Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 50mg/mL (10 mL, single-dose vials)
Mismatch Repair–Deficient (dMMR) Tumors
Indicated for adults with mismatch repair–deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen
Also indicated for adults with dMMR recurrent or advanced solid tumors who have progressed on or following previous treatment and have no satisfactory therapeutic options
Doses 1-4: 500 mg IV q3Weeks, THEN
Dose 5 and thereafter (start 3 weeks after Dose 4): 1,000 mg IV q6Weeks until disease progression or unacceptable toxicity
Dosage Modifications
No dose reductions are recommended
Pneumonitis
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4 or recurrent Grade 2: Permanently discontinue
Colitis
- Grade 2 or 3: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver
- AST or ALT increases to >3 and ≤8x ULN or total bilirubin [TB] increases to >1.5 and <3x ULN: Withhold therapy; resume when complete or partial resolution (Grade <1) occurs after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- AST or ALT increases to >8x ULN or TB increases to >3x ULN: Permanently discontinue
Hepatitis with tumor involvement of liver
-
Withhold therapy
- Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
- Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases >10x ULN or TB increases to >3x ULN
Endocrinopathies
- Grade 2, 3, or 4: Withhold until clinically stable or permanently discontinue depending on severity
- Permanently discontinue if no complete or partial resolution (Grade <1) within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
Nephritis with renal dysfunction
- Grade 2 or 3 increased blood creatinine: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions
Suspected Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug rash with eosinophilia and systemic symptoms (DRESS) syndrome: Withhold therapy
Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
Confirmed SJS, TEN, or DRESS syndrome: Permanently discontinue
Myocarditis
- Grade 2, 3, or 4: Permanently discontinue
Neurologic toxicities
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Infusion-related reactions
- Grade 1 or 2: Interrupt or slow infusion rate
- Grade 3 or 4: Permanently discontinue
Renal or hepatic impairment
- Mild-severe and end-stage renal disease: No dosage adjustment necessary
Hepatic impairment
- Mild-to-moderate (TB ≤3x ULN and any AST): No dose adjustment is recommended
- Severe: Not studied
Dosing Considerations
Females of reproductive potential: Verify pregnancy status before initiation
Recurrent or advanced dMMR endometrial cancer or solid tumors
- Select patients based on presence of dMMR in tumor specimens
- Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
>10%
All grades
- Fatigue (48%)
- Lymphopenia (37%)
- Hypoalbuminemia (30%)
- Nausea (30%)
- Increased creatinine (27%)
- Hyponatremia (26%)
- Diarrhea (26%)
- Increased alkaline phosphatase (25%)
- Anemia (24%)
- Leukopenia (21%)
- Constipation (20%)
- Vomiting (18%)
- Increased AST (16%)
- Hypercalcemia (15%)
- Increased ALT (15%)
- Hypokalemia (15%)
- Decreased appetite (14%)
- Cough (14%)
- Pruritus (14%)
- Urinary tract infection (13%)
- Myalgia (12%)
Grade 3 or 4
- Anemia (13%)
1-10%
All grades
- Sepsis (2.9%)
- Acute kidney injury (2.9%)
- Urinary tract infection (2.9%)
- Abdominal pain (2.9%)
- Pyrexia (2.9%)
Grade 3 or 4
- Lymphopenia (9%)
- Hyponatremia (4.8%)
- Increased ALT (2.9%)
- Leukopenia (2.9%)
- Hypoalbuminemia (2.9%)
- Increased alkaline phosphatase (2.9%)
- Increased creatinine (2.9%)
- Hypercalcemia (1.9%)
- Hypokalemia (1.9%)
- Increased AST (1.9%)
- Urinary tract infection (1.9%)
- Diarrhea (1.9%)
- Pruritus (1%)
- Fatigue (1%)
<1%
Constipation (0.9%)
Warnings
Contraindications
None
Cautions
May cause severe or life-threatening infusion-related reactions; monitor for signs and symptoms of infusion-related reactions
Severe infections (eg, sepsis, herpes encephalitis, mycobacterial infection) leading to retroperitoneal hemorrhage reported; most common infection was upper respiratory tract infection; monitor for signs and symptoms of infection
Can cause fetal harm
Immune-mediated adverse reactions
- Severe or fatal immune-mediated adverse reactions can occur in any organ system or tissue
- May start at any time after initiating a programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1)–blocking antibody; may manifest during treatment and after discontinuation
- Immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, thyroid disorders, thyroiditis, hypothyroidism, nephritis, or hyperthyroidism may occur
- Can cause primary or secondary adrenal insufficiency
- Type 1 diabetes mellitus reported, which can present with diabetic ketoacidosis; monitor for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated; withhold or permanently discontinue depending on severity
- Immune-mediated rash or dermatitis (bullous and exfoliative dermatitis, SJS, TEN, DRESS syndrome) has occurred
