REGKIRONA 60mg / ml perfusive solution concentrate medication leaflet

Regkirona 60 mg/mL concentrate for solution for infusion

Each vial contains 960 mg of regdanvimab*.

Each mL of concentrate contains 60 mg of regdanvimab.

* Regdanvimab is a recombinant human IgG1 monoclonal antibody produced through recombinant

DNA technology in a mammalian cell line (Chinese Hamster Ovary).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Clear to opalescent, colourless to pale yellow solution with pH of 5.7- 6.3 and osmolality of 250 -300 mOsmol/kg

Regdanvimab is indicated for the treatment of adults with coronavirus disease 2019 (COVID-19) whodo not require supplemental oxygen and who are at increased risk of progressing to severe COVID-19(see section 5.1).

Regdanvimab should only be administered in settings in which health care providers have immediateaccess to appropriate resuscitation equipment and medicinal products to treat a severe infusionreaction, including anaphylaxis, and where patients can be clinically monitored during administrationand be observed for at least 1 hour after infusion is complete (see section 4.4).

The recommended dosage of regdanvimab in adults is a single IV infusion of 40 mg/kg. Regdanvimabshould be administered within 7 days of onset of symptoms of COVID-19 (see section 5.1).

The volume of Regkirona is calculated as follows.

Patient’s body weight (kg) x Regkirona dose (40 mg/kg)

Vial concentration (60 mg/mL) = Volume of Regkirona (mL)

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Total Regkirona volume (mL) to be administered

Total volume per vial (16 mL/vial) = Number of Regkirona vials needed

Table 1: Sample calculations for patients receiving the recommended dose of 40 mg/kgof Regkirona for weights ranging from 40 kg to 120 kg

Body weight (kg) Total dose (mg) Volume (mL) Vials (n)40 1,600 27 260 2,400 40 380 3,200 53 4100 4,000 67 5120 4,800 80 5

Note: If a patient’s weight is more than 200 kg, the dose calculation should use 200 kg. The maximalrecommended dose is 8,000 mg.

No dose adjustment of regdanvimab is required in elderly patients (see section 5.2).

No dose adjustments are recommended.

No dose adjustments are recommended.

The safety and efficacy of regdanvimab in paediatric patients have not yet been established. No dataare available.

For intravenous use only.

Regdanvimab should be diluted and administered intravenously over 60 minutes.

The rate of infusion may be slowed or interrupted if the patient develops any signs of infusion-relatedreactions or other adverse reactions and appropriate treatment should be initiated as necessary (seesection 4.4).

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

Hypersensitivity to the active substance(s) 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.

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Hypersensitivity reactions, including infusion-related and anaphylactic reactions, have been observedduring and following administration of regdanvimab (see section 4.8).

Patients should be clinically monitored during administration and be observed for at least 1 hour afterinfusion is complete.

Signs and symptoms of infusion-related reactions may include fever, difficulty breathing, reducedoxygen saturation, chills, fatigue, arrhythmia (e.g., atrial fibrillation, tachycardia, bradycardia,palpitation), chest pain or discomfort, weakness, altered mental status, nausea, headache,bronchospasm, hypotension, hypertension, angioedema, throat irritation, rash including urticaria,pruritus, myalgia, vaso-vagal reactions (e.g., presyncope, syncope), dizziness and diaphoresis.

If an infusion-related reaction occurs, slowing or stopping the infusion should be considered andappropriate medicinal products and/or supportive care should be administered.

The clinical trials with regdanvimab were conducted in subjects who were predominantly infectedwith the wild-type virus and the Alpha (UK origin/B.1.1.7 lineage) variant. Clinical efficacy data forregdanvimab against some circulating SARS-CoV-2 variants with decreased in vitro susceptibility iscurrently limited (see section 5.1).

No interaction studies have been performed with regdanvimab.

Regdanvimab is a monoclonal antibody, which is not renally excreted or metabolised by cytochrome

P450 enzymes; therefore, interactions with concomitant medicinal products that are renally excreted orthat are substrates, inducers, or inhibitors of cytochrome P450 enzymes are considered unlikely.

No interaction studies have been performed.

Reproductive and developmental studies have not been performed with regdanvimab.

Nonclinical reproductive toxicity studies have not been conducted with regdanvimab (see section 5.3).

In tissue cross-reactivity (TCR) studies with regdanvimab using human foetal and neonatal tissues, nobinding of clinical concern was detected in the foetal tissues. Human immunoglobulin G1 (IgG1)antibodies are known to cross the placental barrier; therefore, regdanvimab has the potential to betransferred from the mother to the developing foetus. It is unknown whether the potential transfer ofregdanvimab provides any treatment benefit or risk to the developing foetus.

