Keytruda

Name: Keytruda

How is pembrolizumab given?

Before you start treatment, your doctor will perform tests to make sure pembrolizumab is the best treatment for your type of cancer.

Pembrolizumab is injected into a vein through an IV. A healthcare provider will give you this injection.

Pembrolizumab is usually given once every 3 weeks. Your doctor will determine how long to treat you with this medicine. Follow your doctor's dosing instructions.

Pembrolizumab can cause certain side effects by changing the way your immune system works. These side effects can cause symptoms in many different parts of your body. Some side effects may need to be treated with other medicine, and your cancer treatments may be delayed or stopped altogether.

You will need frequent medical tests to help your doctor determine if it is safe for you to keep receiving pembrolizumab. Do not miss any follow-up visits to your doctor.

Introduction

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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.)

Before Using Keytruda

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of pembrolizumab injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of pembrolizumab injection in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Pneumonitis (inflammation of the lungs) or
  • Colitis (inflammation of the intestine) or
  • Diabetic ketoacidosis or
  • Hepatitis (inflammation of the liver) or
  • Hyperthyroidism (high levels of thyroid hormone) or
  • Hypophysitis (inflammation of the pituitary gland) or
  • Hypothyroidism (low levels of thyroid hormone) or
  • Nephritis (inflammation of the kidneys) or
  • Type 1 diabetes—Use with caution. May make these conditions worse.

Proper Use of Keytruda

A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins. It must be given slowly, so the needle will remain in place for 30 minutes and the infusion will be given every 3 weeks.

This medicine comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.

How is this medicine (Keytruda) best taken?

Use Keytruda as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

  • Call your doctor to find out what to do.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • Immune-mediated pneumonitis [see Warnings and Precautions (5.1)].
  • Immune-mediated colitis [see Warnings and Precautions (5.2)].
  • Immune-mediated hepatitis [see Warnings and Precautions (5.3)].
  • Immune-mediated endocrinopathies [see Warnings and Precautions (5.4)].
  • Immune-mediated nephritis and renal dysfunction [see Warnings and Precautions (5.5)].
  • Immune-mediated skin adverse reactions [see Warnings and Precautions (5.6)].
  • Other immune-mediated adverse reactions [see Warnings and Precautions (5.7)].
  • Infusion-related reactions [see Warnings and Precautions (5.8)].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to Keytruda in 2799 patients in three randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010), which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial (KEYNOTE-001) which enrolled 655 patients with melanoma and 550 patients with NSCLC. In addition, these data reflect exposure to Keytruda in a non-randomized, open-label, multi-cohort trial (KEYNOTE-012) which enrolled 192 patients with HNSCC and 241 cHL patients in two non-randomized, open-label trials (KEYNOTE-013 and KEYNOTE-087). Across all studies, Keytruda was administered at doses of 2 mg/kg intravenously every 3 weeks, 10 mg/kg intravenously every 2 weeks, 10 mg/kg intravenously every 3 weeks, or 200 mg intravenously every 3 weeks. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more.

The data described in this section were obtained in five randomized, open-label, active-controlled clinical trials (KEYNOTE-002, KEYNOTE-006, KEYNOTE-010, KEYNOTE-021, and KEYNOTE-045) in which Keytruda was administered to 912 patients with melanoma, 741 patients with NSCLC, and 542 patients with urothelial carcinoma, and three non-randomized, open-label trials (KEYNOTE-012, KEYNOTE-087, and KEYNOTE-052) in which Keytruda was administered to 192 patients with HNSCC, 210 patients with cHL, and 370 patients with urothelial carcinoma. In these trials, Keytruda was administered at 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks.

Melanoma

Ipilimumab-Naive Melanoma

The safety of Keytruda for the treatment of patients with unresectable or metastatic melanoma who had not received prior ipilimumab and who had received no more than one prior systemic therapy was investigated in Study KEYNOTE-006. KEYNOTE-006 was a multicenter, open-label, active-controlled trial where patients were randomized (1:1:1) and received Keytruda 10 mg/kg every 2 weeks (n=278) or Keytruda 10 mg/kg every 3 weeks (n=277) until disease progression or unacceptable toxicity or ipilimumab 3 mg/kg every 3 weeks for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity (n=256) [see Clinical Studies (14.1)]. Patients with autoimmune disease, a medical condition that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or active infection requiring therapy, including HIV or hepatitis B or C, were ineligible.

The median duration of exposure was 5.6 months (range: 1 day to 11.0 months) for Keytruda and similar in both treatment arms. Fifty-one and 46% of patients received Keytruda 10 mg/kg every 2 or 3 weeks, respectively, for ≥6 months. No patients in either arm received treatment for more than one year.

The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 32% had an elevated lactate dehydrogenase (LDH) value at baseline, 65% had M1c stage disease, 9% with history of brain metastasis, and approximately 36% had been previously treated with systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In KEYNOTE-006, the adverse reaction profile was similar for the every 2 week and every 3 week schedule, therefore summary safety results are provided in a pooled analysis (n=555) of both Keytruda arms. Adverse reactions leading to permanent discontinuation of Keytruda occurred in 9% of patients. Adverse reactions leading to discontinuation of Keytruda in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of Keytruda occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions (reported in at least 20% of patients) were fatigue and diarrhea. Table 1 and Table 2 summarize the incidence of selected adverse reactions and laboratory abnormalities that occurred in patients receiving Keytruda.

