Alpelisib
Indications
Alpelisib is indicated in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CAmutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.
Pharmacology
Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα. Gain-of-function mutations in the gene encoding the catalytic α-subunit of PI3K (PIK3CA) lead to activation of PI3Kα and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.
In breast cancer cell lines, Alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, Alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
PI3K inhibition by Alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of Alpelisib and fulvestrant demonstrated increased antitumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
In breast cancer cell lines, Alpelisib inhibited the phosphorylation of PI3K downstream targets, including Akt and showed activity in cell lines harboring a PIK3CA mutation. In vivo, Alpelisib inhibited the PI3K/Akt signaling pathway and reduced tumor growth in xenograft models, including models of breast cancer.
PI3K inhibition by Alpelisib treatment has been shown to induce an increase in estrogen receptor (ER) transcription in breast cancer cells. The combination of Alpelisib and fulvestrant demonstrated increased antitumor activity compared to either treatment alone in xenograft models derived from ER-positive, PIK3CA mutated breast cancer cell lines.
Dosage & Administration
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.
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.
Interaction
Effect of Other Drugs on Alpelisib-
- CYP3A4 Inducer: Coadministration of Alpelisib with a strong CYP3A4 inducer may decrease alpelisib concentration, which may decrease Alpelisib activity. Avoid coadministration of Alpelisib with strong CYP3A4 inducers.
- BCRP Inhibitors: Coadministration of Alpelisib with a BCRP inhibitor may increase Alpelisib concentration, which may increase the risk of toxicities. Avoid the use of BCRP inhibitors in patients treated with Alpelisib. If unable to use alternative drugs, when Alpelisib is used in combination with BCRP inhibitors, closely monitor for increased adverse reactions.
- CYP2C9 Substrates: Coadministration of Alpelisib with CYP2C9 substrates (e.g., Warfarin) may reduce plasma concentration of these drugs. Closely monitor when Alpelisib is used in combination with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs.
Contraindications
Alpelisib is contraindicated in patients with severe hypersensitivity to it or any of its components.
Side Effects
- Severe allergic reactions
- Diarrhea
- Severe skin reactions
- Lung problems (pneumonitis)
- High blood sugar levels (hyperglycemia)
Pregnancy & Lactation
Pregnancy: Based on animal data and mechanism of action, Alpelisib can cause fetal harm when administered to a pregnant woman.
Lactation: There is no data on the presence of Alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with Alpelisib and for 1 week after the last dose.
Infertility: Based on findings from animal studies, Alpelisib may impair fertility in males and females of reproductive potential.
Lactation: There is no data on the presence of Alpelisib in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with Alpelisib and for 1 week after the last dose.
Infertility: Based on findings from animal studies, Alpelisib may impair fertility in males and females of reproductive potential.
Precautions & Warnings
Severe Hypersensitivity: Advise patients of the signs and symptoms of severe hypersensitivity reactions. Permanently discontinue Alpelisib in the event of severe hypersensitivity.
Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson Syndrome (SJS) and Erythema Multiforme (EM) were reported in patients treated with Alpelisib. Advise patients of the signs and symptoms of severe cutaneous reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash).
Hyperglycemia: Before initiating treatment with Alpelisib, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with Alpelisib, monitor blood glucose and/or FPG 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. Based on the severity of the hyperglycemia, Alpelisib may require dose interruption, reduction, or discontinuation.
Pneumonitis: Permanently discontinue Alpelisib in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.
Diarrhea: Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking Alpelisib.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, Alpelisib can cause fetal harm when administered to a pregnant woman.
Severe Cutaneous Reactions: Severe cutaneous reactions, including Stevens-Johnson Syndrome (SJS) and Erythema Multiforme (EM) were reported in patients treated with Alpelisib. Advise patients of the signs and symptoms of severe cutaneous reactions (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash).
Hyperglycemia: Before initiating treatment with Alpelisib, test FPG, HbA1c, and optimize blood glucose. After initiating treatment with Alpelisib, monitor blood glucose and/or FPG 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. Based on the severity of the hyperglycemia, Alpelisib may require dose interruption, reduction, or discontinuation.
Pneumonitis: Permanently discontinue Alpelisib in all patients with confirmed pneumonitis. Advise patients to immediately report new or worsening respiratory symptoms.
Diarrhea: Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking Alpelisib.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, Alpelisib can cause fetal harm when administered to a pregnant woman.
Use in Special Populations
No clinically significant differences in the pharmacokinetics of Alpelisib were predicted 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 based on the Cockcroft-Gault formula), or mild to severe hepatic impairment (Child-Pugh Class A, B, and C). The effect of severe renal impairment (CrCl < 30 mL/min) on the pharmacokinetics of Alpelisib is unknown.
Pediatric Use: The safety and efficacy of Alpelisib in pediatric patients have not been established
Geriatric Use: No overall differences in effectiveness of Alpelisib were observed between patients ≥65 years of age compared to younger patients. There are an insufficient number of patients ≥75 years of age to assess whether there are differences in safety or effectiveness.
Renal Impairment: The effect of severe renal impairment (CLcr <30 mL/min) on Alpelisib pharmacokinetics is unknown. No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min).
Pediatric Use: The safety and efficacy of Alpelisib in pediatric patients have not been established
Geriatric Use: No overall differences in effectiveness of Alpelisib were observed between patients ≥65 years of age compared to younger patients. There are an insufficient number of patients ≥75 years of age to assess whether there are differences in safety or effectiveness.
Renal Impairment: The effect of severe renal impairment (CLcr <30 mL/min) on Alpelisib pharmacokinetics is unknown. No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to <90 mL/min).
Therapeutic Class
Cytotoxic Chemotherapy
Storage Conditions
Store below 30°C, in a cool and dry place. Keep away from light. Keep out of the reach of children.
