 2 or 3 colitis, consider additional treatment, such as steroids.
*As recommended in the phase III clinical study, insulin may be used for 1-2 days until hyperglycemia resolves. However, this may not be necessary in the majority of alpelisib-induced hyperglycemia, given the short half-life of alpelisib and the expectation of glucose levels normalizing after dose interruption.
**For all grades of rash, consider consultation with a dermatologist.
Hepatic Impairment
Fulvestrant is metabolized primarily in the liver. There are no efficacy and safety data in patients with breast cancer and hepatic impairment. Decreased clearance (by 2.2 fold) and changes in exposure (↑ 70%) were observed in women with moderate hepatic impairment compared to patients with normal hepatic function.
| Hepatic Impairment | Alpelisib Dose | Fulvestrant Dose |
| Child-Pugh Class A or B | No dose adjustment required. | Use with caution. No dose adjustment required. |
| Child-Pugh Class C | Not studied. Use not recommended. |
Renal Impairment
| Creatinine Clearance (mL/min) | Alpelisib Dose | Fulvestrant Dose |
| ≥ 30 | No dose adjustment required. | No dosage adjustment required. |
| < 30 | Effect on alpelisib pharmacokinetics is unknown. | Use with caution; no data. |
Dosage in the Elderly
No dose adjustment is required for alpelisib or fulvestrant. For alpelisib, no overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients; however, gastrointestinal toxicity (primarily diarrhea and nausea), hyperglycemia, weight loss, hypokalemia and dyspnea were reported more frequently in older patients.
Dosage based on ethnicity
No dose adjustment is required for alpelisib or fulvestrant. For alpelisib however, rash, severe cutaneous reactions, hypersensitivity and anaphylactic reaction, and pancreatitis were more frequently reported in Asian patients compared to Caucasian patients.
Refer to fulvestrant, alpelisib drug monograph(s) for additional details of adverse effects.
|
Very common (≥ 50%) |
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
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|
|
|
Refer to fulvestrant, alpelisib drug monograph(s) for additional details.
- Avoid co-administration with strong CYP3A4 inducers due to decreased alpelisib concentration/efficacy.
-
Avoid co-administration of alpelisib with BCRP inhibitors due to increased alpelisib concentration and/or toxicity. If concomitant use is unavoidable, closely monitor for increased alpelisib adverse reactions.
-
Fulvestrant may interfere with estradiol immunoassay measurements (falsely elevated estradiol levels) due to its structural similarity with estradiol.
Refer to fulvestrant, alpelisib drug monograph(s) for additional details.
Administration: Fulvestrant
-
Each dose consists of 2 pre-filled syringes (250 mg/5mL). Administer each pre-filled syringe as SLOW intramuscular injection (1-2 minutes per injection) into EACH buttock.
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Caution should be taken due to proximity of the sciatic nerve and large blood vessels.
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Administer according to local guidelines at the Cancer Centre or physician's office.
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Store refrigerated at 2 to 8°C in original package.
Administration: Alpelisib
-
Alpelisib should be administered once daily at approximately the same time each day immediately following a meal.
-
Tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). Tablets that are broken, cracked, or otherwise not intact should not be ingested.
-
If a dose is missed, it can be taken immediately following food and within 9 hours after the time it is usually administered. After more than 9 hours, the dose should be skipped for that day and the next dose should be taken at its usual time. Missed doses should not be made up the next day.
-
If a dose is vomited, do not administer an additional dose on that day; resume the dosing schedule the next day at the usual time.
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Do not store above 30°C.
-
Store in the original package to protect from moisture.
Contraindications
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Patients who are hypersensitive to alpelisib or fulvestrant or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
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Fulvestrant is contraindicated in pregnant or breastfeeding women.
Other Warnings /Precautions
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Due to the route of administration of fulvestrant, use with caution in patients with bleeding disorders or on anticoagulants.
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There is a potential osteoporosis risk due to fulvestrant's mechanism of action.
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Caution should be exercised when alpelisib and drugs known to cause ONJ are used either simultaneously, or sequentially. Alpelisib treatment should not be initiated in patients with ongoing ONJ.
-
Do not initiate alpelisib treatment in patients with history of severe cutaneous reactions.
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Alpelisib is associated with QT prolongation. Exercise caution if alpelisib is used concomitantly with medicinal products that are known to prolong the QTc interval. Patients with uncontrolled heart disease and/or recent cardiac events (including long QT syndrome, QTcF > 450 ms for males or > 460 ms for females) were excluded from the phase III clinical study.
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The safety of alpelisib in patients with Type 1 and uncontrolled Type 2 diabetes has not been established as these patients were excluded from the phase III clinical study. Patients with pre-diabetes, diabetes, BMI ≥ 30, elevated FPG or HbA1c >/= ULN, or age ≥ 75 years have a higher risk of developing severe hyperglycemia and/or associated complications (e.g. ketoacidosis).
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It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.
Pregnancy/Lactation
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This regimen is contraindicated for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.
-
Breastfeeding is contraindicated during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).
-
Fertility effects: Probable
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
Recommended Clinical Monitoring
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CBC; Baseline and as clinically indicated
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Liver function tests, bilirubin; Baseline and as clinically indicated
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Renal function tests; Baseline and as clinically indicated
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ECG; Baseline and as clinically indicated. More frequently if taken concomitantly with medications known to prolong the QTc interval
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Electrolytes, including potassium and calcium; Baseline and in patients experiencing gastrointestinal toxicity as clinically indicated
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Fasting glucose; Baseline and at least weekly for the first 2 weeks of treatment, followed by every 4 weeks and as clinically indicated. Monitor more frequently for the first few weeks in patients with pre-diabetes, diabetes, BMI ≥ 30, or age ≥ 75 years
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Fasting glucose (if patient experiences hyperglycemia after initiating alpelisib); Regularly, at least until fasting glucose decreases to normal levels. During treatment with antidiabetic medications, monitor at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated
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HbA1c; Baseline, every 3 months and as clinically indicated
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Clinical toxicity assessment for injection site reactions, estrogen deprivation symptoms, fatigue, thromboembolism, edema, fever/infection, ONJ, pancreatitis, dysgeusia, pneumonitis, hypersensitivity, musculoskeletal, dermatological and gastrointestinal effects (including mucositis); As clinically indicated
-
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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- Outpatient prescription for home administration (alpelisib)
- Outpatient prescription; drug administered at Cancer Centre or physician's office (fulvestrant)
Alpelisib and fulvestrant drug monographs, Ontario Health (Cancer Care Ontario).
Andre F, Ciruelos E, Rubovsky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer. N Engl J Med 2019; 380:1929-1940.
July 2023 Updated Dose modifications, Adverse effects, Drug administration/Special Precautions, and Clinical monitoring sections
Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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