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Keytruda

Generic Name: pembrolizumab
Dosage Form: injection, powder, lyophilized, for solution

Indications and Usage for Keytruda

Melanoma

Keytruda® (pembrolizumab) is indicated for the treatment of patients with unresectable or metastatic melanoma [see Clinical Studies (14.1)].

Non-Small Cell Lung Cancer

Keytruda is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations [see Clinical Studies (14.2)].

Keytruda is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Keytruda [see Clinical Studies (14.2)].

Head and Neck Cancer

Keytruda is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy [see Clinical Studies (14.3)].

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Keytruda Dosage and Administration

Patient Selection

Select patients for treatment of metastatic NSCLC with Keytruda based on the presence of positive PD-L1 expression [see Clinical Studies (14.2)]. Information on FDA-approved tests for the detection of PD-L1 expression in NSCLC is available at: http://www.fda.gov/CompanionDiagnostics.

Recommended Dosage for Melanoma

The recommended dose of Keytruda is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity [see Clinical Studies (14.1)].

Recommended Dosage for NSCLC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression [see Clinical Studies (14.2)].

Recommended Dosage for HNSCC

The recommended dose of Keytruda is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression [see Clinical Studies (14.3)].

Dose Modifications

Withhold Keytruda for any of the following:

Resume Keytruda in patients whose adverse reactions recover to Grade 0-1.

Permanently discontinue Keytruda for any of the following:

  • Any life-threatening adverse reaction (excluding endocrinopathies controlled with hormone replacement therapy)
  • Grade 3 or 4 pneumonitis or recurrent pneumonitis of Grade 2 severity [see Warnings and Precautions (5.1)]
  • Grade 3 or 4 nephritis [see Warnings and Precautions (5.5)]
  • AST or ALT greater than 5 times ULN or total bilirubin greater than 3 times ULN
    • For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week
  • Grade 3 or 4 infusion-related reactions [see Warnings and Precautions (5.7)]
  • Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks
  • Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last dose of Keytruda
  • Any severe or Grade 3 treatment-related adverse reaction that recurs [see Warnings and Precautions (5.6)]

Preparation and Administration

Reconstitution of Keytruda for Injection (Lyophilized Powder)

  • Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL).
  • Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.

Preparation for Intravenous Infusion

  • Visually inspect the solution for particulate matter and discoloration prior to administration. The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible particles are observed.
  • Dilute Keytruda injection (solution) or reconstituted lyophilized powder prior to intravenous administration.
  • Withdraw the required volume from the vial(s) of Keytruda and transfer into an intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL.
  • Discard any unused portion left in the vial.

Storage of Reconstituted and Diluted Solutions

The product does not contain a preservative.

Store the reconstituted and diluted solution from the Keytruda 50 mg vial either:

  • At room temperature for no more than 6 hours from the time of reconstitution. This includes room temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Store the diluted solution from the Keytruda 100 mg/4 mL vial either:

  • At room temperature for no more than 6 hours from the time of dilution. This includes room temperature storage of the infusion solution in the IV bag, and the duration of infusion.
  • Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.

Do not freeze.

Administration

  • Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on filter.
  • Do not co-administer other drugs through the same infusion line.

Dosage Forms and Strengths

  • For injection: 50 mg lyophilized powder in a single-use vial for reconstitution
  • Injection: 100 mg/4 mL (25 mg/mL) solution in a single-use vial

Contraindications

None.

Warnings and Precautions

Immune-Mediated Pneumonitis

Keytruda can cause immune-mediated pneumonitis, including fatal cases. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. Withhold Keytruda for moderate (Grade 2) pneumonitis, and permanently discontinue Keytruda for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving Keytruda, including Grade 1 (0.8%), Grade 2 (1.3%), Grade 3 (0.9%), Grade 4 (0.3%), and Grade 5 (0.1%) pneumonitis. The median time to onset was 3.3 months (range: 2 days to 19.3 months), and the median duration was 1.5 months (range: 1 day to 17.2+ months). Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10.1 months) followed by a corticosteroid taper. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6.9%) than in patients who did not receive prior thoracic radiation (2.9%). Pneumonitis led to discontinuation of Keytruda in 36 (1.3%) patients. Pneumonitis resolved in 55 (59%) of the 94 patients.

Immune-Mediated Colitis

Keytruda can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater colitis. Withhold Keytruda for moderate (Grade 2) or severe (Grade 3) colitis, and permanently discontinue Keytruda for life-threatening (Grade 4) colitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Colitis occurred in 48 (1.7%) of 2799 patients receiving Keytruda, including Grade 2 (0.4%), Grade 3 (1.1%), and Grade 4 (<0.1%) colitis. The median time to onset was 3.5 months (range: 10 days to 16.2 months), and the median duration was 1.3 months (range: 1 day to 8.7+ months). Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 1 day to 5.3 months) followed by a corticosteroid taper. Colitis led to discontinuation of Keytruda in 15 (0.5%) patients. Colitis resolved in 41 (85%) of the 48 patients.

