DRUG INTERACTIONS

• CYP3A Inhibitors: Avoid concomitant use of ketoconazole. Reduce the VERZENIO dose with concomitant use of other strong CYP3A inhibitors. 

• CYP3A Inducers: Avoid concomitant use of strong CYP3A inducers. 

BRIEF SUMMARY

ABEMACICLIB- (Sep 2017)

Indn-      To treat certain advanced or metastatic breast cancers  

Comp-     Tablets: 50 mg, 100 mg, 150 mg, and 200 mg.   • in combination with an aromatase inhibitor as initial endocrinebased therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. 

ADR-     Most common adverse reactions (incidence =20%)were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

CI-     None. 

WARNINGS-

• Diarrhea: Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. 

• Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.

Pat Infn-

Advise patients to read the FDA-approved Patient Information. Diarrhea.May cause diarrhea, which may be severe in some cases 

• Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.

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U.S. FDA APPROVED  DRUGS DURING 2017

Sr.No-  34  

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to useVERZENIO safely and effectively. See full prescribing information for VERZENIO.

VERZENIO™ (abemaciclib) tablets, for oral use

Initial U.S. Approval: 2017

 RECENT MAJOR CHANGES

­ Indications and Usage  2/2018

Dosage and Administration, Recommended Dose and Schedule  2/2018

Warnings and Precautions,

Diarrhea 2/2018                                                                                                      Neutropenia  2/2018                                                                                      Hepatotoxicity  2/2018                                                                                               Venous Thromboembolism ) 2/2018 

INDICATIONS AND USAGE

­ VERZENIO™ is a kinase inhibitor indicated:

• in combination with an aromatase inhibitor as initial endocrinebased therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. 

• in combination with fulvestrant for the treatment of women with hormone receptor        (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. 

• as monotherapy for the treatment of adult patients with HRpositive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. 

ADVERSE REACTIONS

 Most common adverse reactions (incidence =20%)were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

 CONTRAINDICATIONS                                                                                             None. 

WARNINGS AND PRECAUTIONS­

• Diarrhea: Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. 

• Neutropenia: Monitor complete blood counts prior to the start of VERZENIO therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.

• Hepatotoxicity: Increases in serum transaminase levels have been observed. Perform liver function tests (LFTs) before initiating treatment with VERZENIO. Monitor LFTs every two weeks for the first two months, monthly for the next 2 months, and as clinically indicated.

• Venous Thromboembolism: Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate.

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

INDICATIONS AND USAGE 

VERZENIO™ is a kinase inhibitor indicated: 

• in combination with an aromatase inhibitor as initial endocrinebased therapy for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. 

• in combination with fulvestrant for the treatment of women with hormone receptor        (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. 

• as monotherapy for the treatment of adult patients with HRpositive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. 

DOSAGE AND ADMINISTRATION

VERZENIO tablets are taken orally with or without food.

 • Recommended starting dose in combination with fulvestrant or an aromatase inhibitor: 150 mg twice daily. 

• Recommended starting dose as monotherapy: 200 mg twice daily. 

• Dosing interruption and/or dose reductions may be required based on individual safety and tolerability. 

DOSAGE FORMS AND STRENGTHS

Tablets: 50 mg, 100 mg, 150 mg, and 200 mg. 

PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved Patient Information. Diarrhea VERZENIO may cause diarrhea, which may be severe in some cases 

• Early identification and intervention is critical for the optimal management of diarrhea. Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy (for example, loperamide) and notify their healthcare provider for further instructions and appropriate follow up.

• Encourage patients to increase oral fluids. • If diarrhea does not resolve with antidiarrheal therapy within 24 hours to =Grade 1, suspend VERZENIO dosing 

Neutropenia 

 Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any signs of infection.

Hepatotoxicity

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

Venous Thromboembolism

Advise patients to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia 

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during VERZENIO therapy and for at least 3 weeks after the last dose.

Advise patients to inform their healthcare provider of a known or suspected pregnancy .

Lactation

Advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose .

Drug Interactions •

Inform patients to avoid concomitant use of ketoconazole. Dose reduction may be required for other strong CYP3A inhibitors  

• Grapefruit may interact with VERZENIO. Advise patients not to consume grapefruit products while on treatment with VERZENIO.

• Advise patients to avoid concomitant use of CYP3A inducers and to consider alternative agents 

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products 

Dosing

• Instruct patients to take the doses of VERZENIO at approximately the same times every day and to swallow whole (do not chew, crush, or split them prior to swallowing) 

 • If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time 

. • Advise the patient that VERZENIO may be taken with or without food 

Marketed by:Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2017, 2018, Eli Lilly and Company.

 CLINICAL PHARMACOLOGY

 Mechanism of Action

Abemaciclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). These kinases are activated upon binding to D-cyclins.

In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation. In vitro, continuous exposure to abemaciclib inhibited Rb phosphorylation and blocked progression from G1 into S phase of the cell cycle, resulting in senescence and apoptosis.

In breast cancer xenograft models, abemaciclib dosed daily without interruption as a single agent or in combination with antiestrogens resulted in reduction of tumor size.

 Pharmacodynamics -Cardiac Electrophysiology

Based on evaluation of the QTc interval in patients and in a healthy volunteer study, abemaciclib did not cause large mean increases (i.e., 20 ms) in the QTc interval.

