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Pembrolizumab

Pronunciation

(pem broe LIZ ue mab)

Index Terms

  • Anti-PD-1 Monoclonal Antibody MK-3475
  • Lambrolizumab
  • MK-3475
  • SCH 90045

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Keytruda: 100 mg/4 mL (4 mL) [contains polysorbate 80]

Solution Reconstituted, Intravenous [preservative free]:

Keytruda: 50 mg (1 ea) [contains polysorbate 80]

Brand Names: U.S.

  • Keytruda

Pharmacologic Category

  • Antineoplastic Agent, Anti-PD-1 Monoclonal Antibody
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Highly selective anti-PD-1 humanized monoclonal antibody which inhibits programmed cell death-1 (PD-1) activity by binding to the PD-1 receptor on T-cells to block PD-1 ligands (PD-L1 and PD-L2) from binding. Blocking the PD-1 pathway inhibits the negative immune regulation caused by PD-1 receptor signaling (Hamid 2013). Anti-PD-1 antibodies (including pembrolizumab) reverse T-cell suppression and induce antitumor responses (Robert 2014).

Distribution

Vdss: 7.38 L

Half-Life Elimination

27 days

Use: Labeled Indications

Melanoma, unresectable or metastatic: Treatment of unresectable or metastatic melanoma.

Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in patients with PD-L1-expressing tumors (as determined by an approved test) who have disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression (on approved EGFR- or ALK-directed therapy) prior to receiving pembrolizumab.

Head and neck cancer, squamous cell, recurrent or metastatic: Treatment of recurrent or metastatic squamous cell carcinoma of the head and neck in patients with disease progression on or after platinum-containing chemotherapy.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to pembrolizumab or any component of the formulation.

Dosing: Adult

Melanoma, unresectable or metastatic: IV: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.

Non-small cell lung cancer, metastatic: IV: 2 mg/kg once every 3 weeks until disease progression or unacceptable toxicity.

Head and neck cancer, squamous cell, recurrent or metastatic: IV: 200 mg once every 3 weeks until disease progression, unacceptable toxicity, or (in patients without disease progression) for up to 24 months.

Merkel cell carcinoma, advanced (off-label use): IV: 2 mg/kg once every 3 weeks for up to 2 years or until complete response, or until disease progression or unacceptable toxicity (Nghiem 2016).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary. In a pharmacokinetic study, no difference in clearance was noted for patients with eGFR ≥15 mL/minute/1.73 m2.

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment initiation:

Mild impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any AST): No dosage adjustment necessary.

Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Hepatotoxicity during treatment: Note: For patients with baseline grade 2 ALT or AST abnormalities due to liver metastases, permanently discontinue if AST or ALT increases by ≥50% (relative to baseline) and persists at least 1 week.

AST or ALT >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN: Withhold treatment; may resume therapy upon recovery to grade 0 or 1 toxicity. Also administer corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] followed by a taper).

AST or ALT >5 times ULN or total bilirubin >3 times ULN: Permanently discontinue. Also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed a taper).

Dosing: Adjustment for Toxicity

Withhold treatment for any of the following (may resume upon recovery to grade 0 or 1 toxicity):

Colitis, moderate (grade 2) or severe (grade 3); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Endocrinopathies:

Hyperglycemia, severe; also administer antihyperglycemics.

Hyperthyroidism, severe (grade 3) or life threatening (grade 4); manage with thionamides and beta-blockers as appropriate.

Hypophysitis, grade 2 (symptomatic); also administer corticosteroids (followed by a taper) and hormone replacement therapy if appropriate.

Nephritis, grade 2; also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Pneumonitis, moderate (grade 2); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Other treatment-related toxicity, severe or grade 3; may require corticosteroids (based on severity). Upon improvement to grade 0 or 1, initiate corticosteroid taper and continue to taper over at least 1 month. Restart pembrolizumab if the adverse reaction remains at grade 0 or 1 following corticosteroid taper. May consider other systemic immunosuppressants if not controlled by corticosteroids (based on limited data).

Withhold (may resume upon recovery to grade 0 or 1 toxicity) or discontinue for:

Hyperthyroidism, severe (grade 3) or life-threatening (grade 4); manage with thionamides and beta-blockers as appropriate.

Hypophysitis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids and hormone replacement as appropriate.