Immune-Mediated Hepatitis

Keytruda can cause immune-mediated hepatitis. Monitor patients for changes in liver function. Administer corticosteroids (initial dose of 0.5 to 1 mg/kg/day [for Grade 2 hepatitis] and 1 to 2 mg/kg/day [for Grade 3 or greater hepatitis] prednisone or equivalent followed by a taper) and, based on severity of liver enzyme elevations, withhold or discontinue Keytruda [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Hepatitis occurred in 19 (0.7%) of 2799 patients receiving Keytruda, including Grade 2 (0.1%), Grade 3 (0.4%), and Grade 4 (<0.1%) hepatitis. The median time to onset was 1.3 months (range: 8 days to 21.4 months), and the median duration was 1.8 months (range: 8 days to 20.9+ months). Thirteen (68%) of the 19 patients received systemic corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days) followed by a corticosteroid taper. Hepatitis led to discontinuation of Keytruda in 6 (0.2%) patients. Hepatitis resolved in 15 (79%) of the 19 patients.

Immune-Mediated Endocrinopathies

Hypophysitis

Keytruda can cause hypophysitis. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold Keytruda for moderate (Grade 2) hypophysitis and withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hypophysitis [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving Keytruda, including Grade 2 (0.2%), Grade 3 (0.3%), and Grade 4 (<0.1%) hypophysitis. The median time to onset was 3.7 months (range: 1 day to 11.9 months), and the median duration was 4.7 months (range: 8+ days to 12.7+ months). Sixteen (94%) of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Hypophysitis led to discontinuation of Keytruda in 4 (0.1%) patients. Hypophysitis resolved in 7 (41%) of the 17 patients.

Thyroid Disorders

Keytruda can cause thyroid disorders, including hyperthyroidism, hypothyroidism and thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) hyperthyroidism [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving Keytruda, including Grade 2 (0.8%) and Grade 3 (0.1%) hyperthyroidism. The median time to onset was 1.4 months (range: 1 day to 21.9 months), and the median duration was 2.1 months (range: 3 days to 15.0+ months). Hyperthyroidism led to discontinuation of Keytruda in 2 (<0.1%) patients. Hyperthyroidism resolved in 71 (74%) of the 96 patients.

Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving Keytruda, including Grade 2 (6.2%) and Grade 3 (0.1%) hypothyroidism. The median time to onset was 3.5 months (range: 1 day to 18.9 months), and the median duration was not reached (range: 2 days to 27.7+ months). Hypothyroidism led to discontinuation of Keytruda in 1 (<0.1%) patient. Hypothyroidism resolved in 48 (20%) of the 237 patients. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients receiving Keytruda, including Grade 3 (0.5%) hypothyroidism. Of these 28 patients, 15 had no prior history of hypothyroidism.

Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving Keytruda, including Grade 2 (0.3%) thyroiditis. The median time of onset was 1.2 months (range: 0.5 to 3.5 months).

Type 1 Diabetes mellitus

Keytruda can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients receiving Keytruda. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold Keytruda and administer anti-hyperglycemics in patients with severe hyperglycemia [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Immune-Mediated Nephritis and Renal Dysfunction

Keytruda can cause immune-mediated nephritis. Monitor patients for changes in renal function. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. Withhold Keytruda for moderate (Grade 2), and permanently discontinue Keytruda for severe (Grade 3) or life-threatening (Grade 4) nephritis [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

Nephritis occurred in 9 (0.3%) of 2799 patients receiving Keytruda, including Grade 2 (0.1%), Grade 3 (0.1%), and Grade 4 (<0.1%) nephritis. The median time to onset was 5.1 months (range: 12 days to 12.8 months), and the median duration was 3.3 months (range: 12 days to 8.9+ months). Eight (89%) of the 9 patients received systemic corticosteroids, with 7 of the 8 receiving high-dose corticosteroids for a median duration of 15 days (range: 3 days to 4.0 months) followed by a corticosteroid taper. Nephritis led to discontinuation of Keytruda in 3 (0.1%) patients. Nephritis resolved in 5 (56%) of the 9 patients.

Other Immune-Mediated Adverse Reactions

Keytruda can cause other clinically important immune-mediated adverse reactions.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold Keytruda and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume Keytruda when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue Keytruda for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction [see Dosage and Administration (2.5) and Adverse Reactions (6.1)].

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients treated with Keytruda: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

Infusion-Related Reactions

Keytruda can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients receiving Keytruda. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, stop infusion and permanently discontinue Keytruda [see Dosage and Administration (2.5)].

