HETRONIFLY 10mg / ml perfusive solution concentrate medication leaflet

HETRONIFLY 10 mg/ml concentrate for solution for infusion.

Each ml of concentrate for solution for infusion contains 10 mg of serplulimab.

One vial of 10 ml of concentrate contains 100 mg of serplulimab.

Serplulimab is a humanised antibody (IgG4/kappa isotype with a stabilising sequence alteration in thehinge region) produced in Chinese hamster ovary cells by recombinant DNA technology.

Each 10 ml vial contains 0.98 mmol (22.5 mg) sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Colourless to slightly yellow, clear to slightly opalescent solution, pH 5.2-5.8, osmolality ofapproximately 280-340 mOsm/kg.

HETRONIFLY in combination with carboplatin and etoposide is indicated for the first-line treatmentof adult patients with extensive-stage small cell lung cancer (ES-SCLC).

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

The recommended dose is 4.5 mg/kg serplulimab every 3 weeks until disease progression orunacceptable toxicity.

Dose escalation or reduction of HETRONIFLY is not recommended. Dose withholding ordiscontinuation may be required based on individual safety and tolerability. Dose withholding for upto 12 weeks for tolerability is acceptable (see section 4.4).

Serplulimab should be withheld or discontinued to manage adverse reactions as described in Table 1.

Table 1. Recommended treatment modifications

Immune-related Severity Treatment modification#adverse reactions

Immune-related Grade 2 Withhold until adverselung disease reactions recover or improve to

Grade 1

Grade 3 or 4 or recurrent Grade 2 Permanently discontinue

Colitis Grade 2 or 3 Withhold until adversereactions recover or improve to

Grade 1

Grade 4 or recurrent Grade 3 Permanently discontinue

Hepatitis Grade 2 with AST or ALT > 3 to 5 times Withhold until adverse

ULN, or total bilirubin > 1.5 to 3 times reactions recover or improve to

ULN Grade 1

Grade 3 or 4 with AST or ALT > 5 times Permanently discontinue

ULN, or total bilirubin > 3 times ULN

Nephritis and renal Grade 2 elevation of serum creatinine Withhold until adversedysfunction reactions recover or improve to

Grade 1

Grade 3 or 4 elevation of serum creatinine Permanently discontinue

Endocrinopathies Symptomatic Withhold until symptoms

Grade 2 or 3 hypothyroidism, resolve and management with

Grade 2 or 3 hyperthyroidism, corticosteroids is complete.

Grade 2 or 3 hypophysitis, Treatment should be continued

Grade 2 adrenal insufficiency, in the presence of hormone

Grade 3 hyperglycaemia or type 1 diabetes replacement therapy as long asmellitus no symptoms are present

Grade 4 hypothyroidism Permanently discontinue

Grade 4 hyperthyroidism

Grade 4 hypophysitis

Grade 3 or 4 adrenal insufficiency

Grade 4 hyperglycaemia

Skin adverse Grade 3 Withhold until adversereactions reactions recover or improve to

Grade 1

Grade 4 Stevens Johnson Syndrome (SJS) Permanently discontinueor toxic epidermal necrolysis (TEN)

Other Grade 3 or 4 elevation of serum amylase or Withhold until adverseimmune-related lipase reactions recover or improve toadverse reactions Grade 2 or 3 pancreatitis Grade 1

Grade 2 myocarditis*

Grade 2 or 3 other immune-mediatedadverse reactions occurred for the firsttime

Grade 3 decreased platelet count(thrombocytopenia) or white blood cellcount

Grade 4 pancreatitis or recurrent Permanently discontinuepancreatitis of any grade

Grade 3 or 4 myocarditis

Grade 3 or 4 encephalitis

Grade 4 other immune-related adversereactions occurred for the first time

Immune-related Severity Treatment modification#adverse reactions

Grade 4 or recurrent Grade 3 decreasedplatelet count (thrombocytopenia) or whiteblood cell count

Infusion-related Grade 2 Reduce infusion rate to halfreactions rate or interrupt. Treatmentmay be resumed when theevent is resolved

Grade 3 or 4 Permanently discontinue

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteriafor Adverse Events Version 5.0 (NCI-CTCAE v5.0).

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal.#: Serplulimab must be permanently discontinued for any Grade 3 immune-related adverse reactionthat recurs and for any Grade 4 immune-mediated adverse reactions, except for endocrinopathiesthat are controlled with replacement hormones (see sections 4.4 and 4.8).

*: The safety of retreatment with serplulimab in patients who experienced immune-related myocarditisis not clear.

No dose adjustment is needed for elderly patients (≥ 65 years) (see section 5.1 and section 5.2).

No dose adjustment is needed for patients with mild (CRCL=60-89 ml/min) or moderate(CRCL=30-59 ml/min) renal impairment. There are insufficient data and no dose recommendation canbe made in patients with severe (CRCL=15-29 ml/min) renal impairment (see section 5.2).

No dose adjustment is needed for patients with mild (BIL ≤ ULN and AST > ULN or BIL > 1 to 1.5 ×

ULN and any AST) hepatic impairment. There are insufficient data in patients with moderate (BIL >1.5 to 3 × ULN and any AST) hepatic impairments and no data are available in severe (BIL > 3 ×

ULN and any AST) hepatic impairments. No dose recommendation can be made for patients withmoderate or severe hepatic impairment (see section 5.2).

There is no relevant use of serplulimab in the paediatric population in the indication of small cell lungcancer.

HETRONIFLY is for intravenous use.

The initial infusion rate should be set up to 100 ml per hour. If the first infusion is well tolerated, allsubsequent infusions may be shortened to 30 minutes (± 10 minutes).

When administered in combination with chemotherapy, HETRONIFLY should be given first followedby chemotherapy on the same day. Use separate infusion bags for each infusion.

HETRONIFLY must not be administered as an intravenous push or bolus injection.

The total dose of HETRONIFLY required should be diluted with sodium chloride 9 mg/ml (0.9%)solution for injection (see section 6.6).