Regdanvimab should be used during pregnancy only if the expected benefit to the mother justifies thepotential risk to the foetus.

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It is not known whether regdanvimab is excreted in human milk or absorbed systemically afteringestion. Administration of regdanvimab while breast-feeding can be considered when clinicallyindicated.

No fertility studies have been performed.

Regkirona has no or negligible influence on the ability to drive and use machines.

Overall, 906 subjects have been exposed to regdanvimab in clinical trials in both healthy subjects andnon-hospitalised patients. The safety of regdanvimab is based on exposure of ambulatory (non-hospitalised) patients with COVID-19.

Adverse reactions reported with regdanvimab based on experience from clinical trials in healthy subjectsand mild to moderate COVID-19 patients as well as adverse reactions reported from post-marketingexperience are listed in Table 2 by system organ class and frequency. Frequencies are defined as follows: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). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

Table 2: Tabulated list of adverse reactions

System organ class Adverse reaction

Frequency

Uncommon Infusion-related reactions11 Infusion-related reaction (IRR) includes hypersensitivity and anaphylaxis, and symptoms reported as

IRRs are described below in ‘Infusion-related reactions’. Anaphylaxis was identified from post-marketing experience.

Immediate infusion-related reactions were noted for 0.6% of regdanvimab-treated patients and 1.2% ofplacebo-treated patients. Reported events of fever, pruritus, hypertension and dyspnoea were mild withtwo cases of fever being moderate and one case of hypertension being severe and palpitation,presyncope and urticaria were moderate in the regdanvimab-treated patients. All patients in theregdanvimab treatment group recovered from the events.

In post-marketing experience, one case of anaphylaxis was reported during infusion of regdanvimabwith symptoms of dyspnoea, chest discomfort and cough.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

Medici al product no longer authorisedprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 8,000 mg have been administered in clinical trials without dose-limiting toxicity.

Treatment of overdose should consist of general supportive measures including monitoring of vitalsigns and observation of the clinical status of the patient. There is no specific antidote for overdosewith regdanvimab.

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies,

ATC code: J06BD06

Regdanvimab is a recombinant human IgG1 monoclonal antibody that binds to the receptor bindingdomain (RBD) of the spike(s) protein of SARS-CoV-2 consequently blocking cellular entry and

SARS-CoV-2 infection.

The in vitro neutralisation activity of regdanvimab against SARS-CoV-2 (BetaCoV/Korea/KCDC03/2020) was assessed by plaque reduction neutralisation test (PRNT) using VeroE6 cells. Regdanvimabneutralised this SARS-CoV-2 strain with an IC50 value of 9.70 ng/mL and an IC90 value of 25.09ng/mL.

The plaque reduction neutralisation test (PRNT) using authentic SARS-CoV-2 variant virus indicatethat regdanvimab retained activity against the Alpha (UK origin/B.1.1.7 lineage), Zeta (Brazilianorigin/P.2), Iota (New York origin/B.1.526) and Eta (Nigerian origin/B.1.525) variants. Reducedneutralising activity against Gamma (Brazilian origin/P.1), Beta (South African origin/B.1.351),

Epsilon (Californian origin/B.1.427 and B.1.429), Kappa (Indian origin/B.1.617.1) and Delta (Indianorigin/B.1.617.2) variants were observed (Table 3). Microneutralisation data using authentic SARS-

CoV-2 variant virus indicate that regdanivimab retains activity against the Alpha variant and hasreduced activity against the Beta and Gamma variants (Table 3).

Table 3: Authentic SARS-CoV-2 and Pseudovirus Neutralisation Data for Regdanvimab

Lineage with Spike Protein Key Substitutions Fold Reduction in Fold Reduction

Substitution Testeda Susceptibility in Susceptibility(Authentic Virus) (Pseudovirus)f

B.1.1.7 (Alpha, UK) N501Y/P681H No changeb, d, e No changeb

P.1 (Gamma, Brazil) K417T/E484K/N501Y 137.88e/167.90d61.42

P.2 (Zeta, Brazil) E484K No changeb, d 8.66

B.1.351 (Beta, South Africa) K417N/E484K/N501Y 19.75e/310.06d 184.29

B.1.427 (Epsilon, California) L452R 73.89d 34.97

B.1.429 (Epsilon, California) L452R 54.08d 34.97

B.1.526 (Iota, New York)c E484K/A701V No changeb, d 6.84

B.1.525 (Eta, Nigeria) E484K/Q677H No changeb, d 7.22

B.1.617.1 (Kappa, India) L452R/E484Q/P681R 23.89d 44.14

B.1.617.2 (Delta, India) L452R/T478K/P681R 182.99d 27.70

AY.1 (Delta plus, India) K417N/L452R/T478K Not determined 63.65

C.37 (Lambda, Peru) L452Q/F490S Not determined 15.50

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Lineage with Spike Protein Key Substitutions Fold Reduction in Fold Reduction