Embryofetal Toxicity

Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman. Animal models link the PD-1/PD-L1 signaling pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment with Keytruda and for 4 months after the last dose of Keytruda [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

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

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, which enrolled 912 patients with melanoma and 682 patients with NSCLC, and one single-arm trial 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 which enrolled 192 patients with HNSCC. 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 below were obtained in three randomized, open-label, active-controlled clinical trials which enrolled 912 patients with melanoma, 682 patients with NSCLC, and one non-randomized, open-label, multi-cohort trial which enrolled 192 patients with HNSCC. 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 (Trial 1)

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 Trial 1. Trial 1 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 one or more lines of systemic therapy which included a BRAF inhibitor (15%), chemotherapy (13%), and immunotherapy (6%).

In Trial 1, 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, respectively, that occurred in at least 10% of patients receiving Keytruda.

Table 1: Selected* Adverse Reactions Occurring in ≥10% of Patients Receiving Keytruda (Trial 1)
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 (Trial 1)
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 (Trial 2)

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 Trial 2. Trial 2 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 Trial 2, 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 (Trial 2)
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 (Trial 2)
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

The safety of Keytruda was investigated in Trial 3, 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 Trial 3, 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 (Trial 3)
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 (Trial 3)
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).

HNSCC

Among the 192 patients with HNSCC enrolled in Trial 4, 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 Trial 4. 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)].

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 two or three 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 (5.8) 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

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

Geriatric Use

Of 3145 patients with melanoma, NSCLC, or HNSCC who were treated with Keytruda in clinical studies, 43% were 65 years and over and 12% were 75 years and over. No overall differences in safety or effectiveness were observed between elderly patients and younger patients.

Overdosage

There is no information on overdosage with Keytruda.

Keytruda Description

Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa.

Keytruda for injection is a sterile, preservative-free, white to off-white lyophilized powder in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.

Keytruda injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.

Keytruda - Clinical Pharmacology

Mechanism of Action

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

Pharmacodynamics

Based on dose/exposure efficacy and safety relationships, there are no clinically significant differences in efficacy and safety between pembrolizumab doses of 200 mg or 2 mg/kg every 3 weeks in patients with NSCLC.

Pharmacokinetics

The pharmacokinetics (PK) of pembrolizumab was characterized using a population PK analysis with concentration data collected from 2841 patients with various cancers who received pembrolizumab doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Pembrolizumab clearance (CV%) is approximately 20% lower [geometric mean, 212 mL/day (46%)] at steady state than that after the first dose [267 mL/day (43.1%)]; this decrease in clearance with time is not considered clinically important. The geometric mean value (CV%) for volume of distribution at steady state is 6.1 L (21%) and for terminal half-life (t1/2) is 23 days (30%).

Steady-state concentrations of pembrolizumab were reached by 19 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2.2-fold. The peak concentration (Cmax), trough concentration (Cmin), and area under the plasma concentration versus time curve at steady state (AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 10 mg/kg every 3 weeks.

Specific Populations: The following factors had no clinically important effect on the CL of pembrolizumab: age (range: 15 to 94 years), sex, race (94% White), renal impairment (eGFR greater than or equal to 15 mL/min/1.73 m2), mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and AST greater than ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or tumor burden. There is insufficient information to determine whether there are clinically important differences in the CL of pembrolizumab in patients with moderate or severe hepatic impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to test the potential of pembrolizumab for carcinogenicity or genotoxicity.

Fertility studies have not been conducted with pembrolizumab. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature.

Animal Toxicology and/or Pharmacology

In animal models, inhibition of PD-1 signaling resulted in an increased severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus (LCMV). Administration of pembrolizumab in chimpanzees with naturally occurring chronic hepatitis B infection resulted in two out of four animals with significantly increased levels of serum ALT, AST, and GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.

Clinical Studies

Melanoma

Ipilimumab-Naive Melanoma (Trial 1)

The safety and efficacy of Keytruda were evaluated in Trial 1, a randomized (1:1:1), open-label, multicenter, active-controlled trial. Patients were randomized to receive Keytruda at a dose of 10 mg/kg every 2 weeks or 10mg/kg every 3 weeks as an intravenous infusion until disease progression or unacceptable toxicity or to ipilimumab 3 mg/kg every 3 weeks as an intravenous infusion for 4 doses unless discontinued earlier for disease progression or unacceptable toxicity. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Randomization was stratified by line of therapy (0 vs. 1), ECOG PS (0 vs. 1), and PD-L1 expression (≥1% of tumor cells [positive] vs. <1% of tumor cells [negative]) according to an investigational use only (IUO) assay. Key eligibility criteria were unresectable or metastatic melanoma with progression of disease; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy. Patients with autoimmune disease; a medical condition that required immunosuppression; previous severe hypersensitivity to other monoclonal antibodies; and HIV, hepatitis B or hepatitis C infection, were ineligible. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS; as assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors [RECIST v1.1]). Additional efficacy outcome measures were overall response rate (ORR) and response duration.

