Drug Information

Drug Interaction:

DRUG INTERACTIONS

• CYP3A4 Inducers: Avoid coadministration of PIQRAY with a strong CYP3A4 inducer.

• BCRP Inhibitors: Avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions.

• CYP2C9 Substrates: Closely monitor when PIQRAY is coadministered with CYP2C9 substrates where decreases in the plasma concentration of these drugs may reduce activity.

Indication:

BRIEF SUMMARY

ALPELISIB- (May 2019)

Indn- To treat brest cancer

Comp- Tablets: 50 mg, 150 mg, 200 mg • Recommended dose: 300 mg (two 150 mg tablets) taken orally once daily with food.

• For adverse reactions, consider dose interruption, dose reduction, or discontinuation

ADR- Most common adverse reactions including laboratory abnormalities (all grades, incidence = 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased.

CI- Severe hypersensitivity to PIQRAY or to any of its components

WARNINGS-

• Severe Hypersensitivity:

Permanently discontinue Promptly initiate appropriate treatment.

• Severe Cutaneous Reactions:

Cases of severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and Erythema Multiforme (EM) were reported. Do not initiate treatment in patients with a history of SJS, EM.

Pat Inform-

Severe Hypersensitivity- Inform patients of the signs and symptoms of hypersensitivity. Advise patients to contact their healthcare provider immediately for signs and symptoms of hypersensitivity

Severe Cutaneous Reactions- Inform patients of the signs and symptoms of severe cutaneous reactions. Advise patients to contact their healthcare provider immediately for signs and symptoms of severe cutaneous reactions

================================================================

U.S. FDA APPROVED DRUGS DURING 2019

Sr.No.11.

Name of the Drug- PIRQRAY

Active Ingredient - Alpelisib

Pharmacological Classification-

To treat brest cancer

Date of Approval - 5/24/2019

(Ref- FDA approved List 2019 )

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

PIQRAY safely and effectively. See full prescribing information for PIQRAY. PIQRAY® (alpelisib) tablets, for oral use

Initial U.S. Approval: 2019

INDICATIONS AND USAGE

PIQRAY is a kinase inhibitor 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, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

Adverse Reaction:

ADVERSE REACTIONS

Most common adverse reactions including laboratory abnormalities (all grades, incidence = 20%) were glucose increased, creatinine increased, diarrhea, rash, lymphocyte count decreased, GGT increased, nausea, ALT increased, fatigue, hemoglobin decreased, lipase increased, decreased appetite, stomatitis, vomiting, weight decreased, calcium decreased, glucose decreased, aPTT prolonged, and alopecia

Contra-Indications:

CONTRAINDICATIONS

Severe hypersensitivity to PIQRAY or to any of its components

WARNINGS AND PRECAUTIONS

• Severe Hypersensitivity:

Permanently discontinue PIQRAY. Promptly initiate appropriate treatment.

• Severe Cutaneous Reactions:

Cases of severe cutaneous reactions, including Stevens-Johnson syndrome (SJS) and Erythema Multiforme (EM) were reported. Do not initiate treatment in patients with a history of SJS, EM, or Toxic Epidermal Necrolysis (TEN).

Interrupt PIQRAY if signs or symptoms of severe cutaneous reactions are present, until etiology of the reaction has been determined.

Consider consultation with a dermatologist. Permanently discontinue PIQRAY if SJS, EM, or TEN is confirmed.

• Hyperglycemia:

Severe hyperglycemia, including ketoacidosis, was reported. The safety of PIQRAY in patients with Type 1 or uncontrolled Type 2 diabetes has not been established. Before initiating treatment with PIQRAY, test fasting plasma glucose (FPG), HbA1c, and optimize blood glucose.

After initiating treatment, monitor periodically. Initiate or optimize anti-hyperglycemic medications as clinically indicated.

Interrupt, reduce dose, or discontinue PIQRAY if severe hyperglycemia occurs.

• Pneumonitis:

Severe cases of pneumonitis and interstitial lung disease have been reported. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs.

• Diarrhea:

Severe cases of diarrhea, including dehydration and acute kidney injury, have been reported. Most patients experience diarrhea (Grade = 2) during treatment with PIQRAY. Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs.

Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea occurs.

• Embryo-Fetal Toxicity:

PIQRAY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception

Also, refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

• Pneumonitis: Severe cases of pneumonitis and interstitial lung disease have been reported. Monitor for clinical symptoms or radiological changes. Interrupt or discontinue PIQRAY if severe pneumonitis occurs.

