Leaflet ZYNYZ 500mg concentrate for solution for infusion

ZYNYZ 500 mg concentrate for solution for infusion

One vial of 20 mL concentrate contains 500 mg of retifanlimab.

Each mL of concentrate contains 25 mg of retifanlimab.

Retifanlimab is an anti-programmed cell death protein-1 (PD-1) immunoglobulin G4 (IgG4)humanised monoclonal antibody produced by recombinant DNA technology in Chinese hamster ovary(CHO) cell suspension culture.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear to slightly opalescent, colourless to pale yellow solution, with a pH of 5.1 and osmolalitybetween 275 and 355 mOsm/kg.

Squamous cell carcinoma of the anal canal (SCAC)

ZYNYZ is indicated in combination with carboplatin and paclitaxel for the first-line treatment of adultpatients with metastatic or with inoperable locally recurrent squamous cell carcinoma of the anal canal(SCAC).

Merkel cell carcinoma (MCC)

ZYNYZ is indicated as monotherapy for the first-line treatment of adult patients with metastatic orrecurrent locally advanced Merkel cell carcinoma (MCC) not amenable to curative surgery orradiation therapy.

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.

Squamous cell carcinoma of the anal canal (SCAC)

The recommended dose is 500 mg retifanlimab every 4 weeks administered as an intravenous infusionover 30 minutes, in combination with carboplatin and paclitaxel for 6 cycles followed by retifanlimab500 mg as monotherapy every 4 weeks for all cycles thereafter. Treatment should continue untildisease progression or unacceptable toxicity for up to 1 year.

For the dosing and administration of carboplatin and paclitaxel, including recommended patientmanagement, refer to the respective Summary of Product Characteristics (SmPC).

Merkel cell carcinoma (MCC)

The recommended dose is 500 mg retifanlimab every 4 weeks administered as an intravenous infusionover 30 minutes. Treatment should continue until disease progression or unacceptable toxicity for upto 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 for ZYNYZ

Adverse reaction Severitya Dose modification

Pneumonitis Grade 2 Withhold until adverse reactionsrecover to Grades 0-1.

Grades 3 or 4 Permanently discontinue.

Colitis Grades 2 or 3 Withhold until adverse reactionsrecover to Grades 0-1.

Recurrent Grade 3 or Grade 4 Permanently discontinue.

Hepatitis with no tumour Grade 3 with AST or ALT greater than Withhold until adverse reactionsinvolvement of the liver 3 but no more than 8 times ULN recover to Grades 0-1.

OR

OR TB increases to more Permanently discontinue if nothan 1.5 and up to 3 times ULN resolution within 12 weeks of

Increased total bilirubin initiating steroids or inability toreduce prednisone to less than10 mg/day (or equivalent) within12 weeks of initiating steroids.

Grade 4 with AST or ALT increases to Permanently discontinue.more than 8 times ULN

OR

TB greater than 3 times ULN

Hepatitis with tumour Grade 3 with AST or ALT more than 5 Withhold until adverse reactionsinvolvement of the liver and up to 10 times ULN recover to Grades 0-1.

OR

OR TB greater than 1.5 but no more than 3 Permanently discontinue if notimes ULN resolution within 12 weeks of

Increased total bilirubin initiating steroids or inability toreduce prednisone to less than10 mg/day (or equivalent) within12 weeks of initiating steroids.

Grade 4 with AST or ALT increase tomore than 10 times ULN Permanently discontinue.

OR

TB greater than 3 times ULN

Endocrinopathies Grade 2 adrenal insufficiency Withhold until adverse reactions

* Adrenal insufficiency recover to Grades 0-1 or otherwise

* Hypothyroidism clinically stable.

* Hyperthyroidism Grades 3 or 4 adrenal insufficiency Withhold until adverse reactions

* Type 1 diabetes recover to Grades 0-1.

mellitus

* Hyperglycaemia Permanently discontinue if no

* Hypophysitis resolution within 12 weeks ofinitiating steroids or inability to

Adverse reaction Severitya Dose modificationreduce prednisone to less than10 mg/day (or equivalent) within12 weeks of initiating steroids.

Grades 3 or 4 hypothyroidism Withhold until adverse reactionsrecover to Grades 0-1 or is otherwiseclinically stable.

Grades 3 or 4 hyperthyroidism Withhold until adverse reactionsrecover to Grades 0-1 or is otherwiseclinically stable.

Grades 3 or 4 type 1 diabetes Withhold until adverse reactionsmellitus (or hyperglycaemia) recover to Grades 0-1 or is otherwiseclinically stable.

Grade 2 hypophysitis (asymptomatic) Withhold until adverse reactionsrecover to Grades 0-1.

May restart after controlled byhormone replacement therapy.

Grade 2 hypophysitis (symptomatic e.g., Withhold until adverse reactionsheadaches, visual disturbances) recover to Grades 0-1.

May restart after controlled byhormone replacement therapy, ifindicated and steroid taper iscomplete.

Grade 3 or 4 hypophysitis Withhold until adverse reactions(symptomatic) recover to Grades 0-1.

Permanently discontinue if noresolution within 12 weeks ofinitiating steroids or inability toreduce prednisone to less than10 mg/day (or equivalent) within12 weeks of initiating steroids.

Nephritis with renal Grade 2 increased blood creatinine Withhold until adverse reactionsdysfunction recover to Grades 0-1.

Grade 3 or 4 increased blood creatinine Permanently discontinue.b

Skin reactions Grade 3 or suspected SJS or suspected Withhold until adverse reactions

TEN recover to Grades 0-1.

Persistent Grade 2 (≥ 2 weeks)

Grade 4 or confirmed SJS or confirmed Permanently discontinue.

TEN

Myocarditis Confirmed Grades 2, 3 or 4 Permanently discontinue.

