ZYNYZ 500 mg concentrate for solution for infusion

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.

Posology

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 modifications

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

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.

Patient card

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.

Special populations

Elderly

No dose adjustment is needed for patients who are aged 65 years or over (see sections 5.1 and 5.2).

Renal impairment

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).

Hepatic impairment

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).

Paediatric population

There is no relevant use of retifanlimab in children and adolescents below the age of 18 years with Merkel cell carcinoma.

Method of administration

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.

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

Traceability

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

Immune‑related adverse reactions

Immune‑related adverse reactions, which may be severe or fatal, can occur in patients treated with retifanlimab. Immune‑related adverse reactions can occur in any organ or tissue and may affect more than one body system simultaneously. While immune‑related adverse reactions usually occur during treatment, symptoms can also manifest after discontinuation. Important immune‑related adverse reactions 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 safe use of retifanlimab. Patients should be monitored for symptoms and signs of immune‑related adverse reactions. Blood chemistries, including liver tests and thyroid function tests, should be evaluated at start of treatment and periodically during treatment. For suspected immune‑related adverse reactions, adequate evaluation including specialty consultation should be ensured to confirm aetiology or exclude other causes.

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

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

Immune‑related pneumonitis

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 should be confirmed with radiographic imaging and other causes excluded. Patients should be managed with retifanlimab treatment modifications and corticosteroids (see Table 1).

Immune‑related colitis

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

Immune‑related hepatitis

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 as indicated based on clinical evaluation and managed with retifanlimab treatment modifications and corticosteroids (see Table 1). For Grade 1 hepatitis, liver chemistry monitoring should be increased to twice per week until liver chemistry tests return to baseline.

Immune‑related endocrinopathies

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

Hypothyroidism and hyperthyroidism

Immune‑related hypothyroidism and hyperthyroidism (including thyroiditis) have been reported in patients receiving retifanlimab. Immune‑related hypothyroidism and hyperthyroidism (including thyroiditis) 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 retifanlimab treatment modifications, corticosteroids and hormone replacement, as clinically indicated (see Table 1).

Adrenal insufficiency

Immune‑related adrenal insufficiency has been reported in patients receiving retifanlimab. Patients should be monitored for clinical signs and symptoms of adrenal insufficiency and managed with corticosteroids 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 of diabetes as indicated based on clinical evaluation and managed with oral anti‑hyperglycaemics or insulin and retifanlimab treatment modifications (see Table 1).

Immune‑related nephritis

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 treatment modifications and corticosteroids (see section 4.2).

Immune‑related skin reactions

Immune‑related skin reactions, such as toxic epidermal necrolysis, have been reported in patients receiving retifanlimab (see section 4.8). Events of Stevens‑Johnson syndrome have been reported in patients treated with PD‑1 inhibitors. Patients should be monitored for signs and symptoms of skin reactions. 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 previously experienced a severe or life‑threatening skin adverse reaction on prior treatment with other checkpoint inhibitors.

Other immune‑related adverse reactions

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

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

Infusion‑related reactions

As with any therapeutic protein, retifanlimab can cause infusion‑related reactions, some of which may be 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 be permanently 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 have had previous clinically significant reactions to infusions of therapeutic proteins (see section 4.8).

Transplant‑related adverse reactions

Solid organ transplant rejection

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 organ transplant recipients. The benefit of treatment with retifanlimab versus the risk of possible organ rejection 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 haematopoietic 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). These complications may occur despite intervening therapy between PD‑1/PD‑L1 blockade and allogeneic HSCT. Patients should be closely followed for evidence of transplant‑related complications and prompt intervention may be required. Consider the benefit versus risks of treatment with a PD‑1/PD‑L1–blocking antibody prior 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 system metastases; prior immunotherapy or autoimmune disease that required systemic therapy with immunosuppressant agents; history of other malignancies within the last 3 years; organ transplant; or active 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.

