Alpelisib

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# Black Box Warning

# Overview
Alpelisib is a kinase inhibitors that is FDA approved for the treatment of . There is a Black Box Warning for this drug as shown here.  Common adverse reactions include The most common adverse reactions for patients indicated for Alpelisib come in the form of laboratory abnormalities. They include increase in glucose, creatinine, GGT, ALT, or lipase, decrease in lymphocyte count, hemoglobin, appetite, weight, calcium, or glucose, the presence of  diarrhea, rash, nausea, fatigue or alopecia.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### ALPELISIB is indicated for:
- PIQRAY is indicated for advanced metastatic breast cancer- hormone receptor positive, human epidermal growth factor receptor 2 negative, and PIK3CA mutated
- The breast cancer is measured by an approved FDA test
- It is a kinase inhibitor that is given concurrently with fulvestrant, a medication used to treat post menopause women with the conditions listed above

### Limitations of Use
- Patients may have severe reactions to the treatment of Alpelisib (see warnings and adverse reactions for more in depth description)
- Alpelisib can cause impairment of fertility and fetal health problems

### Dosing Considerations
- Alpelisib appears as tablets, and comes in the dose strengths 50 mg, 150 mg, and 200 mg
- Continue the recommended dose of 300 mg or the other prescribed dose by the medical administrator until the disease progresses or the toxicity becomes unacceptable
- The recommended dose of fulvestrant is 500 mg along with Alpelisib. This should be administered on days 1, 15, and 29 of treatment and continue with once monthly after.

### Administration of ALPELISIB
- The recommended dose for patients is 300 mg taken orally daily once along with food
- The tablets appear in various strengths because adverse reactions (see adverse reactions) may cause patients to temporarily or permanently discontinue this medication

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding ALPELISIB Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding ALPELISIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding ALPELISIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding ALPELISIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
- Patients may be advised to withhold this medication for a certain time period because of severe hypersensitivity to Alpelisib or any of its components (check components on the label or talk to a medical professional for more information)

# Warnings

### Severe Cutaneous Reaction
- Less than 2 percent of the patients have shown these possibly lethal reactions connected to the skin and mucous membranes that could be linked to eyes, ears, nose, mouth, lips etc
- Diseases including Stevens-Johns Syndrome (0.4% of the patients) and Erythema Multiforme (1.1% of the patients) were linked to patients consuming or using this medication
- Treatment with Piqray will not be initiated in patients with histories of this disease. Additionally patients who have had severe cutaneous reactions while undergoing treatment with this disease will not be reintroduced to Piqray
- If symptoms appear in patients, temporarily discontinue the medications immediately
If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication
- If the signs/ symptoms are confirmed to be associated with Severe Cutaneous Reactions, patients will have to permanently discontinue the medication
- If the reactions are not associated with Severe Cutaneous Reactions, there may be a need of dose modifications
- Hyperglycemia has been reported in 65% of patients utilizing this medication. Some signs and symptoms of this disease could include excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss.
Ketoacidosis was reported in 0.7% of patients
- Ketoacidosis was reported in 0.7% of patients
- Studies have shown patients usually show signs of hyperglycemia a median time of 15 days into treatment
- It is advised for patients to be tested to track FPG, HbA1c levels, and to optimize the blood glucose before initiating Piqray treatment
- The FPG and blood glucose levels should be monitored for at least the first 8 weeks, once a week. Later, there should be a checkup every 2 weeks, and the time indicated by the doctor.
- Patients should consider meeting with a professional with expertise in treating hyperglycemia. They may be able to help counsel the patients on lifestyle changes.
- Clinical studies have not tested the effect of Piqray on patients with Type 1 diabetes and uncontrolled Type 2 diabetes. Therefore, the safety of combining these diseases with Piqray has not yet been established. Patients should check with a medical practitioner and weight the pros and cons.
Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray.
- Patients with controlled Type 2 diabetes and Diabetes Mellitus were included, and it is advised to closely monitor these patients using Piqray.
- Patients may have to temporarily or permanently discontinue or reduce dose and treatment of Piqray based on the severity of the hyperglycemia present.