- Monitor closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions
- If immune-mediated adverse reactions are suspected, initiate appropriate workup to exclude alternative etiologies, including infection; institute medical management promptly, including specialty consultation as appropriate
-
Other immune-mediated adverse reactions are the following
- Nervous system: Meningitis, encephalitis, myelitis, myasthenic syndrome/myasthenia gravis, Guillain Barre syndrome, nerve paresis, autoimmune neuropathy
- Cardiac/vascular: Myocarditis, pericarditis, vasculitis
- Ocular: Uveitis, iritis, other ocular inflammatory toxicities; some cases can be associated with retinal detachment; various grades of visual impairment to include blindness can occur; if uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi–Harada like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss
- Gastrointestinal: Pancreatitis, including increases in serum amylase and lipase levels, gastritis, duodenitis
- Musculoskeletal and connective tissue: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica
- Endocrine: Hypoparathyroidism
- Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection
Complications of allogeneic hematopoietic stem cell transplantation
- Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
- Transplantation-related complications include hyperacute graft versus host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause)
- These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT
- Closely monitor for evidence of transplantation-related complications and intervene promptly; consider benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, can cause fetal harm when administered during pregnancy
No available data on use in pregnant females
Verify pregnancy status in females of reproductive potential before initiation
Animal data
- Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased risk of immune-related rejection of the developing fetus, resulting in fetal death
Contraception
Females of reproductive potential: Use effective contraception during treatment and for at least 4 months following the last dose
Lactation
No data are available on presence in human milk, effects on breastfed children, or on milk production
Maternal IgG is known to be present in human milk; the effects of local gastrointestinal exposure and limited systemic exposure in breastfed child to this medication are unknown
Advise lactating females not to breastfeed during treatment and for at least 4 months after the last dose
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
Mechanism of Action
Humanized monoclonal antibody of the IgG4 isotype binds to PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response
Binding of PD-1 ligands, PD-L1 and PD-L2, to PD-1 receptor found on T-cells; inhibits T-cell proliferation and cytokine production
Up-regulation of PF-1 ligands occurs in some tumors; signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors
Absorption
Peak plasma concentration
- 500-mg dose: 171 mcg/mL
- 1,000-mg dose: 309 mcg/mL
AUC
- 500-mg dose: 35,730 mcg·hr/mL
- 1,000-mg dose: 95,820 mcg·hr/mL
Distribution
Vd (steady-state): 5.3 L
Metabolism
Metabolized into small peptides and amino acids by catabolic pathways
Elimination
Half-life: 25.4 days
Clearance (steady-state): 0.007 L/hr
Administration
IV Incompatibilities
Do not coadminister other drugs through same infusion line
IV Compatibilities
0.9% NaCl
Dextrose 5% (D5W)
IV Preparation
Visually inspect vials for particulate matter and discoloration; solution is clear to slightly opalescent, colorless to yellow; discard if visible particles are observed
Do not shake
500-mg dose
Withdraw 10 mL (from 1 vial) using disposable polypropylene sterile syringe
- Dilute into IV infusion bag (not to exceed 250 mL) containing 0.9% NaCl or D5W; resulting final concentration is 2-10 mg/mL
1,000-mg dose
- Withdraw 20 mL (from 2 vials) using a disposable polypropylene sterile syringe
- Dilute into IV infusion bag (not to exceed 250 mL) containing 0.9% NaCl or D5W; resulting final concentration is 4-10 mg/mL
Gently invert to mix diluted solution; do NOT shake
Discard any unused portion left in vial(s)
IV Administration
Infuse over 30 minutes through IV line using tubing made of polyvinyl chloride or platinum-cured silicon; fittings made of polyvinyl chloride or polycarbonate; and a sterile, nonpyrogenic, low-protein–binding, 0.2-micron, inline or add-on filter
Do not administered as IV push or bolus injection
Do not coadminister other drugs through same infusion line
Storage
Unopened vials
- Refrigerate at 2-8°C (36-46°F)
- Protect from light
Diluted solutions
From time of preparation until end of infusion
- Store at room temperature for ≤6 hr, OR
- Refrigerate at 2-8°C (36-46°F) for ≤24 hr
- Discard after 6 hr at room temperature or after 24 hr under refrigeration; do not freeze
Images
Formulary
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