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Keytruda

Generic Name: Pembrolizumab
Class: Antineoplastic Agents
Chemical Name: Anti-(human protein PDCD1 (programmed cell death 1)) (human-Mus musculus monoclonal heavy chain), disulfide with human-Mus musculus monoclonal light chain immunoglobulin G4 dimer
Molecular Formula: C6504H10004N1716O2036S46 (peptide)
CAS Number: 1374853-91-4

Introduction

Antineoplastic agent; humanized anti-programmed-death receptor-1 (anti-PD-1) monoclonal antibody.1 7 8

Uses for Keytruda

Melanoma

Treatment of unresectable or metastatic melanoma following failure of ipilimumab and, in patients with tumors bearing the b-Raf serine-threonine kinase (BRAF) V600 mutation, therapy with a BRAF inhibitor1 3 5 (designated an orphan drug by FDA for this use).4

Efficacy based on overall response rate and response duration; improvement in patient-reported outcomes and overall survival not demonstrated.1

Keytruda Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Pembrolizumab powder for injection must be reconstituted and diluted prior to administration.1 (See Storage under Stability.)

Do not infuse simultaneously through the same IV line with other drugs.1

Administer using a sterile, nonpyrogenic, low-protein-binding 0.2- to 5-μm inline or add-on filter.1

Reconstitution

Reconstitute vial containing 50 mg of pembrolizumab with 2.3 mL of sterile water for injection to provide a solution containing 25 mg/mL; direct diluent toward wall of vial.1 Gently swirl vial to ensure dissolution.1 Allow solution to stand for up to 5 minutes to let bubbles dissipate.1 Do not shake reconstituted solution.1

Reconstituted solution should be clear to slightly opalescent and colorless to slightly yellow.1 Do not use if foreign particles other than translucent to white proteinaceous particles are present.1

Dilution

Dilute appropriate dose in a sufficient volume of 0.9% sodium chloride injection to yield a final concentration of 1–10 mg/mL.1 Mix the diluted solution by gentle inversion.1 Discard any partially used vials.1

Rate of Administration

Administer by IV infusion over 30 minutes.1

Dosage

Adults

Melanoma
IV

2 mg/kg every 3 weeks.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Therapy Interruption for Toxicity

Discontinue therapy in patients experiencing any life-threatening immune-mediated adverse effect, patients with persistent grade 2 or 3 immune-mediated adverse effects that do not recover to grade 0 or 1 within 12 weeks of the last dose of pembrolizumab, and those unable to reduce corticosteroid dosage to ≤10 mg of prednisone (or equivalent) daily within 12 weeks.1 (See Warnings/Precautions under Cautions.)

Discontinue therapy if severe or grade 3 immune-mediated adverse effects recur.1

Immune-mediated Pneumonitis

If grade 2 immune-mediated pneumonitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Pneumonitis under Cautions.)

If grade 3 or 4 immune-mediated pneumonitis occurs, discontinue drug.1

Immune-mediated GI Effects

If grade 2 or 3 immune-mediated colitis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated GI Effects under Cautions.)

If grade 4 immune-mediated colitis occurs, discontinue drug.1

Immune-mediated Hepatic Effects

For ALT or AST concentrations >3 to 5 times the ULN or total bilirubin concentrations >1.5 to 3 times the ULN, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Hepatic Effects under Cautions.)

For ALT or AST concentrations >5 times the ULN or total bilirubin concentrations >3 times the ULN, discontinue drug.1

If ALT or AST concentration increases by ≥50% from baseline for ≥1 week in patients with liver metastasis and baseline grade 2 serum aminotransferase elevations, discontinue drug.1

Immune-mediated Endocrine Effects

If symptomatic or grade 2 immune-mediated hypophysitis or grade 3 immune-mediated hyperthyroidism occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Endocrine Effects under Cautions.)

If grade 3 immune-mediated hypophysitis occurs, interrupt therapy or discontinue drug.1

If grade 4 immune-mediated hyperthyroidism or hypophysitis occurs, discontinue drug.1

Immune-mediated Renal Effects

If grade 2 immune-mediated nephritis occurs, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Immune-mediated Renal Effects under Cautions.)

If grade 3 or 4 immune-mediated nephritis occurs, discontinue drug.1

Infusion-related Effects

If grade 3 or 4 infusion-related reactions occur, discontinue drug.1

Other Immune-mediated Adverse Effects

If any other severe or grade 3 immune-mediated adverse effects occur, interrupt therapy until toxicity resolves to grade 0 or 1.1 (See Other Immune-mediated Effects under Cautions.)