### Pneumonitis
- Pneumonitis was discovered in 1.8% of the patients who were treated with Piqray
- Common forms of pneumonitis present within these patients are acute interstitial pneumonitis and interstitial lung disease
- If patients begin showing signs and symptoms of pneumonitis, immediately discontinue the drug until the presence of the disease is either confirmed or denied.
Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation.
- Symptoms of non-infectious pneumonitis include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. There are no studies performed on patients with infectious or neoplastic pneumonitis because there are no means for an appropriate investigation.
- If patients are diagnosed with pneumonitis, discontinue the drug immediately. If they continue to have worsening symptoms, contact a medical professional immediately.

### Diarrhea
- Severe diarrhea, that resulted in dehydration and acute kidney injury, have been present in 58% of patients undergoing treatment with Piqray.
- In a study, 6% of patients required dose reduction, and 2.8% of the people were required to permanently discontinue the drug. There were a total of 164 patients that experienced a case of diarrhea, and 63% of the patients needed to take anti-diarrheal medications.
- Patients may have to temporarily or permanently discontinue the drug, or reduce the dose if a problem with diarrhea persists or becomes severe

### Embryo-Fetal Toxicity
- Female rats and rabbits pregnant were administered doses of Piqray. These studies have shown the effect Piqray can have on the mothers, and fetuses. It caused adverse developmental outcomes including embryo-fetal mortality, loss of fetal weight, and increased cases in fetal malformation.
- Pregnant females, and females with reproductive potential should be advised to use effective contraception during treatment, and 1 week after the last dose. Male patients should also use effective contraception and condoms during treatment and for 1 week after the last dose.
- Patients are advised to reach out to healthcare professionals if any adverse reactions persist.
- Patients should talk to their healthcare provider for more information on routine checkups after discontinuing treatment

### Infusion Reactions
- There is limited information on infusion reactions pertaining to Alpelisib. Contact a doctor immediately if an adverse reactions occur (see adverse reactions)

# Adverse Reactions

## Clinical Trials Experience
There is limited information regarding Alpelisib Clinical Trials Experience in the drug label.

## Postmarketing Experience
There is limited information regarding Alpelisib Postmarketing Experience in the drug label.

# Drug Interactions

### CYP3A4 Inducer
Administering Alpelisib along with a CYP3A4 Inducer may result in a decrease in Alpelisib concentration, and a decrease in effectiveness and activity. Patients should avoid co-administering Alpelisib with strong CYP3A4 inducers.

### BCRP Inhibitors
Administering Alpelisib with BCRP inhibitors increases Alpelisib concentrations that can result in the risk of toxicity in patients. Coadministering Alpelisib with BCRP inhibitors should be avoided. If it is not possible to completely avoid, patients should be closely monitored for adverse reactions.

### CYP2C9 Substrates
Administering Alpelisib with CYP2C9 substrates may result in reduced plasma concentrations of the drugs it is administered with. It is advised to monitor patients closely for a decrease in plasma concentrations because that can cause reduced activity and effectiveness of the drugs.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
There are no available data on ALPELISIB use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Alpelisib in women who are pregnant.

### Labor and Delivery
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

### Nursing Mothers
Women should not breastfeed while undergoing treatment with this medication and for 1 week after the last dose.

### Pediatric Use
The safety and efficacy of ALPELISIB for the treatment of PNH in pediatric patients have not been established.

### Geriatic Use
There were 117 patients in Solar-1 Clinical Trial that were of age 65 or older, and of that 75 patients were of the age 75 and up. There was a higher percentage of cases of Grade 3 or 4 hyperglycemia (44%)  in patients of the age 65 and older compared to the incidence in patients less than the age of 65 (32%). Studies did not show a significant gap in effectiveness of Piqray comparing patients less than 65 years, and patients greater than 65 years of age.

### Gender
There is no FDA guidance on the use of ALPELISIB with respect to specific gender populations.

### Race
There is no FDA guidance on the use of ALPELISIB with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of ALPELISIB in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of ALPELISIB in patients with hepatic impairment.