Other immune-related Grade 3 Withhold until adverse reactionsadverse reactions recover to Grades 0-1.(including myositis, Grade 4 Permanently discontinue.encephalitis, demyelinatingneuropathy, Guillain Barrésyndrome, sarcoidosis,autoimmune haemolyticanaemia, pancreatitis,uveitis, diabeticketoacidosis, arthralgia)

Adverse reaction Severitya Dose modification

Persistent Grade 2 or 3 Grade 2 or 3 (≥ 12 weeks after last dose) Permanently discontinue.immune-related adversereactions (excluding Recurrent Grade 3 or 4endocrinopathies)

Recurrent Grade 2 pneumonitis

Infusion-related reactions Grade 1 Interrupt or slow the rate of infusion.

Grade 2 First occurrence: Interrupt infusionand resume at 50% of the originalrate if symptoms resolve within 1hour.

Subsequent occurrences:

Permanently discontinue afterrecommended prophylaxis.

Grade 3 Permanently discontinue.

If rapidly responsive to symptomaticmanagement and/or to briefinterruption of infusion, retifanlimabdoes not need to be permanentlydiscontinued.

Grade 4 Permanently discontinue.

AST = aspartate aminotransferase; ALT = alanine aminotransferase; ULN = upper limit of normal; TB = totalbilirubin; 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 cardexplaining what to do should they experience any symptom of immune-related adverse reactions. Thepatient 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 isinsufficient data in patients with severe renal impairment (creatinine clearance < 30 mL/min) and nodata 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 inpatients with moderate hepatic impairment and no data in patients with severe hepatic impairment andtherefore 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 withsquamous cell carcinoma of the anal canal and Merkel cell carcinoma.

ZYNYZ is for intravenous use. It must be diluted and administered by intravenous infusion over30 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 to5 micron in-line or add-on filter or 15 micron mesh in-line or add-on filter. Other medicinal productsshould not be co-administered through the same infusion line.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Immune-related adverse reactions, which may be severe or fatal, can occur in patients treated withretifanlimab. Immune-related adverse reactions can occur in any organ or tissue and may affect morethan one body system simultaneously. While immune-related adverse reactions usually occur duringtreatment, symptoms can also manifest after discontinuation. Important immune-related adversereactions listed in this section are not inclusive of all possible immune-related reactions.

Early identification and management of immune-related adverse reactions is essential to ensure safeuse of retifanlimab. Patients should be monitored for symptoms and signs of immune-related adversereactions. Blood chemistries, including liver tests and thyroid function tests, should be evaluated atstart of treatment and periodically during treatment. For suspected immune-related adverse reactions,adequate evaluation including specialty consultation should be ensured to confirm aetiology orexclude other causes.

Based on the severity of the adverse reaction, treatment with retifanlimab should be withheld orpermanently discontinued and corticosteroids (1 to 2 mg/kg/day prednisone or equivalent) or otherappropriate therapy administered. Upon improvement to Grade ≤ 1, corticosteroid taper should beinitiated and continued for at least 1 month (see Table 1).

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest thatthe risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy maybe increased as compared with the risk in patients without pre-existing AID. In addition, flares of theunderlying AID were frequent, but the majority were mild and manageable. However, data specific toretifanlimab are scarce.

Immune-related pneumonitis has been reported in patients receiving retifanlimab (see section 4.8).

Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis shouldbe confirmed with radiographic imaging and other causes excluded. Patients should be managed withretifanlimab treatment modifications and corticosteroids (see Table 1).

Immune-related colitis has been reported in patients receiving retifanlimab (see section 4.8). Patientsshould be monitored for signs and symptoms of colitis and managed with retifanlimab treatmentmodifications, anti-diarrhoeal agents and corticosteroids (see Table 1).

Immune-related hepatitis has been reported in patients receiving retifanlimab (see section 4.8).

Patients should be monitored for abnormal liver tests prior to and periodically during treatment asindicated based on clinical evaluation and managed with retifanlimab treatment modifications andcorticosteroids (see Table 1). For Grade 1 hepatitis, liver chemistry monitoring should be increased totwice per week until liver chemistry tests return to baseline.

Immune-related endocrinopathies, including hypothyroidism, hyperthyroidism, adrenal insufficiency,hypophysitis and diabetic ketoacidosis have been reported in patients receiving retifanlimab (seesection 4.8). Patients should be monitored for abnormal thyroid function tests prior to and periodicallyduring treatment and for cortisol, as indicated based on symptoms and/or falling thyroid-stimulatinghormone.

Hypothyroidism and hyperthyroidism

Immune-related hypothyroidism and hyperthyroidism (including thyroiditis) have been reported inpatients receiving retifanlimab. Immune-related hypothyroidism and hyperthyroidism (includingthyroiditis) should be managed with retifanlimab treatment modifications as recommended in Table 1.

Hypophysitis

Immune-related hypophysitis has been observed in patients receiving retifanlimab (see section 4.8).

Patients should be monitored for signs and symptoms of hypophysitis and managed with retifanlimabtreatment modifications, corticosteroids and hormone replacement, as clinically indicated (see

Table 1).

Immune-related adrenal insufficiency has been reported in patients receiving retifanlimab. Patientsshould be monitored for clinical signs and symptoms of adrenal insufficiency and managed withcorticosteroids and hormone replacement, as clinically indicated (see Table 1).

Type 1 Diabetes mellitus

Immune-related type 1 diabetes mellitus has been observed in patients treated with PD-1 inhibitors(see section 4.8). Patients should be monitored for hyperglycaemia and signs and symptoms ofdiabetes as indicated based on clinical evaluation and managed with oral anti-hyperglycaemics orinsulin and retifanlimab treatment modifications (see Table 1).

Immune-related nephritis has been reported in patients receiving retifanlimab (see section 4.8).

Patients should be monitored for changes in renal function and managed with retifanlimab treatmentmodifications and corticosteroids (see section 4.2).

Immune-related skin reactions

Immune-related skin reactions, such as toxic epidermal necrolysis, have been reported in patientsreceiving retifanlimab (see section 4.8). Events of Stevens-Johnson syndrome have been reported inpatients treated with PD-1 inhibitors. Patients should be monitored for signs and symptoms of skinreactions. Immune-related skin reactions should be managed as recommended in Table 1.

Caution should be used when considering the use of retifanlimab in a patient who has previouslyexperienced a severe or life-threatening skin adverse reaction on prior treatment with other checkpointinhibitors.

