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Dosing and administration for ZYNYZ1

IV dosing every 4 weeks may align with routine office visits1

QUICK INFUSION DELIVERS 500 MG OVER 30 MINUTES1

  • Continue until disease progression, unacceptable toxicity, or up to 24 months
  • Routine prophylaxis for infusion-related reactions is not required
  • Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins

Please see Complete Preparation and Administration Instructions in the Full Prescribing Information.

Recommended dosing 500 mg IV over 30 minutes every 4 weeks
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No dose reduction of ZYNYZ for adverse reactions is recommended1

  • In general, withhold ZYNYZ for severe (Grade 3) immune-mediated adverse reactions
  • Permanently discontinue ZYNYZ for:
    • life-threatening (Grade 4) immune-mediated adverse reactions,
    • recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or
    • an inability to reduce corticosteroid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating steroids
  • Dosage modifications for ZYNYZ for adverse reactions that require management different from these general guidelines are summarized below

Dosage modifications for adverse reactions1 

Recommended dosage modifications for adverse reactions1

 

 

ADVERSE REACTIONSEVERITYaZYNYZ DOSAGE MODIFICATIONS
IMMUNE-MEDIATED ADVERSE REACTIONS
PneumonitisGrade 2Withholdb
Grade 3 or 4Permanently discontinue
ColitisGrade 2 or 3Withholdb
Grade 4Permanently discontinue
Hepatitis with no tumor involvement of the liverAST or ALT greater than 3 but no more than 8 times ULN
OR 
Total bilirubin increases to more than 1.5 and up to 3 times ULN		Withholdb
AST or ALT increases to more than 8 times ULN 
OR
Total bilirubin greater than 3 times ULN		Permanently discontinue
Hepatitis with tumor involvement of the livercBaseline AST or ALT is more than 1 and up to 3 times ULN and increases more than 5 and up to 10 times ULN
OR
Baseline AST or ALT is more than 3 and up to 5 times ULN and increases more than 8 and up to 10 times ULN		Withholdb
AST or ALT increases to more than 10 times ULN
OR
Total bilirubin increases to more than 3 times ULN		Permanently discontinue
EndocrinopathiesdGrade 3 or 4Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with renal dysfunctionGrade 2 or 3 increased blood creatinineWithholdb
Grade 4 increased blood creatininePermanently discontinue
Exfoliative dermatologic conditionsGrade 3 or suspected SJS, TEN, or DRESSWithholdb
Grade 4 or confirmed SJS, TEN, or DRESSPermanently discontinue
MyocarditisGrade 2, 3, or 4Permanently discontinue
Neurological toxicitiesGrade 2Withholdb
Grade 3 or 4Permanently discontinue
OTHER ADVERSE REACTIONS
Infusion-related reactionsGrade 1 or 2Interrupt or slow the rate of infusion
Grade 3 or 4Permanently discontinue

Please see Warnings and Precautions in the Full Prescribing Information.

a Toxicity graded per NCI CTCAE v5.

b Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no resolution within 12 weeks of initiating steroids or inability to reduce prednisone to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids.

c If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue ZYNYZ based on recommendations for hepatitis with no liver involvement.

d Depending on clinical severity, consider withholding for Grade 2 endocrinopathy until symptom improvement with hormone replacement. Resume once acute symptoms have resolved.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DRESS, drug rash with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; ULN, upper limit of normal.

ZYNYZ storage, preparation, and administration

Reference: 1. ZYNYZ Prescribing Information. Wilmington, DE: Incyte Corporation.

ZYNYZ storage, preparation, and administration

A single-dose vial is how ZYNYZ is supplied

Supplied in a carton containing one single-dose vial of 500 mg/20 mL (25 mg/mL) (NDC 50881-006-03)1

  • ZYNYZ injection is a clear to slightly opalescent, colorless to pale yellow solution
  • Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze or shake
A vial and syringe is needed for the first step (withdrawal from vial) of the ZYNYZ preparation process

01

Withdraw 20 mL (500 mg) of ZYNYZ from one vial and discard vial with any unused portion1

A single syringe is needed in the dilution step in the preparation of ZYNYZ

02

Dilute ZYNYZ with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a final concentration between 1.4 mg/mL to 10 mg/mL. Use polyvinylchloride (PVC) and di-2-ethylhexyl phthalate (DEHP), polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetate infusion bags1

An IV bag containing the diluted ZYNYZ solution being gently inverted

03

Mix diluted solution by gentle inversion. Do not shake1

Visually inspect prior to administration

04

Visually inspect the infusion bag for particulate matter and discoloration prior to administration. Discard if the solution is discolored or contains particulate matter1

Storage of diluted ZYNYZ solution

Protect the diluted ZYNYZ solution from light during storage.