For instructions on dilution and handling of the medicinal product before administration, see section6.6.

Hypersensitivity to 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, including severe and fatal cases, have occurred in patients receivingserplulimab (see section 4.8). Most immune-related adverse reactions occurring during treatment werereversible and managed by withholding treatment, administration of corticosteroids, and/or supportivecare (see section 4.2). Immune-related adverse reactions have also occurred up to 3.6 months after thelast dose. Immune-related adverse reactions affecting more than one body system can occursimultaneously.

For suspected immune-related adverse reactions, adequate evaluation to confirm aetiology or excludeother causes should be ensured. Based on the severity of the adverse reaction, treatment should bewithheld, and corticosteroid administered. For most Grade 2 and some specific Grade 3 or 4immune-related adverse reactions, administration should be withheld until recover or improve to

Grade 1. Serplulimab must be permanently discontinued for any Grade 4 and some specific Grade 3immune-related adverse reactions. For Grade 3, 4 and some specific Grade 2 immune-related adversereactions (e.g., immune-related pneumonitis, immune-related myocarditis), corticosteroid(1-2 mg/kg/day prednisone or equivalent) and other symptomatic treatments should be givenaccording to the clinical symptoms until recover or improve to Grade 1. Upon improvement to Grade≤ 1, corticosteroid taper should be initiated and continued over at least 1 month. Rapid tapering maylead to worsening or recurrence of the adverse reaction. Non-corticosteroid immunosuppressivetherapy (e.g., infliximab) should be added if there is worsening or no improvement despitecorticosteroid use.

Immune-related pneumonitis, including fatal cases, has been reported in patients receiving

HETRONIFLY (see section 4.8). Patients should be monitored for signs and symptoms ofimmune-related pneumonitis such as radiographic changes (e.g., focal ground glass opacities, patchyfiltrates), dyspnoea, and hypoxia. Suspected immune-related pneumonitis should be confirmed withradiographic imaging, and other causes excluded. For treatment modification, see section 4.2.

Immune-related colitis, including fatal cases, has been reported in patients receiving serplulimab (seesection 4.8). Patients should be monitored for signs and symptoms of immune-related colitis, such asabdominal pain, diarrhoea, mucus, or blood in stool. Infection and other disease-related aetiologiesshould be ruled out. For treatment modification, see section 4.2. The potential risk of gastrointestinalperforation should be taken into consideration and confirmed by radiographic imaging and/orendoscopy if necessary.

Immune-related hepatitis, including fatal cases, has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for changes in liver function and clinical signs andsymptoms of immune-related hepatitis such as transaminase and total bilirubin elevations periodically(every month). Infection and diseases-related aetiologies should be ruled out. The frequency of liverfunction test should be increased, if immune-related hepatitis occurs. For treatment modification, seesection 4.2.

Immune-related nephritis and renal dysfunction has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for changes in renal function and clinical signs andsymptoms of immune-related nephritis and renal dysfunction periodically (every month). Thefrequency of renal function test should be increased, if immune-related nephritis occurs. Most patientspresent with asymptomatic increases in serum creatinine. Disease-related aetiologies should be ruledout. For treatment modification, see section 4.2.

Thyroid diseases

Thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis, have been reported inpatients receiving serplulimab (see section 4.8). Patients should be monitored for changes in thyroidfunction and clinical signs and symptoms of thyroid disorders. For Grade 2 or 3 symptomatichypothyroidism, serplulimab should be withheld and thyroid hormone replacement should be initiatedas needed. For Grade 2 or 3 symptomatic hyperthyroidism, serplulimab should be withheld andanti-thyroid medicinal product should be initiated as needed. If acute inflammation of the thyroid issuspected, serplulimab should be withheld and initiate hormone therapy. Treatment may be resumedwhen symptoms of hypothyroidism or hyperthyroidism are controlled, and thyroid function isimproved. For life-threatening hyperthyroidism or hypothyroidism, serplulimab must be permanentlydiscontinued. Thyroid function should be monitored continuously to ensure appropriate hormonereplacement (see section 4.2).

Hypophysitis has been reported in patients receiving serplulimab (see section 4.8). Patients should bemonitored for signs and symptoms of hypophysitis, and other causes should be ruled out. For Grade 2or 3 symptomatic hypophysitis, serplulimab should be withheld, and hormone replacement should beinitiated as needed. If acute hypophysitis is suspected, corticosteroids should be initiated. Forlife-threatening Grade 4 hypophysitis, serplulimab must be permanently discontinued (see section 4.2).

Adrenal insufficiency has been reported in patients receiving serplulimab (see section 4.8). Patientsshould be monitored for signs and symptoms, and other causes should be ruled out. For Grade 2adrenal insufficiency, serplulimab should be withheld and hormone replacement should be initiated asneeded. For life-threatening Grade 3 or 4 adrenal insufficiency, serplulimab must be permanentlydiscontinued. Adrenal gland function and hormone levels should be monitored continuously to ensureappropriate hormone replacement (see section 4.2).

Hyperglycaemia or type 1 diabetes mellitus has been reported in patients receiving serplulimab (seesection 4.8). Patients should be monitored for blood glucose level and related clinical signs andsymptoms. Insulin replacement therapy should be initiated as needed. For type 1 diabetes mellitus withpoor blood glucose control, serplulimab should be withheld, and insulin replacement therapy shouldbe initiated until the symptoms are improved. For life-threatening Grade 4 type 1 diabetes, serplulimabmust be permanently discontinued. Blood glucose levels should be monitored continuously to ensureappropriate insulin replacement (see section 4.2).

Immune-related skin adverse reactions have been reported in patients receiving serplulimab (seesection 4.8). For Grade 1 or 2 rash, serplulimab can be continued, and symptomatic treatment or localcorticosteroids treatment can be given. For Grade 3 rash, serplulimab should be withheld, andsymptomatic treatment or local corticosteroids treatment should be given. For Grade 4 rash,

Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN), serplulimab should bepermanently discontinued (see section 4.2).