Clinically significant, immune-related adverse reactions were reported in patients treated withretifanlimab in clinical studies including: uveitis, arthritis, myositis, demyelinating polyneuropathy(e.g. Guillain Barré syndrome), pancreatitis, myocarditis, cholangitis, and stomatitis (see section 4.8).

Patients should be monitored for signs and symptoms of immune-related adverse reactions andmanaged with retifanlimab treatment modifications as described in section 4.2.

As with any therapeutic protein, retifanlimab can cause infusion-related reactions, some of which maybe severe. Patients should be monitored for signs and symptoms of infusion-related reactions.

Retifanlimab treatment should be interrupted or the rate of infusion slowed or treatment should bepermanently discontinued based on severity of reaction and the response to treatment (see section 4.2).

Premedication with an antipyretic and/or an antihistamine should be considered for patients who havehad previous clinically significant reactions to infusions of therapeutic proteins (see section 4.8).

The concomitant administration of retifanlimab with carboplatin and paclitaxel increased the risk andseverity of neutropaenia.

Frequent hematological monitoring is recommended and treatment guidelines for neutropenia shouldbe followed.

Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with

PD-1 inhibitors. Treatment with retifanlimab may increase the risk of rejection in solid organtransplant recipients. The benefit of treatment with retifanlimab versus the risk of possible organrejection should be considered in these patients.

Complications of allogeneic haematopoietic stem cell transplant (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic haematopoieticstem 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 andsteroid-requiring febrile syndrome (without an identified infectious cause). These complications mayoccur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Patientsshould be closely followed for evidence of transplant-related complications and prompt interventionmay be required. Consider the benefit versus risks of treatment with a PD-1/PD-L1-blocking antibodyprior to or after an allogeneic HSCT.

Patients excluded from the clinical programme

Patients with the following status were excluded from the clinical programme: Eastern Cooperative

Oncology Group (ECOG) baseline performance score ≥ 2; symptomatic central nervous systemmetastases; prior immunotherapy or autoimmune disease that required systemic therapy withimmunosuppressant agents; history of other malignancies within the last 3 years; organ transplant; oractive hepatitis infection. Patients with uncontrolled HIV infection (CD4+ count < 300 cells/μL,detectable viral load, or not receiving highly active antiretroviral therapy) were also excluded.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is essentially‘sodium-free’.

No formal pharmacokinetic drug interaction studies have been conducted with retifanlimab. Sinceretifanlimab is cleared from the circulation through catabolism, no metabolic drug-drug interactionsare expected.

The use of systemic corticosteroids or immunosuppressants before starting retifanlimab, except forphysiological doses of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), should beavoided because of their potential interference with the pharmacodynamic activity and efficacy ofretifanlimab. However, systemic corticosteroids or other immunosuppressants can be used afterstarting retifanlimab to treat immune-related adverse reactions (see sections 4.2 and 4.4).

Retifanlimab is not expected to be a victim or perpetrator of drug-drug interactions involving drugtransporters or CYP enzymes.

Women of childbearing potential should use effective contraception during treatment withretifanlimab and for at least 4 months after the last dose of retifanlimab.

There are no data from the use of retifanlimab in pregnant women. Animal reproduction studies havenot been conducted with retifanlimab. Animal studies have demonstrated that inhibition of the

PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developingfoetus resulting in foetal death. Therefore, based on its mechanism of action, retifanlimab can causefoetal harm when administered to a pregnant woman. Human IgG4 immunoglobulins are known tocross the placenta; therefore, retifanlimab has the potential to be transmitted from the mother to thedeveloping foetus. ZYNYZ is not recommended during pregnancy and in women of childbearingpotential not using effective contraception (see section 5.3).

It is unknown whether retifanlimab is excreted in human milk. There is insufficient information on theexcretion of retifanlimab in animal milk.

Human IgGs are known to be excreted in breast milk during the first few days after birth; whichdecreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannotbe excluded during this short period. For this specific period, a decision should be made whether todiscontinue/abstain from retifanlimab therapy, taking into account the benefit of breast-feeding to thechild and the benefit of therapy to the woman. Afterwards, retifanlimab could be used duringbreast-feeding if clinically needed.

No clinical data are available on the possible effects of retifanlimab on fertility. Animal reproductionstudies to evaluate the effect of retifanlimab on fertility have not been conducted.

ZYNYZ has minor influence on the ability to drive and use machines. Because of potential adversereactions such as fatigue (see section 4.8), patients should be advised to use caution when driving oroperating machinery until they are certain that retifanlimab does not adversely affect them.

Immune-related adverse reactions occurred with retifanlimab. Most of these, including severereactions, resolved following initiation of appropriate medical therapy or withdrawal of retifanlimab(see “Description of selected adverse reactions” below).

The safety of retifanlimab as monotherapy has been evaluated in 452 patients with advanced solidmalignancies who received the recommended 500 mg every 4 weeks dose, including 107 patients withmetastatic or recurrent locally advanced MCC. Median duration of treatment was 5.4 months (range,1 day - 27 months). The most common adverse reactions were fatigue (35.4%), rash (18.8%),diarrhoea (18.6%), anaemia (16.2%), pruritus (15.9%), arthralgia (13.3%), constipation (13.3%),nausea (13.3%), pyrexia (13.1%) and decreased appetite (12.6%). Adverse reactions were serious in11.7% of patients; most serious adverse reactions were immune-related adverse reactions. ZYNYZwas permanently discontinued due to adverse reactions in 8% of patients; most of them wereimmune-related events.

The safety of retifanlimab in combination with carboplatin and paclitaxel has been evaluated in154 patients with metastatic or with inoperable locally recurrent SCAC. Median duration ofretifanlimab treatment was 7.4 months (range, 1 day - 14.6 months). The most common adversereactions were neutropenia (70.1%), pruritus (24%), rash (23.4%), lymphopenia (14.3%),hypothyroidism (14.3%), and alanine aminotransferase increased (10.4%). Adverse reactions wereserious in 13.6% of patients; most serious adverse reactions were immune-related adverse reactions.

