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A - Drug Name

alpelisib

COMMON TRADE NAME(S):   Piqray®

 
B - Mechanism of Action and Pharmacokinetics

Alpelisib is an inhibitor of phosphatidylinositol3kinase (PI3K) with inhibitory activity predominantly against PI3Kα. The PI3K signaling pathway plays a role in various biological processes, including proliferation, survival, translational regulation of protein synthesis, glucose metabolism, cell migration, and angiogenesis. Mutations in the gene encoding the catalytic α-subunit of PI3K (PI3KCA) leads to activation of PI3Kα and Akt-signaling, cellular transformation, and tumour generation. In breast cancer cell lines, alpelisib inhibits the phosphorylation of PI3K downstream targets, including Akt, and shows activity in cell lines harbouring a PIK3CA mutation. When compared with either agent alone, the combination of alpelisib with fulvestrant has synergistic antitumor activity in PIK3CA-mutated, estrogen receptor-positive models.



Absorption
Time to reach steady state

3 days

Peak plasma levels

2-4 hours

Effects with food

Alpelisib absorption is affected by food. Co-administration of alpelisib, with a high-fat high-calorie meal increased AUC by 73% and Cmax by 84%, and co-administration with a low-fat low-calorie meal increased AUC by 77% and Cmax by 145%


Distribution
PPB 89%
Metabolism

Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite and to a lesser extent by CYP3A4.

Inactive metabolites

Yes

Elimination
Half-life

~ 9 hours

Feces 81% (36% as unchanged drug)
Urine

14% (2% as unchanged drug)

 
C - Indications and Status
Health Canada Approvals:

  • Breast cancer

Refer to the product monograph for a full list and details of approved indications



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

The following table lists adverse effects that occurred in ≥ 10% of patients and with ≥ 2% higher incidence in the alpelisib arm in a phase III study of fulvestrant with alpelisib or placebo, in patients with hormone receptor positive, HER2-negative advanced breast cancer which progressed on or after aromatase inhibitor treatment. It also includes severe, life-threatening and post-marketing adverse effects from other sources.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Hypertension (9%) (may be severe) E
Dermatological Alopecia (20%) E
Dry skin (18%) E
Erythema multiforme (rare) E  D
Other - Drug reaction with eosinophilia and systemic symptoms (DRESS) (rare, reported post-marketing) E  D
Rash, pruritus (52%) (may be severe) E  D
Stevens-Johnson syndrome (rare) E  D
Toxic epidermal necrolysis (rare) E  D
Gastrointestinal Abdominal pain (17%) E
Anorexia, weight loss (36%) E
Diarrhea (58%) (may be severe) E  D  L
Dyspepsia (11%) E
Mucositis (30%) E
Nausea, vomiting (45%) E
General Edema (15%) E
Fatigue (42%) E
Fever (14%) E
Mucosal dryness (19%) (or inflammation) E
Hematological Anemia (10%) E
Myelosuppression (5%) E
Hepatobiliary ↑ LFTs (10%) (may be severe) E
Pancreatitis (<1%) E
Hypersensitivity Hypersensitivity (4%) (may be severe) I  E
Infection Infection (10%) (UTI) E
Metabolic / Endocrine Hyperglycemia (65%) (including ketoacidosis; 33% severe) E  D  L
Musculoskeletal Osteonecrosis of jaw (4%) (2% severe) D
Nervous System Dysgeusia (18%) E
Headache (18%) E
Ophthalmic Blurred vision , dry eyes (5%) E
Renal Creatinine increased (10%) E
Other (5%) - Acute Kidney Injury E
Respiratory Pneumonitis (2%) (may be severe) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for alpelisib include hyperglycemia, diarrhea, rash, pruritus, nausea, vomiting, fatigue, anorexia, weight loss, mucositis, alopecia, mucosal dryness/inflammation and dry skin.

Severe hyperglycemia, including diabetic ketoacidosis, has been reported. Patients considered pre-diabetic or diabetic at baseline were at a higher risk of developing severe hyperglycemia and associated complications (e.g. ketoacidosis). Among patients who experienced ≥ grade 2 hyperglycemia, the median time to first occurrence of hyperglycemia was 15 days (range: 5 to 517 days). Patients with type I or uncontrolled type II diabetes were excluded from the phase 3 trial. The median duration of ≥ grade 2 hyperglycemia was 10 days. Median time to improvement from the first event for patients with ≥ grade 2 hyperglycemia with at least 1 grade improvement was 8 days (range: 2 to 65 days). All who continued fulvestrant but discontinued alpelisib (due to hyperglycemia) had fasting plasma glucose (FPG) levels that returned to baseline.

Severe diarrhea, including dehydration and acute kidney injury have been reported. Among patients with grade ≥ 2 diarrhea, the median time to onset was 46 days (range: 1 to 442 days).

Serious hypersensitivity reactions, including anaphylactic reaction and anaphylactic shock have been reported. Symptoms include, but are not limited to, dyspnea, flushing, rash, fever or tachycardia. Hypersensitivity and anaphylactic reactions were more common in Asian patients compared to other races.

Cases of osteonecrosis of the jaw (ONJ) have been reported. All patients experiencing ONJ were exposed to prior or concomitant bisphosphonates or denosumab.

Severe cutaneous adverse reactions, including SJS, EM, and DRESS, have been reported. The median time to first onset of ≥ grade 2 rash was 12 days (range: 2 to 220 days).

 
E - Dosing

Refer to protocol by which patient is being treated. 

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.

Oral antihistamine administration may be considered prophylactically for rash and severe cutaneous reactions to decrease incidence and severity, at the time of treatment initiation.



Adults:

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.

For fulvestrant dose please refer to the ALPEFLVS regimen monograph.


Oral: 300 mg Daily

Dosage with Toxicity:

For fulvestrant dose modifications please refer to the ALPEFLVS regimen monograph.

Dose Level Alpelisib Dose (mg/day)
0 300
-1 250
-2 200
-3 Discontinue

 

Hematologic Toxicities

Toxicity Grade Action
Neutropenia

Grade 3

(ANC 0.5 to < 1 x 109/L)

Hold until resolved to ≤ grade 1 then if resolved in:

  • ≤ 7 days, resume at same dose level.
  • > 7 days, resume at 1 dose level ↓.

Grade 4

(ANC < 0.5 x 109/L)

Febrile neutropenia   Hold until resolved then resume at 1 dose level ↓.
Thrombocytopenia

Grade 3

(PLT 25 to <50 x 109/L)

Hold until resolved to ≤ grade 1 then if resolved in:

  • ≤ 7 days, resume at same dose level.
  • > 7 days, resume at 1 dose level ↓.

Grade 4

(PLT < 25 x 109/L)

Hold until resolved to ≤ grade 1 then resume at 1 dose level ↓.

 

Non-Hematologic Toxicities

Toxicity Grade Action
Fasting glucose

 Grade 1 

(> ULN - 8.9 mmol/L)

No dosage adjustment required.

Grade 2

(> 8.9 - 13.9 mmol/L)

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

(> 13.9 - 27.8 mmol/L)

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:

  • 3 to 5 days: consultation with a clinician with expertise in the treatment of hyperglycemia is recommended.
  • 21 days following appropriate treatment: discontinue. 

Grade 4

(≥ 27.8 mmol/L)

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 severe cutaneous reactions**

Grade 1

(< 10% body surface area (BSA) with active skin toxicity)

No dosage adjustment required; initiate or intensify as needed:

  • topical corticosteroid treatment
  • oral antihistamine treatment
  • low dose oral corticosteroid treatment (grade 2)

Grade 2

(10% - 30% BSA with active skin toxicity)

Grade 3 

(> 30% BSA with active skin toxicity; severe rash not responsive to medical management)

Hold and initiate or intensify topical/oral corticosteroid and anti-histamine treatment.

When resolved to ≤ grade 1: 

  • for first occurrence of rash: resume at same dose level.
  • for second occurrence of rash: 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
Stevens-Johnson-Syndrome /Toxic Epidermal Necrolysis or other SJS/TEN like severe skin reactions Any Discontinue
Diarrhea Grade 1 No dosage adjustment required.
Grade 2  Hold until resolved to ≤ grade 1 then resume at same dose level.
≥ Grade 3

Hold until resolution to ≤ grade 1 then resume at 1 dose level ↓.

Creatinine

Grade 2

(2 – 3 x ULN)

Hold until resolved to ≤ grade 1 if:

  • resolution in ≤ 7 days: resume at same dose level.
  • resolution in > 7 days:  resume at 1 dose level ↓.

≥ Grade 3 

(> 3 – 6 x ULN)

Discontinue
Pancreatitis Grade 2 or 3

Hold until resolved to ≤ grade 1 then then resume at 1 dose level ↓.

If toxicity re-occurs, discontinue.

Grade 4 Discontinue
Symptoms of pneumonitis Any  Hold and investigate; discontinue if confirmed

For patients with normal baseline ALT and AST and total bilirubin:

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN

  Discontinue.