### Females of Reproductive Potential and Males
FDA guidance suggests healthcare providers should advise and counsel all patients with reproductive potential that ALPELISIB may impair fertility.

### Immunocompromised Patients
There is no FDA guidance one the use of ALPELISIB in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Piqray is administered orally

### Monitoring
There is limited information regarding Alpelisib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Alpelisib and IV administrations.

# Overdosage
In cases of overdosage with Piqray, patients showed a similar set of adverse reactions as indicated in Piqrays profile. These include hyperglycemia, nausea, rash, and asthenia. 
There are no established protocol to entail to Piqray overdose. As in all cases of overdose with every drug, Initiate general symptomatic and supportive measures in all cases
If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Phosphatidylinositol-3-kinase-a (PI3Ka) mediates cell proliferation as a result of the growth-factor tyrosine kinase pathway activation.  PI3Kas subunit is mutated in some cancers that make it hyperactive and out of control. Alpelisib inhibits PI3Ka with the highest specificity for it.

## Structure
There is limited information regarding ALPELISIB Structure in the drug label.

## Pharmacodynamics
There is limited information regarding Alpelisib Pharmacodynamics in the drug label.

## Pharmacokinetics
- The volume of distribution is 114 L
- 36% of Alpelisib is eliminated as the unchanged drug and 32% as the primary metabolite BZG791 through feces. These are for oral doses.
- 2% of the oral dose for Alpelisib is eliminated as the unchanged drug and 7.1% as the primary metabolite through urine
- 81% of an oral dose is eliminated in the faces and 14% in the urine
- Advise patients to not breastfeed while undergoing treatment with Alpelisib and 1 week after the administration of the last dose

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies of carcinogenicity and mutagenicity have not yet been performed

# Clinical Studies

### Study SOLAR-1 (NCT02437318)
- It was a randomized, placebo controlled trial. The trail had two groups of subjects: the patients who got Piqray and fulvestrant vs the patients who got a placebo and fulvestrant. The trial was conducted with 572 patients with HER2-negative, advanced or metastatic breast cancer whose disease had progressed or recurred on or after an aromatase inhibitor-based treatment.
- Patients with causes of adverse reactions or adverse reactions such as inflammatory breast cancer, Type 1 diabetes,  uncontrolled Type 2 diabetes, or pneumonitis were not included in the study.
- 60% of the enrolled patients had tumors with 1 or more PIK3CA mutations, about 50% had had liver or lung metastases, and about 6% had been previously treated with a CDK4 or 6 inhibitor
The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor
- The randomized section was if the patient had liver/ lung metastases and/or been previously treated with a CDK4 or 6 inhibitor
- Division of patients: there were 341 patients in the trial cohort who had at least one PIK3CA mutation and 231 patients in the trial cohorts who did not show the presence of the mutation. Of the patients who had the mutation, about 99% of the patients also had the 1 or more mutations confirmed with a FDA test.
- Patients were put into 2 different groups, so they either received Piqray and fulvestrant or they received a placebo and fulvestrant. The dose of fulvestrant (500 mg) was administered intramuscularly on Days 1 and 15 of the first Cycle, and every first day of the following cycles. The patients continue the treatment in their respective groups until the cancer is shown to progress on radiographs or the patient experiences unacceptable toxicity. The tumors were assessed once every 8 weeks for the first 18 months, and every 12 weeks following the initial period.
- Demographics: the median age of the patients was 63 years, with patients ranging from 25-92 years old. The majority of the patients 999.8%) were women as breast cancer is more common among women. The racial distribution was the following: White patients were 66%, Asian patients were 22%, other/ unknown patients were 10%, Black/ African American patients were 1.4%, and American Indian/ Alaskan Natives were 0.9%.
- The median duration of treatment and exposure to Piqray was about 8.2 months, with an average of 59% of patients treatment lasting more than 6 months.
- About 98% of the patients received hormonal therapy prior to initiating the treatment with the study.  About 13% of the patients showed signs of primary endocrine resistance which means patients diseases progress in less than 6months of endocrine therapy, or relapse within 24 months of initiating therapy. About 72% of patients were observed to have secondary resistance defined as relapse after 24 months consecutive months of hormone therapy, relapsed within 12 months with the same criteria, or disease progression within 6 months of initiating therapy.
- There was no benefit of PFS (Progression-free survival) shown for patients who did not have a PIK3CA tissue mutation. The results for patients with the PIK3CA tissue or plasma mutations showed consistency.
- About 27% of the patients in the 341 patients cohort had died by the evaluation of PFS