Immune-related pancreatitis, including increases in serum amylase and lipase levels and fatal cases,has been reported in patients receiving serplulimab (see section 4.8). Patients should be monitored forchanges in serum lipase and amylase (at the beginning of treatment, periodically during treatment, andas indicated based on clinical evaluation), and clinical signs and symptoms of pancreatitis.

Serplulimab should be withheld for Grade 3 or 4 increase in serum amylase or lipase levels, and Grade2 or 3 pancreatitis. For Grade 4 pancreatitis or recurrent pancreatitis of any grade, serplulimab shouldbe permanently discontinued (see section 4.2).

Immune-related myocarditis, including fatal cases, has been reported in patients receiving serplulimab(see section 4.8). Patients should be monitored for clinical signs and symptoms of myocarditis.

Suspected immune-mediated myocarditis should be confirmed with myocardial enzyme examinations,and other causes excluded. For Grade 2 myocarditis, serplulimab should be withheld, andcorticosteroid treatment should be given. The safety of restarting serplulimab treatment in patientspreviously experiencing immune-related myocarditis is unclear. A multidisciplinary discussion isrecommended before restarting serplulimab in patients with previous Grade 2 myocarditis, and thedecision should be based on various clinical factors, including the degree of cardiac recovery,oncological response to the treatment, availability of alternative oncology treatments and prognosis.

For Grade 3 or 4 myocarditis, serplulimab must be permanently discontinued and corticosteroidstherapy should be initiated. Once a diagnosis of myocarditis is established, serplulimab should bewithheld or permanently discontinued. Myocardial enzymes and cardiac function should be monitoredclosely for any grade myocarditis (see section 4.2).

If uveitis and other immune-mediated adverse reactions occur at the same time, such as

Vogt-Koyanagi-Harada syndrome, systemic corticosteroids should be given to prevent permanentblindness.

Given the mechanism of action of serplulimab, other potential immune-related adverse reactions mayoccur. Other fatal and life-threatening immune-mediated adverse reactions have been observed inpatients treated with serplulimab in clinical trials across doses and tumour types: thrombocytopenia,acute coronary syndrome, myocardial infarction and immune-mediated encephalitis (see section 4.8).

For other suspected immune-related adverse reactions, adequate evaluation should be performed toconfirm aetiology and exclude other causes. Based on the severity of adverse reactions, serplulimabshould be withheld for Grade 2 or 3 immune-related adverse reactions which occur for the first time.

For recurrent Grade 3 immune-related adverse reactions (except endocrinopathies) and Grade 4immune-related adverse reactions, serplulimab must be permanently discontinued. Corticosteroids canbe initiated as clinically indicated (see section 4.2).

Infusion-related reactions have been reported in patients receiving serplulimab. Patients should bemonitored for clinical signs and symptoms of infusion-related reactions. Patients with Grade 1infusion-related reactions may continue administration under close monitoring. The rate of infusionshould be reduced, or treatment should be interrupted in patients with Grade 2 infusion-relatedreactions. Antipyretic and antihistamines may be considered. Treatment with serplulimab may beresumed under close monitoring when Grade 2 infusion-related reactions are controlled. For Grade ≥ 3infusion-related reactions, infusion should be stopped immediately, treatment should be permanentlydiscontinued, and appropriate treatment should be given (see section 4.2).

Patients with the following conditions were excluded from clinical trials: a history of active or priordocumented autoimmune disease, patients with active tuberculosis or hepatitis B or C or HIV infectionor patients receiving live attenuated vaccine within 28 days prior to serplulimab administration,patients with any active infection requiring systemic anti-infective therapy within 14 days prior to thefirst dose, history of pneumonitis or interstitial lung disease, patients with active brain metastases,history of significant cardiovascular disease (e.g. myocardial infarction within half a year), a history ofhypersensitivity to another monoclonal antibody, systemic immunosuppressive medicinal productswithin 2 weeks prior to receiving serplulimab.

This medicinal product contains 0.98 mmol (or 22.5 mg) sodium per 10 ml vial, equivalent to 1.1% ofthe WHO recommended maximum daily intake of 2 g sodium for an adult.

The prescriber must discuss the risks of serplulimab therapy with the patient. The patient will beprovided with the patient card with each prescription.

Drug-drug interaction studies have not been conducted. As monoclonal antibodies are not metabolisedby cytochrome P450 (CYP) enzymes or other drug metabolising enzymes, inhibition, or induction ofthese enzymes by co-administered medicinal products is not anticipated to affect the pharmacokineticsof HETRONIFLY.

The use of systemic corticosteroids or immunosuppressants before starting serplulimab should beavoided because of their potential interference with the pharmacodynamic activity and efficacy.

However, systemic corticosteroids or other immunosuppressants can be used to treat immune-relatedadverse reactions after starting serplulimab (see section 4.4).

Women of childbearing potential should use effective contraception during treatment and for at least 6months after the last dose of serplulimab.

There is no data on the use of serplulimab in pregnant women. Animal studies have demonstrated thatinhibition of the PD-1 pathway causes embryofoetal toxicity (see section 5.3). Human IgG is known tocross the placental barrier and serplulimab is an IgG4; therefore, it has the potential to be transmittedfrom the mother to the developing foetus. Serplulimab is not recommended during pregnancy and inwomen of childbearing potential not using contraception.

It is unknown whether serplulimab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which is decreasing to low concentrations soon;consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards,serplulimab could be used during breast-feeding if clinically needed.

Studies to evaluate fertility have not been performed. Thus, the effect of serplulimab on male andfemale fertility is unknown.

Serplulimab 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 serplulimab does not adversely affect them.

The safety of serplulimab in combination with chemotherapy is based on data in 389 patients with

ES-SCLC. The most common adverse reactions were neutropenia (82.8%), leukopenia (74.0%),anaemia (72.8%), thrombocytopenia (56.0%), alopecia (54.2%), nausea (36.2%), hyperlipidaemia(32.1%), decreased appetite (28.3%), hypoproteinaemia (25.4%), and hyponatraemia (25.4%).