Table 1: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-006
Keytruda
10 mg/kg every 2 or 3 weeks
Ipilimumab
n=555 n=256
Adverse Reaction All Grades†
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
* Adverse reactions occurring at same or higher incidence than in the ipilimumab arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, and exfoliative rash. § Includes skin hypopigmentation
General Disorders and Administration Site Conditions
  Fatigue 28 0.9 28 3.1
Skin and Subcutaneous Tissue Disorders
  Rash‡ 24 0.2 23 1.2
  Vitiligo§ 13 0 2 0
Musculoskeletal and Connective Tissue Disorders
  Arthralgia 18 0.4 10 1.2
  Back pain 12 0.9 7 0.8
Respiratory, Thoracic and Mediastinal Disorders
  Cough 17 0 7 0.4
  Dyspnea 11 0.9 7 0.8
Metabolism and Nutrition Disorders
  Decreased appetite 16 0.5 14 0.8
Nervous System Disorders
  Headache 14 0.2 14 0.8

Other clinically important adverse reactions occurring in ≥10% of patients receiving Keytruda were diarrhea (26%), nausea (21%), and pruritus (17%).

Table 2: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Keytruda in KEYNOTE-006
Keytruda
10 mg/kg every 2 or 3 weeks
Ipilimumab
Laboratory Test† All Grades‡
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
* Laboratory abnormalities occurring at same or higher incidence than in ipilimumab arm † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (520 to 546 patients) and ipilimumab (237 to 247 patients); hypertriglyceridemia: Keytruda n=429 and ipilimumab n=183; hypercholesterolemia: Keytruda n=484 and ipilimumab n=205. ‡ Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 45 4.2 45 3.8
  Hypertriglyceridemia 43 2.6 31 1.1
  Hyponatremia 28 4.6 26 7
  Increased AST 27 2.6 25 2.5
  Hypercholesterolemia 20 1.2 13 0
Hematology
  Anemia 35 3.8 33 4.0
  Lymphopenia 33 7 25 6

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were increased hypoalbuminemia (27% all Grades; 2.4% Grades 3-4), increased ALT (23% all Grades; 3.1% Grades 3-4), and increased alkaline phosphatase (21% all Grades, 2.0% Grades 3-4).

Ipilimumab-Refractory Melanoma

The safety of Keytruda in patients with unresectable or metastatic melanoma with disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, was evaluated in Study KEYNOTE-002. KEYNOTE-002 was a multicenter, partially blinded (Keytruda dose), randomized (1:1:1), active-controlled trial in which 528 patients received Keytruda 2 mg/kg (n=178) or 10 mg/kg (n=179) every 3 weeks or investigator's choice of chemotherapy (n=171), consisting of dacarbazine (26%), temozolomide (25%), paclitaxel and carboplatin (25%), paclitaxel (16%), or carboplatin (8%) [see Clinical Studies (14.1)]. The trial excluded patients with autoimmune disease, severe immune-related toxicity related to ipilimumab, defined as any Grade 4 toxicity or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks; medical conditions that required systemic corticosteroids or other immunosuppressive medication; a history of interstitial lung disease; or an active infection requiring therapy, including HIV or hepatitis B or C.

The median duration of exposure to Keytruda 2 mg/kg every 3 weeks was 3.7 months (range: 1 day to 16.6 months) and to Keytruda 10 mg/kg every 3 weeks was 4.8 months (range: 1 day to 16.8 months). The data described below reflect exposure to Keytruda 2 mg/kg in 36% of patients exposed to Keytruda for ≥6 months and in 4% of patients exposed for ≥12 months. In the Keytruda 10 mg/kg arm, 41% of patients were exposed to Keytruda for ≥6 months and 6% of patients were exposed to Keytruda for ≥12 months.

The study population characteristics were: median age of 62 years (range: 15 to 89 years), 61% male, 98% White, 41% with an elevated LDH value at baseline, 83% with M1c stage disease, 73% received two or more prior therapies for advanced or metastatic disease (100% received ipilimumab and 25% a BRAF inhibitor), and 15% with history of brain metastasis.

In KEYNOTE-002, the adverse reaction profile was similar for the 2 mg/kg dose and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=357) of both Keytruda arms. Adverse reactions resulting in permanent discontinuation occurred in 12% of patients receiving Keytruda; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of Keytruda occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions (reported in at least 20% of patients) of Keytruda were fatigue, pruritus, rash, constipation, nausea, diarrhea, and decreased appetite.

Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda.

Table 3: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-002
Keytruda
2 mg/kg or 10 mg/kg every 3 weeks
Chemotherapy†
n=357 n=171
Adverse Reaction All Grades‡
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
* Adverse reactions occurring at same or higher incidence than in chemotherapy arm † Chemotherapy: dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin ‡ Graded per NCI CTCAE v4.0 § Includes rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, and rash pruritic
General Disorders and Administration Site Conditions
  Pyrexia 14 0.3 9 0.6
  Asthenia 10 2.0 9 1.8
Skin and Subcutaneous Tissue Disorders
  Pruritus 28 0 8 0
  Rash§ 24 0.6 8 0
Gastrointestinal Disorders
  Constipation 22 0.3 20 2.3
  Diarrhea 20 0.8 20 2.3
  Abdominal pain 13 1.7 8 1.2
Respiratory, Thoracic and Mediastinal Disorders
  Cough 18 0 16 0
Musculoskeletal and Connective Tissue Disorders
  Arthralgia 14 0.6 10 1.2

Other clinically important adverse reactions occurring in patients receiving Keytruda were fatigue (43%), nausea (22%), decreased appetite (20%), vomiting (13%), and peripheral neuropathy (1.7%).