Substitution Testeda Susceptibility in Susceptibility(Authentic Virus) (Pseudovirus)f

B.1.621 (Mu, Columbia) R346K/E484K/N501Y/ Not determined 38.65

P681H

B.1.1.529 (Omicron, South K417N/T478K/E484A/ Not determined Not calculatedg

Africa) N501Ya For variants with more than one substitution of concern, only the one(s) with the greatest impacton activity is(are) listedb No change: <5-fold reduction in susceptibilityc Not all isolates of the New York lineage harbours E484K substitution (as of February 2021)d The study was conducted using plaque reduction neutralisation teste The study was conducted using microneutralisation assayf Key substitutions for global variants have been tested in a pseudovirus assayg Not calculated (IC50 > 1 mg/ml)

In vitro virus passaging with authentic SARS-CoV-2 viruses in VeroE6 cells in the presence/absenceof regdanvimab identified a S494P amino acid substitution located in the RBD of the spike protein.

Pseudovirus assay results with Q493K, Q493R, S494L and S494P showed IC50 above 500 ng/mL.

In Study CT-P59 3.2 (Phase 3), sequencing data collected at study visits were available for 557patients with COVID-19 (240 regdanvimab-treated patients and 317 placebo-treated patients). At anallele fraction of ≥15%, N501Y was the most frequently detected variant present in 76.7% (184/240)of patients in the regdanvimab group and 79.5% (252/317) of patients in the placebo group. Atbaseline, no patients had a combination of L452R, T478K and P681R mutations (associated with the

Delta variant). Three patients (none from the regdanvimab group and 3 patients from the placebogroup) had the combination of K417N, E484K and N501Y mutations (the Beta variant), and 10patients (5 patients from each group) had the combination of K417T, E484K and N501Y mutations(the Gamma variant).

Variants with in vitro reduced susceptibility at spike protein amino acid positions Q493K/R or

S494P/L at an allele fraction of ≥15% were detected for 17.9% (43/240) of patients in theregdanvimab group and none in the placebo group at posttreatment. Phenotyping assessments weredone with variants in RBD at an allelic frequency of ≥15% and all variants in epitope found ingenotyping from the regdanvimab-treated patients in Study CT-P59 3.2 (Phase 3) including F342S,

R403G/T, Y449H, Y453C, L455F/S, K458R, F486I, L492S, Q493L, S494T and F490I using aluciferase-based pseudovirus assay. The reduction in susceptibility was below five-fold for all of theseexcept for L455F/S, F486I, Q493L and S494T variants. For these variants, the fold-change was >20.

A Phase 3 of Study CT-P59 3.2 was a randomised, double-blind, placebo-controlled clinical trialstudying regdanvimab for the treatment of unvaccinated adult patients with mild to moderate COVID-19 and was conducted in multiple countries including the European Union (79.5%), the United States(7.6%) and Asia (0.9%). This study enrolled adult patients who were not hospitalised, had at least oneor more symptoms of COVID-19 for ≤7 days, oxygen saturation >94% on room air and not requiringsupplemental oxygen therapy and they were enrolled from January 18, 2021 and clinical efficacyendpoints were analysed based on data up to the cut-off date of May 21, 2021. Treatment was initiatedafter obtaining a positive SARS-CoV-2 viral infection determination.

A total of 1315 patients were randomised in a 1:1 manner to receive a single infusion of regdanvimabat doses of 40 mg/kg (N=656) or placebo (N=659) over 60 minutes.

The primary efficacy endpoint was the proportion of patients with clinical symptoms requiringhospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28.

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This was analysed in all patients randomly assigned to the study drug, who are at increased risk ofprogressing to severe COVID-19 and/or hospitalisation (defined as having at least one of the followingrisk factors for severe COVID-19: age >50 years; BMI >30 kg/m2; cardiovascular disease, includinghypertension; chronic lung disease, including asthma; type 1 or type 2 diabetes mellitus; chronickidney disease, including those on dialysis; chronic liver disease; and immunosuppressed, based oninvestigator’s assessment).