# How Supplied
- Alpelisib comes in 3 strengths: 50 mg, 150 mg, and 200 mg film-coated tablets
- Patients may be advised to take this medication in strengths of 300 mg, 250 mg, and 200 mg
- 300 mg: They come in cartons with 2 blister packs. Each of the blister packs has a 14-day supply of 28 tablets because the strengths of each tablet is 150 mg.
- 250 mg: This carton contains 2 blister packs. Each of the packs contains a 14-day supply of 28 tablets which means that there are 14 tablets of 200 mg strength and 14 tablets of 50 mg strength in each packet.
- 200 mg: Each carton for a 200 mg strength supply contains one blister pack with 28 tablets for 28 days

## Storage
Alpelisib should be stored at 20C to 25C (68F to 77F), but is allowed to be exposed to temperatures ranging from 15C and 30C (59F and 86F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information

### Severe Hypersensitivity
- Advise patients of the risk of severe hypersensitivity to Alpelisib or any of its contents. Symptoms of severe hypersensitivity include dyspnea, flushing, rash, fever, and/or tachycardia.
- If these signs or symptoms occur, advise patients to call their healthcare professional immediately.
- This may result in discontinuation of the drug

### Severe Cutaneous Reaction
- Advise and counsel patients on the signs and symptoms of severe cutaneous reactions: prodrome of fever, flu-like symptoms, mucosal lesions or progressive skin rash)
These reactions could possibly be lethal if nothing is done about it
- These reactions could possibly be lethal if nothing is done about it
- Advise patients to immediately call their doctor if any of these signs/ symptoms occurs.
- Inform patients that there is a possibility of developing hyperglycemia through the treatment of Alpelisib
- Patients must note the importance of monitoring blood-glucose levels periodically throughout treatment and for a while after
- Patients should be made aware of the signs and symptoms of hyperglycemia: excessive thirst, urinating more often than usual or higher amount of urine than usual, or increased appetite with weight loss.

### Pneumonitis
- Patients should be asked if they have a history of pneumonitis
- Advise patients to contact the healthcare provider immediately if they experience any respiratory problems including hypoxia, cough, dyspnea, or interstitial infiltrates
- Depending on the severity of the disease, patients may be required to stop treatment and use of Alpelisib

### Diarrhea
- Warn patients that treatment of Alpelisib may cause mild to severe diarrhea
- If diarrhea is severe, patients will need to discontinue the drug
- Advise and counsel patients that they may need to take antidiarrheal medication and increase fluids
- Additionally, patients will need to contact their healthcare provider if this problem occurs because severe cases may require patients to permanently discontinue the medication

### Embryo-Fetal Toxicity
- Counsel pregnant women and women with reproductive potential on the effects Alpelisib may have on a fetus (see warnings)
A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib
- A patient should notify their healthcare provider immediately if they become/ suspect they are pregnant while undergoing treatment with Alpelisib
- Females undergoing treatment with reproductive potential are strongly advised to wear contraception during treatment and 1 week after the last dose. Males/ male patients with female partners of the same caliber are strongly advised to wear protections and contraception during treatment and 1 week after the last dose

### Discontinuation
- Patients will be advised to temporarily or permanently discontinue the medication if adverse reactions become severe or persist.

### Infusion reactions
- Advise patients that administration of ALPELISIB may result in infusion reactions.

# Precautions with Alcohol
Alcohol-Alpelisib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Piqray

# Look-Alike Drug Names
There is limited information regarding ALPELISIB Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price