Table 4: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Melanoma Patients Receiving Keytruda in KEYNOTE-002
Keytruda
2 mg/kg or 10 mg/kg every 3 weeks
Chemotherapy
Laboratory Test† All Grades‡
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
* Laboratory abnormalities occurring at same or higher incidence than in chemotherapy arm. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 320 to 325 patients) and chemotherapy (range: 154 to 161 patients); hypertriglyceridemia: Keytruda n=247 and chemotherapy n=116; bicarbonate decreased: Keytruda n=263 and chemotherapy n=123. ‡ Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 49 6 44 6
  Hypoalbuminemia 37 1.9 33 0.6
  Hyponatremia 37 7 24 3.8
  Hypertriglyceridemia 33 0 32 0.9
  Increased Alkaline Phosphatase 26 3.1 18 1.9
  Increased AST 24 2.2 16 0.6
  Bicarbonate Decreased 22 0.4 13 0
  Hypocalcemia 21 0.3 18 1.9
  Increased ALT 21 1.8 16 0.6

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were anemia (44% all Grades; 10% Grades 3-4) and lymphopenia (40% all Grades; 9% Grades 3-4).

NSCLC

Previously Treated NSCLC

The safety of Keytruda was investigated in Study KEYNOTE-010, a multicenter, open-label, randomized (1:1:1), active-controlled trial, in patients with advanced NSCLC who had documented disease progression following treatment with platinum-based chemotherapy and, if positive for EGFR or ALK genetic aberrations, appropriate therapy for these aberrations. A total of 991 patients received Keytruda 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or docetaxel (n=309) at 75 mg/m2 every 3 weeks. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible.

The median duration of exposure to Keytruda 2 mg/kg every 3 weeks was 3.5 months (range: 1 day to 22.4 months) and to Keytruda 10 mg/kg every 3 weeks was 3.5 months (range 1 day to 20.8 months). The data described below reflect exposure to Keytruda 2 mg/kg in 31% of patients exposed to Keytruda for ≥6 months. In the Keytruda 10 mg/kg arm, 34% of patients were exposed to Keytruda for ≥6 months.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 years or older, 61% male, 72% white and 21% Asian, 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease.

In KEYNOTE-010, the adverse reaction profile was similar for the 2 mg/kg and 10 mg/kg dose, therefore summary safety results are provided in a pooled analysis (n=682). Treatment was discontinued for adverse reactions in 8% of patients receiving Keytruda. The most common adverse events resulting in permanent discontinuation of Keytruda was pneumonitis (1.8%). Adverse reactions leading to interruption of Keytruda occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%).

Table 5 summarizes the adverse reactions that occurred in at least 10% of patients treated with Keytruda.

Table 5: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-010
Keytruda
2 or 10 mg/kg every 3 weeks
n=682
Docetaxel
75 mg/m2 every 3 weeks
n=309
Adverse Reaction All Grades†
(%)
Grade 3-4
(%)
All Grades†
(%)
Grade 3-4
(%)
* Adverse reactions occurring at same or higher incidence than in docetaxel arm † Graded per NCI CTCAE v4.0 ‡ Includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic
Metabolism and Nutrition Disorders
  Decreased appetite 25 1.5 23 2.6
Gastrointestinal Disorders
  Nausea 20 1.3 18 0.6
  Constipation 15 0.6 12 0.6
  Vomiting 13 0.9 10 0.6
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 23 3.7 20 2.6
  Cough 19 0.6 14 0
Musculoskeletal and Connective Tissue Disorders
  Arthralgia 11 1.0 9 0.3
  Back pain 11 1.5 8 0.3
Skin and Subcutaneous Tissue Disorders
  Rash‡ 17 0.4 8 0
  Pruritus 11 0 3 0.3

Other clinically important adverse reactions occurring in patients receiving Keytruda were fatigue (25%), diarrhea (14%), asthenia (11%) and pyrexia (11%).

Table 6: Selected* Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of NSCLC Patients Receiving Keytruda in KEYNOTE-010
Keytruda
2 or 10 mg/kg every 3 weeks
Docetaxel
75 mg/m2 every 3 weeks
Laboratory Test† All Grades‡
%
Grades 3-4
%
All Grades‡
%
Grades 3-4
%
* Laboratory abnormalities occurring at same or higher incidence than in docetaxel arm. † Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 631 to 638 patients) and docetaxel (range: 274 to 277 patients). ‡ Graded per NCI CTCAE v4.0
Chemistry
  Hyponatremia 32 8 27 2.9
  Alkaline phosphatase increased 28 3.0 16 0.7
  Aspartate aminotransferase increased 26 1.6 12 0.7
  Alanine aminotransferase increased 22 2.7 9 0.4

Other laboratory abnormalities occurring in ≥20% of patients receiving Keytruda were hyperglycemia (44% all Grades; 4.1% Grades 3-4), anemia (37% all Grades; 3.8% Grades 3-4), hypertriglyceridemia (36% all Grades; 1.8% Grades 3-4), lymphopenia (35% all Grades; 9% Grades 3-4), hypoalbuminemia (34% all Grades; 1.6% Grades 3-4), and hypercholesterolemia (20% all Grades; 0.7% Grades 3-4).

Previously Untreated Nonsquamous NSCLC, in Combination with Chemotherapy

The safety of Keytruda in combination with pemetrexed and carboplatin was investigated in a randomized (1:1) open-label cohort in Study KEYNOTE-021. Patients with previously untreated, metastatic nonsquamous NSCLC received Keytruda 200 mg with pemetrexed and carboplatin (n=59), or pemetrexed and carboplatin alone (n=62). Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14.2)].