Store diluted ZYNYZ solution:

prep-carousel-infusiontime-icon

At room temperature (up to 25°C [77°F]) for no more than 8 hours from the time of preparation to the end of the infusion.

OR

prep-carousel-refrigeration-icon

Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of preparation to the end of the infusion. If refrigerated, allow the diluted solution to come to room temperature prior to administration. The diluted solution must be administered within 4 hours (including infusion time) once it is removed from the refrigerator. Do not freeze or shake diluted solution.

DO

The infusion of ZYNYZ occurs within a 30-minute time period
  • Administer diluted ZYNYZ solution by IV infusion over 30 minutes1
A polyethylene or PVC with DEHP intravenous line should be used when administering ZYNYZ
  • Use a polyethylene or PVC with DEHP intravenous line containing a sterile, non-pyrogenic, low-protein binding polyethersulfone, polyvinylidene fluoride, or cellulose acetate 0.2 micron to 5 micron in-line or add-on filter or 15 micron mesh in-line or add-on filter1

DO NOT

ZYNYZ should not be administered using a polyurethane infusion set
  • Do not administer ZYNYZ using a polyurethane infusion set1
Other drugs cannot be co-administered through the same infusion line as ZYNYZ
  • Do not co-administer other drugs through the same infusion line1
ZYNYZ should not be administered as an intravenous push or bolus injection
  • Do not administer ZYNYZ as an intravenous push or bolus injection1

Reference: 1. ZYNYZ Prescribing Information. Wilmington, DE: Incyte Corporation.

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IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Important immune-mediated adverse reactions listed may not be inclusive of all possible severe and fatal immune-mediated reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can occur at any time after starting or discontinuing treatment with a PD-1/PD-L1–blocking antibody, and can affect more than one body system simultaneously.

Monitor patients closely for symptoms and signs that may be clinical manifestations of such reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1–blocking antibodies. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. If suspected, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue ZYNYZ depending on severity. In general, if ZYNYZ requires interruption or discontinuation, administer systemic corticosteroid therapy (1-2 mg/kg/day prednisone or equivalent) until improvement to ≤ Grade 1. Then, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroids.

Immune-Mediated Pneumonitis

ZYNYZ can cause immune-mediated pneumonitis. Immune-mediated pneumonitis occurred in 3% (13/440) of patients, including fatal (0.2%), Grade 3 (0.9%), and Grade 2 (1.4%) reactions. Pneumonitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding in 0.9%.

Systemic corticosteroids were required in 77% (10/13) of patients. Pneumonitis resolved in 10 of the 13 patients.

Immune-Mediated Colitis

ZYNYZ can cause immune-mediated colitis. Cytomegalovirus infections/reactivations have occurred in patients with corticosteroid-refractory immune-mediated colitis treated with PD-1/PD-L1–blocking antibodies. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated colitis occurred in 1.6% (7/440) of patients, including Grade 4 (0.2%), Grade 3 (0.2%), and Grade 2 (0.7%). Colitis led to permanent discontinuation of ZYNYZ in 1 patient and withholding in 0.9%.

Systemic corticosteroids were required in 71% (5/7) of patients. Colitis resolved in 4/7 patients.

Immune-Mediated Hepatitis

ZYNYZ can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 3% (13/440) of patients, including Grade 4 (0.2%), Grade 3 (2.3%), and Grade 2 (0.5%). Hepatitis led to permanent discontinuation of ZYNYZ in 1.4% of patients and withholding in 0.9%.

Systemic corticosteroids were required in 85% (11/13) of patients. Hepatitis resolved in 6/13 patients.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

ZYNYZ can cause primary or secondary adrenal insufficiency. For ≥ Grade 2 adrenal insufficiency, initiate symptomatic treatment per institutional guidelines, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Adrenal insufficiency occurred in 0.7% (3/440) of patients, including Grade 3 (0.5%) and Grade 2 (0.2%). ZYNYZ was permanently discontinued in no patients and was withheld for 1 patient with adrenal insufficiency.

All patients required systemic corticosteroids. Adrenal insufficiency resolved in 1 of the 3 patients.

Hypophysitis

ZYNYZ can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts, and can cause hypopituitarism. Initiate hormone replacement as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Hypophysitis occurred in 0.5% (2/440, both Grade 2) of patients. No patients discontinued or withheld ZYNYZ due to hypophysitis.