A total of 834 patients were randomized: 277 patients to the Keytruda 10 mg/kg every 3 weeks arm, 279 to the Keytruda 10 mg/kg every 2 weeks arm, and 278 to the ipilimumab arm. The study population characteristics were: median age of 62 years (range: 18 to 89 years), 60% male, 98% White, 66% had no prior systemic therapy for metastatic disease , 69% ECOG PS of 0, 80% had PD-L1 positive melanoma, 18% had PD-L1 negative melanoma, and 2% had unknown PD-L1 status using the IUO assay, 65% had M1c stage disease, 68% with normal LDH, 36% with reported BRAF mutation-positive melanoma, and 9% with a history of brain metastases. Among patients with BRAF mutation-positive melanoma, 139 (46%) were previously treated with a BRAF inhibitor.

The study demonstrated statistically significant improvements in OS and PFS for patients randomized to Keytruda as compared to ipilimumab (Table 7 and Figure 1).

Table 7: Efficacy Results in Trial 1
Keytruda
10 mg/kg every 3 weeks
n=277
Keytruda
10 mg/kg every 2 weeks
n=279
Ipilimumab
3 mg/kg every 3 weeks
n=278
*
Hazard ratio (Keytruda compared to ipilimumab) based on the stratified Cox proportional hazard model
OS
  Deaths (%) 92 (33%) 85 (30%) 112 (40%)
  Hazard ratio* (95% CI) 0.69 (0.52, 0.90) 0.63 (0.47, 0.83) ---
  p-Value (stratified log-rank) 0.004 <0.001 ---
PFS by BICR
  Events (%) 157 (57%) 157 (56%) 188 (68%)
  Median in months (95% CI) 4.1 (2.9, 6.9) 5.5 (3.4, 6.9) 2.8 (2.8, 2.9)
  Hazard ratio* (95% CI) 0.58 (0.47, 0.72) 0.58 (0.46, 0.72) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Best overall response by BICR
  ORR (95% CI) 33% (27, 39) 34% (28, 40) 12% (8, 16)
    Complete response rate 6% 5% 1%
    Partial response rate 27% 29% 10%

Among the 91 patients randomized to Keytruda 10 mg/kg every 3 weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months. Among the 94 patients randomized to Keytruda 10 mg/kg every 2 weeks with an objective response, response durations ranged from 1.4+ to 8.2 months.

Figure 1: Kaplan-Meier Curve for Overall Survival in Trial 1

Ipilimumab-Refractory Melanoma (Trial 2)

The safety and efficacy of Keytruda were evaluated in Trial 2, a multicenter, randomized (1:1:1), active-controlled trial. Patients were randomized to receive one of two doses of Keytruda in a blinded fashion or investigator's choice chemotherapy. The treatment arms consisted of Keytruda 2 mg/kg or 10 mg/kg intravenously every 3 weeks or investigator's choice of any of the following chemotherapy regimens: dacarbazine 1000 mg/m2 intravenously every 3 weeks (26%), temozolomide 200 mg/m2 orally once daily for 5 days every 28 days (25%), carboplatin AUC 6 intravenously plus paclitaxel 225 mg/m2 intravenously every 3 weeks for four cycles then carboplatin AUC of 5 plus paclitaxel 175 mg/m2 every 3 weeks (25%), paclitaxel 175 mg/m2 intravenously every 3 weeks (16%), or carboplatin AUC 5 or 6 intravenously every 3 weeks (8%). Randomization was stratified by ECOG performance status (0 vs. 1), LDH levels (normal vs. elevated [≥110% ULN]) and BRAF V600 mutation status (wild-type [WT] or V600E). The trial included patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. The trial excluded patients with uveal melanoma and active brain metastasis. Patients received Keytruda until unacceptable toxicity; disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging; withdrawal of consent; or physician's decision to stop therapy for the patient. Assessment of tumor status was performed at 12 weeks after randomization, then every 6 weeks through week 48, followed by every 12 weeks thereafter. Patients on chemotherapy who experienced progression of disease were offered Keytruda. The major efficacy outcomes were progression-free survival (PFS) as assessed by BICR per RECIST v1.1 and overall survival (OS). Additional efficacy outcome measures were confirmed overall response rate (ORR) as assessed by BICR per RECIST v1.1 and duration of response.

The treatment arms consisted of Keytruda 2 mg/kg (n=180) or 10 mg/kg (n=181) every 3 weeks or investigator's choice chemotherapy (n=179). Among the 540 randomized patients, the median age was 62 years (range: 15 to 89 years), with 43% age 65 or older; 61% male; 98% White; and ECOG performance score was 0 (55%) and 1 (45%). Twenty-three percent of patients were BRAF V600 mutation positive, 40% had elevated LDH at baseline, 82% had M1c disease, and 73% had two or more prior therapies for advanced or metastatic disease.