• Diarrhea: Severe cases of diarrhea, including dehydration and acute kidney injury, have been reported. Most patients experience diarrhea (Grade = 2) during treatment with PIQRAY.

Advise patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs. Interrupt, reduce dose, or discontinue PIQRAY if severe diarrhea occurs.

• Embryo-Fetal Toxicity: PIQRAY can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception

Also, refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

Dosages/ Overdosage Etc:

INDICATIONS AND USAGE

PIQRAY is a kinase inhibitor 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, PIK3CA-mutated, advanced or metastatic breast cancer as detected by an FDA-approved test following progression on or after an endocrine-based regimen.

DOSAGE AND ADMINISTRATION

• Recommended dose: 300 mg (two 150 mg tablets) taken orally once daily with food.

• For adverse reactions, consider dose interruption, dose reduction, or discontinuation.

DOSAGE FORMS AND STRENGTHS

Tablets: 50 mg, 150 mg, 200 mg

Patient Information:

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Severe Hypersensitivity

Inform patients of the signs and symptoms of hypersensitivity. Advise patients to contact their healthcare provider immediately for signs and symptoms of hypersensitivity

Severe Cutaneous Reactions

Inform patients of the signs and symptoms of severe cutaneous reactions. Advise patients to contact their healthcare provider immediately for signs and symptoms of severe cutaneous reactions

Hyperglycemia

Advise patients of the possibility of developing hyperglycemia and the need to monitor blood glucose periodically during therapy.

Advise patients to contact their healthcare provider immediately for signs and symptoms of hyperglycemia

Pneumonitis

Inform patients of the possibility of developing pneumonitis and to immediately contact their healthcare provider if they experience respiratory problems

Diarrhea

Advise patients that PIQRAY may cause diarrhea, which may be severe in some cases. Inform patients to start antidiarrheal treatment, increase oral fluids, and notify their healthcare provider if diarrhea occurs while taking PIQRAY

Embryo-Fetal Toxicity

• Inform pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.

• Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose.

• Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose.

• Refer to the Full Prescribing Information of fulvestrant for pregnancy and contraception information.

Lactation

Advise women not to breastfeed during treatment with PIQRAY and for 1 week after the last dose .Refer to the Full Prescribing Information of fulvestrant for lactation information.

Infertility Advise males and females of reproductive potential that PIQRAY may impair fertility.Refer to the Full Prescribing Information of fulvestrant for infertility information.

Drug Interactions

Advise patients to avoid the use of strong CYP3A4 inducers in patients treated with PIQRAY.

Advise patients to avoid the use of BCRP inhibitors in patients treated with PIQRAY. If unable to use alternative drugs, closely monitor for increased adverse reactions.

Advise patients that close monitoring may be required when PIQRAY is coadministered with CYP2C9 substrates where decreases in the plasma concentration of CYP2C9 substrates may reduce activity of these drugs

Dosing

• Instruct patients to take PIQRAY at approximately the same time each day and to swallow the tablet(s) whole (tablets should not be chewed, crushed, or split prior to swallowing

• Advise patients to take PIQRAY with food

• Instruct patients that if a dose of PIQRAY 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 PIQRAY at the usual time.

Instruct patients not to take 2 doses to make up for a missed dose.

• Instruct patients that if they vomit after taking the dose of PIQRAY, they should not take an additional dose on that day, and to resume the usual dosing schedule the next day at the usual time

Distributed by:

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 © Novartis T2019-XX

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Alpelisib is an inhibitor of phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Ka. Gain-of-function mutations in the gene encoding the catalytic a-subunit of PI3K (PIK3CA) lead to activation of PI3Ka and Akt-signaling, cellular transformation and the generation of tumors in in vitro and in vivo models.

2. Pharmacodynamics

Cardiac Electrophysiology Serial ECGs were collected following a single dose and at steady-state to evaluate the effect of alpelisib on the QTcF interval in patients with advanced cancer.

An analysis of clinical ECG data demonstrates the absence of a large effect (i.e., > 20 ms) on QTcF prolongation at the recommended 300 mg dose with or without fulvestrant.

3. Pharmacokinetics

The pharmacokinetics of alpelisib has been studied in healthy subjects and adult patients with solid tumors. Steady-state alpelisib maximum plasma concentration (Cmax) and AUC increased proportionally over the dose range of 30 mg to 450 mg (0.1 to 1.5 times the approved recommended dosage) under fed conditions.

The mean accumulation of alpelisib is 1.3 to 1.5 and steady-state plasma concentrations are reached within 3 days following daily dosage.

