What are the warnings, precautions, monitoring requirements, and dose‑modification guidelines for alpelisib?

Warnings and Precautions of Alpelisib

Alpelisib requires intensive monitoring for hyperglycemia (weekly for 4 weeks, then every 4 weeks), strict patient selection excluding uncontrolled diabetes (baseline HbA1c must be <6.5%), and prophylactic antihistamines to prevent severe rash, with dose modifications or discontinuation needed in approximately 70% of patients due to significant toxicities. 1

Critical Patient Selection and Contraindications

Baseline screening requirements:

• Measure baseline HbA1c and fasting glucose before initiating therapy – patients with HbA1c ≥6.5% or uncontrolled diabetes should NOT receive alpelisib 1
• Patients with well-controlled type 2 diabetes can be treated, but require more intensive monitoring 1
• Consider risk factors including elevated baseline HbA1c, obesity (BMI ≥30), and age ≥75 years before initiating therapy 2
• Alpelisib is contraindicated in patients with severe hypersensitivity to alpelisib or any ingredients 2

Hyperglycemia Management (Most Critical Toxicity)

Monitoring protocol:

• Monitor fasting glucose weekly for the first 2 weeks, then at least every 4 weeks thereafter 1, 2
• Monitor HbA1c every 3 months and as clinically indicated 2
• Grade 3 hyperglycemia occurs at a median of 15 days after treatment initiation, making early monitoring critical 1
• For patients with risk factors (obesity, elevated baseline glucose, concurrent corticosteroids, age ≥75), monitor fasting glucose more frequently in the first few weeks 2

Management approach:

• Initiate or intensify anti-hyperglycemic therapy immediately when hyperglycemia develops 2
• Metformin alone or in combination with other hypoglycemic agents was used in the majority of SOLAR-1 patients 1
• Collaboration with diabetes specialists is recommended for challenging cases 1
• Severe hyperglycemia including diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar non-ketotic syndrome (HHNKS) have been reported and can be fatal 2, 3

Dose modifications for hyperglycemia:

• Grade 3 (fasting glucose >250-500 mg/dL): Interrupt alpelisib until improvement to Grade ≤1, then resume at next lower dose 2
• Grade 4 (fasting glucose >500 mg/dL): Permanently discontinue alpelisib 2

Severe Cutaneous Adverse Reactions

Prevention and monitoring:

• Start prophylactic non-sedating antihistamines at treatment initiation to reduce incidence of higher-grade rash 1
• Antihistamines can be discontinued after 4-8 weeks as rash risk is highest in the first 2 weeks of therapy 1
• Grade 3 rash occurs at a median of 13 days after treatment initiation 1
• Rash affects approximately 40-50% of patients, typically distributed on trunk (78%) and extremities (70%) 4

Management approach:

• Maculopapular rash is the most common presentation (90%) and is associated with increased blood eosinophils 4
• For Grade 3 rash: Interrupt alpelisib, treat with topical and systemic corticosteroids, antihistamines 4
• Consultation with a dermatologist is recommended for severe cases 2
• 75% of patients can be successfully re-challenged after rash resolution, often at maintained or reduced dose 4

Severe cutaneous adverse reactions (SCARs):

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), erythema multiforme (EM), and DRESS have occurred 2
• If SCARs suspected: Interrupt alpelisib immediately until etiology determined 2
• If SCAR confirmed: Permanently discontinue alpelisib 2

Hypersensitivity Reactions

• Severe hypersensitivity including anaphylaxis, anaphylactic shock, and angioedema have been reported 2
• Permanently discontinue alpelisib in the event of severe hypersensitivity 2

Gastrointestinal Toxicity

Common GI adverse events:

• Diarrhea is a later toxicity with Grade 3 events occurring at median of 139 days (not early like hyperglycemia and rash) 1
• Other GI toxicities include nausea, vomiting, decreased appetite, and mucositis 1
• Manage with antipropulsive agents for diarrhea as needed 1

Pancreatitis:

• Grade 2 pancreatitis: Interrupt alpelisib until improvement to Grade <2, then resume at next lower dose (only one dose reduction permitted) 2
• Grade 3 pancreatitis in adults: Interrupt until improvement, resume at lower dose; in pediatrics: permanently discontinue 2
• Grade 4 pancreatitis: Permanently discontinue alpelisib 2

Other Significant Toxicities

Pneumonitis:

• Monitor for new or worsening respiratory symptoms 2
• Interrupt alpelisib for Grade 2 pneumonitis until improvement, then resume at lower dose 2
• Permanently discontinue for Grade 3-4 pneumonitis 2

Quality of Life Impact:

• Despite significant toxicity burden, Global Health Status and overall QoL deterioration was similar between alpelisib and placebo arms 1
• Symptom subscales showed worsening in appetite loss, diarrhea, nausea/vomiting, fatigue, and social functioning with alpelisib 1
• Pain scores actually improved with alpelisib treatment 1

Overall Toxicity Management Strategy

Key statistics:

• Approximately 70% of patients require dose reductions or interruptions due to adverse events 1
• 25% of patients discontinue therapy due to toxicity 1
• Using detailed side-effect management guidelines resulted in decreased discontinuations for higher-grade adverse events in SOLAR-1 1

General dose modification principles:

• For Grade 3 adverse events (excluding specific toxicities above): Interrupt alpelisib until improvement to Grade ≤1, then resume at next lower dose 2
• For Grade 4 adverse events: Permanently discontinue alpelisib 2
• Dose delays and reductions are commonly used to manage toxicity effectively 1

Common Pitfalls to Avoid

• Do not start alpelisib without baseline glucose screening – this is the most preventable serious toxicity 1
• Do not wait for symptoms to check glucose – hyperglycemia develops rapidly (median 15 days) and can progress to DKA 1, 3
• Do not skip antihistamine prophylaxis – this simple intervention significantly reduces severe rash 1
• Do not assume diarrhea will occur early – unlike hyperglycemia and rash, diarrhea is a late toxicity (median 139 days) requiring ongoing vigilance 1