The median duration of exposure to Keytruda was 8 months (range: 1 day to 16 months). Sixty-eight percent of patients in the Keytruda arm were exposed to Keytruda 200 mg for ≥6 months. The study population characteristics were: median age of 64 years (range: 37 to 80), 48% age 65 years or older, 39% male, 87% White and 8% Asian, 97% with metastatic disease, and 12% with brain metastases.

Keytruda was discontinued for adverse reactions in 10% of patients. The most common adverse reaction resulting in discontinuation of Keytruda (≥ 2%) was acute kidney injury (3.4%). Adverse reactions leading to interruption of Keytruda occurred in 39% of patients; the most common (≥ 2%) were fatigue (8%), neutrophil count decreased (8%), anemia (5%), dyspnea (3.4%), and pneumonitis (3.4%).

Table 7 summarizes the adverse reactions that occurred in at least 20% of patients treated with Keytruda. KEYNOTE-021 was not designed to demonstrate a statistically significant difference in adverse reaction rates for pembrolizumab plus chemotherapy, as compared to chemotherapy alone, for any specified adverse reaction listed in Table 7.

Table 7: Adverse Reactions Occurring in ≥20% of Patients in KEYNOTE-021
Keytruda Pemetrexed Carboplatin
n=59
Pemetrexed Carboplatin
n=62
Adverse Reaction All Grades*
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
* Graded per NCI CTCAE v4.0 † Includes rash, rash generalized, rash macular, rash maculo-papular, and rash pruritic.
General Disorders and Administration Site Conditions
  Fatigue 71 3.4 50 0
  Peripheral Edema 22 0 18 0
Gastrointestinal Disorders
  Nausea 68 1.7 56 0
  Constipation 51 0 37 1.6
  Vomiting 39 1.7 27 0
  Diarrhea 37 1.7 23 1.6
Skin and Subcutaneous Tissue Disorders
  Rash† 42 1.7 21 1.6
  Pruritus 24 0 4.8 0
  Alopecia 20 0 3.2 0
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnea 39 3.4 21 0
  Cough 24 0 18 0
Metabolism and Nutrition Disorders
  Decreased Appetite 31 0 23 0
Nervous System Disorders
  Headache 31 0 16 1.6
  Dizziness 24 0 16 0
  Dysgeusia 20 0 11 0
Psychiatric Disorders
  Insomnia 24 0 15 0
Infections and Infestations
  Upper respiratory tract infection 20 0 3.2 0
Musculoskeletal and Connective Tissue Disorders
  Arthralgia 15 0 24 1.6
Table 8: Laboratory Abnormalities Worsened from Baseline in ≥20% of Patients in KEYNOTE-021
Keytruda Pemetrexed Carboplatin Pemetrexed Carboplatin
Laboratory Test* All Grades†
%
Grades 3-4
%
All Grades
%
Grades 3-4
%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda pemetrexed carboplatin (range: 56 to 58 patients) and pemetrexed carboplatin (range: 55 to 61 patients). † Graded per NCI CTCAE v4.0
Chemistry
  Hyperglycemia 74 9 61 5
  Lymphocytes decreased 53 23 60 28
  Aspartate aminotransferase increased 51 3.5 46 1.7
  Hypertriglyceridemia 50 0 43 0
  Alanine aminotransferase increased 40 3.5 32 1.7
  Creatinine increased 34 3.4 19 1.7
  Hyponatremia 33 5 35 3.5
  Hypoalbuminemia 32 0 31 0
  Hypocalcemia 30 5 19 1.7
  Hypokalemia 29 5 22 1.7
  Hypophosphatemia 29 5 24 11
  Alkaline phosphatase increased 28 0 9 0
Hematology
  Hemoglobin decreased 83 17 84 19
  Neutrophils decreased 47 14 43 8
  Platelets decreased 24 9 36 10

HNSCC

Among the 192 patients with HNSCC enrolled in Study KEYNOTE-012, the median duration of exposure to Keytruda was 3.3 months (range: 1 day to 27.9 months). Patients with autoimmune disease or a medical condition that required immunosuppression were ineligible for KEYNOTE-012. The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. Baseline ECOG PS was 0 (30%) or 1 (70%) and 86% had M1 disease.

Keytruda was discontinued due to adverse reactions in 17% of patients. Serious adverse reactions occurred in 45% of patients receiving Keytruda. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); these data were pooled. The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3-4) and new or worsening hypothyroidism [see Warnings and Precautions (5.4)].

cHL

Among the 210 patients with cHL enrolled in Study KEYNOTE-087 [see Clinical Studies (14.4)], the median duration of exposure to Keytruda was 8.4 months (range: 1 day to 15.2 months). Keytruda was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. Serious adverse reactions occurred in 16% of patients. The most frequent serious adverse reactions (≥1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Two patients died from causes other than disease progression; one from GVHD after subsequent allogeneic HSCT and one from septic shock.

Table 9 summarizes the adverse reactions that occurred in at least 10% of patients treated with Keytruda.

Table 9: Adverse Reactions in ≥10% of Patients with cHL in KEYNOTE-087
Keytruda
200 mg every 3 weeks
N=210
Adverse Reaction All Grades*
(%)
Grade 3
(%)
* Graded per NCI CTCAE v4.0 † Includes fatigue, asthenia ‡ Includes cough, productive cough § Includes dyspnea, dyspnea exertional, wheezing ¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain # Includes diarrhea, gastroenteritis, colitis, enterocolitis Þ Includes rash, rash maculo-papular, drug eruption, eczema, eczema asteatotic, dermatitis, dermatitis acneiform, dermatitis contact, rash erythematous, rash macular, rash papular, rash pruritic, seborrhoeic dermatitis, dermatitis psoriasiform ß Includes neuropathy peripheral, peripheral sensory neuropathy, hypoesthesia, paresthesia, dysesthesia, polyneuropathy
General Disorders and Administration Site Conditions
  Fatigue† 26 1.0
  Pyrexia 24 1.0
Respiratory, Thoracic and Mediastinal Disorders
  Cough‡ 24 0.5
  Dyspnea§ 11 1.0
Musculoskeletal and Connective Tissue Disorders
  Musculoskeletal pain¶ 21 1.0
  Arthralgia 10 0.5
Gastrointestinal Disorders
  Diarrhea# 20 1.4
  Vomiting 15 0
  Nausea 13 0
Skin and Subcutaneous Tissue Disorders
  Rash Þ 20 0.5
  Pruritus 11 0
Endocrine Disorders
  Hypothyroidism 14 0.5
Infections and Infestations
  Upper respiratory tract infection 13 0
Nervous System Disorders
  Headache 11 0.5
  Peripheral neuropathyß 10 0

Other clinically important adverse reactions that occurred in less than 10% of patients on KEYNOTE-087 included infusion reactions (9%), hyperthyroidism (3%), pneumonitis (3%), uveitis and myositis (1% each), myelitis and myocarditis (0.5% each).

Table 10: Selected Laboratory Abnormalities Worsened from Baseline Occurring in ≥15% of cHL Patients Receiving Keytruda in KEYNOTE-087
Keytruda
200 mg every 3 weeks
Laboratory Test* All Grades†
(%)
Grade 3-4
(%)
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 208 to 209 patients) † Graded per NCI CTCAE v4.0 ‡ Includes elevation of AST or ALT
Chemistry
  Hypertransaminasemia‡ 34% 2%
  Alkaline phosphatase increased 17% 0%
  Creatinine increased 15% 0.5%
Hematology
  Anemia 30% 6%
  Thrombocytopenia 27% 4%
  Neutropenia 24% 7%

Hyperbilirubinemia occurred in less than 15% of patients on KEYNOTE-087 (10% all Grades, 2.4% Grade 3-4).

Urothelial Carcinoma

Cisplatin Ineligible Patients with Urothelial Carcinoma

The safety of Keytruda was investigated in Study KEYNOTE-052, a single-arm trial that enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were not eligible for cisplatin-containing chemotherapy. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible. Patients received Keytruda 200 mg every 3 weeks until unacceptable toxicity or either radiographic or clinical disease progression. The median duration of exposure to Keytruda was 2.8 months (range: 1 day to 15.8 months).

The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, decreased appetite, constipation, rash and diarrhea. Keytruda was discontinued due to adverse reactions in 11% of patients. Eighteen patients (5%) died from causes other than disease progression. Five patients (1.4%) who were treated with Keytruda experienced sepsis which led to death, and three patients (0.8%) experienced pneumonia which led to death. Adverse reactions leading to interruption of Keytruda occurred in 22% of patients; the most common (≥1%) were liver enzyme increase, diarrhea, urinary tract infection, acute kidney injury, fatigue, joint pain, and pneumonia. Serious adverse reactions occurred in 42% of patients. The most frequent serious adverse reactions (≥2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis.

Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose ≥ 40 mg oral prednisone equivalent.

Table 11 summarizes the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda.

Table 11: Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-052
Keytruda
200 mg every 3 weeks
N=370
Adverse Reaction All Grades*
(%)
Grades 3 – 4
(%)
* Graded per NCI CTCAE v4.0 † Includes diarrhea, colitis, enterocolitis, gastroenteritis, frequent bowel movements ‡ Includes abdominal pain, pelvic pain, flank pain, abdominal pain lower, tumor pain, bladder pain, hepatic pain, suprapubic pain, abdominal discomfort, abdominal pain upper § Includes autoimmune hepatitis, hepatitis, hepatitis toxic, liver injury, transaminases increased, hyperbilirubinemia, blood bilirubin increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased, liver function tests increased ¶ Includes fatigue, asthenia # Includes back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, myalgia, neck pain, pain in extremity, spinal pain Þ Includes dermatitis, dermatitis bullous, eczema, erythema, rash, rash macular, rash maculo-papular, rash pruritic, rash pustular, skin reaction, dermatitis acneform, seborrheic dermatitis, palmar-plantar erythrodysesthesia syndrome, rash generalized
All Adverse Reactions 96 49
Blood and Lymphatic System Disorders
Anemia 17 7
Gastrointestinal Disorders
Constipation 21 1.1
Diarrhea† 20 2.4
Nausea 18 1.1
Abdominal pain‡ 18 2.7
Elevated LFTs§ 13 3.5
Vomiting 12 0
General Disorders and Administration Site Conditions
Fatigue¶ 38 6
Pyrexia 11 0.5
Weight decreased 10 0
Infections and Infestations
Urinary tract infection 19 9
Metabolism and Nutrition Disorders
Decreased appetite 22 1.6
Hyponatremia 10 4.1
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain# 24 4.9
Arthralgia 10 1.1
Renal and Urinary Disorders
Blood creatinine increased 11 1.1
Hematuria 13 3.0
Respiratory, Thoracic, and Mediastinal Disorders
Cough 14 0
Dyspnea 11 0.5
Skin and Subcutaneous Tissue Disorders
RashÞ 21 0.5
Pruritis 19 0.3
Edema peripheral 14 1.1

