Alpelisib is used together with Fulvestrant to treat postmenopausal women and men who have hormone receptor (HR)-positive, HER2-negative, Metastatic Breast Cancer with a PIK3CA mutation. It is prescribed when the disease has progressed after previous endocrine therapy and the mutation is confirmed by an FDA-approved test.

Alpelisib is a phosphatidylinositol-3-kinase (PI3K) inhibitor that mainly targets the PI3Kα isoform.
Mutations that enhance the function of the PIK3CA gene, which encodes the catalytic α-subunit of PI3K, result in activation of PI3Kα and Akt signaling pathways, leading to cellular transformation and tumor formation in both laboratory (in vitro) and living (in vivo) models.

In breast cancer cell lines, Alpelisib reduces phosphorylation of downstream PI3K targets such as Akt and shows effectiveness in cells with PIK3CA mutations. In animal studies, it suppresses the PI3K/Akt signaling pathway and decreases tumor growth in xenograft models, including breast cancer models.

Treatment with Alpelisib has also been found to increase estrogen receptor (ER) transcription in breast cancer cells. When combined with fulvestrant, Alpelisib demonstrates greater antitumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA-mutated breast cancer cell lines.

The recommended dose of Alpelisib is 300 mg (two 150 mg film coated tablets) taken orally, once daily, with food. Continue treatment until disease progression or unacceptable toxicity occurs. Patients should take their dose of Alpelisib at approximately the same time each day. Swallow Alpelisib 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 Alpelisib 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 Alpelisib 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 Alpelisib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29, and once monthly thereafter.

Effect of Other Drugs on Alpelisib

• CYP3A4 Inducers: When Alpelisib is used together with strong CYP3A4 inducers, the concentration of Alpelisib in the body may decrease, leading to reduced effectiveness. Therefore, concurrent use with strong CYP3A4 inducers should be avoided.
• BCRP Inhibitors: Co-administration with BCRP inhibitors may increase the concentration of Alpelisib, which can raise the risk of toxicity. The use of BCRP inhibitors should generally be avoided. If no suitable alternatives are available, patients should be closely monitored for increased adverse effects when both are used together.

Effect of Alpelisib on Other Drugs

• CYP2C9 Substrates: Using Alpelisib with drugs metabolized by CYP2C9 (such as warfarin) may lower their plasma levels, potentially reducing their effectiveness. Careful monitoring is recommended when these drugs are used together, especially if reduced drug activity could impact treatment outcomes.

Alpelisib should not be used in patients who have severe hypersensitivity to the drug or any of its components.

• Severe hypersensitivity reactions
• Diarrhea
• Serious dermatological reactions
• Pulmonary complications (pneumonitis)
• Elevated blood glucose levels (hyperglycemia)

Pregnancy: Based on animal study findings and its mechanism of action, Alpelisib may cause harm to the fetus when administered to a pregnant woman.

Lactation: There is no available information regarding the presence of Alpelisib in human milk, its effects on milk production, or its impact on the breastfed infant. Due to the potential risk of serious adverse reactions in the nursing child, lactating women are advised not to breastfeed during treatment with Alpelisib and for 1 week after the final dose.

Infertility: Findings from animal studies suggest that Alpelisib may reduce fertility in both males and females of reproductive potential.

Severe Hypersensitivity: Inform patients about the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue Alpelisib if severe hypersensitivity occurs.

Severe Cutaneous Reactions: Serious skin reactions, including Stevens-Johnson Syndrome (SJS) and Erythema Multiforme (EM), have been reported in patients receiving Alpelisib. Educate patients about the symptoms of severe skin reactions (e.g., early signs such as fever, flu-like symptoms, mucosal lesions, or worsening skin rash).

Hyperglycemia: Prior to starting Alpelisib, assess fasting plasma glucose (FPG) and HbA1c, and ensure blood glucose is well controlled. After initiation, monitor blood glucose and/or FPG at least once weekly for the first 2 weeks, then at least once every 4 weeks, and as clinically required. HbA1c should be monitored every 3 months and as needed. Depending on the severity of hyperglycemia, dose interruption, reduction, or discontinuation of Alpelisib may be necessary.

Pneumonitis: Permanently discontinue Alpelisib in patients with confirmed pneumonitis. Patients should be advised to report any new or worsening respiratory symptoms immediately.

Diarrhea: Advise patients to begin antidiarrheal therapy, maintain adequate oral fluid intake, and inform their healthcare provider if diarrhea develops during treatment with Alpelisib.

Embryo-Fetal Toxicity: Based on animal study results and its mechanism of action, Alpelisib may cause harm to the fetus when administered to a pregnant woman.

Use in Special Populations No clinically meaningful differences in the pharmacokinetics of Alpelisib were observed based on age (21 to 87 years), sex, race/ethnicity (Japanese or Caucasian), body weight (37 to 181 kg), mild to moderate renal impairment (CrCl 30 to <90 mL/min using the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The impact of severe renal impairment (CrCl <30 mL/min) on the pharmacokinetics of Alpelisib remains unknown.

Pediatric Use: The safety and effectiveness of Alpelisib in pediatric patients have not been established.

Geriatric Use: No overall differences in the effectiveness of Alpelisib were observed in patients aged ≥65 years compared to younger individuals. However, there is an insufficient number of patients aged ≥75 years to determine differences in safety or effectiveness.

Renal Impairment: The effect of severe renal impairment (CLcr <30 mL/min) on the pharmacokinetics of Alpelisib is not known. No dose adjustment is required for patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min).

Cytotoxic Chemotherapy.

Store below 30°C in a cool and dry place, away from light. Keep out of reach of children.