 Pharmacokinetics

The pharmacokinetics of abemaciclib were characterized in patients with solid tumors, including metastatic breast cancer, and in healthy subjects.

Following single and repeated twice daily dosing of 50 mg (0.3 times the approved recommended 150 mg dosage) to 200 mg of abemaciclib, the increase in plasma exposure (AUC) and Cmax was approximately dose proportional.

Steady state was achieved within 5 days following repeated twice daily dosing, and the estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.

Absorption

The absolute bioavailability of abemaciclib after a single oral dose of 200 mg is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).

Effect of Food

A high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) administered to healthy subjects increased the AUC of abemaciclib plus its active metabolites by 9% and increased Cmax by 26%.

Distribution

In vitro, abemaciclib was bound to human plasma proteins, serum albumin, and alpha-1-acid glycoprotein in a concentration independent manner from 152 ng/mL to 5066 ng/mL. In a clinical study, the mean (standard deviation, SD) bound fraction was 96.3% (1.1) for abemaciclib, 93.4% (1.3) for M2, 96.8% (0.8) for M18, and 97.8% (0.6) for M20.

The geometric mean systemic volume of distribution is approximately 690.3 L (49% CV). In patients with advanced cancer, including breast cancer, concentrations of abemaciclib and its active metabolites M2 and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.

Elimination

The geometric mean hepatic clearance (CL) of abemaciclib in patients was 26.0 L/h (51% CV), and the mean plasma elimination half-life for abemaciclib in patients was 18.3 hours (72% CV). Reference ID: 4226487

 Metabolism

Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A4, with formation of N-desethylabemaciclib (M2) representing the major metabolism pathway.

Additional metabolites include hydroxyabemaciclib (M20), hydroxy-N-desethylabemaciclib (M18), and an oxidative metabolite (M1). M2, M18, and M20 are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively.

Excretion

After a single 150 mg oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.

Specific Populations

Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in patients with cancer, age (range 24-91 years), gender (134 males and 856 females), and body weight (range 36-175 kg) had no effect on the exposure of abemaciclib.

Patients with Renal Impairment

In a population pharmacokinetic analysis of 990 individuals, in which 381 individuals had mild renal impairment (60 mL/min = CLcr <90 mL/min) and 126 individuals had moderate renal impairment (30 mL/min = CLcr <60 mL/min), mild and moderate renal impairment had no effect on the exposure of abemaciclib 

The effect of severe renal impairment (CLcr <30 mL/min) on pharmacokinetics of abemaciclib is unknown.

Patients with Hepatic Impairment

Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9),

1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and 2.4-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10) 

In subjects with severe hepatic impairment, the mean plasma elimination half-life of abemaciclib increased to 55 hours compared to 24 hours in subjects with normal hepatic function.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary

Based on findings in animals and its mechanism of action, VERZENIO can cause fetal harm when administered to a pregnant woman 

There are no available human data informing the drug-associated risk.

Advise pregnant women of the potential risk to a fetus.

In animal reproduction studies, administration of abemaciclib during organogenesis was teratogenic and caused decreased fetal weight at maternal exposures that were similar to human clinical exposure based on AUC at the maximum recommended human dose . Advise pregnant women of the potential risk to a fetus.

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

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

 2. Lactation Risk Summary 

There are no data on the presence of abemaciclib in human milk, or its effects on the breastfed child or on milk production.

Because of the potential for serious adverse reactions in breastfed infants from VERZENIO, advise lactating women not to breastfeed during VERZENIO treatment and for at least 3 weeks after the last dose.

3.Females and Males of Reproductive Potential Pregnancy Testing

Based on animal studies, VERZENIO can cause fetal harm when administered to a pregnant woman. Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with VERZENIO. 

 Contraception Females-

VERZENIO can cause fetal harm when administered to a pregnant woman.             Advise females of reproductive potential to use effective contraception during VERZENIO treatment and for at least 3 weeks after the last dose.

Infertility Males -

Based on findings in animals, VERZENIO may impair fertility in males of reproductive potential 

4. Pediatric Use

The safety and effectiveness of VERZENIO have not been established in pediatric patients.

5.Geriatric Use

Of the 900 patients who received VERZENIO in MONARCH 1, MONARCH 2, and MONARCH 3, 38% were 65 years of age or older and 10% were 75 years of age or older.

The most common adverse reactions (=5%) Grade 3 or 4 in patients =65 years of age across MONARCH 1, 2, and 3 were neutropenia, diarrhea, fatigue, nausea, dehydration, leukopenia, anemia, infections, and ALT increased.

No overall differences in safety or effectiveness of VERZENIO were observed between these patients and younger patients.

6. Renal Impairment

No dosage adjustment is required for patients with mild or moderate renal impairment (CLcr =30-89 mL/min, estimated by Cockcroft-Gault [C-G]).

The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr <30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown 

7. Hepatic Impairment

No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B). Reduce the dosing frequency when administering VERZENIO to patients with severe hepatic impairment (Child-Pugh C) 

 OVERDOSAGE

There is no known antidote for VERZENIO. The treatment of overdose of VERZENIO should consist of general supportive measures.