ZYNYZ was permanently discontinued due to adverse reactions in 5.8% of patients; most of themwere immune-related events.

Adverse reactions reported in the pooled dataset for patients treated with ZYNYZ monotherapy (N =452) and in combination with carboplatin and paclitaxel (N = 154) are presented in Table 2.

These reactions are presented by system organ class and by frequency. Frequencies are defined as:very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare(≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing incidence.

Table 2: Adverse reactions in patients treated with retifanlimab

Retifanlimab monotherapy Retifanlimab in combination with(N = 452) carboplatin and paclitaxel(N = 154)

System organ class Frequency of all Frequency of grades Frequency of all Frequency of gradesgrades 3-4 grades 3-4

Blood and lymphatic Very common Common Very common Very commonsystem disorders Anaemiaa Anaemiaa Lymphopeniab Neutropeniac

Neutropeniac

Common

Lymphopeniab

Endocrine disorders Common Uncommon Very common Common

Hypothyroidism, Adrenal insufficiency Hypothyroidism Adrenal insufficiency

Hyperthyroidism Hypophysitis

Type 1 diabetes Common Uncommon

Uncommon mellituse Adrenal insufficiency Hypothyroidism

Adrenal insufficiency Hyperthyroidism Hyperthyroidism

Thyroiditisd Hypophysitis Secondary

Hypophysitis Hyperglycaemia adrenocortical

Type 1 diabetes insufficiencymellituse Uncommon

Autoimmunethyroiditis

Secondaryadrenocorticalinsufficiency

Metabolism and Very common Uncommon Common Commonnutrition disorders Decreased appetite Decreased appetite Hyponatraemia Hyponatraemia

Nervous system Common Uncommon Very common Commondisorders Paraesthesia Polyneuropathyf Peripheral sensory Peripheral

Radiculopathy neuropathy sensorimotor

Uncommon neuropathy

Polyneuropathyf Common

Radiculopathy Peripheral motor

Vocal cord paralysis neuropathy

Peripheralsensorimotorneuropathy

Eye disorders Uncommon Uncommon

Uveitisg Uveitisg

Keratitis

Cardiac disorders Uncommon Uncommon

Pericarditis Myocarditis

Respiratory, thoracic Common Uncommonand mediastinal Pneumonitish Pneumonitishdisorders

Retifanlimab monotherapy Retifanlimab in combination with(N = 452) carboplatin and paclitaxel(N = 154)

Gastrointestinal Very common Uncommon Very common Commondisorders Diarrhoea Diarrhoea Colitisj Colitisj

Nausea Pancreatitis

Constipation Colitisi Common

Stomatitis

Common

Colitisi

Uncommon

Hepatobiliary Common Uncommon Common Commondisorders Hepatocellular injury Hepatitisk Hepatitisl Hepatitisl

Hepatitisk Hepatocellular injury

Cholangitis Uncommon Uncommon

Uncommon Hyperbilirubinaemia Immune-mediated Immune-mediated

Hyperbilirubinaemia cholangitis cholangitis

Cholangitis

Skin and Very common Common Very common Commonsubcutaneous skin Rashm Rashm Pruritus Rashndisorders Pruritus Rashn

Uncommon

Pruritus

Musculoskeletal and Very common Uncommon Commonconnective tissue Arthralgia Arthralgia Arthritisdisorders Arthritiso

Uncommon Myositis

Arthritiso Eosinophilic fasciitis

Myositis

Eosinophilic fasciitis

Polymyalgiarheumatica

Renal and urinary Common Uncommondisorders Acute kidney injury Acute kidney injury

Renal failure Tubulointerstitialnephritis

Uncommon

Tubulointerstitialnephritis

General disorders Very common Common Very common Commonand administration Fatiguep Fatiguep Asthenia Astheniasite conditions Pyrexia

Uncommon

Investigations Common Common Very common Common

Transaminases Transaminases Alanine Alanineincreasedq increasedq aminotransferase aminotransferase

Blood creatinine increased increasedincreased Uncommon Aspartate

Amylase increased Blood bilirubin Common aminotransferase

Lipase increased increased Aspartate increased

Blood bilirubin Lipase increased aminotransferase Lipase increasedincreased increased

Retifanlimab monotherapy Retifanlimab in combination with(N = 452) carboplatin and paclitaxel(N = 154)

Blood thyroid Blood creatinine Lipase increased Uncommonstimulating hormone increased Blood creatinine Blood creatinineincreased Amylase increased increased increased

Amylase increased Amylase increased

Uncommon

Blood thyroidstimulating hormonedecreased

Injury, poisoning Common Uncommon Common Uncommonand procedural Infusion-related Infusion-related Infusion-related Infusion-relatedcomplications reactionr reactionr reaction reactiona Includes anaemia, iron deficiency anaemia, anaemia of malignant disease and anaemia vitamin B12 deficiency.b Includes lymphopenia and lymphocyte count decreased.c Includes neutropenia and neutrophil count decreased.d Includes thyroiditis and autoimmune thyroiditis.e Includes diabetic ketoacidosis.f Includes polyneuropathy and demyelinating polyneuropathy.g Includes uveitis and iritis.h Includes pneumonitis, interstitial lung disease, organising pneumonia and lung infiltration.i Includes colitis and immune mediated enterocolitis.j Includes colitis, immune mediated enterocolitis and immune mediated diarrhoea.k Includes hepatitis and autoimmune hepatitis.l Includes hepatitis and immune-mediated hepatitis.m Includes rash, rash maculo-papular, rash erythematous, rash pruritic, dermatitis, psoriasis, rash macular, rash papular,lichenoid keratosis, rash pustular, dermatitis bullous, palmar-plantar erythrodyseasthesia syndrome, toxic epidermalnecrolysis and toxic skin eruption.

n Includes rash, rash erythematous, rash maculo-papular and rash pruritic.o Includes arthritis and polyarthritis.p Includes asthenia and fatigue.q Includes transaminases increased, alanine aminotransferase increased and aspartate aminotransferase increased.r Includes drug hypersensitivity and infusion related reaction.

