Givosiran: Injection Site Reactions
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Givosiran: Injection Site Reactions
The full Prescribing Information for GIVLAARI® (givosiran) is provided here. Alnylam Pharmaceuticals does not recommend the use of its products in any manner that is inconsistent with the approved Prescribing Information. This resource may contain information that is not in the approved Prescribing Information.
If you are seeking additional scientific information related to Alnylam medicines, you may visit the Alnylam US Medical Affairs website at RNAiScience.com.
Summary
A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any new safety concerns involving ISRs with the use of givosiran.5 No additional information is available regarding the management of ISRs. |
Clinical Data – Global Safety Database – Label Information – Abbreviations – References
Phase 1 Study
The Phase 1 study was a multicenter, randomized, placebo-controlled, 3-part study designed to evaluate the safety, tolerability, PK, and PD of givosiran in patients with AIP.1
In the Phase 1 study of givosiran, ISRs (including injection site erythema and pain) were reported in 6 out of 33 (18%) patients who received givosiran and no patients who received placebo. All ISRs were mild or moderate in severity and resolved spontaneously.1
Phase 1/2 Open-Label Extension Study
The Phase 1/2 OLE study (N=16) was an extension of the Phase 1 clinical study to evaluate the long-term safety and tolerability of givosiran in patients with AIP for up to 48 months. At study entry, patients received subcutaneous injections of givosiran 2.5 mg/kg once a month, or 5.0 mg/kg once a month or every 3 months. All patients enrolled in the OLE were transitioned to receive subcutaneous injections of givosiran 2.5 mg/kg once a month.2
A total of 7 out of 16 (44%) patients experienced ISRs, all of which were classified as mild or moderate in severity and did not lead to treatment discontinuation or study withdrawal. ISRs were reported in 28 out of 1,246 total doses (2.2%) of givosiran administered. The most common symptoms included erythema, pruritus, rash, swelling, and discoloration at or near the injection site.2
One patient receiving givosiran experienced 2 ISRs that led to treatment interruption, and which were assessed as moderate in severity and subsequently resolved. The first ISR was described as injection site erythema, pain, and pruritus. The second ISR was described as injection site erythema with associated recall phenomenon. No other ISRs led to treatment interruption or were associated with recall phenomenon.6
Phase 3 ENVISION Study
The ENVISION study was a phase 3, randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of givosiran in patients with a documented diagnosis of AHP. Enrolled patients were randomized on a 1:1 basis to receive subcutaneous injections of givosiran 2.5 mg/kg (N=48) or placebo (N=46) once a month for 6 months, followed by an optional 30-month OLE. The primary endpoint was the annualized rate of composite porphyria attacks among patients with AIP at 6 months.3
Double-Blind Period
In the 6-month double-blind period of the ENVISION study, 12 out of 48 (25%) patients receiving givosiran and no patients on placebo experienced ISRs. These ISRs were associated with 7% of 279 givosiran doses and were mild or moderate in severity.3 One patient receiving givosiran experienced an ISR of erythema involving the contralateral abdomen at location of a prior injection, which suggested the possibility of a recall phenomenon. This ISR event was assessed as mild and resolved within 1 day. No ISRs led to treatment interruption, discontinuation, or withdrawal from the double-blind portion of the study. ISRs were managed by using proper technique and rotation of injection sites.7
Open-Label Extension
Upon completion of the ENVISION 6-month double-blind period, eligible patients (N=93) continued in the optional 30-month OLE study evaluating the long-term efficacy and safety of givosiran. ISRs were observed in 37 out of 93 (39%) patients and occurred in 142 out of 2,820 (5%) total doses of givosiran administered.4 The most common signs and symptoms of ISRs reported in ≥5% of patients were injection site erythema (25.5%), pruritus (10.6%), rash (10.6%), pain (10.6%), and swelling (9.6%). The majority of ISRs were non-serious AEs that were mild or moderate in severity.8
One patient (in the placebo/givosiran 1.25 mg/kg group) experienced recurrent ISRs with severity that increased from mild to severe during the OLE period, and the event was categorized as a serious AE. The serious ISR occurred within the first 5 minutes after the injection (on day 720 of the study), and was characterized as shaking chills, chest tightness, acute dyspnea, erythroderma of the face, neckline, and upper arms, swelling of the hands, and an urticarial reaction on the left and right upper arms at the injection sites. Management included dimetindene maleate and sodium chloride 0.9% and cooling elements for swelling. The event resolved in 3 hours. The event was considered related to study drug and resulted in discontinuation of the study drug and subsequent withdrawal from the study. The patient also had a concurrent elevation of blood homocysteine.8
Two patients experienced ISRs with potential recall reactions. One patient (described earlier in the double-blind period of the study), had an ISR of erythema which suggested the possibility of a recall phenomenon. This patient has subsequently received 20 additional doses of givosiran in the OLE without any additional ISRs or recall reactions. A second patient experienced ISRs at both the site of the most recent injection and the site of a previous injection while receiving givosiran in the OLE. The patient was treated with topical hydrocortisone gel, and the ISRs resolved. Subsequently, the patient received 10 additional doses of givosiran in the study and experienced minor ISRs without any additional cases of recall phenomenon.9
A cumulative post-marketing review of Alnylam Pharmaceuticals’ global safety database did not identify any new safety concerns involving ISRs with the use of givosiran.5
GIVLAARI Prescribing Information – Relevant content
The WARNINGS AND PRECAUTIONS section provides the following information10:
Injection Site Reactions
Injection site reactions have been reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. Among 12 patients with reactions, the highest severity of the reaction was mild among 11 (92%) patients and moderate in one (8%) patient. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.
The PATIENT COUNSELING INFORMATION section provides the following information10:
Advise patients of the potential risks of GIVLAARI treatment:
Injection Site Reactions
Inform patient of the signs and symptoms of injection site reactions (examples include redness, pain, itching, rash, discoloration, or localized swelling).
ADR = adverse drug reaction; AE = adverse event; AHP = acute hepatic porphyria; AIP = acute intermittent porphyria; ISR = injection site reaction; OLE = open-label extension; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event.
Updated 14 October 2025
5. Alnylam Pharmaceuticals. Data on file. MED-ALL-GIVO-2500004.
6. Alnylam Pharmaceuticals. Data on file. MED-ALL-AS1-2300005.
7. Alnylam Pharmaceuticals. Data on File. MED-CEMEA-AS1-1900039.
8. Alnylam Pharmaceuticals. Data on File. MED-ALL-AS1-2200003.
9. Alnylam Pharmaceuticals. Data on File. MED-ALL-AS1-2100024.
10. GIVLAARI (givosiran) Prescribing Information. Cambridge, MA: Alnylam Pharmaceuticals, Inc.
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MED-ALL-AS1-1900096 6.0 Approved through Oct 2027 |
