Brand Information

Strength	Rate	Packing Style
mg	0.00	unit

Drug Interaction:

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

Indication:

Proprietary Name- KEYTRUDA*

Established Name- Pembrolizumab

Applicant- MERCK SHARP & DHOME CORP.

Indication- For the treatment of patients with unresectable or metastatic melanoma

and disease progression following Ipilmimab and if BRAF V600 mutation

positive a BRAF Inhibitor

Approval Date- 4/9/2014

Approved by U.S.FDA (Ref- FDA approved List- 2014)

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

KEYTRUDA safely and effectively.

See full prescribing information for KEYTRUDA. KEYTRUDA® (pembrolizumab) for injection, for intravenous use KEYTRUDA® (pembrolizumab) injection, for intravenous use

Initial U.S. Approval: 2014

RECENT MAJOR CHANGES

Indications and Usage 10/2015

Dosage and Administration 10/2015

Dosage and Administration 01/2015

Warnings and Precautions 10/2015

Warnings and Precautions 06/2015

INDICATIONS AND USAGE

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:

i. patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

ii. patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

These indications are approved under accelerated approval based on tumor response rate and durability of response.

An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Adverse Reaction:

ADVERSE REACTIONS

Most common adverse reactions (reported in =20% of patients) with:

melanoma included fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

NSCLC included fatigue, decreased appetite, dyspnea and cough.

Contra-Indications:

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

Immune-mediated Pneumonitis: Withhold for moderate, and permanently discontinue for severe, life-threatening or recurrent moderate pneumonitis.

Immune-mediated Colitis: Withhold for moderate or severe, and permanently discontinue for life-threatening colitis.

Immune-mediated Hepatitis: Monitor for changes in hepatic function. Based on severity of liver enzyme elevations, withhold or discontinue.

Immune-mediated Endocrinopathies : - Hypophysitis: Withhold for moderate and withhold or permanently discontinue for severe or life-threatening hypophysitis.

-Thyroid disorders: Monitor for changes in thyroid function. Withhold or permanently discontinue for severe or lifethreatening hyperthyroidism.

- Type 1 diabetes mellitus: Monitor for hyperglycemia.

Withhold KEYTRUDA in cases of severe hyperglycemia.

Immune-mediated nephritis: Monitor for changes in renal function. Withhold for moderate, and permanently discontinue for severe or life-threatening nephritis.

Infusion-related reactions: Stop infusion and permanently discontinue KEYTRUDA for severe or life-threatening infusion reactions.

Embryofetal toxicity: KEYTRUDA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus.

Dosages/ Overdosage Etc:

Indication- For the treatment of patients with unresectable or metastatic melanoma

and disease progression following Ipilmimab and if BRAF V600 mutation

positive a BRAF Inhibitor

INDICATIONS AND USAGE

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of:

i. patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.

ii. patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

These indications are approved under accelerated approval based on tumor response rate and durability of response.

An improvement in survival or disease-related symptoms has not yet been established. Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

DOSAGE AND ADMINISTRATION

Administer 2 mg/kg as an intravenous infusion over 30 minutes every 3 weeks.

Dilute prior to intravenous infusion.

DOSAGE FORMS AND STRENGTHS

For injection: 50 mg lyophilized powder in single-use vial for reconstitution

Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial

Patient Information:

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

i. Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of KEYTRUDA, including:

ii. Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath .

iii.Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain .

iv. Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding.

v.Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes

vi.Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism [see

vii.Type 1 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 1 diabetes.

viii. Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis

ix. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusionrelated reactions

x.Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests

xi. Advise women that KEYTRUDA can cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of KEYTRUDA .

xii.Advise nursing mothers not to breastfeed while taking KEYTRUDA and for 4 months after the final dose

. U.S. License No. 0002 For KEYTRUDA for injection, at:

Schering-Plough (Brinny) Co., County Cork, Ireland For KEYTRUDA injection, at: MSD Ireland (Carlow) County Carlow, Ireland For patent information: www.merck.com/product/patent/home.html

Pharmacology/ Pharmacokinetics:

CLINICAL PHARMACOLOGY

1.Mechanism of Action- Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

2.Pharmacokinetics

The pharmacokinetics of pembrolizumab was studied in 1645 patients who received doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks.

Based on population pharmacokinetic analyses in patients with solid tumors, the geometric mean [% coefficient of variation (CV%)] for clearance, steadystate volume of distribution, and terminal half-life were 209 mL/day (38%), 7.75 L (20%) and 28 days (41%), respectively.

Steady-state concentrations of pembrolizumab were reached by 18 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was approximately 2-fold.

The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.

Specific Populations:

The effects of various covariates on the pharmacokinetics of pembrolizumab were assessed in population pharmacokinetic analyses. The CL of pembrolizumab increased with increasing body weight; the resulting exposure differences were adequately addressed by the administration of a weight-based dose.

The following factors had no clinically important effect on the CL of pembrolizumab: age (range 15 to 94 years), gender, renal impairment, mild hepatic impairment, and tumor burden. The effect of race could not be assessed due to limited data available in non-White patients.

Renal Impairment:

No clinically important differences in the CL of pembrolizumab were found between patients with renal impairment and patients with normal renal function].

Hepatic Impairment:

No clinically important differences in the CL of pembrolizumab were found between patients with mild hepatic impairment and normal hepatic function.

There is insufficient information to determine whether there are clinically important differences in the CL of pembrolizumab in patients with moderate or severe hepatic impairment

Pregnancy and lactation:

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman.

Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus.

There are no available human data informing the risk of embryo-fetal toxicity. Apprise pregnant women of the potential risk to a fetus.

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.

Data Animal Data

Animal reproduction studies have not been conducted with KEYTRUDA to evaluate its effect on reproduction and fetal development, but an assessment of the effects on reproduction was provided

Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immunemediated disorders or of altering the normal immune response.

2.Lactation Risk Summary

It is not known whether KEYTRUDA is excreted in human milk.

No studies have been conducted to assess the impact of KEYTRUDA on milk production or its presence in breast milk.

Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

3. Females and Males of Reproductive Potential Contraception

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman

. Advise females of to use effective contraception during treatment with KEYTRUDA and for at least 4 months following the final dose.

4.Pediatric Use

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

5.Geriatric Use

Of the 411 patients with melanoma treated with KEYTRUDA, 39% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients

. Of the 550 patients with NSCLC treated with KEYTRUDA, 47% were 65 years and over. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

6. Renal Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with renal impairment.

7. Hepatic Impairment

Based on a population pharmacokinetic analysis, no dose adjustment is needed for patients with mild hepatic impairment [total bilirubin (TB) less than or equal to ULN and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST].

KEYTRUDA has not been studied in patients with moderate (TB greater than 1.5 to 3 times ULN and any AST) or severe (TB greater than 3 times ULN and any AST) hepatic impairment

OVERDOSAGE

There is no information on overdosage with KEYTRUDA.

KEYTRUDA*

Drug Interaction

Indication

Adverse Reaction

Contra-Indications

Dosages/ Overdosage Etc

Patient Information

Pharmacology/ Pharmacokinetics

Pregnancy and lactation