The most common Grade ≥ 3 adverse reactions were neutropenia (65.3%), leukopenia (33.7%),thrombocytopenia (23.1%), anaemia (19.8%), hyponatraemia (10.0%), and lymphopenia (5.1%).

The most common serious adverse reactions were thrombocytopenia (9.3%), neutropenia (7.7%),leukopenia (6.7%), pneumonia (3.3%), and hyperglycaemia or diabetes mellitus (2.3%).

The most common immune-related adverse reactions were hypothyroidism (13.1%), hyperthyroidism(10.8%), immune-related skin adverse reactions (7.5%), abnormal liver function (4.1%),immune-related lung disease (3.1%), anaemia (2.8%), malaise (2.1%), hyperglycaemia or diabetesmellitus (1.8%), immune-related colitis (1.8%), and platelet count decreased (1.5%).

Serplulimab was discontinued due to adverse reactions in 5.4% of patients.

Adverse reactions reported in clinical trial and in post-marketing experience are listed by system organclass and frequency (see Table 2). Unless otherwise stated, the frequencies of adverse reactions arebased on all-cause adverse event frequencies identified in ASTRUM-005 trial, in which 389 patientswere exposed to serplulimab in combination with chemotherapy for a median duration of 22 weeks.

See section 5.1 for information about the main characteristics of patients in the pivotal clinical trial.

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); not known (cannot beestimated from the available data). Within each frequency grouping, adverse reactions are presented inthe order of decreasing seriousness.

Table 2. Adverse reactions in patients treated with HETRONIFLY* in ASTRUM-005

Serplulimab with carboplatin and etoposide

Very common pneumonia a

Common urinary tract infection b, respiratory tract infection c

Uncommon septic shock, skin infection, enteritis infectious, lip infection,meningoencephalitis herpetic

Very common neutropenia, leukopenia, anaemia, thrombocytopenia, lymphopenia

Common coagulation function test abnormal d, granulocytopenia

Uncommon lymphadenitis

Common infusion-related reaction e

Uncommon anaphylactic reaction

Very common hypothyroidism f, hyperthyroidism, hyperglycaemia or diabetes mellitus g

Common thyroid function test abnormal h, thyroiditis i

Uncommon adrenal insufficiency j, other thyroid disorder k, hyperadrenocorticism l,hypophysitis

Very common hyperlipidaemia, decreased appetite, hypoproteinaemia, hyperuricaemia,electrolyte imbalance m

Common weight decreased, hypoglycaemia

Uncommon lipoprotein abnormal

Very common insomnia

Common paraesthesia, headache, dizziness, neuropathy peripheral n

Uncommon immune-mediated encephalitis o, vertigo, neurotoxicity, motor dysfunction

Uncommon vision blurred

Very common arrhythmia p

Common sinus tachycardia, conduction defects q, sinus bradycardia, cardiac failure r,

N-terminal prohormone brain natriuretic peptide increased

Uncommon cardiomyopathy s, myocardial ischaemia, pericardial effusion, myocardialnecrosis marker increased, myocarditis

Common hypertension, vasculitis t

Very common cough

Common pneumonitis u, dyspnoea, chest pain

Very common nausea, constipation, abdominal pain, diarrhoea, vomiting

Common dysphagia, flatulence, gastrointestinal disorder v, stomatitis, dyspepsia

Uncommon dry mouth, enteritis w, gastritis, immune-mediated pancreatitis, gingivalbleeding

Very common alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyltransferase increased

Common hyperbilirubinaemia, liver injury x

Very common rash y, alopecia

Common pruritus, dermatitis z, hyperhidrosis

Uncommon pigmentation disorder, psoriasis, dry skin

Very common musculoskeletal pain aa

Common arthralgia, pain in extremity, musculoskeletal discomfort bb

Uncommon autoimmune myositis, arthritis

Not known myositis cc

Common blood urea increased, protein urine present, haematuria, renal injury dd, bloodcreatinine increased, glycosuria, white blood cells urine positive

Very common pyrexia, asthenia

Common fatigue, malaise, oedema ee

Uncommon chills

Very common blood alkaline phosphatase increased

Common myoglobin blood increased, blood creatine phosphokinase increased, troponinincreased

* Adverse reaction frequencies presented in Table 2 may not be fully attributable to HETRONIFLYalone but may contain contributions from the underlying disease or from other medicinal productsused in a combination.

The following terms represent a group of related events that describe a medical condition rather than asingle event:

a. Includes pneumonia, pneumonia fungal.

b. Includes urinary tract infection, asymptomatic bacteriuria.

c. Includes upper respiratory tract infection, pharyngotonsillitis, tonsillitis.

d. Includes activated partial thromboplastin time prolonged, activated partial thromboplastin time,activated partial thromboplastin time shortened, international normalised ratio decreased,prothrombin level increased.

e. Includes drug hypersensitivity, infusion-related reaction.

f. Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroxine freedecreased, central hypothyroidism, tri-iodothyronine decreased.

g. Includes hyperglycaemia, diabetes mellitus, diabetic ketoacidosis, blood ketone body increased,glucose tolerance impaired, ketoacidosis.

h. Includes blood thyroid stimulating hormone decreased, tri-iodothyronine increased, anti-thyroidantibody positive, thyroglobulin increased, thyroxine increased.

i. Includes thyroid disorder, thyroiditis.j. Includes adrenal insufficiency, cortisol decreased.k. Includes euthyroid sick syndrome, ultrasound thyroid abnormal.l. Includes cortisol increased, hyperadrenocorticism.m. Includes hyponatraemia, hypocalcaemia, hypokalaemia, hypomagnesaemia,hypophosphataemia, hypochloraemia, hyperphosphataemia, hyperkalaemia,hypermagnesaemia, hypercalcaemia.

n. Includes neuropathy peripheral, peripheral sensorimotor neuropathy, immune-mediatedneuropathy **.