Previously Treated Urothelial Carcinoma

The safety of Keytruda for the treatment of patients with locally advanced or metastatic urothelial carcinoma with disease progression following platinum-containing chemotherapy was investigated in Study KEYNOTE-045. KEYNOTE-045 was a multicenter, open-label, randomized (1:1), active-controlled trial in which 266 patients received Keytruda 200 mg every 3 weeks or investigator's choice of chemotherapy (n=255), consisting of paclitaxel (n=84), docetaxel (n=84) or vinflunine (n=87) [see Clinical Studies (14.5)]. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. The median duration of exposure was 3.5 months (range: 1 day to 20 months) in patients who received Keytruda and 1.5 months (range: 1 day to 14 months) in patients who received chemotherapy.

Keytruda was discontinued due to adverse reactions in 8% of patients. The most common adverse reaction resulting in permanent discontinuation of Keytruda was pneumonitis (1.9%). Adverse reactions leading to interruption of Keytruda occurred in 20% of patients; the most common (≥1%) were urinary tract infection (1.5%), diarrhea (1.5%), and colitis (1.1%). The most common adverse reactions (occurring in at least 20% of patients who received Keytruda) were fatigue, musculoskeletal pain, pruritus, decreased appetite, nausea and rash. Serious adverse reactions occurred in 39% of Keytruda-treated patients. The most frequent serious adverse reactions (≥2%) in Keytruda-treated patients were urinary tract infection, pneumonia, anemia, and pneumonitis.

Table 12 summarizes the incidence of adverse reactions occurring in at least 10% of patients receiving Keytruda. Table 13 summarizes the incidence of laboratory abnormalities that occurred in at least 20% of patients receiving Keytruda.

Table 12: Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda in KEYNOTE-045
Keytruda
200 mg every 3 weeks
Chemotherapy*
n=266 n=255
Adverse Reaction All Grades†
(%)
Grade 3-4
(%)
All Grades†
(%)
Grade 3-4
(%)
* Chemotherapy: paclitaxel, docetaxel, or vinflunine † Graded per NCI CTCAE v4.0 ‡ Includes diarrhea, gastroenteritis, colitis, enterocolitis § Includes asthenia, fatigue, malaise lethargy ¶ Includes back pain, myalgia, bone pain, musculoskeletal pain, pain in extremity, musculoskeletal chest pain, musculoskeletal discomfort, neck pain # Includes blood urine present, hematuria, chromaturia Þ Includes cough, productive cough ß Includes dyspnea, dyspnea exertional, wheezing à Includes rash maculo-papular, rash genital rash, rash erythematous, rash papular, rash pruritic, rash pustular, erythema, drug eruption, eczema, eczema asteatotic, dermatitis contact, dermatitis acneiform, dermatitis, seborrhoeic keratosis, lichenoid keratosis
Gastrointestinal Disorders
  Nausea 21 1.1 29 1.6
  Constipation 19 1.1 32 3.1
  Diarrhea‡ 18 2.3 19 1.6
  Vomiting 15 0.4 13 0.4
  Abdominal pain 13 1.1 13 2.7
General Disorders and Administration Site Conditions
  Fatigue§ 38 4.5 56 11
  Pyrexia 14 0.8 13 1.2
Infections and Infestations
  Urinary tract infection 15 4.9 14 4.3
Metabolism and Nutrition Disorders
  Decreased appetite 21 3.8 21 1.2
Musculoskeletal and Connective Tissue Disorders
  Musculoskeletal pain¶ 32 3.0 27 2.0
Renal and Urinary Disorders
  Hematuria# 12 2.3 8 1.6
Respiratory, Thoracic and Mediastinal Disorders
  CoughÞ 15 0.4 9 0
  Dyspneaß 14 1.9 12 1.2
Skin and Subcutaneous Tissue Disorders
  Pruritus 23 0 6 0.4
  Rashà 20 0.4 13 0.4
Table 13: Laboratory Abnormalities Worsened from Baseline Occurring in ≥20% of Urothelial Carcinoma Patients Receiving Keytruda in KEYNOTE-045
Keytruda
200 mg every 3 weeks
Chemotherapy
Laboratory Test* All Grades†
%
Grades 3-4
%
All Grades†
%
Grades 3-4
%
* Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: Keytruda (range: 240 to 248 patients) and chemotherapy (range: 238 to 244 patients); phosphate decreased: Keytruda n=232 and chemotherapy n=222. † Graded per NCI CTCAE v4.0
Chemistry
  Glucose increased 52 8 60 7
  Hemoglobin decreased 52 13 68 18
  Lymphocytes decreased 45 15 53 25
  Albumin decreased 43 1.7 50 3.8
  Sodium decreased 37 9 47 13
  Alkaline phosphatase increased 37 7 33 4.9
  Creatinine increased 35 4.4 28 2.9
  Phosphate decreased 29 8 34 14
  Aspartate aminotransferase increased 28 4.1 20 2.5
  Potassium increased 28 0.8 27 6
  Calcium decreased 26 1.6 34 2.1

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. Trough levels of pembrolizumab interfere with the electrochemiluminescent (ECL) assay results; therefore, a subset analysis was performed in the patients with a concentration of pembrolizumab below the drug tolerance level of the anti-product antibody assay. In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 26 (2.0%) of 1289 evaluable patients tested positive for treatment-emergent anti-pembrolizumab antibodies. Among the 26 patients who tested positive for treatment emergent anti-pembrolizumab antibodies, only 4 patients were tested for neutralizing antibodies and one was positive. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Keytruda with the incidences of antibodies to other products may be misleading.

