Leaflet RONAPREVE 120mg / ml+120mg / ml solution for injection / infusion

Ronapreve 120 mg/mL+ 120 mg/mL solution for injection/infusion

Co-packaged 1 332 mg multidose vials

Each casirivimab multidose vial contains 1 332 mg of casirivimab per 11.1 mL (120 mg/mL).

Each imdevimab multidose vial contains 1 332 mg imdevimab per 11.1 mL (120 mg/mL).

Casirivimab and imdevimab are two IgG1 recombinant human monoclonal antibodies produced byrecombinant DNA technology in Chinese hamster ovary cells.

For the full list of excipients, see section 6.1.

Solution for injection/infusion.

Clear to slightly opalescent and colourless to pale yellow solution with a pH of 6.0.

Ronapreve is indicated for:● Treatment of COVID-19 in adults and adolescents aged 12 years and older weighing at least40 kg who do not require supplemental oxygen and who are at increased risk of progressing tosevere COVID-19 (see section 4.2).

● Prevention of COVID-19 in adults and adolescents aged 12 years and older weighing at least40 kg (see section 4.2).

The use of Ronapreve should take into account information on the activity of Ronapreve against viralvariants of concern. See sections 4.4 and 5.1.

Administration should be under conditions where management of severe hypersensitivity reactions,such as anaphylaxis, is possible. Individuals should be monitored after administration according tolocal medical practice.

The dosage in adult patients and in adolescent patients 12 years of age and older weighing at least40 kg is 600 mg of casirivimab and 600 mg of imdevimab administered as a single intravenousinfusion or by subcutaneous injection (see Table 1). See sections 4.4 and 5.1.

Casirivimab with imdevimab should be given within 7 days of the onset of symptoms of COVID-19.

The dosage in adult patients and in adolescent patients 12 years of age and older weighing at least40 kg is 600 mg of casirivimab and 600 mg of imdevimab administered as a single intravenousinfusion or by subcutaneous injection (see Tables 1 and 2).

Casirivimab with imdevimab should be given as soon as possible after contact with a case of COVID-19.

The initial dose in adult patients and in adolescent patients 12 years of age and older weighing at least40 kg is 600 mg of casirivimab and 600 mg of imdevimab administered as a single intravenousinfusion or by subcutaneous injection (see Tables 1 and 2). Subsequent doses of 300 mg ofcasirivimab and 300 mg of imdevimab administered as a single intravenous infusion or bysubcutaneous injection may be given every 4 weeks until prophylaxis is no longer required. There areno data on repeat dosing beyond 24 weeks (6 doses).

In case of repeated dosing for pre-exposure prophylaxis, if a dose of Ronapreve is missed it should beadministered as soon as possible. Thereafter, the schedule of administration should be adjusted tomaintain the appropriate interval between doses.

No dosage adjustment is required (see section 5.2).

No dosage adjustment is required (see section 5.2).

No dosage adjustment is required (see section 5.2).

The safety and efficacy of casirivimab and imdevimab in children < 12 years of age has not yet beenestablished. No data are available.

Ronapreve is for intravenous or subcutaneous use only.

Intravenous infusion

For detailed instructions on the preparation and administration of Ronapreve, see section 6.6.

Table 1: Recommended dilution instructions for Ronapreve (casirivimab and imdevimab) forintravenous infusion

Indication Ronapreve Dose Total Volume to be withdrawn from each respective vial

Volume and injected into a single prefilled 0.9% sodiumfor 1 chloride or 5% dextrose infusion bag of 50-250 mL

Dose for co-administration

Treatment,

Post-exposureprophylaxis 600 mg casirivimab(single dose), and 10 mL 5 mL from one 1 332 mg multidose vial of casirivimab

Pre-exposure 600 mg imdevimab 5 mL from one 1 332 mg multidose vial of imdevimabprophylaxis(initial dose)

Pre-exposure 300 mg casirivimab 2.5 mL from one 1 332 mg multidose vial ofprophylaxis and 5 mL casirivimab(repeat dose) 300 mg imdevimab 2.5 mL from one 1 332 mg multidose vial ofimdevimab

The infusion should be administered over 20-30 minutes. The rate of infusion may be slowed,interrupted or discontinued if the patient develops any signs of infusion-associated events or otheradverse reactions (see section 4.4).