The study demonstrated a statistically significant improvement in PFS for patients randomized to Keytruda as compared to control arm (Table 8). There was no statistically significant difference between Keytruda 2 mg/kg and chemotherapy or between Keytruda 10 mg/kg and chemotherapy in the interim OS analysis with 220 deaths (59% of required events for the final analysis).

Table 8: Efficacy Results in Trial 2
Keytruda
2 mg/kg every 3 weeks
Keytruda
10 mg/kg every 3 weeks
Chemotherapy
n=180 n=181 n=179
*
Hazard ratio (Keytruda compared to chemotherapy) based on the stratified Cox proportional hazard model
Progression-Free Survival
  Number of Events, n (%) 129 (72%) 126 (70%) 155 (87%)
  Progression, n (%) 105 (58%) 107 (59%) 134 (75%)
  Death, n (%) 24 (13%) 19 (10%) 21 (12%)
  Median in months (95% CI) 2.9 (2.8, 3.8) 2.9 (2.8, 4.7) 2.7 (2.5, 2.8)
  P Value (stratified log-rank) <0.001 <0.001 ---
  Hazard ratio* (95% CI) 0.57 (0.45, 0.73) 0.50 (0.39, 0.64) ---
Objective Response Rate
  ORR (95% CI) 21% (15, 28) 25% (19, 32) 4% (2, 9)
    Complete response rate 2% 3% 0%
    Partial response rate 19% 23% 4%
Figure 2: Kaplan-Meier Curve for Progression-Free Survival in Trial 2

Among the 38 patients randomized to Keytruda 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to Keytruda 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months.

Non-Small Cell Lung Cancer

First-line treatment of patients with NSCLC (Trial 5)

Trial 5 was a randomized, multicenter, open-label, active-controlled trial in patients with metastatic NSCLC, whose tumors had high PD-L1 expression [tumor proportion score (TPS) of 50% or greater] by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit, and had not received prior systemic treatment for metastatic NSCLC. Patients with EGFR or ALK genomic tumor aberrations; 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 radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG performance status (0 vs. 1), histology (squamous vs. non-squamous), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to receive Keytruda 200 mg intravenously every 3 weeks or investigator's choice of any of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every three weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with non-squamous histologies;
  • Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with non-squamous histologies;
  • Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles;
  • Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on day 1 for 4 to 6 cycles;
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for non-squamous histologies).

Treatment with Keytruda continued until RECIST 1.1-defined progression of disease as determined by an independent radiology committee, unacceptable toxicity, or for up to 24 months. Treatment could continue beyond disease progression if the patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients randomized to chemotherapy were offered Keytruda at the time of disease progression.

Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was PFS as assessed by a blinded independent central radiologists' (BICR) review according to RECIST 1.1. Additional efficacy outcome measures were OS and ORR as assessed by the BICR according to RECIST 1.1.

A total of 305 patients were randomized: 154 patients to the Keytruda arm and 151 to the chemotherapy arm. The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% white and 15% Asian; 65% ECOG performance status of 1; 18% with squamous and 82% with non-squamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received Keytruda at the time of disease progression.

The trial demonstrated a statistically significant improvement in PFS for patients randomized to Keytruda as compared with chemotherapy. Additionally, a pre-specified interim OS analysis at 108 events (64% of the events needed for final analysis) also demonstrated statistically significant improvement of OS for patients randomized to Keytruda as compared with chemotherapy. Table 9 summarizes key efficacy measures for Trial 5.

Table 9: Efficacy Results in Trial 5
Endpoint Keytruda
200 mg every 3 weeks
Chemotherapy
n=154 n=151
NR = not reached
*
Based on the stratified Cox proportional hazard model
P-value is compared with 0.0118 of the allocated alpha for this interim analysis.
PFS
  Number (%) of patients with event 73 (47%) 116 (77%)
  Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2)
  Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
  p-Value (stratified log-rank) <0.001
OS
  Number (%) of patients with event 44 (29%) 64 (42%)
  Median in months (95% CI) NR
(NR, NR)
NR
(9.4, NR)
  Hazard ratio* (95% CI) 0.60 (0.41, 0.89)
  p-Value (stratified log-rank) 0.005
Objective Response Rate
  ORR % (95% CI) 45% (37, 53) 28% (21, 36)
    Complete response % 4% 1%
    Partial response % 41% 27%
  p-Value (Miettenen-Nurminen) 0.001
  Median duration of response in months (range) NR
(1.9+, 14.5+)
6.3
(2.1+, 12.6+)
Figure 3: Kaplan-Meier Curve for Overall Survival in Trial 5

Previously treated NSCLC (Trial 3)

Trial 3 was a randomized, multicenter, open-label, active-controlled trial in patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients must have PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx Kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG performance scale (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive Keytruda 2 mg/kg intravenously every 3 weeks, Keytruda 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to Keytruda were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression.

Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by the BICR according to RECIST 1.1 in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and response duration in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%.

A total of 1033 patients were randomized: 344 to the Keytruda 2 mg/kg arm, 346 patients to the Keytruda 10 mg/kg arm, and 343 patients to the docetaxel arm. The study population characteristics were: median age 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG performance status 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with non-squamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.

Tables 10 and 11 summarize key efficacy measures in the subgroup with TPS ≥50% population and in all patients, respectively. The Kaplan-Meier curve for OS (TPS ≥1%) is shown in Figure 4.

Table 10: Efficacy Results of the Subgroup of Patients with TPS ≥50% in Trial 3
Endpoint Keytruda
2 mg/kg every 3 weeks
n=139
Keytruda
10 mg/kg every 3 weeks
n=151
Docetaxel
75 mg/m2 every 3 weeks
n=152
NR = not reached
*
Hazard ratio (Keytruda compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
  Deaths (%) 58 (42%) 60 (40%) 86 (57%)
  Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7)
  Hazard ratio* (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 89 (64%) 97 (64%) 118 (78%)
  Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3)
  Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) ---
  p-Value (stratified log-rank) <0.001 <0.001 ---
Objective response rate
  ORR (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13)
  p-Value (Miettenen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 16.8+)
NR
(2.1+, 17.8+)
8.1
(2.1+, 8.8+)
Table 11: Efficacy Results of All Randomized Patients (TPS ≥1%) in Trial 3
Endpoint Keytruda
2 mg/kg every 3 weeks
n=344
Keytruda
10 mg/kg every 3 weeks
n=346
Docetaxel
75 mg/m2 every 3 weeks
n=343
NR = not reached
*
Hazard ratio (Keytruda compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
  Deaths (%) 172 (50%) 156 (45%) 193 (56%)
  Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8)
  Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) ---
  p-Value(stratified log-rank) <0.001 <0.001 ---
PFS
  Events (%) 266 (77%) 255 (74%) 257 (75%)
  Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2)
  Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) ---
  p-Value (stratified log-rank) 0.068 0.005 ---
Objective response rate
  ORR (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13)
  p-Value (Miettenen-Nurminen) <0.001 <0.001 ---
  Median duration of response in months (range) NR
(0.7+, 20.1+)
NR
(2.1+, 17.8+)
6.2
(1.4+, 8.8+)
Figure 4: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in Trial 3 (TPS ≥1%)

Head and Neck Cancer

The efficacy of Keytruda was investigated in Trial 4, a multicenter, nonrandomized, open-label, multi-cohort study that enrolled 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum-containing chemotherapy administered for recurrent or metastatic HNSCC or following platinum-containing chemotherapy administered as part of induction, concurrent, or adjuvant therapy. Patients with active autoimmune disease, a medical condition that required immunosuppression, evidence of interstitial lung disease, or ECOG PS ≥2 were ineligible.

Patients received Keytruda 10 mg/kg every 2 weeks (n=53) or 200 mg every 3 weeks (n=121) until unacceptable toxicity or disease progression that was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Treatment with pembrolizumab could be reinitiated for subsequent disease progression and administered for up to 1 additional year. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were ORR according to RECIST 1.1, as assessed by blinded independent central review, and duration of response.

Among the 174 patients, the baseline characteristics were median age 60 years (32% age 65 or older); 82% male; 75% White, 16% Asian, and 6% Black; 87% had M1 disease; 33% had HPV positive tumors; 63% had prior cetuximab; 29% had an ECOG PS of 0 and 71% had an ECOG PS of 1; and the median number of prior lines of therapy administered for the treatment of HNSCC was 2.

The ORR was 16% (95% CI: 11, 22) with a complete response rate of 5%. The median follow-up time was 8.9 months. Among the 28 responding patients, the median duration of response had not been reached (range 2.4+ to 27.7+ months), with 23 patients having responses of 6 months or longer. The ORR and duration of response were similar irrespective of dosage regimen (10 mg/kg every 2 weeks or 200 mg every 3 weeks) or HPV status.

How Supplied/Storage and Handling

Keytruda for injection (lyophilized powder): carton containing one 50 mg single-use vial (NDC 0006-3029-02).

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).

Keytruda injection (solution): carton containing one 100 mg/4 mL (25 mg/mL), single-use vial (NDC 0006-3026-02)

Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze. Do not shake.