The selected adverse reactions described below are based on the safety of retifanlimab monotherapy ina pooled safety population of 452 patients with advanced solid malignancies, including patients withmetastatic or recurrent locally advanced MCC and on the safety of retifanlimab in combination withcarboplatin and paclitaxel in 154 patients with metastatic or with inoperable locally recurrent SCAC.

The management guidelines for these adverse reactions are described in section 4.2.

Immune-related pneumonitis occurred in 3.1% of patients receiving retifanlimab monotherapy,including 1.3% of patients with Grade 2, 0.9% of patients with Grade 3 and 0.2% of patients with

Grade 5. The median time to onset of pneumonitis was 100 days (range, 43 - 673 days). Pneumonitisled to discontinuation of retifanlimab in 0.2% of patients. Among the patients with pneumonitis,71.4% received systemic corticosteroids. Pneumonitis resolved in 78.6% of patients, with a mediantime to resolution of 37 days (range, 9 - 104 days).

Immune-related colitis occurred in 2.7% of patients receiving retifanlimab monotherapy, including1.1% of patients with Grade 2, 0.4% of patients with Grade 3 and 0.2% of patients with Grade 4. Themedian time to onset of colitis was 165.5 days (range, 11 - 749 days). Colitis led to discontinuation ofretifanlimab in 0.9% of patients. Among the patients with colitis, 75% received systemiccorticosteroids and 8.3% received another immunosuppressant (infliximab). Colitis resolved in 66.7%of patients, with a median time to resolution of 83.5 days (range, 15 - 675 days).

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,immune-related colitis occurred in 10.4% of patients, including 3.2% of patients with Grade 2, 2.6%of patients with Grade 3 and 0.6% of patients with Grade 4. The median time to onset of colitis was83.5 days (range, 3 - 271 days). Colitis led to discontinuation of retifanlimab in 1.3% of patients.

Among the patients with colitis, 93.8% received systemic corticosteroids and 6.3% received anotherimmunosuppressant (infliximab). Colitis resolved in 93.8% of patients, with a median time toresolution of 27 days (range, 1 - 102 days).

Immune-related nephritis occurred in 2% of patients receiving retifanlimab monotherapy, including0.4% of patients with Grade 2, 1.1% of patients with Grade 3 and 0.4% of patients with Grade 4. Themedian time to onset of nephritis was 176 days (range, 15 - 515 days). Nephritis led to discontinuationof retifanlimab in 1.1% of patients. Among the patients with nephritis, 66.7% received systemiccorticosteroids. Nephritis resolved in 44.4% of patients, with a median time to resolution of 22.5 days(range, 9 - 136 days).

Hypothyroidism occurred in 10.2% of patients receiving retifanlimab monotherapy, including 4.9% ofpatients with Grade 2. The median time to onset of hypothyroidism was 88 days (range, 1 - 505 days).

None of the events led to discontinuation of retifanlimab. Hypothyroidism resolved in 32.6% ofpatients, with a median time to resolution of 56 days (range, 2 - 224 days).

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,hypothyroidism occurred in 14.3% of patients, including 9.1% of patients with Grade 2 and 0.6% ofpatients with Grade 4. The median time to onset of hypothyroidism was 138.5 days (range,55 - 390 days). Hypothyroidism led to discontinuation of retifanlimab in 1 patient. Hypothyroidismresolved in 27.3% of patients, with a median time to resolution of 114 days (range, 57 - 212 days).

Hyperthyroidism occurred in 5.8% of patients receiving retifanlimab monotherapy, including 2.7% ofpatients with Grade 2. The median time to onset of hyperthyroidism was 55.5 days (range,8 - 575 days). None of the events led to discontinuation of retifanlimab. Hyperthyroidism resolved in61.5% of patients, with a median time to resolution of 74 days (range, 15 - 295 days).

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,hyperthyroidism occurred in 8.4% of patients, including 3.2% of patients with Grade 2 and 0.6% ofpatients with Grade 3. The median time to onset of hyperthyroidism was 82 days (range,8 - 278 days). None of the events led to discontinuation of retifanlimab. Hyperthyroidism resolved in76.9% of patients, with a median time to resolution of 29 days (range, 8 - 130 days).

Hypophysitis occurred in 0.7% of patients receiving retifanlimab monotherapy, including 0.4% ofpatients with Grade 2 and 0.2% of patients with Grade 3. The median time to onset of hypophysitiswas 308 days (range, 266 - 377 days). Hypophysitis led to discontinuation of retifanlimab in 0.2% ofpatients. Hypophysitis resolved in 33.3% of patients, with a time to resolution of 6 days.

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,hypophysitis occurred in 2 patients (1.3%, both Grade 2). The median time to onset of hypophysitiswas 192 days (range, 90 - 294 days). Neither of the events led to discontinuation of retifanlimab.

Hypophysitis resolved in 1 of the 2 patients, with a time to resolution of 8 days.

Adrenal insufficiency occurred in 0.9% of patients receiving retifanlimab monotherapy, including0.4% of patients with Grade 2 and 0.4% of patients with Grade 3. The median time to onset of adrenalinsufficiency was 220.5 days (range, 146 - 275 days). None of the events led to discontinuation ofretifanlimab. Adrenal insufficiency resolved in 25% of patients, with a time to resolution of 12 days.

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel, adrenalinsufficiency occurred in 5.8% of patients, including 1.9% of patients with Grade 2 and 1.9% ofpatients with Grade 3. The median time to onset of adrenal insufficiency was 197 days (range,63 - 302 days). One event led to discontinuation of retifanlimab. Adrenal insufficiency resolved in44.4% of patients, with a time to resolution of 13.5 days.

Type 1 diabetes mellitus presenting as diabetic ketoacidosis (Grade 3) occurred in 0.2% of patientsreceiving retifanlimab monotherapy. The time to onset of diabetic ketoacidosis was 284 days. Theevent did not lead to discontinuation of retifanlimab and resolved with a time to resolution of 6 days.