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment: No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Moderate or severe preexisting hepatic impairment: Not studied; no dosage recommendations at this time.1

Renal Impairment

Mild, moderate, or severe preexisting renal impairment: No dosage adjustment required.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No special dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Keytruda

Contraindications

  • No known contraindications.1

Warnings/Precautions

Immune-mediated Pneumonitis

Immune-mediated pneumonitis reported.1

Monitor patients for manifestations of pneumonitis.1 If pneumonitis is suspected, evaluate patients using radiographic imaging.1 If grade 2 or greater pneumonitis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated GI Effects

Immune-mediated colitis, including microscopic colitis, reported.1

Monitor patients for manifestations of colitis.1 If grade 2 or greater colitis occurs, temporarily withhold or discontinue pembrolizumab and initiate systemic corticosteroid therapy.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Hepatic Effects

Immune-mediated hepatitis, including autoimmune hepatitis, reported.1 3

Monitor patients for changes in liver function.1 If grade 2 or greater hepatitis occurs, initiate systemic corticosteroid therapy.1 If elevations in AST, ALT, or bilirubin concentrations occur, temporarily withhold or discontinue pembrolizumab.1 (See Therapy Interruption for Toxicity under Dosage and Administration.)

Immune-mediated Endocrine Effects

Immune-mediated endocrinopathies, including hypophysitis, hyperthyroidism, and hypothyroidism, reported.1

Evaluate thyroid function prior to initiation of therapy, periodically during therapy, and as clinically indicated.1 Monitor for manifestations of hypothyroidism, hyperthyroidism, and hypophysitis.1

If hyperthyroidism or hypophysitis occurs, temporarily withhold or discontinue pembrolizumab.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) If grade 2 or greater hypophysitis or grade 3 or greater hyperthyroidism occurs, initiate systemic corticosteroid therapy.1

Isolated hypothyroidism may be managed with thyroid hormone replacement therapy without interruption of pembrolizumab therapy or initiation of systemic corticosteroid therapy.1

Immune-mediated Renal Effects

Immune-mediated nephritis, including autoimmune nephritis and interstitial nephritis with renal failure, reported.1

Monitor patients for changes in renal function.1 If nephritis occurs, temporarily withhold or discontinue pembrolizumab.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) If grade 2 or greater nephritis occurs, initiate systemic corticosteroid therapy.1

Other Immune-mediated Effects

Other immune-mediated adverse effects (e.g., exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, rhabdomyolysis) reported.1 3 6

If an immune-mediated adverse effect is suspected, ensure adequate evaluation to exclude other causes.1

Depending on severity of immune-mediated adverse effect, temporarily withhold pembrolizumab and initiate systemic corticosteroid therapy.1 (See Therapy Interruption for Toxicity under Dosage and Administration.) Once toxicity has resolved to grade 0 or 1, taper corticosteroid dosage over ≥1 month.1 If severe or grade 3 immune-mediated adverse effects occur, temporarily withhold or discontinue pembrolizumab.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 May disrupt maternal immune tolerance to the fetus and increase risk of fetal loss (abortion, stillbirth); also may increase risk of immune-mediated disorders or alter normal immune response of the developing fetus.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use a highly effective contraceptive method while receiving pembrolizumab and for ≥4 months after the drug is discontinued.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1

Immunogenicity

Potential for immunogenicity.1 Development of binding antibodies to pembrolizumab not detected to date.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether pembrolizumab is distributed into milk.1 Discontinue nursing.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

In melanoma clinical trial, 39% of patients were ≥65 years of age; no overall differences in safety or efficacy relative to younger adults.1

Hepatic Impairment

Clearance not affected by mild hepatic impairment.1 Not studied in patients with moderate or severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Renal Impairment

Clearance not affected by mild, moderate, or severe renal impairment.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Fatigue,1 peripheral edema,1 chills,1 pyrexia,1 nausea,1 constipation,1 diarrhea,1 vomiting,1 abdominal pain,1 cough,1 dyspnea,1 pruritus,1 rash,1 vitiligo,1 decreased appetite,1 arthralgia,1 pain in extremity,1 myalgia,1 back pain,1 headache,1 dizziness,1 insomnia,1 upper respiratory tract infection,1 anemia,1 hyperglycemia,1 hyponatremia,1 hypoalbuminemia,1 hypertriglyceridemia,1 increased AST concentrations,1 hypocalcemia.1

Interactions for Keytruda

No formal drug interaction studies to date.1

Keytruda Pharmacokinetics

Absorption

Bioavailability

Steady-state concentrations achieved within 18 weeks.1

AUC, peak plasma concentration, and trough concentration are dose proportional over the dosage range of 2–10 mg/kg every 3 weeks; systemic accumulation is 2.1-fold when administered every 3 weeks.1

Distribution

Extent

Not known whether pembrolizumab is distributed into milk.1

Elimination

Half-life

26 days.1

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN, or total bilirubin concentration >1 times but not >1.5 times the ULN with any AST concentration) does not affect clearance.1 Data not available for moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration).1

Mild, moderate, or severe renal impairment (estimated GFR 15–89 mL/minute per 1.73 m2) does not affect clearance.1

Age, gender, and tumor burden do not have meaningful effects on pharmacokinetics of pembrolizumab.1

Stability

Storage

Parenteral

Powder for Injection

Unreconstituted drug: 2–8°C.1

Reconstituted drug: Room temperature for up to 4 hours after reconstitution (including infusion time) or 2–8°C for up to 24 hours after reconstitution.1 Do not freeze.1

Diluted infusion solution: Room temperature for up to 4 hours after reconstitution (including infusion time) or 2–8°C for up to 24 hours after reconstitution.1 Do not freeze.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Actions

  • An IgG4 kappa immunoglobulin that is highly selective for PD-1, an immune-checkpoint receptor expressed on activated T-cells, monocytes, B-cells, natural killer (NK) T-cells, and dendritic cells.1 3 5 8

  • Overexpression of PD-1 ligands on surface of tumor cells results in activation of PD-1 activity and suppression of cytotoxic T-cell activity.1 8

  • Blocks interaction between PD-1 and its ligands, resulting in enhanced immune response, including enhanced antitumor immune response.1 8

Advice to Patients

  • Importance of reading the manufacturer's medication guide before beginning treatment and each time the drug is administered.1 2

  • Risk of immune-mediated pneumonitis.1 2 Importance of informing clinician immediately if new or worsening cough, chest pain, or shortness of breath occurs.1 2

  • Risk of immune-mediated colitis.1 2 Importance of informing clinician immediately if diarrhea, severe abdominal pain, or changes in stool occur.1 2

  • Risk of immune-mediated hepatitis.1 2 Importance of informing clinician immediately if signs and symptoms of liver damage (e.g., jaundice, nausea, vomiting, dark urine, abdominal pain [particularly in right upper quadrant], easy bruising or bleeding, lack of appetite) occur.1 2

  • Risk of immune-mediated hypophysitis.1 2 Importance of informing clinician immediately if persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes occur.1 2

  • Risk of immune-mediated nephritis.1 2 Importance of informing clinician immediately if signs and symptoms of renal damage (e.g., decreased urine output, change in color of urine) occur.1 2

  • Risk of immune-mediated thyroid dysfunction.1 Importance of informing clinician immediately if symptoms of abnormal thyroid function (e.g., palpitations, hair loss, weight gain or loss, feeling hot or cold) occur.1 2

  • Importance of laboratory monitoring during therapy.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use a highly effective method of contraception while receiving the drug and for 4 months after discontinuance of therapy.1 Importance of women informing clinicians if they are or plan to become pregnant.2 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving pembrolizumab therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., autoimmune disorders, history of organ transplantation, liver damage).2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pembrolizumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

50 mg

Keytruda

Merck

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Merck & Co., Inc. Keytruda (pembrolizumab) for injection prescribing information. Whitehouse Station, NJ; 2014 Sep.

2. Merck & Co., Inc. Keytruda (pembrolizumab) medication guide. Whitehouse Station, NJ; 2014 Sep.

3. Robert C, Ribas A, Wolchok JD et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384:1109-17. [PubMed 25034862]

4. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2014 Nov 19.

5. Hamid O, Robert C, Daud A et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013; 369:134-44. [PubMed 23724846]

6. Mandel JJ, Olar A, Aldape KD et al. Lambrolizumab induced central nervous system (CNS) toxicity. J Neurol Sci. 2014; 344:229-31. [PubMed 24980937]

7. Karimkhani C, Gonzalez R, Dellavalle RP. A review of novel therapies for melanoma. Am J Clin Dermatol. 2014; 15:323-37. [PubMed 24928310]

8. Poole RM. Pembrolizumab: first global approval. Drugs. 2014; 74:1973-81. [PubMed 25331768]

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