Sodium content

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

Polysorbate 80 content

ZYNYZ contains 2 mg polysorbate 80 in each 20 mL of concentrate which is equivalent to 0.1 mg/mL. Polysorbates may cause allergic reactions.

No formal pharmacokinetic drug interaction studies have been conducted with retifanlimab. Since retifanlimab is cleared from the circulation through catabolism, no metabolic drug‑drug interactions are expected.

The use of systemic corticosteroids or immunosuppressants before starting retifanlimab, except for physiological doses of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent), should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of retifanlimab. However, systemic corticosteroids or other immunosuppressants can be used after starting 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 drug transporters or CYP enzymes.

Women of childbearing potential/Contraception

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

Pregnancy

There are no data from the use of retifanlimab in pregnant women. Animal reproduction studies have not 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 developing foetus resulting in foetal death. Therefore, based on its mechanism of action, retifanlimab can cause foetal harm when administered to a pregnant woman. Human IgG4 immunoglobulins are known to cross the placenta; therefore, retifanlimab has the potential to be transmitted from the mother to the developing foetus. ZYNYZ is not recommended during pregnancy and in women of childbearing potential not using effective contraception (see section 5.3).

Breast‑feeding

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

Human IgGs are known to be excreted in breast milk during the first few days after birth; which decreases to low concentrations soon afterwards; consequently, a risk to the breast‑fed infant cannot be excluded during this short period. For this specific period, a decision should be made whether to discontinue/abstain from retifanlimab therapy, taking into account the benefit of breast‑feeding to the child and the benefit of therapy to the woman. Afterwards, retifanlimab could be used during breast‑feeding if clinically needed.

Fertility

No clinical data are available on the possible effects of retifanlimab on fertility. Animal reproduction studies 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 adverse reactions such as fatigue (see section 4.8), patients should be advised to use caution when driving or operating machinery until they are certain that retifanlimab does not adversely affect them.

Summary of the safety profile

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

The most common adverse reactions are 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 in 11.7% of patients; most serious adverse reactions were immune‑related adverse reactions.

ZYNYZ was permanently discontinued due to adverse reactions in 8% of patients; most of them were immune‑related events.

Tabulated list of adverse reactions

The safety of retifanlimab has been evaluated in 452 patients with advanced solid malignancies who received the recommended 500 mg every 4 weeks dose, including 107 patients with metastatic or recurrent locally advanced MCC. Median duration of treatment was 5.4 months (range, 1 day – 27 months). The frequencies included below are based on all reported adverse drug reactions, regardless of the investigator assessment of causality.

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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing incidence.

Table 2: Adverse reactions in patients treated with retifanlimab (N = 452)

Description of selected adverse reactions

The selected adverse reactions described below are based on the safety of retifanlimab in a pooled safety population of 452 patients with advanced solid malignancies, including patients with metastatic or recurrent locally advanced MCC. The management guidelines for these adverse reactions are described in section 4.2.

Immune‑related adverse reactions (see section 4.4)

Immune‑related pneumonitis

Immune‑related pneumonitis occurred in 3.1% of patients receiving retifanlimab, 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). Pneumonitis led 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 median time to resolution of 37 days (range, 9 – 104 days).

Immune‑related colitis

Immune‑related colitis occurred in 2.7% of patients receiving retifanlimab, including 1.1% of patients with Grade 2, 0.4% of patients with Grade 3 and 0.2% of patients with Grade 4. The median time to onset of colitis was 165.5 days (range, 11 – 749 days). Colitis led to discontinuation of retifanlimab in 0.9% of patients. Among the patients with colitis, 75% received systemic corticosteroids 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).

Immune‑related nephritis

Immune‑related nephritis occurred in 2% of patients receiving retifanlimab, including 0.4% of patients with Grade 2, 1.1% of patients with Grade 3 and 0.4% of patients with Grade 4. The median time to onset of nephritis was 176 days (range, 15 – 515 days). Nephritis led to discontinuation of retifanlimab in 1.1% of patients. Among the patients with nephritis, 66.7% received systemic corticosteroids. Nephritis resolved in 44.4% of patients, with a median time to resolution of 22.5 days (range, 9 – 136 days).