Immune-related hepatitis occurred in 3.5% of patients receiving retifanlimab monotherapy, including0.9% of patients with Grade 2, 2.4% of patients with Grade 3 and 0.2% of patients with Grade 4. Themedian time to onset of hepatitis was 70.5 days (range, 8 - 580 days). Hepatitis led to discontinuationof retifanlimab in 1.5% of patients. Among the patients with hepatitis, 81.3% of patients receivedsystemic corticosteroids and 6.3% of patients received another immunosuppressant (mycophenolatemofetil). Hepatitis resolved in 56.3% of patients, with a median time to resolution of 22 days (range,6 - 104 days).

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,immune-related hepatitis occurred in 2 patients (1.3%, both Grade 3). The median time to onset ofhepatitis was 195.5 days (range, 140 - 251 days). Hepatitis led to discontinuation of retifanlimab in 1patient. Both patients with hepatitis received systemic corticosteroids and another immunosuppressant(mycophenolate mofetil). Hepatitis resolved in both patients, with a median time to resolution of58.5 days (range, 57 - 60 days).

Immune-related skin reactions

Immune-related skin reactions occurred in 9.5% of patients receiving retifanlimab monotherapy,including 8% of patients with Grade 2, 1.1% of patients with Grade 3 and 0.2% of patients with Grade4. The median time to onset of skin reactions was 86 days (range, 2 - 589 days). Skin reactions led todiscontinuation of retifanlimab in 0.7% of patients. Among the patients with skin reactions, 32.6% ofpatients received systemic corticosteroids. Skin reactions resolved in 72.1% of patients, with a mediantime to resolution of 37 days (range, 3 - 470 days).

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,immune-related skin reactions occurred in 11.7% of patients, including 9.7% of patients with Grade 2and 1.9% of patients with Grade 3. The median time to onset of skin reactions was 46.5 days (range, 2- 443 days). Skin reactions led to discontinuation of retifanlimab in 2 patients. Among the patientswith skin reactions, 33.3% of patients received systemic corticosteroids. Skin reactions resolved in72.2% of patients, with a median time to resolution of 22 days (range, 5 - 385 days).

Infusion related-reactions

Infusion-related reactions occurred in 6.2% of patients receiving retifanlimab monotherapy, including2.2% of patients with Grade 2 and 0.4% of patients with Grade 3. Infusion-related reactions led todiscontinuation of retifanlimab in 0.4% patients.

In patients with SCAC receiving retifanlimab in combination with carboplatin and paclitaxel,infusion-related reactions occurred in 9.7% of patients, including 1.9% of patients with Grade 3. Noneof the infusion-related reactions led to discontinuation of retifanlimab.

In patients with SCAC receiving retifanlimab in combination with chemotherapy, the proportion ofpatients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality occurring in> 3% of patients was 42.8% for decreased lymphocytes, 52% for decreased neutrophils, 4.5 % forlipase, 3.9 % for alanine aminotransferase, and 3.9% for aspartate aminotransferase.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, patients must be closely monitored for signs or symptoms of adverse reactionsand appropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Antineoplastic agents, PD-1/PD-L1 (Programmed cell death protein1/death ligand 1) inhibitors. ATC code: L01FF10

Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmeddeath receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2. Engagement of

PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may beexpressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of

T-cell function such as proliferation, cytokine secretion and cytotoxic activity. Retifanlimab binds tothe PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cellactivity.

Anti-drug antibodies (ADA) were uncommonly detected. No evidence of ADA impact onpharmacokinetics, efficacy or safety was observed.

Squamous cell carcinoma of the anal canal (SCAC)

The efficacy and safety of retifanlimab in combination with carboplatin and paclitaxel was studied inthe POD1UM-303/InterAACT-2 study, a randomised, multicenter, double-blind phase III study thatenrolled patients with chemotherapy-naïve metastatic or inoperable locally recurrent SCAC. Patientswith active autoimmune disease or a medical condition that required immunosuppression, severehepatic or renal impairment, clinically significant cardiac disease, history of organ transplant, Eastern

Cooperative Oncology Group (ECOG) performance score (PS) ≥ 2, or evidence of interstitial lungdisease or active noninfectious pneumonitis were ineligible. Patients who had not received priorsystemic therapy other than a radiosensitising agent or neoadjuvant or adjuvant therapy completed> 6 months prior to study entry were eligible as were patients who were HIV-positive if they had anundetectable viral load, a CD4+ count ≥ 200 cells/microliter and were receiving antiretroviral therapy.

The study did not enroll patients who received prior treatment with PD-(L)1 directed therapies.

Randomisation was stratified by PD-L1 expression (< 1% versus ≥ 1%), region, and extent of disease(locally recurrent versus metastatic). Patients were randomised (1:1) to receive either:

* Retifanlimab 500 mg intravenously every 4 weeks on Day 1, carboplatin AUC of 5 mg/mL on

Day 1, and paclitaxel 80 mg/m2 on Days 1, 8, and 15 for 6 cycles followed by retifanlimab500 mg intravenously every 4 weeks.

* Placebo intravenously every 4 weeks on Day 1, carboplatin AUC 5 mg/mL on Day 1, andpaclitaxel 80 mg/m2 on Days 1, 8, and 15 for 6 cycles followed by placebo 500 mgintravenously every 4 weeks.

Treatment with retifanlimab continued until disease progression, unacceptable toxicity, death, orwithdrawal of consent, for up to 12 months. Tumour response assessments were performed every 8weeks throughout the treatment period. Patients who received placebo in combination with carboplatinand paclitaxel and who experienced documented disease progression (verified by blinded independentcentral review (BICR)), had the option of receiving retifanlimab 500 mg monotherapy in a crossovertreatment period.

Among the 308 patients enrolled, the median age was 62 years (range, 29 - 86 years) with 31 (10.1%)age 75 or older; 27.9% of patients were male, 87.3% of patients were Caucasian and the ECOGperformance status was 0 (54.5%) or 1 (45.1%). Seventy-one percent of patients were reported to havehad prior radiotherapy and 34.7% had prior surgery. Four percent of patients were HIV-positive.

