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Hibsago (bepirovirsen)

Chronic hepatitis B virus infection in adults without cirrhosis

Also known as GSK3228836
Manufacturer
GSK
Last updated
190 sources

Product information and disease descriptionProduct descriptionProduct information

Contraindications/Warnings/Precautions/Adverse effects

25 evidence topics · 2 sources

Warnings and precautions
Boxed warning: on-treatment hepatic flares

“HIBSAGO may cause on-treatment hepatic flares with increases in ALT of >20-40x ULN associated with decline in HBsAg. Some cases were associated with hyperbilirubinemia. Most occurred in the first 12 weeks of treatment and resolved when treatment was interrupted or permanently discontinued” (opens the prescribing information at this quote)

“ALT and total bilirubin must be measured prior to initiation of HIBSAGO and frequently monitored during treatment” (opens the prescribing information at this quote)

“Interruption of treatment, followed by reducing the dose or discontinuation of HIBSAGO, may be necessary based on the results of liver laboratory tests” (opens the prescribing information at this quote)

Boxed warning: thrombocytopenia

“HIBSAGO may cause reductions in platelet counts that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening.” (opens the prescribing information at this quote)

“Prior to starting HIBSAGO, obtain a platelet count to ensure the patient is eligible for treatment” (opens the prescribing information at this quote)

“During treatment, monitor platelet counts weekly if values are 75 x 109/L or greater, and more frequently if values are less than 75 x 109/L” (opens the prescribing information at this quote)

“If a patient develops signs or symptoms of thrombocytopenia, obtain a platelet count as soon as possible. The patient should not receive additional doses of HIBSAGO unless platelet counts return to 100 x 109/L or greater. If platelet count falls below 50 x 109/L, treatment with HIBSAGO should be permanently discontinued” (opens the prescribing information at this quote)

Contraindications: hepatic impairment, cirrhosis, and low platelet count

“HIBSAGO is contraindicated in patients:” (opens the prescribing information at this quote)

“with acute hepatic impairment, or cirrhosis who have mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C)” (opens the prescribing information at this quote)

“with a platelet count below 100 x 109/L prior to initiation of treatment” (opens the prescribing information at this quote)

Warning: on-treatment hepatic flares

“During treatment with HIBSAGO, increases in ALT ≥3 x ULN to 69 x ULN were observed in clinical trials” (opens the prescribing information at this quote)

“Most ALT increases occurred in the first 12 weeks of treatment (typically between Weeks 5 to 10), started to resolve within 2 weeks, and were not associated with any clinical signs or symptoms of liver dysfunction. The ALT increases were temporally associated with a preceding or concurrent decline in HBsAg suggesting host immune response. Two percent of participants receiving HIBSAGO had ALT increases ≥20 x ULN that resolved when treatment was interrupted or permanently discontinued.” (opens the prescribing information at this quote)

“isolated cases of ALT increases associated with an increase in total bilirubin up to 4 x ULN that resolved when treatment was permanently discontinued.” (opens the prescribing information at this quote)

“In all patients, the minimum recommended on-treatment monitoring of ALT and total bilirubin is weekly through Week 12 and every other week from Weeks 12 through 24, but more frequent monitoring may be necessary.” (opens the prescribing information at this quote)

Warning: thrombocytopenia

“HIBSAGO may cause reductions in platelet count at any time during treatment that may result in sudden and unpredictable thrombocytopenia that can be life-threatening. In the HIBSAGO clinical trials, two participants reported serious adverse reactions of thrombocytopenia <50 × 10⁹/L, including one participant with immune thrombocytopenia” (opens the prescribing information at this quote)

“In addition, a gradual, dose-dependent decline in platelet count was observed in most patients that continued to worsen while on HIBSAGO.” (opens the prescribing information at this quote)

“In patients with platelet count below the normal range but ≥100 x 109/L, rule out cirrhosis before initiating HIBSAGO” (opens the prescribing information at this quote)

“In all patients, the minimum recommended on-treatment monitoring of platelet counts is weekly through Week 24, but more frequent monitoring may be necessary.” (opens the prescribing information at this quote)

“If platelet count falls below 50 x 109/L, permanently discontinue treatment with HIBSAGO and consider corticosteroid treatment in consultation with an expert.” (opens the prescribing information at this quote)

“Consider the risks and benefits of treatment with HIBSAGO when treating patients who may be particularly susceptible to platelet count decreases, e.g., elderly patients, or patients with bleeding diathesis/coagulopathy, history of major bleeding events or patients taking antiplatelets, anticoagulants, or drugs that lower platelet count” (opens the prescribing information at this quote)

Warning: worsening renal function

“In the HIBSAGO clinical trials, mean eGFR declined within 4 weeks of initiation of HIBSAGO and continued to decline during treatment. These changes were generally reversible after treatment discontinuation. The mechanism of the decrease in eGFR is not clear” (opens the prescribing information at this quote)

“Obtain eGFR and uACR in all patients prior to initiation of treatment.” (opens the prescribing information at this quote)

