Dosing and uses of Keytruda (pembrolizumab)
Adult dosage forms and strengths
lyophilized powder for reconstitution
- 50mg/vial
solution for injection
- 100mg/4mL (25mg/mL)
Melanoma
Indicated for unresectable or metastatic melanoma
2 mg/kg IV q3wk until disease progression or unacceptable toxicity
Infuse IV over 30 minutes
Non-Small Cell Lung Cancer
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
Also 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 pembrolizumaB
200 mg IV q3wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression
Infuse IV over 30 minutes
Information on FDA-approved tests for detection of PD-L1 expression in NSCLC is available at: https://www.fda.gov/CompanionDiagnostics
Head & Neck Squamous Cell Carcinoma
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
200 mg IV q3wk infused over 30 minutes until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression
Dosing considerations (HNSCC)
- Indication for HNSCC 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
Dosage modifications
Renal impairment: No dosage adjustment required
Mild hepatic impairment: No dosage adjustment required
Moderate or severe hepatic impairment: Not studied
Withhold for any of the following (may resume when recover to grade 0-1)
- Grade 2 pneumonitis
- Grade 2 or 3 colitis
- Grade 3 or 4 endocrinopathies (eg, hypophysitis, hypo- or hyperthyroidism)
- Grade 2 nephritis
- AST or ALT >3 and up to 5 x ULN or total bilirubin >1.5 and up to 3 x ULN
- Any other severe or grade 3 treatment-related adverse reaction
Permanently discontinue 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
- Grade 3 or 4 nephritis
- AST or ALT >5 x ULN or total bilirubin >3 x ULN
- For patients with liver metastasis who begin treatment with grade 2 AST or ALT, discontinue if AST or ALT increases by ≥50% relative to baseline and lasts for at least 1 week
- Grade 3 or 4 infusion-related reactions
- Inability to reduce corticosteroid dose to ≤10 mg/day of prednisone or equivalent within 12 weeks
- Persistent grade 2 or 3 adverse reactions that do not recover to grade 0-1 within 12 weeks after last dose of pembrolizumab
- Any severe or grade 3 treatment-related adverse reaction that recurs
Orphan Designations
Gastric cancer, including gastroesophageal junction adenocarcinoma
Primary mediastinal B cell lymphoma
Hodgkin lymphoma
Multiple myeloma
Nasopharyngeal carcinoma
Sponsor
- Merck, Sharp & Dohme a subsidiary of Merck & Co, Inc; One Merck Drive, Whitehouse Station, NJ 08889
Pediatric dosage forms and strengths
Safety and efficacy not established
Keytruda (pembrolizumab) adverse (side) effects
>10%
Fatigue (47%)
Anemia (55%)
Hyperglycemia (40%)
Hyponatremia (35%)
Hypoalbuminemia (34%)
Nausea (30%)
Cough (30%)
Pruritus (30%)
Rash (29%)
Decreased appetite (26%)
Hypertriglyceridemia (25%)
Increased AST (24%)
Constipation (21%)
Diarrhea (20%)
Arthralgia (20%)
Pain in extremity (18%)
Dyspnea (18%)
Peripheral edema (17%)
Vomiting (16%)
Headache (16%)
Myalgia (14%)
Chills (14%)
Insomnia (14%)
Abdominal pain (12%)
Back pain (12%)
Dizziness (11%)
Pyrexia (11%)
Upper respiratory tract infection (11%)
Vitiligo (11%)
1-10%
Sepsis (up to 10%)
Immune-mediated hypothyroidism (8.3%)
Immune-mediated pneumonitis (2.9%)
Immune-mediated hyperthyroidism (1.2%)
Immune-mediated colitis (1%)
<1%
Immune-mediated nephritis (0.7%)
Renal failure (0.5%)
Immune-mediated hepatitis (0.5%)
Immune-mediated hypophysitis (0.5%)
Postmarketing reports
Infusion-related reactions
Warnings
Contraindications
None
Cautions
Clinical trials reported immune-mediated pneumonitis, colitis, hepatitis, nephritis and other immune-mediated adverse reactions (eg, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, myasthenic syndrome, optic neuritis, and rhabdomyolysis)
Severe dermatitis including bullous pemphigoid and exfoliative dermatitis reported
Immune-mediated endocrinopathies reported adrenal insufficiency, changes in thyroid function, and type 1 diabetes mellitus including diabetic ketoacidosis (withhold therapy in case of severe hyperglycemia until metabolic control achieved)
Infusion-related reactions, including severe and life-threatening reactions, reported; monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritis, flushing, rash, hypotension, hypoxemia, and fever; permanently discontinue therapy for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions
Hypophysitis reported; monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency); administer corticosteroids for Grade 2 or greater hypophysitis; withhold therapy for moderate (Grade 2) hypophysitis, withhold or discontinue for severe (Grade 3) hypophysitis, and permanently discontinue for life-threatening (Grade 4) hypophysitis
Thyroid disorders can occur; 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 corticosteroids for Grade 3 or greater hyperthyroidism; withhold treatment for severe (Grade 3) hyperthyroidism, and permanently discontinue for life-threatening (Grade 4) hyperthyroidism; isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids
Renal failure reported
Embryofetal toxicity is likely, based on the drug’s mechanism of action; women of reproductive potential should use highly effective contraception during treatment and for 4 months after the last dose
Pregnancy and lactation
Pregnancy category: d
Animal models link the PD-1/PDL-1 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 pembrolizumab, apprise the patient of the potential hazard to a fetus
Lactation: Unknown if distributed in human breast milk; not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Keytruda (pembrolizumab)
Mechanism of action
Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2
PD-1 and PD-L1
- PD-1 and related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions; PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound
- This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation
- Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells
Pharmacokinetics
Steady-state concentration reached by 18 weeks of q3wk dosing
Half-life: 26 days
Clearance: 0.22 L/day
Administration
IV Compatibilities
0.9% NaCL
Dextrose 5%
IV Preparation
Reconstitute vial by adding 2.3 mL of sterile water for injection 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
Visually inspect reconstituted solution for particulate matter and discoloration prior to administration
Reconstituted solution is a clear to slightly opalescent, colorless to slightly yellow solution; discard reconstituted vial if extraneous particulate matter other than translucent to white proteinaceous particles is observed
IV infusion preparation
- Dilute the solution for injection or reconstituted lyophilized powder before IV administration
- Withdraw the required volume from the vial(s) and transfer into IV bag containing 0.9% NaCl or D5W; mix diluted solution by gentle inversion
- Final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL
- Discard any unused portion left in the vial
IV Administration
Administer IV infusion over 30 minutes through an IV line containing a sterile, nonpyrogenic, low-protein binding 0.2-5 micron in-line or add-on filter
Do not coadminister other drugs through the same infusion line
Storage
Unopened vials (lyophilized powder or solution for injection): Refrigerate between 2-8°C (36-46°F)
Does not contain preservatives
Do not freeze
Reconstituted/diluted solution
- Diluted solution from 100 mg/4 mL (25 mg/mL) vial or from 50 mg vial lyophilized powder
- Room temperature: No to exceed 6 hr from time of reconstitution; this includes room temperature storage of reconstituted vials and/or dilution, and duration of infusion
- Refrigerate at 2-8°C (36-46°F): Not to exceed 24 hr from time of reconstitution/dilution
- If refrigerated, allow the diluted solution to come to room temperature prior to administration