Permanently discontinue for:

Adverse reactions that are life-threatening, persistent grade 2 or 3 adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy) that does not recover to grade 0 or 1 within 12 weeks after the last pembrolizumab dose, or any recurrent severe or grade 3 treatment-related adverse reaction. Also administer corticosteroids (may consider other systemic immunosuppressants if not controlled by corticosteroids [based on limited data]).

Colitis, life-threatening (grade 4); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Immune mediated adverse reactions: Discontinue permanently if unable to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks.

Infusion-related reaction, grade 3 or 4.

Nephritis, severe (grade 3) or life-threatening (grade 4); also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Pneumonitis, severe (grade 3), life-threatening (grade 4), or moderate (grade 2) that recurs; also administer corticosteroids (prednisone 1 to 2 mg/kg/day [or equivalent] followed by a taper).

Reconstitution

Injection solution (100 mg/4 mL vial): Withdraw appropriate volume from vial and transfer to IV bag containing NS or D5W; final concentration should be between 1 to 10 mg/mL. Mix by gently inverting bag. Discard unused portion of the vial.

Lyophilized powder (50 mg vial): Reconstitute by adding 2.3 mL SWFI along the vial wall (do not add directly to lyophilized powder); resulting vial concentration is 25 mg/mL. Slowly swirl vial; do not shake. Allow up to 5 minutes for bubbles to dissipate. Reconstituted solution is a clear to slightly opalescent and colorless to slightly yellow solution; discard if visible particles present. Withdraw appropriate volume from vial and transfer to IV bag containing NS or D5W; final concentration should be between 1 to 10 mg/mL. Mix by gently inverting bag. Discard unused portion of the vial.

Administration

IV: Infuse over 30 minutes through a 0.2 to 5 micron sterile, nonpyrogenic, low-protein binding inline or add-on filter. Do not infuse other medications through the same infusion line.

Storage

Lyophilized powder (50 mg vial) and injection solution (100 mg/4 mL vial): Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); protect injection solution vials from light and do not shake or freeze. Reconstituted solutions and solutions diluted for infusion in NS or D5W may be stored at room temperature for up to 6 hours (infusion must be completed within 6 hours of reconstitution) or refrigerated at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. Do not freeze. If refrigerated, allow to reach room temperature prior to administration.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

Incidence of adverse reactions include unapproved dosing regimens.

>10%:

Cardiovascular: Peripheral edema (10%)

Central nervous system: Fatigue (43% to ≤44%)

Dermatologic: Pruritus (12% to 28%), skin rash (18% to 24%; immune-mediated <1%)

Endocrine & metabolic: Hyperglycemia (48% to 49%; grades 3/4: 3% to 6%), hyponatremia (37% to 38%), hypoalbuminemia (32% to 37%), hypertriglyceridemia (23% to 33%), decreased serum bicarbonate (22%), hypocalcemia (21%), hypercholesterolemia (20%)

Gastrointestinal: Decreased appetite (20% to 25%), nausea (18% to 22%), constipation (15% to 22%), diarrhea (15% to 20%), abdominal pain (13%), vomiting (12% to 13%)

Hematologic & oncologic: Anemia (12% to 44%; grades 3/4: ≤10%), lymphocytopenia (40%; grades 3/4: 9%)

Hepatic: Increased serum alkaline phosphatase (26%), increased serum AST (20% to 24%; grades 3/4: 1% to 2%), increased serum ALT (21%; grades 3/4: 2%)

Neuromuscular & skeletal: Weakness (10% to ≤44%), arthralgia (14% to 15%)

Respiratory: Cough (18% to 29%), dyspnea (23%)

Miscellaneous: Fever (12% to 14%)

1% to 10%:

Cardiovascular: Pulmonary embolism (≥2%)

Central nervous system: Peripheral neuropathy (2%)

Endocrine & metabolic: Hypothyroidism (immune-mediated; 7% to 8%), hyperthyroidism (immune-mediated; 2% to 3%; grade 2: <1%; grade 3: <1%)

Gastrointestinal: Colitis (immune-mediated; ≤2%; grade 2: <1%, grade 3: <1%)

Neuromuscular & skeletal: Back pain (10%)

Respiratory: Pneumonitis (2% to 4%; grade 2: ≤1%; grade 3: ≤1%; grade 4: <1%), pleural effusion (≥2%), pneumonia (≥2%)