All patients required systemic steroids. Hypophysitis resolved in 1 of the 2 patients.

Thyroid Disorders

ZYNYZ can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement or medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue ZYNYZ depending on severity.

Thyroiditis occurred in 0.7% (3/440, all Grade 1) of patients. No patients discontinued or withheld ZYNYZ due to thyroiditis. Thyroiditis resolved in 1 of the 3 patients.

Hypothyroidism

Hypothyroidism occurred in 10% (42/440) of patients receiving ZYNYZ, including Grade 2 (4.8%). No patients discontinued due to hypothyroidism. ZYNYZ was withheld in 0.5% of patients.

Systemic corticosteroids were required for 1 patient, and 79% (33/42) of patients received endocrine therapy.

Hyperthyroidism

Hyperthyroidism occurred in 6% (24/440) of patients receiving ZYNYZ, including Grade 2 (2.5%).

ZYNYZ was not discontinued in any patient and was withheld in 1 patient. Systemic corticosteroids were required for 13% (3/24) of patients, and 46% (11/24) of patients received endocrine therapy.

Type 1 Diabetes Mellitus, Which Can Present with Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold ZYNYZ depending on severity.

Type 1 diabetes mellitus occurred in 0.2% (1/440) of patients, including Grade 3 (0.2%) adverse reactions.

Immune-Mediated Nephritis with Renal Dysfunction

ZYNYZ can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 1.6% (7/440) of patients receiving ZYNYZ, including Grade 4 (0.5%), Grade 3 (0.7%), and Grade 2 (0.5%). Nephritis led to permanent discontinuation of ZYNYZ in 0.9% of patients and withholding in 1 patient.

Systemic corticosteroids were required in 57% (4/7) of patients. Nephritis resolved in 3/7 patients.

Immune-Mediated Dermatologic Adverse Reactions

ZYNYZ can cause immune-mediated rash or dermatitis. Bullous and exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with PD-1/PD-L1–blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue ZYNYZ depending on severity.

Immune-mediated skin reactions occurred in 8% (36/440) of patients, including Grade 3 (1.1%) and Grade 2 (7%). Immune-mediated dermatologic adverse reactions led to permanent discontinuation of ZYNYZ in 1 patient and withholding in 2.3% of patients.

Systemic corticosteroids were required in 25% (9/36) of patients. Immune-mediated dermatologic adverse reactions resolved in 75% (27/36) of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of < 1% in 440 patients who received ZYNYZ or were reported with the use of other PD-1/PD-L1–blocking antibodies, including severe or fatal cases.

Cardiac/vascular: myocarditis, pericarditis, vasculitis

Gastrointestinal: pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis

Musculoskeletal: myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica

Neurological: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy

Ocular: uveitis, iritis, and 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.

Endocrine: hypoparathyroidism

Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection, other transplant (including corneal graft) rejection.

Infusion-Related Reactions

A severe infusion-related reaction (Grade 3) occurred in 1 (0.2%) of 440 patients. Monitor patients for signs and symptoms; interrupt or slow the rate of infusion or permanently discontinue ZYNYZ based on severity of reaction. Consider premedication with an antipyretic and/or an antihistamine for patients who have had previous systemic reactions to infusions of therapeutic proteins.

Complications of Allogeneic HSCT

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. Transplant-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), which may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1–blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

ZYNYZ can cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus, resulting in fetal death. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose.

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the last dose.

Adverse Reactions

The safety of ZYNYZ was evaluated in 105 patients with metastatic or recurrent locally advanced MCC.

Serious adverse reactions occurred in 22% of patients receiving ZYNYZ. The most frequent serious adverse reactions (≥ 2% of patients) were fatigue, arrhythmia, and pneumonitis.

Permanent discontinuation of ZYNYZ due to an adverse reaction occurred in 11% of patients. These included asthenia, atrial fibrillation, concomitant disease progression of chronic lymphocytic leukemia, demyelinating polyneuropathy, eosinophilic fasciitis, increased transaminases, infusion-related reaction, lung disorder, pancreatitis, polyarthritis, and radiculopathy (1 patient each).

Dosage interruptions due to an adverse reaction occurred in 25% of patients. Adverse reactions or laboratory abnormalities that required dosage interruption in ≥ 2% of patients were increased transaminases, increased lipase, increased amylase, pneumonitis, and pyrexia.

The most common (≥ 10%) adverse reactions were fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea.

 

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Incyte Corporation at 1-855-463-3463.

Please see the full Prescribing Information for ZYNYZ for additional Important Safety Information.