Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Subsequent doses of Ronapreve should not be given to those who have experienced severe allergic reactions (e.g. anaphylaxis, generalized urticarial) to the first dose.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity reactions, including anaphylaxis, have been reported with administration of Ronapreve. If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, immediately discontinue administration and initiate appropriate medications and/or supportive care.
Infusion-related reactions (IRRs) have been observed with IV administration of Ronapreve. IRRs observed in clinical studies were mostly mild to moderate in severity and were typically observed during or within 24 hours of infusion. The commonly reported signs and symptoms for these reactions included nausea, chills, dizziness (or syncope), rash, urticaria 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, consider interrupting, slowing or stopping the infusion and administer appropriate medications and/or supportive care.
Ronapreve is not intended to be used as a substitute for vaccination against COVID-19.
No 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 medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
Casirivimab and imdevimab binds to epitopes on spike protein used as immunogen in all COVID-19 vaccines, therefore it is possible that casirivimab and imdevimab may interfere with the development of effective immune responses to COVID-19 vaccines. Refer to current vaccination guidelines with respect to timing of vaccination post treatment with anti-SARS-CoV-2 monoclonal antibodies. Limited safety data are available from the study HV-2093 where COVID-19 vaccine was permitted and no safety concerns were identified.
There are no or limited amount of data from the use of casirivimab and imdevimab in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. In a tissue crossreactivity study with casirivimab and imdevimab using human foetal tissues, no binding was detected (see section 5.3). 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. 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.
It is unknown whether casirivimab and imdevimab are excreted in human milk.
A risk to the newborns/infants cannot be excluded.
Maternal IgG is known to be present in human milk and any potential risk of adverse reactions from the drug in breast-feeding infants is unknown, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ronapreve therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Breast-feeding mothers with COVID19 should follow practices according to clinical guidelines to avoid exposing the infant to COVID-19.
No fertility studies have been performed.
Ronapreve has no or negligible influence on the ability to drive and use machines.
Overall, approximately 7,116 subjects (approximately 4666 via IV administration and 2450 via subcutaneous administration) have been treated with Ronapreve in clinical trials which support the listed indications. Since Ronapreve can be administered either as intravenous infusion or as subcutaneous injection for the treatment and prevention of COVID-19, the safety profile has been presented in relation to the route of administration. The safety profile of IV administration is primarily based on the pooled safety data analysis of the study COV-2067 (phase 1/2/3) while for the subcutaneous route, it is based primarily on the study COV-2069. Expanded analysis has also been performed on safety data from the supportive studies (COV-20145, HV-2093).
The Analysis Set for intravenous administration provides data from 4666 patients with 597 patientyears of exposure; 51.3% (n=2394) were female and 48.7% (n=2,272) were male; most (89.6% [n=4,180] were 18 to <65 years of age. No exposure data for subjects <18 years are available).
The Single Dose Safety Analysis Set for subcutaneous administration provides data from 1721 patients with 468 patient-years of exposure; 53.3% (n=917) were female and 46.7% [n=804] were male; most (88.0% [n=1,515] were 18 to <65 years of age. A total of 4.0% (n=68) were paediatric patients aged 12 to <18.
The Repeat Dose Safety Analysis Set for subcutaneous administration provides data from 729 subjects with 285 person-years of exposure; 55.1% (n=402) were male and 44.9% (n=327) were female; most (87.7% [n=639] were 18 to <65 years of age.
No exposure data for subjects <12 years are available.
Reported adverse drug reactions (ADRs) identified from the clinical development programme relate to hypersensitivity reactions which include infusion related reactions and injection site reactions (ISRs). In some cases, symptoms of IRRs and ISRs were reported as individual ADRs, the more frequently reported symptoms are included in Table 4 below.
The adverse reactions in Table 4 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:
| System organ class | Adverse Reaction | Frequency Category |
|---|---|---|
| Intravenous administration | ||
| Immune system disorders | Anaphylaxis3 | Very rare |
| Nervous system disorders | Dizziness2* | Uncommon |
| Vascular disorders | Flushing2* | Rare |
| Gastrointestinal disorders | Nausea2* | Uncommon |
| Skin and subcutaneous tissue disorders | Rash2* | Uncommon |
| Urticaria2* | Rare | |
| General disorders and administration site conditions | Chills2* | Uncommon |
| Injury, poisoning and procedural complications | Infusion related reactions2 | Uncommon |
| Subcutaneous administration | ||
| Blood and lymphatic system disorders | Lymphadenopathy1,4* | Uncommon |
| Nervous system disorders | Dizziness5 | Uncommon |
| Skin and subcutaneous tissue disorders | Pruritus5* | Rare |
| General disorders and administration site conditions | Injection site reactions5 | Common |
1 Observed with repeat dose subcutaneous administration in Study HV-2093
2 Frequency determined from study COV 2067
3 Frequency determined using all studies i.e. both IV and subcutaneous (2066, 2067, 2069, 20145 and 2093)
4 Frequency determined from study HV 2093 (repeat dose subcutaneous study)
5 Frequency determined from study COV 2069
* In some cases, symptoms of IRRs and ISRs have been reported as individual ADRs
The following hypersensitivity reactions of varying severity were observed across the clinical development programme.
Anaphylaxis/anaphylactic reaction has been observed in the clinical development programme but was a very rare event and occurred within 1 hour of completion of the infusion and resolved after supportive treatment, which included epinephrine (see section 4.4).
Infusion-related reactions have been observed with IV administration of casirivimab and imdevimab across all dose groups in clinical studies. These reactions were mostly mild to moderate in severity and were typically observed during or within 24 hours of infusion and resolved either without intervention or with usual standard of care. Commonly reported signs and symptoms for infusion related reactions included nausea, chills, dizziness (or syncope), rash, urticaria and flushing. Other known clinical presentations of IRR may also be expected (see section 4.4).
Injection site reactions were reported in all studies with subcutaneous administration including single dose and repeat dose studies. All ISRs were mainly local, mild to moderate in severity and resolved either without intervention or with usual standard of care. Commonly reported signs and symptoms for these reactions included erythema, pruritis, ecchymosis, oedema, pain/tenderness and urticaria. In the repeat dose study, (HV-2093) localised lymphadenopathy was also observed.
No data are available for paediatric patients <18 years old.
45 (3%) and 21 (14%) adolescents ≥12 and <18 years old received treatment with Ronapreve in study COV-2069 cohort A and B, respectively and safety profile observed was similar to that in adult patients.
No exposure data for subjects <12 years are available.
In studies COV-2067, 485 (12%) patients who were ≥65 years old, received treatment with Ronapreve. The safety profile of these patients was similar to that in adult patients <65 years old.
In studies COV-2069 (cohort A and cohort B) and HV-2093, a total of 120 (9%), 15 (10.0%) and 90 (12%) individuals who were ≥65 years old respectively, were treated with Ronapreve and the safety profile was similar to adults <65 years old.
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 (see details below).
United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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