<1% (Limited to important or life-threatening): Adrenocortical insufficiency (immune-mediated), antibody development, arthritis (immune-mediated), bullous pemphigoid (immune-mediated), diabetic ketoacidosis, exfoliative dermatitis (immune-mediated), Guillain-Barré syndrome (immune-mediated), hemolytic anemia (immune-mediated), hepatitis (including autoimmune hepatitis), hypophysitis, infusion-related reaction, interstitial nephritis (with renal failure), Lambert-Eaton syndrome (immune-mediated), myasthenia gravis (immune-mediated), myositis (immune-mediated), nephritis (autoimmune), optic neuritis (immune-mediated), pancreatitis (immune-mediated), partial epilepsy (immune-mediated; in a patient with inflammatory foci in brain parenchyma), rhabdomyolysis (immune-mediated), serum sickness (immune-mediated), severe dermatitis, type 1 diabetes mellitus, uveitis (immune-mediated), vasculitis (immune-mediated)

Warnings/Precautions

Concerns related to adverse effects:

• Diabetes mellitus: Type 1 diabetes mellitus has occurred (including diabetic ketoacidosis). Monitor closely for hyperglycemia and other signs/symptoms of diabetes. Insulin therapy may be required; if severe hyperglycemia is observed, administer antihyperglycemics and withhold pembrolizumab treatment until glucose control has been accomplished.

• Gastrointestinal toxicity: Immune-mediated colitis has occurred, including cases of grade 2 to 4 colitis. The median time to onset of colitis was 3.4 months (range: 10 days to ~10 months) and the median duration was 1.4 months (range: 1 day to ~7 months) in patients with melanoma. In patients with NSCLC, the median time to onset was 1.6 months (range: ~1 to ~2 months) and the median duration was 16 days (range: 1 to ~6 weeks). In some melanoma patients, colitis was managed with high-dose systemic corticosteroids for a median duration of 6 days (range: 1 day to 5.3 months), followed by a corticosteroid taper. Most patients with colitis experienced complete resolution. May require treatment interruption, systemic corticosteroid therapy, and/or permanent discontinuation. Monitor for signs and symptoms of colitis; administer systemic corticosteroids for grade 2 or higher colitis.

• Hepatotoxicity: Immune-mediated hepatitis occurred (grades 2 to 4 hepatitis). The median onset for hepatitis was 26 days (range: 8 days to 21.4 months); the median duration was 1.2 months (range: 8 days to 4.7 months). Hepatitis resolved in most patients. Administer corticosteroids (prednisone 0.5 to 1 mg/kg/day [or equivalent] for grade 2 hepatitis, and prednisone 1 to 2 mg/kg/day [or equivalent] for grade 3 or higher, each followed by a taper), and withhold or discontinue therapy based on the severity of liver enzyme elevations. The median duration of high-dose corticosteroid therapy was 5 days (range: 1 to 14 days) followed by a taper. Monitor for liver function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

• Hypophysitis: Immune-mediated hypophysitis occurred (grades 2, 3, and 4). In patients with melanoma, the median time to onset was 3.3 months (range: 1 days to 7.2 months) and the median duration was 2.7 months (range 12 days to 12.7 months). The time to onset in NSCLC (1 patient) was 3.7 months. Monitor for signs/symptoms of hypophysitis (eg, hypopituitarism, adrenal insufficiency). May require treatment interruption, systemic corticosteroids and hormone replacement therapy (as clinically indicated), and/or permanent discontinuation.

• Infusion-related reactions: Infusion-related reactions (including severe and life-threatening cases) have occurred. Monitor for signs/symptoms of a reaction (eg, rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever). Interrupt infusion and permanently discontinue for severe (grade 3) or life-threatening (grade 4) infusion-related reactions.

• Nephrotoxicity: Immune-mediated nephritis has occurred. The onset for autoimmune nephritis in melanoma patients was 5.1 months (range: 12 days to 12.8 months) and the median duration was 1.1 months (range: 3 days to 3.3 months). Grade 2 or higher nephritis should be managed with systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg/day [or equivalent], followed by a taper). The median duration of corticosteroid use was 15 days (range: 3 days to 1.6 months), followed by a taper. Nephritis resolved in some patients. Monitor for renal function changes. May require treatment interruption, systemic corticosteroids (for grade 2 or higher toxicity), and/or permanent discontinuation.