Eighty-three percent of patients had metastatic disease at baseline. PD-L1 expression of ≥ 1% waspresent in 91% of tumours.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by a BICR accordingto Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the key secondary endpoint wasoverall survival (OS). Additional secondary efficacy endpoints included objective response rate (ORR)and duration of response (DOR).

Efficacy results are summarised in Table 3, Figure 1, and Figure 2.

Table 3: Efficacy results in POD1UM-303/InterAACT-2 for patients with metastatic orinoperable locally recurrent SCAC

ZYNYZ in combination Placebo in combinationwith carboplatin and with carboplatin andpaclitaxel paclitaxel

Endpoint (N = 154) (N = 154)

Progression-free survivala,b

Events, n (%) 92 (59.7) 110 (71.4)

Median in months (95% CI) 9.3 (7.5, 11.3) 7.4 (7.1, 7.7)

Hazard ratio (95% CI) 0.63 (0.47, 0.84)p-valuec 0.0013

Overall survivald

Deaths, n (%) 78 (50.6) 94 (61.0)

Median in months (95% CI) 32.8 (25.7, 44.5) 22.2 (15.7, 27.2)

Hazard ratio (95% CI) 0.75 (0.55, 1.01)

Objective response ratea

Objective response rate (95% CI) 55.8% (47.6, 63.8) 44.2% (36.2, 52.4)

CI = confidence interval.a Based on primary analysis.b Median duration of follow-up for PFS: ZYNYZ in combination with carboplatin and paclitaxel = 7.6 months (range,0 - 33.9 months); placebo in combination with carboplatin and paclitaxel = 7.1 months (range, 0 - 27.4 months).c Two-sided p-value based on the stratified log-rank test.d Based on final analysis; OS did not reach the prespecified threshold for statistical significance.

Figure 1: Kaplan-Meier curve for PFS in POD1UM-303/InterAACT-2 (Final Analysis)

Figure 2: Kaplan-Meier curve for OS in POD1UM-303/InterAACT-2 (Final Analysis)

Merkel cell carcinoma (MCC)

The efficacy and safety of retifanlimab was studied in the POD1UM-201 study, an open-label,single-arm, multiregional study that enrolled patients with metastatic or recurrent locally advanced

MCC who had not received prior systemic therapy for their advanced disease. Patients with activeautoimmune disease or a medical condition that required immunosuppression, severe hepatic or renalimpairment, clinically significant cardiac disease, history of organ transplant, or ECOG PS ≥ 2 wereineligible. Patients who were HIV-positive, with an undetectable viral load, a CD4+ count ≥ 300cells/microliter and receiving antiretroviral therapy were eligible.

Patients received retifanlimab 500 mg every 4 weeks until disease progression or unacceptable toxicityfor a maximum of 2 years. Assessment of efficacy was performed every 8 weeks for the first year oftherapy and 12 weeks thereafter. The major efficacy outcome measure of confirmed objectiveresponse rate, and duration of response were assessed by an independent central review committeeaccording to RECIST v1.1. All ongoing responses were followed for a minimum of 12 months.

A total of 101 patients were analysed for efficacy. The median age of enrolled patients was 71.1 years(range, 38 - 90 years) with 39 (39%) age 75 or older; 67.3% of patients were male, all but one patientwere Caucasian and the Eastern Cooperative Oncology Group performance status was 0 (73.3%) or1 (26.7%). Thirty-seven percent of patients were reported to have had prior radiotherapy and 68.3%had prior surgery. Ninety percent of patients had metastatic disease. One patient was HIV-positive.

The majority of tumour samples tested (72.3%) were positive for Merkel cell polyomavirus (MCPyV).

Efficacy results are summarised in Table 4. The median duration of treatment was 10.3 months (range,1 day - 24.8 months).

Table 4: Efficacy results in POD1UM-201 study for patients with metastatic or recurrent locallyadvanced MCC

ZYNYZ

Endpoint (N = 101)

Objective response rate

Objective response rate (95% CI) 53.5% (43.3, 63.5)

Complete response 16.8%

Partial response 36.6%

Duration of response

Median in months (95% CI) 25.3 (14.2, NE)

Minimum, maximum (months) 1.1, 38.7+

CI = confidence interval; NE = not estimable; + denotes ongoing response.

Median duration of follow-up: 17.6 months (range, 1.1 - 38.7 months).

Efficacy and PD-L1/MCPyV status

Clinical activity was observed regardless of PD-L1 or MCPyV status. Table 5 summarises theobjective response rates by tumour PD-L1 expression and MCPyV status of chemotherapy-naïve MCCpatients with central biomarker results in the POD1UM-201 study.

Table 5: Objective response rates by tumour PD-L1 expression and MCPyV status

ZYNYZ

Objective response rates (95% CI)

N = 101

PD-L1 expressiona at cut-off of ≥ 1%

Positive (n=83) 57.8% (46.5, 68.6)

Negative or missing (n=18) 33.3% (13.3, 59.0)

MCPyV status

Positive (n=73) 52.1% (40, 63.9)

Negative, equivocal, or missing (n=28) 57.1% (37.2, 75.5)

MCPyV = Merkel cell polyomavirus.a PD-L1 expression was determined by IHC using Combined Positive Score (CPS) interpretation.

Squamous cell carcinoma of the anal canal (SCAC)

Of the 154 patients treated with retifanlimab in combination with carboplatin and paclitaxel in theefficacy population in POD1UM-303/InterAACT-2, 37.7% (58/154) were 65 years or older, and 9.1%(14/154) were 75 years or older. No overall differences in efficacy were observed between elderlypatients and younger patients treated with retifanlimab in combination with carboplatin and paclitaxel.

Merkel cell carcinoma (MCC)

Of the 101 patients treated with retifanlimab in the efficacy population in POD1UM-201, 76.2%(77/101) were 65 years or older, and 38.6% (39/101) were 75 years or older. Objective response ratesin these age groups were 55.8% (95% CI: 44.1, 67.2) and 48.7% (95% CI: 32.4, 65.2), respectively.