Immune‑related endocrinopathies

Hypothyroidism occurred in 10.2% of patients receiving retifanlimab, including 4.9% of patients 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% of patients, with a median time to resolution of 56 days (range, 2 – 224 days).

Hyperthyroidism occurred in 5.8% of patients receiving retifanlimab, including 2.7% of patients 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 in 61.5% of patients, with a median time to resolution of 74 days (range, 15 – 295 days).

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

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

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

Immune‑related hepatitis

Immune‑related hepatitis occurred in 3.5% of patients receiving retifanlimab, including 0.9% of patients with Grade 2, 2.4% of patients with Grade 3 and 0.2% of patients with Grade 4. The median time to onset of hepatitis was 70.5 days (range, 8 – 580 days). Hepatitis led to discontinuation of retifanlimab in 1.5% of patients. Among the patients with hepatitis, 81.3% of patients received systemic corticosteroids and 6.3% of patients received another immunosuppressant (mycophenolate mofetil). Hepatitis resolved in 56.3% of patients, with a median time to resolution of 22 days (range, 6 – 104 days).

Immune‑related skin reactions

Immune‑related skin reactions occurred in 9.5% of patients receiving retifanlimab, including 8% of patients with Grade 2, 1.1% of patients with Grade 3 and 0.2% of patients with Grade 4. The median time to onset of skin reactions was 86 days (range, 2 – 589 days). Skin reactions led to discontinuation of retifanlimab in 0.7% of patients. Among the patients with skin reactions, 32.6% of patients received systemic corticosteroids. Skin reactions resolved in 72.1% of patients, with a median time to resolution of 37 days (range, 3 – 470 days).

Infusion‑related reactions

Infusion‑related reactions occurred in 6.2% of patients, including 2.2% of patients with Grade 2 and 0.4% of patients with Grade 3. Infusion‑related reactions led to discontinuation of retifanlimab in 0.4% patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

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

Mechanism of action

Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed death 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 be expressed 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 to the PD‑1 receptor, blocks interaction with its ligands PD‑L1 and PD‑L2, and potentiates T‑cell activity.

Pharmacodynamic effects

Immunogenicity

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

Clinical efficacy and safety

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 active autoimmune disease or a medical condition that required immunosuppression, severe hepatic or renal impairment, clinically significant cardiac disease, history of organ transplant, or Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≥ 2 were ineligible. Patients who were HIV‑positive, with an undetectable viral load, a CD4+ count ≥ 300 cells/microliter and receiving antiretroviral therapy were eligible.

Patients received retifanlimab 500 mg every 4 weeks until disease progression or unacceptable toxicity for a maximum of 2 years. Assessment of efficacy was performed every 8 weeks for the first year of therapy and 12 weeks thereafter. The major efficacy outcome measure of confirmed objective response rate, and duration of response were assessed by an independent central review committee according to Response Evaluation Criteria in Solid Tumours (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 patient were Caucasian and the Eastern Cooperative Oncology Group performance status was 0 (73.3%) or 1 (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 summarized in Table 3. The median duration of treatment was 10.3 months (range, 1 day – 24.8 months).

Table 3: Efficacy results in POD1UM‑201 study for patients with metastatic or recurrent locally advanced MCC

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 4 summarises the objective response rates by tumour PD‑L1 expression and MCPyV status of chemotherapy‑naïve MCC patients with central biomarker results in the POD1UM‑201 study.

Table 4: Objective response rates by tumour PD‑L1 expression and MCPyV status

MCPyV = Merkel cell polyomavirus.

^a PD-L1 expression was determined by IHC using Combined Positive Score (CPS) interpretation.

Elderly population

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

Paediatric population

The Medicines and Healthcare products Regulatory 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. See section 4.2 for information on paediatric use.