Patient Counseling Information

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

  • Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of Keytruda, including:
    • Pneumonitis: Advise patients to contact their healthcare provider immediately for new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions (5.1)].
    • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions (5.2)].
    • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, or easy bruising or bleeding [see Warnings and Precautions (5.3)].
    • Hypophysitis: Advise patients to contact their healthcare provider immediately for persistent or unusual headache, extreme weakness, dizziness or fainting, or vision changes [see Warnings and Precautions (5.4)].
    • Hyperthyroidism and Hypothyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hyperthyroidism and hypothyroidism [see Warnings and Precautions (5.4)].
    • Type 1 Diabetes Mellitus: Advise patients to contact their healthcare provider immediately for signs or symptoms of type 1 diabetes [see Warnings and Precautions (5.4)].
    • Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis [see Warnings and Precautions (5.5)].
  • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.7)].
  • Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions (5.3, 5.4, 5.5)].
  • Advise women that Keytruda can cause fetal harm. Instruct women of reproductive potential to use highly effective contraception during and for 4 months after the last dose of Keytruda [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3)].
  • Advise nursing mothers not to breastfeed while taking Keytruda and for 4 months after the final dose [see Use in Specific Populations (8.2)].

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

U.S. License No. 0002

For Keytruda for injection, at:
Schering-Plough (Brinny) Co.,
County Cork, Ireland

For Keytruda injection, at:
MSD Ireland (Carlow)
County Carlow, Ireland

For patent information: www.merck.com/product/patent/home.html

The trademarks depicted herein are owned by their respective companies.

Copyright © 2014-2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk3475-iv-1610r006

MEDICATION GUIDE
Keytruda® (key-true-duh)
(pembrolizumab)
for injection
Keytruda® (key-true-duh)
(pembrolizumab)
injection
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: October 2016

What is the most important information I should know about Keytruda?

Keytruda is a medicine that may treat your melanoma, lung cancer, or head and neck cancer by working with your immune system. Keytruda can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.

Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:

Lung problems (pneumonitis). Symptoms of pneumonitis may include:

  • shortness of breath
  • chest pain
  • new or worse cough

Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include:

  • diarrhea or more bowel movements than usual
  • stools that are black, tarry, sticky, or have blood or mucus
  • severe stomach-area (abdomen) pain or tenderness

Liver problems (hepatitis). Signs and symptoms of hepatitis may include:

  • yellowing of your skin or the whites of your eyes
  • nausea or vomiting
  • pain on the right side of your stomach area (abdomen)
  • dark urine
  • feeling less hungry than usual
  • bleeding or bruising more easily than normal

Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include:

  • rapid heart beat
  • weight loss or weight gain
  • increased sweating
  • feeling more hungry or thirsty
  • urinating more often than usual
  • hair loss
  • feeling cold
  • constipation
  • your voice gets deeper
  • muscle aches
  • dizziness or fainting
  • headaches that will not go away or unusual headache

Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include:

  • change in the amount or color of your urine.

Problems in other organs. Signs of these problems may include:

  • rash
  • changes in eyesight
  • severe or persistent muscle or joint pains
  • severe muscle weakness
  • low red blood cells (anemia)

Infusion (IV) reactions, that can sometimes be severe and life-threatening. Signs and symptoms of infusion reactions may include:

  • chills or shaking
  • shortness of breath or wheezing
  • itching or rash
  • flushing
  • dizziness
  • fever
  • feeling like passing out

Getting medical treatment right away may help keep these problems from becoming more serious.

Your doctor will check you for these problems during treatment with Keytruda. Your doctor may treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay or completely stop treatment with Keytruda, if you have severe side effects.

What is Keytruda?

Keytruda is a prescription medicine used to treat:

  • a kind of skin cancer called melanoma. Keytruda may be used when your melanoma has spread or cannot be removed by surgery (advanced melanoma).
  • a kind of lung cancer called non-small cell lung cancer (NSCLC). Keytruda may be used when your lung cancer:
    • has spread (advanced NSCLC) and,
    • tests positive for "PD-L1" and,
      • you have not received chemotherapy to treat your advanced NSCLC and your tumor does not have an abnormal "EGFR" or "ALK" gene, or
      • you have received chemotherapy that contains platinum to treat your advanced NSCLC, and it did not work or it is no longer working, and
      • if your tumor has an abnormal "EGFR" or "ALK" gene, you have also received an EGFR or ALK inhibitor medicine and it did not work or is no longer working.
  • a kind of cancer called head and neck squamous cell cancer (HNSCC). Keytruda may be used when your HNSCC:
    • has returned or spread (advanced HNSCC) and
    • you have received chemotherapy that contains platinum to treat your advanced HNSCC, and it did not work or is no longer working.

It is not known if Keytruda is safe and effective in children less than 18 years of age.

What should I tell my doctor before receiving Keytruda?