• Pulmonary toxicity: Immune-mediated pneumonitis has been observed, including fatal cases. For patients with melanoma, the median time to development was 4.3 months (range: ~2 days to ~19 months) and the median duration was 2.6 months (range: 2 days to ~15 months). Some patients required initial management with high-dose systemic corticosteroids, the median duration of initial corticosteroid therapy was 8 days (range: 1 to 34 days) followed by a corticosteroid taper. Pneumonitis completely resolved in nearly two-thirds of melanoma patients. For patients with NSCLC, the median time to development was 1.7 months (range: 4 days to ~13 months) and the median duration was 1.2 months (range: 5 days to ~12 months). Some NSCLC patients had complete resolution of pneumonitis. May require treatment interruption, corticosteroid therapy (prednisone 1 to 2 mg/kg /day [or equivalent] followed by a taper, for grade 2 or higher pneumonitis), and/or permanent discontinuation. Monitor for signs and symptoms of pneumonitis; if pneumonitis is suspected, evaluate with radiographic imaging and administer systemic corticosteroids for grade 2 or higher pneumonitis. For NSCLC, pneumonitis occurred more frequently in patients with a history of asthma, COPD, or prior thoracic radiation.

• Thyroid disorders: Immune-mediated hyperthyroidism and hypothyroidism have occurred. The median onset for hyperthyroidism was 1.4 to 1.8 months (range: 1 day to ~22 months), and the median duration was 1.7 to 4.5 months (range: 1 day to ~13 months). Hyperthyroidism resolved in over two-thirds of melanoma patients. Hypothyroidism occurred with a median onset of 3.3 to 4.2 months (range: 5 days to 19 months) and median duration of 5.4 to 5.84 months (range: 6 days to 24.3 months), and occurred in some patients with no prior history of thyroid disorders. Hypothyroidism was generally managed with long-term thyroid hormone replacement therapy, although some patients only required short-term replacement therapy. Hypothyroidism did not require systemic corticosteroid therapy or discontinuation. Thyroid disorders may occur at any point in pembrolizumab therapy. Monitor for changes in thyroid function (at baseline, periodically during treatment and as clinically indicated) and for signs/symptoms of thyroid disorders. Administer thionamides and beta-blockers for hyperthyroidism as appropriate; may require treatment interruption and/or permanent discontinuation. Isolated hypothyroidism may be managed with replacement therapy (without corticosteroids and treatment interruption).

• Other immune-mediated toxicities: Other clinically relevant immune-mediated disorders have been observed, including rash, exfoliative dermatitis, bullous pemphigoid, uveitis, arthritis, vasculitis, myositis, Guillain-Barré syndrome, pancreatitis, hemolytic anemia, serum sickness, myasthenia gravis, and partial seizures (in a patient with inflammatory foci in brain parenchyma). If an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes; withhold treatment and administer systemic corticosteroids based on severity of reaction. Upon resolution to grade 0 or 1, initiate corticosteroid taper (continue tapering over at least 1 month). When reaction remains at grade 1 or less during taper may reinitiate pembrolizumab. Immune-mediated adverse reactions that do not resolve with systemic corticosteroids may be managed with other systemic immunosuppressants (based on limited data). Discontinue permanently for severe or grade 3 immune-mediated adverse event that is recurrent or life-threatening.

Monitoring Parameters

PD-L1 expression status in patients with NSCLC; liver function tests (AST, ALT, and total bilirubin); renal function; thyroid function (at baseline, periodically during treatment and as clinically indicated); glucose; signs/symptoms of colitis, hypophysitis, thyroid disorders, pneumonitis, infusion reactions.

Pregnancy Considerations

Animal reproduction studies have not been conducted. Immunoglobulins are known to cross the placenta; therefore fetal exposure to pembrolizumab is expected. Based on the mechanism of action, pembrolizumab may cause fetal harm if administered during pregnancy; an alteration in the immune response or immune mediated disorders may develop following in utero exposure. Women of reproductive potential should use highly effective contraception during therapy and for at least 4 months after treatment is complete.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, lack of appetite, constipation, diarrhea, abdominal pain, headache, back pain, rhinitis, pharyngitis, or insomnia. Have patient report immediately to prescriber signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of thyroid problems (change in weight without trying, feeling nervous and excitable, feeling restless, feeling very weak, hair thinning, low mood (depression), neck swelling, not able to focus, not able to handle heat or cold, period (menstrual) changes, shakiness, or sweating), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; or diarrhea), angina, tachycardia, shortness of breath, cough, wheezing, bruising, bleeding, vision changes, severe joint pain, severe muscle pain, severe muscle weakness, severe loss of strength and energy, passing out, severe dizziness, swelling of arms or legs, chills, flushing, or sweating a lot (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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