Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Incyte Biosciences Distribution B.V., Paasheuvelweg 25, 1105 BP Amsterdam, Netherlands
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 number of the administered product should be clearly recorded.
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).
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 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 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, 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 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, 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.
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.
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).
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.
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 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.
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. 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 should use effective contraception during treatment with retifanlimab 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 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).
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.
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 conducte
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.
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.
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):
| System organ class | Frequency of all grades | Frequency of grades 3-4 |
|---|---|---|
| Blood and lymphatic system disorders | Very common Anaemiaa | Common Anaemiaa |
| Endocrine disorders | Common Hypothyroidism, Hyperthyroidism Uncommon Adrenal insufficiency Thyroiditisb Hypophysitis Type 1 diabetes mellitusc | Uncommon Adrenal insufficiency Hypophysitis Type 1 diabetes mellitusc |
| Metabolism and nutrition disorders | Very common Decreased appetite | Uncommon Decreased appetite |
| Nervous system disorders | Common Paraesthesia Uncommon Polyneuropathyd Radiculopathy Vocal cord paralysis | Uncommon Polyneuropathyd Radiculopathy |
| Eye disorders | Uncommon Uveitise Keratitis | Uncommon Uveitise |
| Cardiac disorders | Uncommon Pericarditis Myocarditis | Uncommon Myocarditis |
| Respiratory, thoracic and mediastinal disorders | Common Pneumonitisf | Uncommon Pneumonitisf |
| Gastrointestinal disorders | Very common Diarrhoea Nausea Constipation Common Colitisg Uncommon Pancreatitis | Uncommon Diarrhoea Pancreatitis Colitisg |
| Hepatobiliary disorders | Common Hepatocellular injury Hepatitish Uncommon Hyperbilirubinaemia Cholangitis | Uncommon Hepatitish Hepatocellular injury Cholangitis Hyperbilirubinaemia |
| Skin and subcutaneous skin disorders | Very common Rashi Pruritus | Common Rashi |
| Musculoskeletal and connective tissue disorders | Very common Arthralgia Uncommon Arthritisj Myositis Eosinophilic fasciitis Polymyalgia rheumatica | Uncommon Arthralgia Arthritisj Myositis Eosinophilic fasciitis |
| Renal and urinary disorders | Common Acute kidney injury Renal failure Uncommon Tubulointerstitial nephritis | Uncommon Acute kidney injury Tubulointerstitial nephritis |
| General disorders and administration site conditions | Very common Fatiguek Pyrexia | Common Fatiguek Uncommon Pyrexia |
| Investigations | Common Transaminases increasedl Blood creatinine increased Amylase increased Lipase increased Blood bilirubin increased Blood thyroid stimulating hormone increased Uncommon Blood thyroid stimulating hormone decreased | Common Transaminases increasedl Uncommon Blood bilirubin increased Lipase increased Blood creatinine increased Amylase increased |
| Injury, poisoning and procedural complications | Common Infusion-related reactionm | Uncommon Infusion-related reactionm |
a Includes anaemia, iron deficiency anaemia, anaemia of malignant disease and anaemia vitamin B12 deficiency.
b Includes thyroiditis and autoimmune thyroiditis.
c Includes diabetic ketoacidosis.
d Includes polyneuropathy and demyelinating polyneuropathy.
e Includes uveitis and iritis.
f Includes pneumonitis, interstitial lung disease, organising pneumonia and lung infiltration.
g Includes colitis and immune-mediated enterocolitis.
h Includes hepatitis and autoimmune hepatitis.
i 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 epidermal necrolysis and toxic skin eruption.
j Includes arthritis and polyarthritis.
k Includes asthenia and fatigue.
l Includes transaminases increased, alanine aminotransferase increased and aspartate aminotransferase increased.
m Includes drug hypersensitivity and infusion-related reaction.
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 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 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 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).
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 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 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 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 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 national reporting system listed in Appendix V.
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.
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