o. Includes immune-mediated encephalitis, encephalitis autoimmune.p. Includes supraventricular extrasystoles, supraventricular tachycardia, arrhythmia, ventricularextrasystoles, arrhythmia supraventricular, atrial fibrillation, atrial tachycardia,bradyarrhythmia, early repolarisation syndrome, ventricular arrhythmia, electrocardiogram QTprolonged, electrocardiogram repolarisation abnormality, electrocardiogram T wave abnormal.

q. Includes atrioventricular block first degree, bundle branch block right, atrial conduction timeprolongation, bundle branch block left, defect conduction intraventricular.

r. Includes cardiac failure, cardiac failure acute, left ventricular failure.s. Includes cardiomyopathy, metabolic cardiomyopathy.t. Includes phlebitis, phlebitis superficial.u. Includes immune-mediated lung disease, pneumonitis, interstitial lung disease.v. Includes gastrointestinal haemorrhage, gastrointestinal disorder, lower gastrointestinalhaemorrhage.w. Includes enteritis, immune-mediated enterocolitis **.x. Includes hepatic function abnormal, drug-induced liver injury, liver injury, immune-mediatedhepatitis, immune-mediated hepatic disorder **, hepatic failure **.y. Includes rash, rash maculo-papular, eczema, drug eruption, erythema, skin toxicity.z. Includes autoimmune dermatitis, dermatitis, dermatitis allergic, dermatitis bullous, seborrhoeicdermatitis.aa. Includes back pain, myalgia, musculoskeletal chest pain, spinal pain, neck pain.bb. Includes muscular weakness, musculoskeletal discomfort.cc. Includes myositis **, immune-mediated myositis **.dd. Includes acute kidney injury, renal failure, renal impairment, renal injury.ee. Includes face oedema, oedema peripheral, peripheral swelling, swelling, swelling face.

** Post-marketing event.

Serplulimab is associated with immune-related adverse reactions. The data for the followingimmune-related adverse reactions are based on 1 172 patients who received serplulimab monotherapy(n=263) or in combination with other medicinal products (n=909) across eight doses (0.3, 1, 3,10 mg/kg every 2 weeks, 4.5 mg/kg every 3 weeks, 200 mg every 2 weeks, 300 mg every 3 weeks, or400 mg every 4 weeks) in eight clinical trials. The management guidelines for these adverse reactionsare described in sections 4.2 and 4.4.

Immune-related lung disease occurred in 3.5% of patients, including Grade 3, 4 or 5 in 0.9%, 0.1%,and 0.3% of patients, respectively. The median time to onset was 3.25 months (range: 0.03-34.53months). The median duration was 1.91 months (range: 0.26-13.34 months). 1.6% of patients receivedhigh-dose corticosteroid treatment. Immune-related lung disease led to discontinuation in 1.0% ofpatients.

Immune-related colitis occurred in 2.4% of patients, including Grade 3 in 0.6% of patients and Grade5 in 0.1% of patients. The median time to onset was 3.01 months (range: 0.03-20.11 months). Themedian duration was 0.43 months (range: 0.03-4.40 months). 0.5% of patients received high-dosecorticosteroid treatment. Immune-related colitis led to discontinuation in 0.3% of patients.

Hepatitis occurred in 0.7% of patients, including Grade 3 in 0.3% of patients, Grade 4 in 0.2% ofpatients, and Grade 5 in 0.2% of patients. The median time to onset was 2.48 months (range: 0.43-6.60months). The median duration was 0.95 months (range: 0.53-1.51 months). 0.2% of patients receivedhigh-dose corticosteroid treatment. Hepatitis led to discontinuation in 0.3% of patients. Abnormal liverfunction occurred in 4.5% of patients, including Grade 3 in 1.0% of patients. The median time to onsetwas 1.51 months (range: 0.07-29.73 months). The median duration was 1.41 months (range:0.26-17.54 months). 0.3% of patients received high-dose corticosteroid treatment. Abnormal liverfunction led to discontinuation in 0.3% of patients.

Immune-related nephritis and renal dysfunction occurred in 2.4% of patients, including Grade 3 in0.3% of patients and Grade 4 in 0.1% of patients. The median time to onset was 2.78 months (range:0.23-17.28 months). The median duration was 1.12 months (range: 0.13-5.32 months). 0.2% ofpatients received high-dose corticosteroid treatment. Immune-related nephritis and renal dysfunctionled to discontinuation in 0.2% of patients.

Hypothyroidism occurred in 11.2% of patients, including Grade 3 in 0.1% of patients. The mediantime to onset was 3.84 months (range: 0.62-34.10 months). The median duration was 2.76 months(range: 0.53-7.49 months). 5.9% of patients received thyroid hormone replacement therapy. Nopatients discontinued serplulimab due to hypothyroidism.

Hyperthyroidism occurred in 6.3% of patients, and there were no Grade ≥ 3 hyperthyroidism. Themedian time to onset was 1.79 months (range: 0.69-31.18 months). The median duration was 1.41months (range: 0.07-4.21 months). No patients discontinued serplulimab due to hyperthyroidism.

Thyroiditis occurred in 0.7% of patients, and there were no Grade ≥ 3 thyroiditis. The median time toonset was 5.65 months (range: 1.94-13.50 months). The median duration was 5.93 months (range:0.56-11.30 months). 0.2% of patients received thyroid hormone replacement therapy. No patientsdiscontinued serplulimab due to thyroiditis.

Adrenal gland disorders occurred in 0.3% of patients, all of which were Grade 2. The median time toonset was 5.78 months (range: 5.75-6.93 months). No patients discontinued serplulimab due to adrenalgland disorders.

Pituitary disorders occurred in 0.9% of patients, including Grade 3 in 0.2% of patients. The mediantime to onset was 6.97 months (range: 1.41-20.53 months). The median duration was 2.43 months.0.3% of patients received high-dose corticosteroid treatment. Pituitary disorders led to discontinuationin 0.2% of patients.