For detailed instructions on the preparation and administration of Ronapreve, see section 6.6.

Subcutaneous injections of casirivimab and imdevimab should be made consecutively at separate bodysites (into upper thighs, upper outer arms or abdomen, avoiding 5 cm around the navel and thewaistline).

Table 2: Preparation of Ronapreve (casirivimab and imdevimab) for subcutaneous injection

Total

Indication Ronapreve Dose Volume for Volume to be withdrawn from each respective vial1 Dose to prepare 4 syringes

Treatment,

Post-exposureprophylaxis 600 mg casirivimab 2.5 mL (2x) from one 1 332 mg multidose vial of(single dose), and 10 mL casirivimab

Pre-exposure 600 mg imdevimab 2.5 mL (2x) from one 1 332 mg multidose vial ofprophylaxis imdevimab(initial dose)

Total

Indication Ronapreve Dose Volume for Volume to be withdrawn from each respective vial1 Dose to prepare 2 syringes

Pre-exposure 300 mg casirivimab 2.5 mL from one 1 332 mg multidose vial ofprophylaxis and 5 mL casirivimab(repeat dose) 300 mg imdevimab 2.5 mL from one 1 332 mg multidose vial ofimdevimab

Hypersensitivity to the active substances 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.

Activity against SARS-CoV-2 variants

Decisions regarding the use of Ronapreve for treatment or prophylaxis should take into considerationwhat is known about the characteristics of the circulating SARS-CoV-2 viruses including regional orgeographical differences and available information on Ronapreve susceptibility patterns. See section5.1.

When molecular testing or sequencing data is available, it should be considered when selectingantiviral therapy to rule out SARS-CoV-2 variants that are shown to have reduced susceptibility to

Ronapreve.

The clinical efficacy of Ronapreve when administered by the subcutaneous route for treatment of

COVID-19 has not been evaluated in clinical trials (see section 5.1). The pharmacokinetics ofcasirivimab and imdevimab in the first 48 hours after subcutaneous administration of 600 mg of eachmonoclonal antibody indicate lower serum exposures compared to intravenous administration of thesame dose. It is unknown whether differences in initial systemic exposure result in differences inclinical efficacy. It is recommended that the subcutaneous route of administration is used only ifintravenous administration is not feasible and would lead to a delay in treatment.

Hypersensitivity reactions, including anaphylaxis, have been reported with administration ofcasirivimab and imdevimab (see section 4.8). If signs or symptoms of a clinically significanthypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiateappropriate medications and/or supportive care.

Infusion-related reactions (IRRs) have been observed with intravenous administration of casirivimaband imdevimab.

IRRs observed in clinical studies were mostly moderate in severity and were typically observed duringor within 24 hours of infusion. The frequently reported signs and symptoms for these reactionsincluded nausea, chills, dizziness (or syncope), rash, urticaria and flushing. However, infusion-relatedreactions may present as severe or life-threatening events and may include other signs and symptoms.

If an IRR occurs, the infusion may be interrupted, slowed or stopped.

No formal drug-drug interaction studies have been performed. Casirivimab and imdevimab aremonoclonal antibodies, which are not renally excreted or metabolised by cytochrome P450 enzymes;therefore, interactions with concomitant medicinal products that are renally excreted or that aresubstrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

There are no or limited amount of data from the use of casirivimab and imdevimab in pregnantwomen. Animal studies have not been performed with respect to reproductive toxicity. Humanimmunoglobulin G1 (IgG1) antibodies are known to cross the placenta. It is unknown whether thepotential transfer of casirivimab and imdevimab provides any treatment benefit or risk to thedeveloping foetus. However, as casirivimab and imdevimab directly target the spike protein of SARS-

CoV-2 and in view of lack of cross reactivity with reproductive or foetal tissues in the tissue crossreactivity studies, negative effects on developing foetus are not expected. Ronapreve should be usedduring pregnancy only if the potential benefit justifies the potential risk for the mother and the foetusconsidering all associated health factors. If a woman becomes pregnant while taking this medicine, theindividual should be informed that any potential risk to the foetus is unknown.

It is unknown whether casirivimab and imdevimab are excreted in human milk, but maternal IgG isknown to be transferred to milk during the first days after birth. As casirivimab and imdevimabdirectly target the spike protein of SARS-CoV-2 and in view of low systemic absorption after oralingestion of antibodies, administration of Ronapreve whilst breast-feeding can be considered whenclinically indicated.

No fertility studies have been performed.

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

Overall, 7 116 subjects (4 666 via intravenous administration and 2 450 via subcutaneousadministration) have been treated with casirivimab and imdevimab in clinical trials.

The most frequently reported adverse drug reactions are hypersensitivity reactions, which includeinfusion related reactions (IRRs) and injection site reactions (ISRs).

The adverse reactions in Table 3 are listed below by system organ class and frequency. Frequenciesare 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).

Table 3: Tabulated list of adverse reactions identified from clinical trials:

System organ class Adverse reaction Frequency category

Immune system disorders Anaphylaxis Rare

Nervous system disorders Dizziness* Uncommon

Vascular disorders Flushing* Rare

Gastrointestinal disorders Nausea* Uncommon

Skin and subcutaneous tissue Rash* Uncommondisorders Urticaria* Rare

General disorders and Chills* Uncommonadministration site conditions

Injury, poisoning and procedural Infusion related reactions Uncommoncomplications

Blood and lymphatic system Lymphadenopathy Uncommondisorders

Nervous system disorders Dizziness Uncommon

Skin and subcutaneous tissue Pruritus1* Raredisorders

General disorders and Injection site reactions1 Commonadministration site conditions1ISRs include erythema, pruritus, ecchymosis, oedema, pain, tenderness and urticaria

* In some cases, symptoms of IRRs and ISRs have been reported as individual ADRs

No data are available for paediatric patients <18 years old.

In study COV-2069, 66 adolescents ≥ 12 and < 18 years old received treatment with casirivimab andimdevimab. The safety profile observed was similar to that in adult patients.

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.

Doses up to 4 000 mg each of casirivimab and imdevimab (approximately 7-times the recommendeddose) have been administered in clinical trials. The safety profile for 8 000 mg intravenous was notsubstantially different to that for the recommended dose.

There is no known specific antidote for casirivimab and imdevimab overdose. Treatment of overdoseshould consist of general supportive measures including monitoring of vital signs and observation ofthe clinical status of the patient.

Casirivimab:

Pharmacotherapeutic group: Not yet assigned. ATC code: Not yet assigned.

Imdevimab:

Pharmacotherapeutic group: Not yet assigned. ATC code: Not yet assigned.

Casirivimab (IgG1κ) and imdevimab (IgG1λ) are two recombinant human monoclonal antibodieswhich are unmodified in the Fc regions. Casirivimab and imdevimab bind to non-overlapping epitopesof the spike protein receptor binding domain (RBD) of SARS-CoV-2. This prevents RBD binding tothe human ACE2 receptor, so preventing virus entry into cells.

In a SARS-CoV-2 virus neutralisation assay in Vero E6 cells, casirivimab, imdevimab, andcasirivimab and imdevimab together neutralised SARS-CoV-2 (USA-WA1/2020 isolate) with EC50values of 37.4 pM (0.006 μg/mL), 42.1 pM (0.006 μg/mL), and 31.0 pM (0.005 μg/mL) respectively.

There is a potential risk of treatment failure due to the development of viral variants that are resistantto casirivimab and imdevimab administered together.

The neutralising activity of casirivimab, imdevimab and casirivimab and imdevimab together wasassessed against S protein variants, including known Variants of Concern/Interest, variants identifiedin in vitro escape studies, and variants from publicly available SARS-CoV-2 genome data obtainedfrom the Global Initiative on Sharing All Influenza Data (GISAID). Casirivimab and imdevimabneutralising activity against the Variants of Concern/Interest are shown in Table 4.

Table 4: Pseudotyped virus-like particle neutralisation data for full sequence or key SARS-CoV-2 S-protein variant substitutions from variants of interest/concern* with casirivimaband imdevimab alone or together

Reduced

Lineage with spike Key substitutions susceptibility to Reduced Reducedprotein casirivimab susceptibility susceptibilitysubstitutions tested and imdevimab to casirivimab to imdevimabtogether alone alone

B.1.1.7 (UK a e eorigin/Alpha) Full S protein no change no change no changee

B.1.351 (South

Africa origin/Beta) Full S proteinb no changee 45-fold no changee

P.1 (Brazil corigin/Gamma) Full S protein no changee 418-fold no changee

B.1.427/B.1.429(California L452R no changee no changee no changeeorigin/Epsilon)

B.1.526 (New Yorkorigin/Iota)f E484K no changee 25-fold no changee

B.1.617.1/B.1.617.3(India origin/Kappa) L452R+E484Q no changee 7-fold no changee

B.1.617.2/ AY.3 e e(India origin/Delta) L452R+T478K no change no change no changee

AY.1/AY.2g(India origin/Delta K417N+L452R+ e

T478Kd no change 9-fold no changee[+K417N])

B.1.621/B.1.621.1(Colombia R346K, E484K, no changee 23-fold no changeeorigin/Mu) N501Y

C.37 (Peru eorigin/Lambda) L452Q+F490S no change no changee no changee

B.1.1.529/BA.1(Omicron) Full S proteinh >1013-fold >1732-fold >754-folda Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spikeprotein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H.b Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spikeprotein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V.c Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spikeprotein are found in the variant: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I,

V1176Fd For AY.1: Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-typespike protein are found in the variant: (T19R, G142D, E156G, F157-, F158-, K417N, L452R, T478K, D614G, P681R,

D950N).e No change: ≤ 5-fold reduction in susceptibility.f Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021).g Commonly known as 'Delta plus”.h Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spikeprotein are found in the variant: A67V, del69-70, T95I, G142D/del143-145, del211/L212I, ins214EPE, G339D, S371L,

S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G,

H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F.

*Variants of interest/concern as defined by the Centers for Disease Control and Prevention (CDC, 2021){https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html}

See Table 5 for a comprehensive list of authentic SARS-CoV-2 Variants of Concern/Interest assessedfor susceptibility to casirivimab and imdevimab alone and together.

Table 5: Neutralisation data for authentic SARS-CoV-2 variants of Concern/Interest withcasirivimab and imdevimab alone or together

Lineage with spike Reduced susceptibilityprotein substitution to casirivimab and Reduced susceptibility Reduced susceptibilityimdevimab together to casirivimab alone to imdevimab alone

B.1.1.7 (UK a a aorigin/alpha) no change no change no change

B.1.351 (South a a

Africa origin/beta) no change 5-fold no change

P.1 (Brazil a aorigin/Gamma) no change 371-fold no change

B.1.617.1 (India a aorigin/Kappa) no change 6-fold no change

B.1.617.2 (India a a aorigin/Delta) no change no change no changea No change: ≤ 5-fold reduction in susceptibility.

COV-2067 was a randomised, double-blinded, placebo-controlled clinical trial evaluating casirivimaband imdevimab for the treatment of subjects with COVID-19 (symptomatic with SARS-CoV-2detected by quantitative reverse transcription polymerase chain reaction [RT-qPCR]) who did notrequire supplemental oxygen.

In Phase 3 Cohort 1 of this trial, subjects not previously vaccinated against SARS-CoV-2 wererandomised within 7 days of symptom onset to a single intravenous infusion of 600 mg of casirivimaband 600 mg of imdevimab (n = 1 347), 1 200 mg of casirivimab and 1 200 mg of imdevimab(n = 2 036) or placebo (n = 2 009).

Subjects in Phase 3 Cohort 1 had at least one protocol-listed risk factor for developing severe COVID-19 (these included age > 50 years, obesity defined as BMI ≥ 30 kg/m2, cardiovascular diseaseincluding hypertension, chronic lung disease including asthma, type 1 and 2 diabetes mellitus, chronickidney disease including those on dialysis, chronic liver disease, pregnancy and immunosuppressed).

The median age was 50 years (with 13.1% of subjects aged 65 years or older) and 51.4% of thesubjects were female. Baseline demographics and disease characteristics were well balanced across thecasirivimab and imdevimab and placebo treatment groups.

The primary endpoint was the proportion of subjects with ≥ 1 COVID-19-related hospitalisation or all-cause death through Day 29.

Table 6: Summary of primary endpoint phase 3 results from study COV-20671 200 mg IV Placebo 2 400 mg IV Placebon = 1 192 n = 1 193 n = 1 812 n = 1 790

Patients in the mFAS with ≥1 COVID-19-related hospitalisation or death through day 29

Risk reduction 72.5% 70.9%(p < 0.0001) (p < 0.0001)

Number of patients with 11 (0.9%) 40 (3.4%) 23 (1.3%) 78 (4.4%)eventsmFAS: modified full analysis set included those subjects with a positive SARS-CoV-2 RT-qPCR result from nasopharyngeal (NP) swab atrandomization, and with at least one risk factor for severe COVID-19.

The median time to symptom resolution, as recorded in a trial-specific daily symptom diary, wasreduced from 13 days with placebo to 10 days with both doses of casirivimab and imdevimab(p<0.0001).

COV-2069 was a randomised, double-blind, placebo-controlled clinical trial that compared 600 mgcasirivimab and 600 mg imdevimab given subcutaneously to placebo for prevention of COVID-19 inasymptomatic household contacts of symptomatic individuals infected with SARS-CoV-2 (indexcases). Subjects had not been previously vaccinated against SARS-CoV-2.

Subjects were randomised 1:1 to casirivimab and imdevimab or placebo within 96 hours of collectionof the first index case sample that gave a positive result (RT-qPCR) for SARS-CoV-2.

Randomised subjects with a negative SARS-CoV-2 RT-qPCR test result at baseline were assigned to

Cohort A and those with a positive SARS-CoV-2 RT-qPCR test result were assigned to Cohort B.

The primary analysis population included subjects who were SARS-CoV-2 RT-qPCR negative andseronegative at baseline. Subjects who were seropositive or who had undetermined/missing baselineserology were excluded from the primary efficacy analysis.

For the primary analysis population at baseline, the median age was 44 years (with 9% of subjectsages 65 years or older) and 54% of the subjects were female. The baseline demographics and diseasecharacteristics were well balanced across the casirivimab and imdevimab and placebo treatmentgroups.

The primary endpoint was the proportion of subjects who developed symptomatic RT-qPCR-confirmed COVID-19 through Day 29. There was a statistically significant 81% risk reduction in thedevelopment of COVID-19 with casirivimab and imdevimab treatment versus placebo. In a sensitivityanalysis that included all RT-qPCR negative subjects at baseline, regardless of baseline serologicalstatus, there was a statistically significant 82% risk reduction in development of COVID-19 withcasirivimab and imdevimab treatment compared to placebo.

Table 7: Primary analysis of study COV-2069, Cohort Acasirivimab and Placeboimdevimab(single 1 200 mgdose)

Primary analysis population: seronegative at baseline n = 753 n = 752

Through Day 29 (primary endpoint)

Unadjusted Risk reduction 81%(Adjusted Odds ratio, p-value)1 (0.17; p < 0.0001)

Number of individuals with events 11 (1.5%) 59 (7.8%)1 The confidence interval (CI) with p-value is based on the odds ratio (casirivimab and imdevimab group vs placebo group)using logistic regression model with the fixed categorical effects of treatment group, age group (age in years:>=12 to<50 and>=50), and region (US vs ex-US).

The primary analysis population included asymptomatic subjects who were SARS-CoV-2 RT-qPCRpositive and seronegative at baseline.

For the primary analysis population at baseline, the median age was 40 years (with 11% of subjectsages 65 years or older) and 55% of the subjects were female. The baseline demographics and diseasecharacteristics were well balanced across the casirivimab and imdevimab and placebo treatmentgroups.

The primary efficacy endpoint was the proportion of subjects who developed RT-qPCR-confirmed

COVID-19 through Day 29. There was a 31% risk reduction in the development of COVID-19 withcasirivimab and imdevimab treatment vs. placebo. In a sensitivity analysis that included all RT-qPCRpositive subjects at baseline, regardless of baseline serological status, there was a 35% risk reductionin RT-qPCR-confirmed COVID-19 with casirivimab and imdevimab treatment compared to placebo.

Table 8: Primary analysis study COV-2069, Cohort Bcasirivimab and Placeboimdevimab(single 1 200 mgdose)

Primary analysis population: seronegative at baseline n = 100 n = 104

Overall risk reduction through Day 29 (primary endpoint)

Unadjusted Risk reduction 31%(Adjusted Odds ratio, p-value)1 (0.54; p = 0.0380)

Number of individuals with events 29 (29%) 44 (42.3%)1 The confidence interval (CI) with p-value is based on the odds ratio (casirivimab and imdevimab group vs placebo group)using logistic regression model with the fixed categorical effects of treatment group, age group (age in years:>=12 to<50 and>=50), and region (US vs ex-US).

Both casirivimab and imdevimab exhibited linear and dose-proportional PK across the intravenous(150 to 4 000 mg of each monoclonal antibody) and subcutaneous (300 and 600 mg of eachmonoclonal antibody) dose ranges evaluated in clinical studies.

Mean peak concentration (Cmax), area under the curve from 0 to 28 days (AUC0-28) and concentrationat 28 days after dosing (C28) for casirivimab and imdevimab were comparable after either a single1 200 mg (600 mg of each monoclonal antibody) intravenous dose (182.7 mg/L, 1 754.9 mg.day/L,37.9 mg/L, respectively for casirivimab, and 181.7 mg/L, 1 600.8 mg.day/L, 27.3 mg/L, respectivelyfor imdevimab), or a single 1 200 mg (600 mg of each monoclonal antibody) subcutaneous dose(52.5 mg/L, 1 121.7 mg.day/L, 30.5 mg/L, respectively for casirivimab, and 49.2 mg/L,1 016.9 mg.day/L, 25.9 mg/L, respectively for imdevimab).

For the pre-exposure prophylaxis of intravenous and subcutaneous regimens at monthly administrationof 300 mg each for casirivimab and imdevimab following an initial (loading) dose of 600 mg each forcasirivimab and imdevimab, the median predicted casirivimab and imdevimab trough serumconcentrations at steady state are similar to observed mean day 29 concentrations in serum for a singlesubcutaneous dose of casirivimab and imdevimab 1 200 mg (600 mg of casirivimab and 600 mg ofimdevimab).

Casirivimab and imdevimab administered as a single intravenous dose of 600 mg for each monoclonalantibody results in peak serum concentrations at the end of infusion. The median (range) time to reachmaximum serum concentration of casirivimab and imdevimab (Tmax) estimates following a singlesubcutaneous dose of 600 mg of each monoclonal antibody are 6.7 (range 3.4 - 13.6) days and 6.6(range 3.4 - 13.6) days for casirivimab and imdevimab, respectively. After a single subcutaneous doseof 600 mg of each monoclonal antibody, casirivimab and imdevimab had an estimated bioavailabilityof 71.8% and 71.7%, respectively.

The total volume of distribution estimated via population pharmacokinetic analysis is 7.161 L and7.425 L for casirivimab and imdevimab, respectively.

As human monoclonal IgG1 antibodies, casirivimab and imdevimab are expected to be degraded intosmall peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

The mean (5th, 95th percentile) serum elimination half-lives after a 600 mg dose of each monoclonalantibody were 29.8 (16.4, 43.1) days and 26.2 (16.9, 35.6) days, respectively, for casirivimab andimdevimab.

For adolescent patients with COVID-19 (12 years of age and older and weighing at least 40 kg in

COV-2067) receiving a single 1200 mg IV dose, the mean ± SD concentration at the end of infusionand at 28 days after dosing was 172 ± 96.9 mg/L and 54.3 ± 17.7 mg/L for casirivimab and183 ± 101 mg/L and 45.3 ± 13.1 mg/L for imdevimab.

For adolescents not infected with SARS-CoV-2 (12 years of age and older and weighing at least 40 kgin COV-2069) receiving a single 1200 mg SC dose, the mean ± SD concentration 28 days after dosingwas 44.9 ± 14.7 mg/L for casirivimab and 36.5 ± 13.2 mg/L for imdevimab.

The pharmacokinetics of casirivimab and imdevimab in children < 12 years of age has not yet beenestablished.

In the population PK analysis, age (18 years to 96 years) was not identified as a significant covariateon PK of casirivimab and imdevimab.

Casirivimab and imdevimab are not expected to undergo significant renal elimination due to theirmolecular weight (> 69 kDa).

Casirivimab and imdevimab are not expected to undergo significant hepatic elimination.

Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted withcasirivimab and imdevimab. Antibodies such as casirivimab and imdevimab are not expected todisplay genotoxic or carcinogenic potential. In tissue cross-reactivity studies with casirivimab andimdevimab using human and monkey adult tissues and human foetal tissues, no binding was detected.

In a toxicology study in cynomolgus monkeys, non-adverse liver findings (minor transient increases in

AST and ALT) were observed.

L-histidine

L-histidine monohydrochloride monohydratepolysorbate 80sucrose

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial: 2 years

Co-packaged 1 332 mg multidose vials

After initial puncture: If not used immediately, the product in the vial can be stored for 16 hours atroom temperature up to 25 °C or for no more than 48 hours in a refrigerator (2 °C to 8 °C). Beyondthese times and conditions, in-use storage is the responsibility of the user.

Diluted solution for intravenous administration

Solution in vial requires dilution prior to administration. The prepared infusion solution is intended tobe used immediately. The chemical and physical in-use stability data has been demonstrated for20 hours at room temperature (up to 25 °C) and 72 hours at 2 °C to 8 °C. From a microbiological pointof view, the prepared infusion solution should be used immediately. If not used immediately, in-usestorage times and conditions prior to use are the responsibility of the user and would normally not belonger than 24 hours at 2 °C to 8 °C, unless dilution has taken place in controlled and validated asepticconditions. If refrigerated, allow the intravenous infusion bag to equilibrate to room temperature forapproximately 30 minutes prior to administration.

Storage of syringes for subcutaneous administration

The prepared syringes should be administered immediately. The chemical and physical in-use stabilitydata has been demonstrated for 24 hours at room temperature (up to 25 °C) and 72 hours at 2 °C to8 °C. If not used immediately, in-use storage times and conditions prior to use are the responsibility ofthe user and would normally not be longer than 24 hours at 2 °C to 8 °C, unless preparation has takenplace in controlled and validated aseptic conditions. If refrigerated, allow the syringes to equilibrate toroom temperature for approximately 10-15 minutes prior to administration.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Do not shake.

Keep the vials in the original carton in order to protect from light.

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

Ronapreve is provided in 20 mL clear Type 1 glass vials.

Ronapreve 120 mg/mL + 120 mg/mL solution for injection/infusion, multidose vials

Each carton contains 1 vial of each antibody:

Pack of two 20 mL clear Type I glass vials with butyl rubber stopper containing one vial of 11.1 mLsolution of 1 332 mg of casirivimab and one vial of 11.1 mL solution of 1 332 mg of imdevimab.

Ronapreve should be prepared by a healthcare professional using aseptic technique:

1. Remove the casirivimab and imdevimab vials from refrigerated storage and allow to equilibrateto room temperature for approximately 20 minutes before preparation.

- Do not expose to direct heat.

- Do not shake the vials.

2. Inspect casirivimab and imdevimab vials visually for particulate matter and discolouration priorto administration. Should either be observed, the vial must be discarded and replaced with a newvial.

- The solution for each vial should be clear to slightly opalescent, colourless to pale yellow.

3. Obtain a prefilled intravenous infusion bag [made from polyvinyl chloride (PVC) or polyolefin(PO)] containing either 50 mL, 100 mL, 150 mL, or 250 mL of 0.9% sodium chloride injectionor 5% dextrose injection.

4. Using a sterile syringe and needle, withdraw the appropriate volume of casirivimab andimdevimab from each respective vial and inject into a prefilled infusion bag containing0.9% sodium chloride injection or 5% dextrose injection (see section 4.2, Table 1).

5. Gently mix infusion bag by inversion. Do not shake.6. Ronapreve is preservative-free and therefore, the diluted infusion solution should beadministered immediately.

Administration of Ronapreve by intravenous infusion● Gather the recommended materials for infusion:

- Polyvinyl chloride (PVC), polyethylene (PE)-lined PVC, or polyurethane (PU) infusionset

- In-line or add-on 0.2 μm to 5 μm polyethersulfone, polysulfone, or polyamide filter forintravenous administration.

● Attach the infusion set to the intravenous bag.● Prime the infusion set.● Administer the entire infusion solution in the bag via pump or gravity through an intravenousline containing a sterile, in-line or add-on 0.2 μm to 5 μm polyethersulfone, polysulfone, orpolyamide filter for intravenous administration.

● The prepared infusion solution should not be administered simultaneously with any othermedicinal product. The compatibility of casirivimab and imdevimab injection with intravenoussolutions and medicinal products other than 0.9% sodium chloride injection or 5% dextroseinjection is not known.

● After infusion is complete, flush the tubing with 0.9% sodium chloride injection or 5% dextroseinjection to ensure delivery of the required dose.

● Individuals should be monitored post intravenous infusion according to local medical practice.

Remove the casirivimab and imdevimab vial(s) from refrigerated storage and allow to equilibrate toroom temperature for approximately 20 minutes before preparation.

Do not expose to direct heat.

Do not shake the vials.

Inspect casirivimab and imdevimab vial(s) visually for particulate matter and discolouration prior toadministration. Should either be observed, the vial must be discarded and replaced with a new vial.

The solution for each vial should be clear to slightly opalescent, colourless to pale yellow.

1. Ronapreve should be prepared using the appropriate number of syringes (see section 4.2,

Table 2). Obtain 3 mL or 5 mL polypropylene syringes with luer connection and 21-gaugetransfer needles.

2. Using a sterile needle and syringe, withdraw the appropriate volume of casirivimab andimdevimab from each respective vial into each syringe (see section 4.2, Table 2) for a total of 4syringes for the 1 200 mg combined total dose and a total of 2 syringes for the 600 mgcombined total dose. Store any remaining product as directed in Section 6.3.

3. Replace the 21-gauge transfer needle with a 25-gauge or 27-gauge needle for subcutaneousinjection.

4. This product is preservative-free and therefore, the prepared syringes should be administeredimmediately. If immediate administration is not possible, store the prepared casirivimab andimdevimab syringes at 2 ºC to 8 ºC for no more than 72 hours and at room temperature up to25 ºC for no more than 24 hours. If refrigerated, allow the syringes to equilibrate to roomtemperature for approximately 10-15 minutes prior to administration.

Administration of Ronapreve by subcutaneous injection● For the administration of Ronapreve 1 200 mg dose (600 mg of casirivimab and 600 mg ofimdevimab), gather 4 syringes (see section 4.2, Table 2) and prepare for subcutaneousinjections.

● For the administration of Ronapreve 600 mg dose (300 mg of casirivimab and 300 mg ofimdevimab), gather 2 syringes (see section 4.2, Table 2) and prepare for subcutaneousinjections.

● Due to the volume, administer the subcutaneous injections consecutively, at separate body sites(into upper thighs, upper outer arms, or abdomen, avoiding 5 cm around the navel and thewaistline).

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

The following points should be strictly adhered to regarding the use and disposal of syringes and othermedicinal sharps:● Needles and syringes should never be reused.● Place all used needles and syringes into a sharps container (puncture-proof disposablecontainer).

Roche Registration GmbH

Emil-Barell-Strasse 179639 Grenzach-Wyhlen

Germany

EU/1/21/1601/002

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.