The European Medicines Agency has waived the obligation to submit the results of studies with

ZYNYZ in all subsets of the paediatric population for the treatment of MCC and SCAC. See 4.2 forinformation on paediatric use.

The pharmacokinetics (PK) of retifanlimab were characterised using a population pharmacokineticsanalysis with concentration data collected from 788 patients with various cancers who receivedretifanlimab doses of 1, 3, 10 mg/kg every 2 weeks, 375 mg every 3 weeks, or 3 mg/kg, 10 mg/kg,500 mg and 750 mg every 4 weeks. The AUC was dose proportional in the studied dose range. Thegeometric mean (CV%) of Cmax and AUC at steady state for the recommended 500 mg every 4 weeksdose were 197 mg/L (25.4%) and 2270 day*mg/L (35.1%).

The geometric mean value (CV%) for volume of distribution at steady state is 6 L (19.8%).

The metabolic route of retifanlimab has not been characterised. Retifanlimab is expected to becatabolised through protein degradation processes.

The geometric mean (CV%) clearance of retifanlimab after the first dose was 0.301 L/day (38.3%) anddecreased over time by 22.9%, resulting in a steady-state clearance of 0.232 L/day (35.7%). For therecommended 500 mg every 4 weeks dose, half-life is 15.6 days (31.5%) and 19.8 days (29.9%) afterfirst-dose and at steady-state, respectively.

The following factors are not expected to have clinically important effects on the pharmacokinetics ofretifanlimab: age (range: 18 to 94 years), weight (33 to 133 kg), sex, race, or tumour burden.

The effect of renal impairment on the clearance of retifanlimab was evaluated by populationpharmacokinetic analyses in patients with mild (n = 354) or moderate (n = 151) renal impairment(eGFR between 89 and 30 mL/min/1.73m2; n = 505) compared to patients with normal renal function(eGFR ≥ 90 mL/min/1.73m2; n = 263). No clinically important differences were found in the clearanceof retifanlimab. There are limited data in patients with severe renal impairment (n = 4, lowest eGFR26.0 mL/min/1.73m2). Retifanlimab has not been studied in patients with end-stage renal disease.

The effect of hepatic impairment on the clearance of retifanlimab was evaluated by populationpharmacokinetic analyses in patients with mild (n = 93; TB > ULN to 1.5 ULN or AST > ULN)hepatic impairment compared to patients with normal (n = 692; TB and AST ≤ ULN) hepatic function.

No clinically important differences were found in the clearance of retifanlimab. There are limited datain patients with moderate (n = 1; TB between 1.5 and 3.0 times ULN and any AST) hepaticimpairment. Retifanlimab has not been studied in patients with severe (TB between 3.0 and 10 times

ULN and any AST) hepatic impairment.

No findings of toxicological significance were observed in monkeys in studies of up to 13 weeksduration at exposures sufficiently in excess compared to the clinical exposure at the recommendeddose of 500 mg retifanlimab every 4 weeks.

No studies have been performed to assess the potential of retifanlimab for carcinogenicity orgenotoxicity.

Animal reproduction and development toxicity studies have not been conducted with retifanlimab. Acentral function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternalimmune tolerance to the foetus. In murine models of pregnancy, blockade of PD-L1 signaling hasbeen shown to disrupt tolerance to the foetus and to result in an increase in foetal loss; therefore,potential risks of administering retifanlimab during pregnancy include increased rates of abortion orstillbirth. As reported in the literature, there were no malformations related to the blockade of

PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disordersoccurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, foetal exposure toretifanlimab may increase the risk of developing immune-mediated disorders or altering the normalimmune response.

Sodium acetate trihydrate (for pH adjustment) (E262)

Acetic acid, glacial (E260)

Sucrose

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts and/or diluents except those mentioned in section 6.6. Other medicinal products should notbe co-administered through the same infusion line.

Unopened vial2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 ºC to 8 ºC and 8 hoursat room temperature (20 ºC to 25 ºC).

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 ºC to 8 °C, unless dilution has taken place incontrolled 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 andplastic flip-off cap, containing 20 mL concentrate.

Each carton contains one vial.

Preparation and administration

* Parenteral medicinal products should be inspected visually for particulate matter and discolorationprior to administration. Retifanlimab is a clear to slightly opalescent, colourless to pale yellowsolution, free of visible particles. Discard the vial if the solution is cloudy, discoloured or visibleparticles are observed.

* Do not shake the vial.

* Withdraw 20 mL (500 mg) of retifanlimab concentrate from the vial and transfer into anintravenous infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection orglucose 50 mg/mL (5%) solution for injection to prepare a diluted solution with a finalconcentration between 1.4 mg/mL to 10 mg/mL. Use polyvinylchloride (PVC) and di-2-ethylhexylphthalate (DEHP), polyolefin copolymer, polyolefin with polyamide, or ethylene vinyl acetateinfusion bags.

* Mix the diluted solution by gentle inversion. Do not shake the infusion bag.

* From a microbiological point of view, the diluted solution, once prepared, should be usedimmediately. If not used immediately, chemical and physical in-use stability has beendemonstrated:− For 8 hours at room temperature (20 °C to 25 °C) (including infusion time).

OR− For 24 hours under refrigeration (2 °C to 8 °C). If refrigerated, allow the diluted solution tocome to room temperature prior to administration. The diluted solution must be administeredwithin 4 hours (including infusion time) once it is removed from the refrigerator. Do notfreeze.

* Discard if the diluted solution is discoloured or contains extraneous particulate matter other thantrace amounts of translucent to white particles.

* Administer the retifanlimab solution by intravenous infusion over 30 minutes using a sterile,non-pyrogenic, low-protein binding polyethersulfone, polyvinylidene fluoride, or cellulose acetate0.2 micron to 5 micron in-line or add-on filter or 15 micron mesh in-line or add-on filter.

* Do not co-administer other medicinal products through the same infusion line.

* Retifanlimab is for single use only; discard any unused portion left in the vial.

* Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Incyte Biosciences Distribution B.V.

Paasheuvelweg 251105 BP Amsterdam

Netherlands

EU/1/24/1800/001

Date of first authorisation: 19 April 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.