Before you receive Keytruda, tell your doctor if you:

  • have immune system problems such as Crohn's disease, ulcerative colitis, or lupus
  • have had an organ transplant
  • have lung or breathing problems
  • have liver problems
  • have any other medical problems
  • are pregnant or plan to become pregnant
    • Keytruda can harm your unborn baby.
    • Females who are able to become pregnant should use an effective method of birth control during and for at least 4 months after the final dose of Keytruda. Talk to your doctor about birth control methods that you can use during this time.
    • Tell your doctor right away if you become pregnant during treatment with Keytruda.
  • are breastfeeding or plan to breastfeed.
    • It is not known if Keytruda passes into your breast milk.
    • Do not breastfeed during treatment with Keytruda and for 4 months after your final dose of Keytruda.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How will I receive Keytruda?
  • Your doctor will give you Keytruda into your vein through an intravenous (IV) line over 30 minutes.
  • Keytruda is usually given every 3 weeks.
  • Your doctor will decide how many treatments you need.
  • Your doctor will do blood tests to check you for side effects.
  • If you miss any appointments, call your doctor as soon as possible to reschedule your appointment.
What are the possible side effects of Keytruda?

Keytruda can cause serious side effects. See "What is the most important information I should know about Keytruda?"

Common side effects of Keytruda include: feeling tired, itching, diarrhea, decreased appetite, rash, shortness of breath, constipation, and nausea.

These are not all the possible side effects of Keytruda. For more information, ask your doctor or pharmacist.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of Keytruda

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about Keytruda, talk with your doctor. You can ask your doctor or nurse for information about Keytruda that is written for healthcare professionals. For more information, go to www.Keytruda.com.

What are the ingredients in Keytruda?

Active ingredient: pembrolizumab

Inactive ingredients:

Keytruda for injection: L-histidine, polysorbate 80, and sucrose. May contain hydrochloric acid/sodium hydroxide.

Keytruda injection: L-histidine, polysorbate 80, sucrose, and Water for Injection, USP.

Manufactured by: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
For Keytruda for injection, at:
Schering-Plough (Brinny) Co., County Cork, Ireland
For Keytruda injection, at:
MSD Ireland (Carlow), County Carlow, Ireland
U.S. License No. 0002
For patent information: www.merck.com/product/patent/home.html
Copyright © 2014-2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
usmg-mk3475-iv-1610r006

PRINCIPAL DISPLAY PANEL - 50 mg Vial Carton

NDC 0006-3029-02

Keytruda®
(pembrolizumab)
for Injection

50 mg / vial

For Intravenous Infusion Only

Dispense the enclosed Medication Guide to each patient.

Sterile lyophilized powder must be reconstituted with Sterile Water for
Injection, USP. Reconstituted solution requires further dilution prior
to administration.

Rx only

Single-use vial. Discard unused portion.

PRINCIPAL DISPLAY PANEL - 100 mg/4 mL Vial Carton

NDC 0006-3026-02

Keytruda®
(pembrolizumab)
Injection

100 mg/4 mL
(25 mg/mL)

For Intravenous Infusion Only

Dispense the enclosed Medication
Guide to each patient.

Requires dilution prior to administration.

Rx only
Single-use vial. Discard unused portion.

Keytruda 
pembrolizumab injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3029
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
pembrolizumab (pembrolizumab) pembrolizumab 50 mg  in 2 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 3.1 mg  in 2 mL
SUCROSE 140 mg  in 2 mL
POLYSORBATE 80 0.4 mg  in 2 mL
SODIUM HYDROXIDE  
HYDROCHLORIC ACID  
Packaging
# Item Code Package Description
1 NDC:0006-3029-02 1 VIAL in 1 CARTON
1 NDC:0006-3029-01 15 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125514 09/04/2014
Keytruda 
pembrolizumab injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3026
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
pembrolizumab (pembrolizumab) pembrolizumab 25 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 1.55 mg  in 1 mL
SUCROSE 70 mg  in 1 mL
POLYSORBATE 80 0.2 mg  in 1 mL
WATER  
Packaging
# Item Code Package Description
1 NDC:0006-3026-02 1 VIAL in 1 CARTON
1 NDC:0006-3026-01 10 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
BLA BLA125514 01/15/2015
Labeler - Merck Sharp & Dohme Corp. (001317601)
Establishment
Name Address ID/FEI Operations
Merck Sharp & Dohme Corp. 101740835 PACK(0006-3029, 0006-3026), LABEL(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
Schering-Plough (Ireland) Company 986118438 MANUFACTURE(0006-3029), ANALYSIS(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
MSD Ireland (Carlow) 985084764 MANUFACTURE(0006-3026), ANALYSIS(0006-3026)
Establishment
Name Address ID/FEI Operations
N.V. Organon 404467722 ANALYSIS(0006-3029, 0006-3026)
Establishment
Name Address ID/FEI Operations
Covance Laboratories Limited 213137276 ANALYSIS(0006-3029, 0006-3026)
Revised: 10/2016
 
Merck Sharp & Dohme Corp.
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