Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
ZYNYZ is indicated as monotherapy for the first-line treatment of adult patients with metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) not amenable to curative surgery or radiation therapy.
Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.
The recommended dose is 500 mg retifanlimab every 4 weeks administered as an intravenous infusion over 30 minutes. Treatment should continue until disease progression or unacceptable toxicity for up to 2 years.
Dose escalation or reduction of retifanlimab is not indicated. Recommended dose modifications to manage immune-related adverse reactions are provided in Table 1 (see also sections 4.4 and 4.8).
Table 1. Recommended dose modifications:
| Adverse reaction | Severitya | Dose modification |
|---|---|---|
| Pneumonitis | Grade 2 | Withhold until adverse reactions recover to Grades 0-1. |
| Grades 3 or 4 | Permanently discontinue. | |
| Colitis | Grades 2 or 3 | Withhold until adverse reactions recover to Grades 0-1. |
| Recurrent Grade 3 or Grade 4 | Permanently discontinue. | |
| Hepatitis with no tumour involvement of the liver OR Increased total bilirubin | Grade 3 with AST or ALT greater than 3 but no more than 8 times ULN OR TB increases to more than 1.5 and up to 3 times ULN | Withhold until adverse reactions recover to Grades 0-1. 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. |
| Grade 4 with AST or ALT increases to more than 8 times ULN OR TB greater than 3 times ULN | Permanently discontinue. | |
| Hepatitis with tumour involvement of the liver OR Increased total bilirubin | Grade 3 with AST or ALT more than 5 and up to 10 times ULN OR TB greater than 1.5 but no more than 3 times ULN | Withhold until adverse reactions recover to Grades 0-1. 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. |
| Grade 4 with AST or ALT increase to more than 10 times ULN OR TB greater than 3 times ULN | Permanently discontinue. | |
| Endocrinopathies • Adrenal insufficiency • Hypothyroidism • Hyperthyroidism • Type 1 diabetes mellitus • Hyperglycaemia • Hypophysitis | Grade 2 adrenal insufficiency | Withhold until adverse reactions recover to Grades 0-1 or otherwise clinically stable. |
| Grades 3 or 4 adrenal insufficiency | Withhold until adverse reactions recover to Grades 0-1. 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. | |
| Grades 3 or 4 hypothyroidism | Withhold until adverse reactions recover to Grades 0-1 or is otherwise clinically stable. | |
| Grades 3 or 4 hyperthyroidism | Withhold until adverse reactions recover to Grades 0-1 or is otherwise clinically stable. | |
| Grades 3 or 4 type 1 diabetes mellitus (or hyperglycaemia) | Withhold until adverse reactions recover to Grades 0-1 or is otherwise clinically stable. | |
| Grade 2 hypophysitis (asymptomatic) | Withhold until adverse reactions recover to Grades 0-1. May restart after controlled by hormone replacement therapy. | |
| Grade 2 hypophysitis (symptomatic e.g., headaches, visual disturbances) | Withhold until adverse reactions recover to Grades 0-1. May restart after controlled by hormone replacement therapy, if indicated and steroid taper is complete. | |
| Grade 3 or 4 hypophysitis (symptomatic) | Withhold until adverse reactions recover to Grades 0-1. 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. | |
| Nephritis with renal dysfunction | Grade 2 increased blood creatinine | Withhold until adverse reactions recover to Grades 0-1. |
| Grade 3 or 4 increased blood creatinine | Permanently discontinue.b | |
| Skin reactions | Grade 3 or suspected SJS or suspected TEN Persistent Grade 2 (≥ 2 weeks) | Withhold until adverse reactions recover to Grades 0-1. |
| Grade 4 or confirmed SJS or confirmed TEN | Permanently discontinue. | |
| Myocarditis | Confirmed Grades 2, 3 or 4 | Permanently discontinue. |
| Other immune-related adverse reactions (including myositis, encephalitis, demyelinating neuropathy, Guillain Barré syndrome, sarcoidosis, autoimmune haemolytic anaemia, pancreatitis, uveitis, diabetic ketoacidosis, arthralgia) | Grade 3 | Withhold until adverse reactions recover to Grades 0-1. |
| Grade 4 | Permanently discontinue. | |
| Persistent Grade 2 or 3 immune-related adverse reactions (excluding endocrinopathies) | Grade 2 or 3 (≥ 12 weeks after last dose) Recurrent Grade 3 or 4 Recurrent Grade 2 pneumonitis | Permanently discontinue. |
| Infusion-related reactions | Grade 1 | Interrupt or slow the rate of infusion. |
| Grade 2 | First occurrence: Interrupt infusion and resume at 50% of the original rate if symptoms resolve within 1 hour. Subsequent occurrences: Permanently discontinue after recommended prophylaxis. | |
| Grade 3 | Permanently discontinue. If rapidly responsive to symptomatic management and/or to brief interruption of infusion, retifanlimab does not need to be permanently discontinued. | |
| Grade 4 | Permanently discontinue. |
AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; TB = total bilirubin; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis.
a Toxicity graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.
b Permanently discontinue only if retifanlimab is directly implicated in renal toxicity.
All prescribers of ZYNYZ should be familiar with and inform the patients about the patient card explaining what to do should they experience any symptom of immune-related adverse reactions. The patient card will be provided to each patient treated with retifanlimab.
No dose adjustment is needed for patients who are aged 65 years or over (see sections 5.1 and 5.2).
No dose adjustment is needed for patients with mild or moderate renal impairment. There is insufficient data in patients with severe renal impairment (creatinine clearance <30 mL/min) and no data for patients with end-stage renal disease and therefore no dosing recommendation can be made (see section 5.2).
No dose adjustment is needed for patients with mild hepatic impairment. There are insufficient data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment and therefore no dosing recommendations can be made (see section 5.2).
There is no relevant use of retifanlimab in children and adolescents below the age of 18 years with Merkel cell carcinoma.
ZYNYZ is for intravenous use. It must be diluted and administered by intravenous infusion over 30 minutes.
ZYNYZ must not be administered as an intravenous push or bolus injection.
ZYNYZ can only be administered through an 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 filter. Other medicinal products should not be co-administered through the same infusion line.
For instructions on dilution of the medicinal product before administration, see section 6.6.
In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted.
Unopened vial:
2 years.
After dilution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 2ºC to 8ºC and 8 hours at room temperature (20ºC to 25ºC).
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2ºC to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original carton in order to protect from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
Type I glass vial, closed with a FluroTec-coated chlorobutyl rubber stopper, aluminium seal and plastic flip-off cap, containing 20 mL concentrate.
Each carton contains one vial.
Preparation and administration:
Disposal:
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