Diabetes mellitus/hyperglycaemia occurred in 1.0% of patients, including Grade 3 in 0.5% of patientsand Grade 4 in 0.1% of patients. The median time to onset was 4.09 months (range: 0.69-11.10months). The median duration was 2.96 months. 0.6% of patients received insulin replacementtherapy. Diabetes mellitus/hyperglycaemia led to discontinuation in 0.1% of patients.

Immune-related skin adverse reactions occurred in 8.7% of patients, including Grade 3 in 0.8% ofpatients. The median time to onset was 2.10 months (range: 0.03-30.52months). The median durationwas 0.82 months (range: 0.07-12.39 months). 1.4% of patients received high-dose corticosteroidtreatment. Immune-related skin adverse reactions led to discontinuation in 0.4% of patients.

Immune-related pancreatitis occurred in 1.1% of patients, including Grade 3 in 0.3% of patients,

Grade 4 in 0.2% of patients and Grade 5 in 0.1% of patients. The median time to onset was 2.30months (range: 0.23-12.42 months). The median duration was 0.76 months (range: 0.16-10.12months). 0.2% of patients received high-dose corticosteroid treatment. Immune-related pancreatitis ledto discontinuation in 0.2% of patients.

Immune-related myocarditis occurred in 0.6% of patients, including Grade 3 in 0.2% of patients and

Grade 5 in 0.1% of patients. The median time to onset was 1.87 months (range: 0.26-25.36 months).

The median duration was 0.89 months (range: 0.72-4.57 months). 0.3% of patients received high-dosecorticosteroid treatment. Immune-related myocarditis led to discontinuation in 0.2% of patients.

Immune-related uveitis occurred in 0.1% of patients, which was Grade 1. The time to onset was 6.90months. The duration of immune-related uveitis was 1.35 months. The event resolved for the patient.

Other clinically significant immune-related adverse reactions reported in patients who receivedserplulimab were as follows. Severe or fatal cases have been reported for some of these adversereactions.

Blood and lymphatic system: anaemia, leukopenia, thrombocytopenia, neutropenia.

Nervous system: dizziness, immune-mediated encephalitis, neuropathy peripheral.

Eye disorders: vision blurred.

Cardiac/vascular: acute coronary syndrome, myocardial infarction, cardiac failure acute,cardiotoxicity, troponin increased.

Respiratory, thoracic and mediastinal: dyspnoea, chronic obstructive pulmonary disease, respiratoryfailure.

Gastrointestinal: mouth ulceration, vomiting, proctitis.

General disorders and administration site conditions: asthenia, fatigue, pyrexia.

Other: panic disorder, tinnitus, cholangitis acute, sepsis, cortisol decreased, blood alkalinephosphatase increased, electrolyte imbalance.

Infusion-related reactions occurred in 1.4% of patients, including Grade 3 in 0.2% of patients and

Grade 4 in 0.1% of patients. The median time to onset was 1.02 months (range: 0.03-9.86 months).

The median duration was 0.07 months (range: 0.03-0.53 months). No patients discontinuedserplulimab due to infusion-related reactions.

The proportions of patients who experienced a shift from baseline to a Grade ≥ 3 laboratoryabnormality were as follows: 0.6% for platelet count decreased, 0.4% for neutrophil count decreased,0.3% for blood creatine phosphokinase increased, 0.2% for white blood cell count decreased, 0.1% forblood lactate dehydrogenase increased, and 0.1% for blood cholesterol increased.

No overall differences in safety were reported between elderly (≥ 65 years) and younger patients. Datafor patients ≥ 75 years of age are too limited to draw conclusions on this population.

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 reactions,and appropriate symptomatic treatment instituted immediately.

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies and antibody drugconjugates, PD-1/PD-L1 (Programmed cell death-1/death ligand 1) inhibitors

ATC code: L01FF12.

Serplulimab (HLX10) is a humanised monoclonal IgG4 antibody, which binds to the programmed celldeath-1 (PD-1) receptor and blocks its interaction with ligands PD-L1 and PD-L2. The PD-1 receptoris a negative regulator of T-cell activity that has been shown to be involved in the control of T-cellimmune responses. Engagement of PD-1 with the ligands PD-L1 and PD-L2, which are expressed inantigen presenting cells and may be expressed by tumours or other cells in the tumourmicroenvironment, results in inhibition of T-cell proliferation and cytokine secretion. Serplulimabpotentiates T-cell responses, including anti-tumour responses, through blockade of PD-1 binding to

PD-L1 and PD-L2 ligands.

The PD-1 receptor occupation of peripheral T cells and interleukin-2 (IL-2) release ability in vitrowere studied in the phase 1 trial involving 29 Chinese patients with advanced solid tumour that wereinjected with single and multiple doses (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg) of serplulimab. Theresult showed that serplulimab could stably maintain the saturation state of receptor occupation andsustained functional blockage at the dosage from 0.3 mg/kg to 10 mg/kg every 2 weeks interval.

The efficacy of serplulimab in combination with chemotherapy (carboplatin plus etoposide) for thefirst-line treatment of ES-SCLC was evaluated in ASTRUM-005 trial (NCT04063163), a phase 3,randomised, double-blind, multiregional clinical trial. The primary efficacy endpoint was overallsurvival (OS). Secondary efficacy endpoints were progression free survival (PFS), objective responserate (ORR) and duration of response (DOR) as assessed by independent radiology review committee(IRRC) and investigator based on RECIST 1.1. Analysis for the primary endpoint was performed at 25and 33 months since the start of the clinical trial. The study treatment regimens were unblinded afterthe primary analysis.

The trial included adult patients (18 years or older) with ES-SCLC (according to the Veterans

Administration Lung Study Group [VALG] staging system) who had not been treated with systemictherapy and with an ECOG performance-status score of 0 or 1. Patients were excluded if they hadactive or untreated central nervous system metastases; active autoimmune disease; administration ofsystemic immunosuppressive medicinal products within 14 days prior to the first dose.