Among all randomised patients, 66.9% of patients were at increased risk of progressing to severe

COVID-19 and/or hospitalisation. Among patients at increased risk of progressing to severe COVID-19 and/or hospitalisation, the baseline median age was 54 years (range: 18 to 87); 19.4% of patientsaged 65 or older and 4.0% of patients aged 75 or older; 53.6% of patients were male; 88.6% were

White, 19.9% were Hispanic or Latino, 0.8% were Asian and 0.8% were Black or African American.

The median time from the initial symptom onset was 4 days; mean viral load at baseline was 5.8 log10copies/mL in the regdanvimab treatment group and 5.9 log10 copies/mL in placebo group. Forty-sevenpercent and 52.4% of patients had mild and moderate COVID-19, respectively. The most common riskfactors were advanced age (age >50 years) (66.1%), cardiovascular disease, including hypertension,(50.3%) and obesity (BMI >30 kg/m2) (47.2%).

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Proportion of patients with clinical symptom requiring hospitalisation, oxygen therapy, orexperiencing mortality due to SARS-CoV-2 infection up to Day 28

Table 4: Result of Primary Endpoint in Study CT-P59 3.2 (Phase 3)

Regdanvimab(40 mg/kg IV Placeboinfusion)

Proportion of Patients with

Clinical Symptoms Requiring Proportion (n, %) 14/446 (3.1%) 48/434 (11.1%)

Hospitalisation, Oxygen

Therapy, or Experiencing Difference (95% CI)a -8.0 (-11.7, -4.5)

Mortality due to SARS-CoV-2 b

Infection up to Day 28 P-value <0.0001

Note: Clinical symptom which requires hospitalisation, oxygen therapy, or experiencing mortalitydue to SARS-CoV-2 infection up to Day 28 is included. Criterion of hospitalisation is ≥24 hours ofacute care. Criteria of oxygen therapy are at least 24 hours of supplemental oxygen care and SpO2measure in room air before applying supplemental oxygen showing ≤94%.a The difference of proportions between two treatment groups estimated using CMH (Cochran-

Mantel-Haenszel) weights, and the 95% stratified Newcombe confidence interval (CI) with CMHweights are presented. Analysis was stratified by Age (≥60 years vs. <60 years), baselinecomorbidities (Yes vs. No) and region (United States vs. European Union vs. other).b The p-value from stratified CMH test is presented. The CMH test is stratified by age (≥60 years vs.<60 years), baseline comorbidities (Yes vs. No) and region (United States vs. European Union vs.other).

In addition, a total of 3 patients died (1 regdanvimab-treated patient and 2 placebo-treated patients)due to worsening of COVID-19.

Time to clinical recovery was defined as time from study drug administration to the time whensymptoms, which were scored as ‘moderate’ or ‘severe’ at baseline reduced to ‘mild’ or ‘absent’, andsymptoms scored as ‘mild’ or ‘absent’ at baseline were scored as ‘absent’. Symptoms ‘absent’ inintensity at baseline should maintain as ‘absent’ for at least 48 hours. Symptoms that were absent atbaseline but became ‘severe’, ‘moderate’, or ‘mild’ in intensity during the study were consideredclinically recovered if it changed back to ‘absent’ for at least 48 hours. Missing symptoms at baselinewere considered to be clinically recovered if they were ‘absent’ for at least 48 hours. Symptomsassessed were limited to feeling feverish, cough, shortness of breath or difficulty breathing, sorethroat, body pain or muscle pain, fatigue, and headache.

The median time to clinical recovery (at least 48 hours) in all randomised patients who are at increasedrisk of progressing to severe COVID-19 and/or hospitalisation (as defined above) was significantlyshorter for regdanvimab-treated patients as compared to placebo-treated patients (median, 9.27 daysvs. not calculated). As less than 50% of the patients in the placebo group achieved clinical recovery upto Day 14, it was not possible to calculate the median time to clinical recovery up to Day 14. However,it can be considered that the patients in the regdanvimab treatment group demonstrated a shortenedtime to clinical recovery of at least 4.73 days compared to the placebo group assuming the mediantime to clinical recovery in the placebo-treated patients as a minimum of 14 days. The difference intime to clinical recovery between the treatment groups was statistically significant (p<0.0001[stratified log-rank test]; clinical recovery ratio [95% CI] = 1.58 [1.31, 1.90]).

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

Regkirona in the treatment of Coronavirus disease 2019 (COVID-19) in one or more subsets of thepaediatric population (see section 4.2 and section 5.2 for information on paediatric use).

Medicinal roduct no longer authorised

Following the administration of the recommended dose regimen (a single dose of 40 mg/kg) in

COVID-19 patients, the mean (CV%) Cmax level was 1017 µg/mL (27%).