Use in specific populations

Pregnancy

Risk Summary

Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. In animal models, the PD-1/PD-L1 signaling pathway is important in the maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue [see Data]. 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. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to result in an increase in fetal loss; therefore, potential risks of administering Keytruda during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 knockout mice. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immune-mediated disorders or of altering the normal immune response.

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.

Females and Males of Reproductive Potential

Contraception

Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Keytruda and for at least 4 months following the final dose.

Pediatric Use

There is limited experience with Keytruda in pediatric patients. In a study, 40 pediatric patients (16 children ages 2 years to less than 12 years and 24 adolescents ages 12 years to 18 years) with advanced melanoma, lymphoma, or PD-L1 positive advanced, relapsed, or refractory solid tumors were administered Keytruda 2 mg/kg every 3 weeks. Patients received Keytruda for a median of 3 doses (range 1-17 doses), with 34 patients (85%) receiving Keytruda for 2 doses or more. The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks.

The safety profile in these pediatric patients was similar to that seen in adults treated with pembrolizumab; toxicities that occurred at a higher rate (≥15% difference) in pediatric patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%) and hyponatremia (18%).

Efficacy for pediatric patients with cHL or MSI-H cancers is extrapolated from the results in the respective adult populations [see Clinical Studies (14.4, 14.6)].

Geriatric Use

Of 3991 patients with melanoma, NSCLC, HNSCC, cHL or urothelial carcinoma who were treated with Keytruda in clinical studies, 46% were 65 years and over and 16% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Keytruda dosing information

Usual Adult Dose for Melanoma - Metastatic:

2 mg/kg IV infusion over 30 minutes

Duration of therapy: Administer every 3 weeks until disease progression or unacceptable toxicity.

Uses: Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and a BRAF inhibitor if BRAF V600 mutation positive.

Keytruda side effects

Get emergency medical help if you have any signs of an allergic reaction to Keytruda: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, light-headed, itchy, hot or cold, sweaty, tingly, feverish, or if you have trouble breathing.

Keytruda can change the way your immune system works, which may cause certain side effects that can lead to serious medical problems.

Call your doctor at once if you have:

  • new or worsening cough, chest pain, feeling short of breath;

  • pale skin, easy bruising or bleeding;

  • severe muscle weakness, severe or ongoing muscle aches, joint pain;

  • diarrhea or increased stools, severe stomach pain, stools that contain mucus, black/bloody or tarry stools;

  • low levels of sodium in the body - confusion, slurred speech, severe weakness, loss of coordination, feeling unsteady;

  • signs of a hormonal disorder - frequent or unusual headaches, vision problems, feeling light-headed or very tired, rapid heartbeats, mood or behavior changes, hoarse or deepened voice, increased hunger or thirst, increased urination, constipation, hair loss, sweating, feeling cold, weight gain, or weight loss;

  • symptoms of a kidney problem - urinating more or less than usual, pelvic pain, vomiting, swelling in your ankles or feet, pain or burning when you urinate, bloody or cloudy urine; or

  • liver problems - loss of appetite, right-sided stomach pain, easy bruising or bleeding, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Your cancer treatments may be delayed or permanently discontinued if you have certain side effects.

Common Keytruda side effects may include:

  • nausea, vomiting, stomach pain, loss of appetite, diarrhea, constipation;

  • low sodium levels, abnormal liver function tests;

  • itching or rash;

  • fever, cough, feeling short of breath;

  • pain in your muscles, bones, or joints; or

  • feeling tired.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

For Healthcare Professionals

Applies to pembrolizumab: intravenous powder for injection, intravenous solution

Cardiovascular

Very common (10% or more): Peripheral edema (up to 17%)[Ref]

Dermatologic

Very common (10% or more): Pruritus (up to 30%), rash (up to 29%), vitiligo (up to 11%)
Uncommon (0.1% to 1%): Exfoliative dermatitis[Ref]

Endocrine

Very common (10% or more): Hyperglycemia (up to 40%), hypertriglyceridemia (up to 25%)
Common (1% to 10%): Hypothyroidism, hyperthyroidism
Uncommon (0.1% to 1%): Hypophysitis, adrenal insufficiency[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 30%), constipation (up to 21%), diarrhea (up to 20%), vomiting (up to 16%), abdominal pain (up to 12%)
Common (1% to 10%): Colitis
Uncommon (0.1% to 1%): Pancreatitis[Ref]

Hematologic

Very common (10% or more): Anemia (up to 55%), immune-mediated hemolytic anemia[Ref]

Hepatic

Very common (10% or more): Hypoalbuminemia (up to 34%), increased aspartate aminotransferase (up to 24%)
Uncommon (0.1% to 1%): Hepatitis[Ref]

Metabolic

Very common (10% or more): Hyponatremia (up to 35%), decreased appetite (up to 26%), hypocalcemia (up to 24%)[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia (up to 20%), pain in extremity (up to 18%), myalgia (up to 14%), back pain (up to 12%)
Uncommon (0.1% to 1%): Arthritis, myositis, myasthenic syndrome, rhabdomyolysis[Ref]

Nervous system

Very common (10% or more): Headache (up to 16%), dizziness (up to 11%)
Uncommon (0.1% to 1%): Partial seizures[Ref]