The pharmacokinetics (PK) of retifanlimab were characterised using a population pharmacokinetics analysis with concentration data collected from 634 patients with various cancers who received retifanlimab 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. The geometric mean (CV%) of C_max and AUC at steady state for the recommended 500 mg every 4 weeks dose were 193 mg/L (24.1%) and 2190 day*mg/L (32.4%).

Distribution

The geometric mean value (CV%) for volume of distribution at steady state is 6.1 L (20.2%).

Biotransformation

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

Elimination

A geometric mean (CV%) clearance of 0.314 L/day (36%), without accounting for the time‑varying part of the clearance, with a half‑life of 14.6 days (31.5%) and 18.7 days (28.7%), after first‑dose and at steady‑state, respectively, were estimated in the population pharmacokinetic analyses.

Special Populations

The following factors are not expected to have clinically important effects on the pharmacokinetics of retifanlimab: age (range: 18 to 94 years), weight (35 to 133 kg), sex, race, or tumour burden.

Renal impairment

The effect of renal impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n = 277) or moderate (n = 142) renal impairment (eGFR between 89 and 30 mL/min/1.73m²; n = 419) compared to patients with normal renal function (eGFR ≥ 90 mL/min/1.73m²; n = 200). No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with severe renal impairment (n = 4, lowest eGFR 26.0 mL/min/1.73m²). Retifanlimab has not been studied in patients with end‑stage renal disease.

Hepatic impairment

The effect of hepatic impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n = 78; TB > ULN to 1.5 ULN or AST > ULN) hepatic impairment compared to patients with normal (n = 555; TB and AST ≤ ULN) hepatic function. No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with moderate (n = 1; TB between 1.5 and 3.0 times ULN and any AST) hepatic impairment. 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 weeks duration at exposures sufficiently in excess compared to the clinical exposure at the recommended dose of 500 mg retifanlimab every 4 weeks.

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

Animal reproduction and development toxicity studies have not been conducted with retifanlimab. A central function of the PD‑1/PD‑L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the foetus. In murine models of pregnancy, blockade of PD‑L1 signaling has been 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 or stillbirth. 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 disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, foetal exposure to retifanlimab may increase the risk of developing immune‑mediated disorders or altering the normal immune response.

The safety of retifanlimab was evaluated in a 4-week and a 13-week repeat-dose toxicity study in cynomolgus monkeys administered intravenous doses of 10, 40, or 150 mg/kg once a week in the 4-week study and 5, 20, or 100 mg/kg once a week in the 13-week study, followed by a 9-week treatment-free period. No findings of toxicological significance were observed and the no observed adverse effect level (NOAEL) in both studies was ≥ 100 mg/kg. In the 13-week study, the exposure multiple at the NOAEL relative to the human dose of 500 mg was 26.

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 medicinal products and/or diluents except those mentioned in section 6.6. Other medicinal products should not be co‑administered through the same infusion line.

Unopened vial

2 years

After dilution

Chemical and physical in‑use stability has been demonstrated for 24 hours at 2 °C to 8 °C and 8 hours at room temperature (20 °C to 25 °C).

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 2 °C 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
• Parenteral medicinal products should be inspected visually for particulate matter and discoloration prior to administration. Retifanlimab is a clear to slightly opalescent, colourless to pale yellow solution, free of visible particles. Discard the vial if the solution is cloudy, discoloured or visible particles are observed.
• Do not shake the vial.
• Withdraw 20 mL (500 mg) of retifanlimab concentrate from the vial and transfer into an intravenous infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection or glucose 50 mg/mL (5%) solution for injection to prepare a diluted solution with 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 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 used immediately. If not used immediately, chemical and physical in‑use stability has been demonstrated:
– 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 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.
• Discard if the diluted solution is discoloured or contains extraneous particulate matter other than trace 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 acetate 0.2 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.

Disposal
• 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 local requirements.