A total of 585 patients were enrolled and randomised (2:1) to receive one of the treatment regimensdescribed in Table 3. Randomisation was stratified by PD-L1 expression level (negative: tumourproportion scores [TPS] < 1%, positive: TPS ≥ 1%, or not evaluable/not available, measured by PD-L1

IHC 22C3 pharmDx kit), brain metastasis (yes versus no), and age (≥ 65 years versus < 65 years).

Table 3. Intravenous treatment regimens

Treatment Induction Maintenanceregimen (Four 21-Day Cycles) (21-Day Cycles)

A Serplulimab (4.5 mg/kg) a + carboplatin (AUC=5,up to 750 mg) b + etoposide (100 mg/m2) b,c Serplulimab (4.5 mg/kg) a

B Placebo + carboplatin (AUC=5, up to 750 mg) b +etoposide (100 mg/m2) b,c Placebo

a. Serplulimab was administered until disease progression or unacceptable toxicity.

b. Carboplatin and etoposide were administered until completion of 4 cycles, or progressive disease orunacceptable toxicity, whichever occurred first.

c. Etoposide was administered on day 1, 2 and 3 of each cycle.

Baseline characteristics were balanced between the treatment arms. Among the patients enrolled,68.5% were Asian (401 patients), and 31.5% were non-Asian (184 patients), all of which were White.

The median age was 62 years (range: 28-83) with 39.3% of patients ≥ 65 years of age, and 1.9% ofpatients ≥ 75 years of age. 82.2% of patients were men. Baseline ECOG performance-status score was0 (17.6%) or 1 (82.4%). 16.9% of patients were PD-L1 positive (TPS ≥ 1%). 13.3% of patients had ahistory of brain metastases.

At the time of the interim analysis cut-off on 22 October 2021 when 66% of predefined OS eventswere observed (defined approximately 226, actual 246 OS events), patients had a median survivalfollow-up time of 12.3 months. OS, PFS and ORR results from the interim analysis are summarised in

Table 4.

Table 4. Efficacy data at the primary analysis (data cut-off date: 22 October 2021)

Arm A Arm B(Serplulimab + carboplatin + (Placebo + carboplatin +etoposide) etoposide)

Number of patients 389 196

Primary endpoint

Number of patientswith events, n (%) 146 (37.5%) 100 (51.0%)

Median OS (months) 15.4 10.9

OS Hazard ratio (95%

CI) 0.63 (0.49-0.82)p-value < 0.001

Secondary endpoints

PFS Median PFS

- IRRC per (months) 5.7 4.3

RECIST Hazard ratio (95%1.1 CI) 0.48 (0.38-0.59)

Confirmed

ORR (%) 67.4% 58.7%

Median

DOR Months (95% CI) 5.8 (5.2-7.5) 4.1 (3.0-4.2)

Updated analysis after unblinding with longer follow-up duration (median: 19.7 months) wasconducted by the cut-off date 13 June 2022 when 100% of predefined OS events were observed(defined approximately 342, actual 363 OS events). The median OS was 15.8 months in theserplulimab group and 11.1 months in the placebo group. The stratified HR (95% CI) was 0.62 (0.50,0.76). The median PFS by IRRC assessment per RECIST 1.1 was 5.7 months and 4.3 months,respectively, with a stratified HR (95% CI) of 0.47 (0.38, 0.58). The efficacy results of final analysiswere consistent with the primary analysis. Kaplan-Meier curves for OS and PFS of final analysis arepresented in Figures 1 and 2.

Figure 1. Kaplan-Meier curve of OS in overall population at the updated analysis (ITT) (datacut-off date: 13 June 2022)

Figure 2. Kaplan-Meier curve of PFS (RECIST 1.1) by IRRC in overall population at theupdated analysis (ITT) (data cut-off date: 13 June 2022)

The immunogenicity of serplulimab was evaluated in 389 patients treated with serplulimab at4.5 mg/kg Q3W in the ASTRUM-005 trial. Seven patients (1.8%) were ADA positive at any visit, ofwhom 6 patients (1.5%) were treatment-emergent ADA positive, defined as at least one post-baseline

ADA positive.

In dose escalation and dose expansion study HLX10-001, ADAs were observed in 13 out of 66patients (19.7%).

Neutralising antibodies were not observed in either of the key studies. No evidence of ADA impact onpharmacokinetics, efficacy or safety was observed. However, data are still limited.

In the ASTRUM-005 trial, of the 389 patients in the serplulimab group in the overall population, 153(39.3%) were ≥ 65 years. No overall differences in efficacy were observed between elderly patientsand younger patients.

The European Medicines Agency has waived the obligation to submit the results of studies withserplulimab in all subsets of the paediatric population for lung cancer (small cell and non-small celllung cancer) (see section 4.2 for information on paediatric use).

Serplulimab pharmacokinetics has been investigated in a population pharmacokinetic (popPK)analysis that included 1 144 patients with lung cancer (including ES-SCLC) and other solid cancertypes from 8 studies. The patients received serplulimab intravenously as monotherapy or combinationtherapy in the dose range of 0.3 to 10 mg/kg Q2W, 4.5 mg/kg Q3W, 200 mg Q2W, 300 mg Q3W and400 mg Q4W. The PK was described by a two-compartment model with time-dependent clearance(CL). Inter-individual variability (coefficient of variation, CV) in base CL and central volume ofdistribution (Vc) was 25.8% and 15.4%. The mean (CV) observed trough concentration at steady statein the ASTRUM-005 trial was 62.5 µg/mL (36.3%).

Serplulimab is administered by intravenous infusion and is therefore immediately and completelybioavailable. Other routes of administration have not been investigated.

Based on a popPK analysis the volume of distribution of serplulimab is approximately 5.73 L.

The metabolic pathway of serplulimab has not been characterised. Serplulimab is expected to becatabolised into small peptides and amino acids by general protein degradation processes.