Absorption

The median time to reach peak plasma concentration (Tmax) ranged between 2.0 to 4.0 hours.

Effect of food

A high-fat high-calorie meal (985 calories with 58.1 g of fat) increased alpelisib AUC by 73% and Cmax by 84%, and a low-fat low-calorie meal (334 calories with 8.7 g of fat) increased alpelisib AUC by 77% and Cmax by 145% following a single dose of PIQRAY.

No clinically significant differences in alpelisib AUC were observed between low-fat low-calorie and high-fat high-calorie meals.

Distribution

The mean (% CV) apparent volume of distribution of alpelisib at steady-state is predicted to be 114 L (46%). Protein binding of alpelisib is 89% and is independent of concentration.

Elimination

The half-life of alpelisib is predicted to be 8 to 9 hours. The mean (% CV) clearance of alpelisib is predicted to be 9.2 L/hr (21%) under fed conditions.

Metabolism

Alpelisib is primarily metabolized by chemical and enzymatic hydrolysis to form its metabolite BZG791 and to a lesser extent by CYP3A4, in vitro.

Excretion

Following a single oral dose of 400 mg radiolabeled alpelisib under fasted condition, 81% of the administered dose was recovered in feces (36% unchanged, 32% BZG791) and 14% (2% unchanged, 7.1% BZG791) in urine. CYP3A4-mediated metabolites (12%) and glucuronides amounted to approximately 15% of the dose.

Specific 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 (CLcr 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 (CLcr < 30 mL/min) on the pharmacokinetics of alpelisib is unknown.

Drug Interaction Studies

Clinical Studies Acid Reducing Agents:

PIQRAY can be coadministered with acid reducing agents, since PIQRAY should be taken with food.

Food exhibited a more pronounced effect on the solubility of alpelisib than the effect of gastric pH value.

Coadministration of the H2 receptor antagonist ranitidine in combination with a single 300 mg oral dose of alpelisib decreased the absorption and overall exposure of alpelisib.

In the presence of a low-fat low-calorie meal, AUC was decreased on average by 21% and Cmax by 36% with ranitidine.

Under the fasted state, AUC was decreased on average by 30% and Cmax by 51% with ranitidine.

CYP3A4 Substrates:

No clinically significant differences in pharmacokinetics of everolimus (a substrate of CYP3A4 and P-gp) were observed when coadministered with alpelisib. In Vitro Studies

Effect of Alpelisib on CYP Enzymes:

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

Effect of Transporter on Alpelisib: Alpelisib is a substrate of BCRP.

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for pregnancy information.

Based on animal data and mechanism of action, PIQRAY can cause fetal harm when administered to a pregnant woman

There are no available data in pregnant women to inform the drugassociated risk.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

However, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies in the U.S. general population.

2. Lactation

PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for lactation information.

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 PIQRAY and for 1 week after the last dose.

3. Females and Males of Reproductive Potentia

PIQRAY is used in combination with fulvestrant. Refer to the Full Prescribing Information of fulvestrant for contraception and infertility information.

Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating PIQRAY.

Contraception

Females PIQRAY can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with PIQRAY and for 1 week after the last dose.

Males Advise male patients with female partners of reproductive potential to use condoms and effective contraception during treatment with PIQRAY and for 1 week after the last dose. Infertility

Based on findings from animal studies, PIQRAY may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1)].

4 Pediatric Use

The safety and efficacy of PIQRAY in pediatric patients have not been established.

5. Geriatric Use

Of 284 patients who received PIQRAY in the SOLAR-1 trial, 117 patients were = 65 years of age and 34 patients were = 75 years of age. In patients treated with PIQRAY plus fulvestrant, there was a higher incidence of Grade 3-4 hyperglycemia in patients = 65 years of age (44%) compared to patients < 65 years of age (32%).

No overall differences in effectiveness of PIQRAY 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.

6. 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).

OVERDOSAGE

There is limited experience of overdose with PIQRAY in clinical trials. In the clinical studies, PIQRAY was administered at doses up to 450 mg once daily.

In cases where accidental overdosage of PIQRAY was reported in the clinical studies, the adverse reactions associated with the overdose were consistent with the known safety profile of PIQRAY and included hyperglycemia, nausea, asthenia, and rash.

Initiate general symptomatic and supportive measures in all cases of overdosage where necessary. There is no known antidote for PIQRAY.

11/19. Alpelisib-(PIRQRAY)@ (May-2019)- Anti-cancer

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation