RONAPREVE Solution for injection/infusion Ref.[107202] Active ingredients: Casirivimab and imdevimab

Traceability

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

Activity against SARS-CoV-2 variants

Decisions regarding the use of Ronapreve for treatment or prophylaxis should take into consideration what is known about the characteristics of the circulating SARS-CoV-2 viruses including regional or geographical differences and available information on Ronapreve susceptibility patterns. See section 5.1.

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

Subcutaneous administration for treatment of COVID-19

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 of casirivimab and imdevimab in the first 48 hours after subcutaneous administration of 600 mg of each monoclonal antibody indicate lower serum exposures compared to intravenous administration of the same dose. It is unknown whether differences in initial systemic exposure result in differences in clinical efficacy. It is recommended that the subcutaneous route of administration is used only if intravenous administration is not feasible and would lead to a delay in treatment.

Hypersensitivity reactions including anaphylaxis

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

Cases of convulsive syncope have been observed following intravenous and subcutaneous administration (see section 4.8). Convulsive syncope should be differentiated from seizures and managed as clinically indicated.

Infusion-related reactions

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

IRRs observed in clinical studies were mostly moderate in severity and were typically observed during or within 24 hours of infusion. The frequently reported signs and symptoms for these reactions included nausea, chills, dizziness (or syncope), rash, urticaria, pruritus, tachypnoea and flushing. However, infusion-related reactions 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 are monoclonal antibodies, which are not renally excreted or metabolised by cytochrome P450 enzymes; therefore, interactions with concomitant medicinal products that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.

Pregnancy

There are no or limited amount of data from the use of casirivimab and imdevimab in pregnant women. Animal studies have not been performed with respect to reproductive toxicity. Human immunoglobulin G1 (IgG1) antibodies are known to cross the placenta. It is unknown whether the potential transfer of casirivimab and imdevimab provides any treatment benefit or risk to the developing foetus. However, as casirivimab and imdevimab directly target the spike protein of SARSCoV-2 and in view of lack of cross reactivity with reproductive or foetal tissues in the tissue cross reactivity studies, negative effects on developing foetus are not expected. Ronapreve should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the foetus considering all associated health factors. If a woman becomes pregnant while taking this medicine, the individual should be informed that any potential risk to the foetus is unknown.

Breast-feeding

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

Fertility

No fertility studies have been performed.

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

Summary of the safety profile

Overall, 8 596 subjects (6 173 via intravenous administration and 2 423 via subcutaneous administration) have been treated with casirivimab and imdevimab in clinical trials.

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

Tabulated summary of adverse reactions

The adverse reactions in Table 3 are listed below by system organ class and frequency. Frequencies are defined as Very common (≥1/10), (Common (≥1/100 to 1/10), Uncommon (≥1/1 000 to <1/100), Rare (≥1/10 000 to 1/1 000), Very rare (<1/10 000).

Table 4. Tabulated list of adverse reactions identified from clinical trials and post-marketing:

¹ ISRs include erythema, pruritus, ecchymosis, oedema, pain, tenderness, urticaria, and convulsive syncope
^* In some cases, symptoms of IRRs and ISRs have been reported as individual ADRs

Paediatric population

Intravenous administration

In the RECOVERY study, 4 adolescents ≥12 and <18 years old received treatment with casirivimab and imdevimab. The safety profile observed in this limited population was similar to that in adult patients.

Subcutaneous administration

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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