Ocular

Uncommon (0.1% to 1%): Uveitis, optic neuritis[Ref]

Other

Very common (10% or more): Fatigue (up to 47%), chills (up to 14%), pyrexia (up to 11%), sepsis (up to 10%)[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 14%)[Ref]

Renal

Uncommon (0.1% to 1%): Nephritis, renal failure[Ref]

Respiratory

Very common (10% or more): Cough (up to 30%), dyspnea (up to 18%), upper respiratory tract infection (up to 11%)
Common (1% to 10%): Pneumonitis[Ref]

Some side effects of Keytruda may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Highlights for Keytruda

Keytruda is used to treat some cases of metastatic melanoma, metastatic non-small cell lung cancer, head and neck squamous cell carcinoma (HNSCC), or classical Hodgkin’s lymphoma (cHL).

Keytruda comes as a solution that a healthcare provider injects intravenously (into one of your veins).

Keytruda is a brand name for the drug pembrolizumab. It’s not available as a generic drug.

IMPORTANT INFORMATION
  • Lung problems See Details

  • Inflammation of the colon See Details

  • Liver problems See Details

  • Pituitary gland swelling See Details

What is Keytruda?

This drug is a prescription drug. It comes as an intravenous (IV) solution. A healthcare provider will inject it into one of your veins.

This drug is available as the brand-name drug Keytruda. It’s not available as a generic drug.

This drug may be used as part of a combination therapy. This means you may need to take it with other medications.

Why it's used

This drug is used to treat:

  • certain types of metastatic melanoma (skin cancer) or non-small cell lung cancer
  • recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in people whose cancer has progressed or who have received chemotherapy that contains platinum
  • classical Hodgkin’s lymphoma (cHL) in people who are refractory or who have relapsed after having three other types of treatment for cHL

How it works

This drug belongs to a class of drugs called monoclonal antibodies. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.

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Keytruda Side Effects

More common side effects

The more common side effects of Keytruda are slightly different depending on the type of cancer being treated.

  • When used for melanoma treatment, side effects of this drug can include:

    • tiredness
    • cough
    • nausea
    • itchiness
    • rash
    • decreased appetite
    • constipation
    • joint pain
    • diarrhea
  • When used for non-small cell lung cancer treatment, side effects of this drug can include:

    • tiredness
    • decreased appetite
    • trouble breathing
    • cough
  • The drug manufacturer does not list side effects for pembrolizumab when used to treat head and neck cancer. If you have questions about these side effects, ask your doctor.

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious side effects

Call your doctor right away if you have serious side effects. Call 9-1-1 if your symptoms feel life-threatening or if you think you’re having a medical emergency. Serious side effects and their symptoms can include the following:

  • Inflammation of your colon. Symptoms can include:

    • diarrhea
    • severe pain in your abdomen
  • Lung problems. Symptoms can include:

    • new or worsening cough
    • chest pain
    • shortness of breath
  • Pituitary gland swelling. Symptoms can include:

    • constant or unusual headaches
    • extreme weakness
    • dizziness or fainting
    • vision changes, such as trouble focusing, double vision, or vision loss
  • Liver problems. Symptoms can include:

    • yellowing of your skin or the whites of your eyes
    • severe nausea or vomiting
    • bruising or bleeding easily
  • Thyroid problems. Symptoms can include:

    • trouble sleeping
    • tiredness
    • anxiety
    • double vision
    • unexpected weight loss or weight gain
    • weakness
    • thinning hair or hair loss
    • dry or warm skin
  • Diabetes. Symptoms can include:

    • frequent urination, especially at night
    • extreme thirst
    • unexpected weight loss
    • increased hunger
    • blurry vision
    • extreme tiredness
  • Kidney problems. Symptoms can include:

    • pain in your lower abdomen
    • pain or burning sensation while urinating
    • frequent need to urinate
    • cloudy urine
    • blood or pus in your urine
    • swelling anywhere in your body
    • vomiting
    • fever
    • high blood pressure
Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this information includes all possible side effects. This information is not a substitute for medical advice. Always discuss possible side effects with a healthcare provider who knows your medical history.

How to Take Keytruda (Dosage)

Your doctor will determine a dosage of Keytruda that’s right for you based on your weight. Your general health may also affect your dosage. Tell your doctor about all health conditions you have before your healthcare provider administers the drug to you.

Disclaimer: Our goal is to provide you with the most relevant and current information. However, because drugs affect each person differently, we cannot guarantee that this list includes all possible dosages. This information is not a substitute for medical advice. Always to speak with your doctor or pharmacist about dosages that are right for you. Important considerations for taking this drug

How long does it take?

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Can I drive home after?

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Travel

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Clinical monitoring

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Insurance

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Show Sources

  • Keytruda (pembrolizumab) for injection, for intravenous use; Keytruda (pembrolizumab) injection, for intravenous use. (2017). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf

Content developed in collaboration with University of Illinois-Chicago, Drug Information Group

Medically reviewed by University of Illinois-Chicago, Drug Information Group on June 15, 2017

Disclaimer: Healthline has made every effort to make certain that all information is factually correct, comprehensive, and up-to-date. However, this article should not be used as a substitute for the knowledge and expertise of a licensed healthcare professional. You should always consult your doctor or other healthcare professional before taking any medication. The drug information contained herein is subject to change and is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. The absence of warnings or other information for a given drug does not indicate that the drug or drug combination is safe, effective, or appropriate for all patients or all specific uses.
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