The mean (CV%) apparent volume of distribution at steady-state (Vss) after intravenous administrationof regdanvimab 40 mg/kg was 83 mL/kg (26%) in COVID-19 patients.

Regdanvimab is expected to be degraded into small peptides and amino acids via catabolic pathwaysin the same manner as endogenous IgG. No major age- or weight-related differences in clearance orvolume of distribution were observed in COVID-19 patients.

In studies with COVID-19 patients, the mean (CV%) clearance of regdanvimab 40 mg/kg was 0.20mL/hr/kg (24%).

In patients with COVID-19, the mean (CV%) terminal half-life for 40 mg/kg of regdanvimab was 17days (37%).

Based on the PK analysis in healthy subjects, regdanvimab was approximately dose proportional interms of maximal and systemic exposure (Cmax, AUC0-last, and AUC0-inf) over the dose range of 10mg/kg to 80 mg/kg.

Based on pharmacokinetic subgroup analyses, there is no difference in pharmacokinetics ofregdanvimab in elderly patients compared to younger patients.

The pharmacokinetics of regdanvimab in paediatric patients has not been evaluated.

The pharmacokinetics of regdanvimab has not been evaluated in patients with renal and/or hepaticimpairment. Regdanvimab is not eliminated intact in the urine, thus renal impairment is not expectedto affect the exposure of regdanvimab.

Non-clinical data revealed no special hazard for humans based on conventional studies of tissue cross-reactivity and repeated dose toxicity.

In a 3-week repeat-dose toxicity study in cynomolgus monkeys, transient moderate to markeddecreases in neutrophils and haematology parameter changes were observed in 20% of animals at adose of about 9 times the human clinical exposure.

In the TCR studies with regdanvimab using human adult, neonatal, and cynomolgus tissues, specificpositive stainings in meningeal arachnoid cap cells in the brain and/or spinal cord tissues wereobserved. These findings were not associated with neurological symptoms and histopathologicalfindings in the toxicity study, indicating that this TCR finding is less likely to have clinical relevance.

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Carcinogenicity, genotoxicity and reproductive toxicology studies have not been conducted withregdanvimab.

L-histidine

L-histidine monohydrochloride monohydrate

Polysorbate 80

L-arginine monohydrochloride

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.

Unopened vials30 months

Chemically and physical in-use stability has been demonstrated for 72 hours at 2°C - 8°C or 4 hours at≤30°C after dilution in sodium chloride 9 mg/mL (0.9%) solution for infusion.

From a microbiological point of view, the prepared infusion solution should be used immediately. Ifnot used immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place incontrolled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C).

Do not freeze. Keep the vial in its outer carton in order to protect from light.

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

Type I glass vial with a chlorobutyl rubber stopper.

Pack size of 1 vial.

Regkirona solution for infusion should be prepared by a qualified healthcare professional using aseptictechnique:

Medicinal pr duct no longer authorised

* Remove Regkirona vial(s) from refrigerated storage and allow to equilibrate to roomtemperature (not exceeding 30°C) for approximately 20 minutes before preparation. Do notexpose to direct heat. Do not shake the vial(s).

* Regkirona is a clear to opalescent, colourless to pale yellow solution for infusion. Inspect

Regkirona vial(s) visually for particulate matter and discolouration prior to dilution. Shouldeither be observed, the vial(s) must be discarded, and new vial(s) should be used for preparation.

* Calculate total volume of Regkirona to be administered (see section 4.2).

* Dilute Regkirona in a bag containing sodium chloride 9 mg/mL (0.9%) solution for infusion.

The total volume of the medicinal product and sodium chloride should be 250 mL.o In a 250 mL bag of sodium chloride, withdraw and discard the required volume (which isidentical to the calculated volume of Regkirona) of sodium chloride 9 mg/mL (0.9%) fromthe infusion bag.

o Withdraw the calculated volume of Regkirona from the vial(s) using a sterile syringe.o Transfer Regkirona to the infusion bag.

* Gently invert IV bag by hand approximately 10 times to mix. Do not shake.

Regkirona solution for infusion should be administered by a qualified healthcare professional.

* Gather the recommended materials for infusion: Infusion set with in-line filter (PES(Polyethersulfone) filter with a pore size of 1.2 μm or less would be recommended).

* Attach the infusion set to the IV bag.

* Prime the infusion set.

* Administer as an IV infusion via pump over 60 minutes.

* The prepared solution for infusion should not be administered simultaneously with any othermedicinal product.

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

Celltrion Healthcare Hungary Kft.1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

EU/1/21/1597/001

Date of first authorisation: 12 November 2021

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

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

Medicinal product no longer authorised