For patients with elevated baseline ALT and AST and total bilirubin:

AST or ALT > 8 x ULN, combined with total bilirubin >2x baseline

 
Serious hypersensitivity reactions / Anaphylactic reactions Any
All other non-hematological 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.

*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.



Dosage with Hepatic Impairment:

Hepatic Impairment Alpelisib Dose
Child-Pugh Class A, B or C No dose adjustment required

 



Dosage with Renal Impairment:

Creatinine Clearance (mL/min) Alpelisib Dose
≥ 30 No dose adjustment required
< 30 Effect on alpelisib pharmacokinetics is unknown

 



Dosage in the elderly:

No dose adjustment is required as 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; however, rash, severe cutaneous reactions, hypersensitivity and anaphylactic reaction, and pancreatitis were more frequently reported in Asian patients compared to Caucasian patients.  



Children:

Safety and efficacy in children have not been established.



 
F - Administration Guidelines
  • 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.

  • Do not store above 30°C.

  • Store in the original package to protect from moisture.

 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to alpelisib or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Other Warnings/Precautions:

  • 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.

  • 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.

  • 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.

  • It is currently unknown whether alpelisib may reduce the effectiveness of systemically acting hormonal contraceptives.


Other Drug Properties:

  • Phototoxicity: No

Pregnancy and Lactation:
  • Mutagenicity: No
  • Clastogenicity: No
  • Genotoxicity: No
  • Teratogenicity: Documented in animals
  • Embryotoxicity: Documented in animals

    Alpelisib is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 1 week after the last dose.

  • Excretion into breast milk: Unknown

    Breastfeeding is not recommended during treatment and for at least 1 week after the last dose.

  • Fertility effects:

    Probable

    Based on animal studies, adverse effects were observed in reproductive organs of males and females, including vaginal atrophy and oestrus cycle variations.

    Male patients should not donate or store semen during treatment and for at least 1 week after the last dose.

 
H - Interactions

Alpelisib inhibits CYP3A4 in a time-dependent manner and induces cytochromes CYP2B6, CYP2C9 and CYP3A4.

Alpelisib is an inhibitor of P-gp (P-glycoprotein) and a substrate for BCRP transporter.

Alpelisib can be co-administered with acid reducing agents since it should be taken with food.  Food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH value.

Caution should be exercised when alpelisib and drugs known to cause ONJ are used either simultaneously, or sequentially.

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ alpelisib concentration and/or efficacy ↑ metabolism of alpelisib Avoid co-administration with strong CYP3A4 inducers
BCRP inhibitors (e.g. cyclosporine, eltrombopag, lapatinib) ↑ alpelisib concentration and/or toxicity ↑ alpelisib drug uptake Avoid co-administration with BCRP inhibitors. If concomitant use is unavoidable, closely monitor for increased alpelisib adverse reactions
CYP 2C9 substrates (e.g. warfarin, meloxicam, fluvastatin) ↓ substrate concentration and/or efficacy ↑ metabolism of substrate Caution and monitor CYP2C9 substrates with narrow therapeutic range
Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) ↑ risk of QT prolongation Additive Caution. Perform additional ECG monitoring as clinically indicated.
 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Monitor Type Monitor Frequency

CBC

Baseline and as clinically indicated

Blood glucose

Baseline and at least weekly for the first 2 weeks of treatment, followed by every 4 weeks and as clinically indicated. HbA1c should be monitored every 3 months and as clinically indicated
Blood glucose if patient experiences hyperglycemia after initiating alpelisib At least twice weekly until fasting glucose decreases to ≤ 8.9 mmol/L then at least once a week for 8 weeks, followed by once every 2 weeks and as clinically indicated

ECG

Baseline and as clinically indicated. More frequently if taken concomitantly with medications known to prolong the QTc interval

Electrolytes, including potassium and calcium

Baseline and in patients experiencing gastrointestinal toxicity as clinically indicated

Clinical toxicity assessment for edema, fatigue, fever/infection, ONJ, pancreatitis, dysgeusia, pneumonitis, hypersensitivity, renal, hepatic, dermatological and gastrointestinal effects (including mucositis)

As clinically indicated

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version



 
K - References

André F, et al.; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20):1929-1940.

Prescribing information: Piqray® (alpelisib). Novartis Pharmaceuticals Corporation. September 2020.

Product Monograph: Alpelisib (Piqray®). Novartis Pharmaceuticals Canada Inc. , March 2020.


July 2021 New Drug Monograph

 
L - Disclaimer

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.

The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.

Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.

While care has been taken in the preparation of the information contained in the Formulary, 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.

CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.