Based on a popPK analysis, serplulimab clearance (CL) after the first dose is 0.225 L/day. Theclearance decreases over time by a maximum of 30.5% (CV 26.3%) with 106 days to reach half of themaximum effect. The half-life at steady state is approximately 24.3 days.

Serplulimab exhibited linear pharmacokinetics over the dose range of 0.3 to 10 mg/kg Q2W (includingflat doses of 200 mg Q2W, 300 mg Q3W and 400 mg Q4W) both after single and multiple doses.

No dedicated studies have been performed in special populations. A popPK analysis suggested nodifference in the total systemic clearance of serplulimab based on age (23-83 years), race (n=247

Whites and n=895 Asians), and ECOG performance-status score (0 or 1). Serplulimab clearanceincreased with increasing body weight.

No effect of creatinine or creatinine clearance (CRCL) (Cockcroft-Gault) was found on serplulimab

CL based on a popPK analysis in patients with mild (CRCL=60-89 ml/min; n=448), moderate(CRCL=30-59 ml/min; n=102), and severe (CRCL=15-29 ml/min; n=1) renal impairment, and normalrenal function (CRCL≥ 90 ml/min, n=591). There are insufficient data in patients with severe renalimpairment for dosing recommendations (see section 4.2).

No effect of ALT, AST or total bilirubin was found on serplulimab CL based on a popPK analysis inpatients with mild (BIL ≤ ULN and AST > ULN or BIL > 1 to 1.5 × ULN and any AST; n=176) andmoderate (BIL > 1.5 to 3 × ULN and any AST; n=2) hepatic impairment, and normal (BIL ≤ ULN and

AST ≤ ULN; n=956) hepatic function. There are insufficient data in patients with moderate hepaticimpairment for dosing recommendations. Serplulimab has not been studied in patients with severe(BIL > 3 × ULN and any AST) hepatic impairment (see section 4.2).

In the repeat-dose toxicity study in cynomolgus monkeys dosed for up to 31 weeks, a high incidenceof pharmacology-related perivascular mononuclear cell infiltration in the brain choroid plexus wasobserved at 100 mg/kg. The no observed adverse effect level (NOAEL) in the 31-weeks toxicity studywas 50 mg/kg/week, which produced exposure 36 times (calculated by AUC0-t) the exposure inhumans at dose of 3 mg/kg every two weeks.

Reproductive toxicity studies have not been performed.

The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughoutpregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupttolerance to the foetus and to result in an increase in foetal loss.

Two anti-PD-L1 monoclonal antibodies were evaluated in cynomolgus monkeys for reproductive anddevelopmental toxicity and were shown to cause premature delivery, foetal loss and prematureneonatal death when administrated to pregnant monkeys.

Therefore, potential risks of administering serplulimab during pregnancy include increased rates ofabortion or stillbirth. Based on its mechanism of action, foetal exposure to serplulimab may increasethe risk of developing immune-mediated disorders or altering the normal immune response andimmune-related disorders that have been reported in PD-1 knockout mice.

No studies have been performed to assess the genotoxic or carcinogenic potential of serplulimab.

Citric acid monohydrate

Sodium citrate (E331)

Sodium chloride

Mannitol (E421)

Polysorbate 80 (E433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts, except those mentioned in section 6.6. HETRONIFLY should not be infused concomitantlyin the same intravenous line with other medicinal products.

Unopened vial3 years.

From a microbiological point of view, the product, once diluted, should be used immediately. Thediluted solution must not be frozen. If not used immediately, in-use storage times and conditions priorto use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C. This24-hour hold may include up to 6 hours at room temperature (≤ 25°C). If refrigerated, the vials and/orintravenous bags must be allowed to come to room temperature prior to use.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

10 ml of concentrate in a 10 ml Type I clear glass vial with chlorobutyl rubber stopper andaluminium-plastic combination caps containing 100 mg of serplulimab.

Pack of 1 vial.

Preparation and administration

* Aseptic handling should be ensured during the preparation of infusion.

* Do not shake the vial.

* Equilibrate the vial to room temperature (at or below 25°C).

* The product should be inspected visually for the particulate matters and discoloration prior toadministration. The concentrate is a colourless to slightly yellow, clear to slightly opalescentsolution. Discard the vial if visible particles are observed.

* Confirm the dose of the product and calculate the required volume of HETRONIFLY.

* Withdraw a volume of sodium chloride 9 mg/ml (0.9%) solution for injection corresponding tothe volume of infused product from the target intravenous bag using a sterile syringe anddiscard.

* Use a syringe to withdraw the required volume of HETRONIFLY from the vial and inject it intothe sodium chloride 9 mg/ml (0.9%) solution for injection to prepare a diluted solution with afinal concentration range from 1.0 to 8.0 mg/ml. Mix the diluted solution by gentle inversion.

* Administer the infusion solution intravenously using a sterile, non-pyrogenic, low-proteinbinding 0.2 to 5.0 μm in-line or add-on filter.

* Set the initial infusion rate to 100 ml per hour (25 drops per minute is recommended). Theinfusion rate can be adjusted if infusion-related reactions occur (see section 4.2). If there is noinfusion-related adverse reaction in the first infusion, the duration of subsequent administrationcan be shortened to 30 minutes (± 10 minutes).

* From a microbiological point of view, the product, once diluted, should be used immediately.

The diluted solution must not be frozen. If not used immediately, the diluted solution can bestored for 24 hours at 2°C to 8°C. This 24- hour hold may include up to 6 hours at roomtemperature (≤ 25°C). If refrigerated, the vials and/or intravenous bags must be allowed to cometo room temperature prior to use (see section 6.3).

* At the end of infusion, the infusion tube is flushed with sodium chloride 9 mg/ml (0.9%)solution according to the routine operation procedure of the hospital.

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

* In order to improve the traceability of biological medicinal products, the name and the batchnumber of the administered product should be clearly recorded in the patient file.

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

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n

Edifici Est, 6a Planta08039 Barcelona

Spain

EU/1/24/1870/001

Date of first authorisation: 03 February 2025

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

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