“insufficient data are available on the safety of HIBSAGO in these populations” (opens the prescribing information at this quote)

“In all patients, the minimum recommended on-treatment monitoring of eGFR is every other week through Week 24, but more frequent monitoring may be necessary.” (opens the prescribing information at this quote)

“Although no cases of glomerulonephritis were observed with HIBSAGO administration in the clinical trials, glomerulonephritis has been observed after administration of other antisense oligonucleotides. Consider assessing for proteinuria periodically during treatment, as appropriate. If a diagnosis of glomerulonephritis is suspected or confirmed, permanently discontinue HIBSAGO and consider early initiation of immunosuppressive therapy in consultation with an expert.” (opens the prescribing information at this quote)

Warning: inflammatory and immune effects

“In trials with HIBSAGO, influenza-like symptoms, laboratory test changes (e.g., decreases in complement factors C3 and C4), purpuric leg rashes, cutaneous leukocytoclastic vasculitis, dermatitis, pruritus/erythematous plaque, and polyarthralgia were observed. In addition, serious inflammatory and immune adverse reactions were reported, including immune thrombocytopenia, autoimmune hemolytic anemia, systemic inflammatory response syndrome, and a cryoglobulinemic flare” (opens the prescribing information at this quote)

“Consider the risks and benefits of HIBSAGO when treating patients that may be more susceptible to inflammatory and/or immune effects, e.g., solid organ transplant recipients, patients with autoimmune hepatitis, or patients with a history of vasculitis or conditions associated with vasculitis (including systemic lupus erythematosus, cryoglobulinemia, or rheumatoid arthritis).” (opens the prescribing information at this quote)

“If signs and symptoms suggestive of vasculitis/immune-associated events occur, and no alternative cause is identified, permanently discontinue treatment with HIBSAGO.” (opens the prescribing information at this quote)

Warning: serious adverse reaction with improper administration

“Improper HIBSAGO administration, including not rotating injection sites, has been associated with the serious adverse reaction of omental infarction in one participant.” (opens the prescribing information at this quote)

“A serious adverse reaction of omental infarction requiring surgical intervention occurred at Treatment Week 11 in a participant who had four weeks of persistent erythema at the HIBSAGO injection site and in whom injection sites had not been rotated.” (opens the prescribing information at this quote)

Warning: exacerbations of hepatitis B after nucleos(t)ide analog discontinuation

“Severe acute exacerbations of HBV infection may occur after discontinuation of anti-HBV therapy. If NrtI therapy is discontinued after completing HIBSAGO treatment, frequent monitoring is recommended.” (opens the prescribing information at this quote)

Warning: HIV-1 virologic failure in HBV and HIV-1 coinfection

“Patients who are taking nucleos(t)ide analog reverse transcriptase inhibitors as part of antiretroviral therapy for HIV-1 and HBV coinfection must not stop taking their nucleos(t)ide analog reverse transcriptase inhibitor therapy unless an HIV healthcare provider has directed them to do so.” (opens the prescribing information at this quote)

Warning: hepatitis flare in HBV and hepatitis D virus coinfection

“There are no data on the safety and efficacy of HIBSAGO in patients with HBV and hepatitis D virus (HDV) coinfection. HIBSAGO is not recommended in patients with HDV coinfection due to the potential for an exacerbated risk of clinically significant ALT increases.” (opens the prescribing information at this quote)

Warning: unknown effect on preventing transmission of HBV

“There are no data on the effect of HIBSAGO in preventing transmission of HBV. Patients must be advised to use appropriate precautions to prevent transmission of HBV.” (opens the prescribing information at this quote)

Safety population and discontinuations due to adverse events in B-Well 1 and B-Well 2

“The safety of HIBSAGO in the treatment of chronic HBV infection has been evaluated in two pooled, Phase 3, placebo-controlled randomized trials (B-Well 1 and B-Well 2) in which 1,223 participants received at least one dose of HIBSAGO (300 mg subcutaneously, twice weekly during Weeks 1 and 2, and once weekly during Weeks 3 to 24) and 611 participants received matching placebo.” (opens the prescribing information at this quote)

“In the pooled B-Well 1 and B-Well 2 trials, 3% of participants receiving HIBSAGO and <1% of participants receiving placebo discontinued due to adverse events.” (opens the prescribing information at this quote)

Adverse reactions reported in at least 3% of participants in B-Well 1 and B-Well 2, weeks 1 to 36
Adverse reaction (all grades)Bepirovirsen, N = 1,223Placebo, N = 611
Injection site reactions (all types)“57%”“15%”
Pyrexia“20%”“4%”
Fatigue“16%”“8%”
Headache“14%”“12%”
Myalgia“8%”“4%”
Nausea or vomiting“5%”“3%”
Erythema“5%”“<1%”
Pruritus“5%”“2%”
Influenza-like illness“4%”“2%”
Rash“3%”“1%”
Contusion“3%”“1%”
Adverse reaction definitions and less common adverse reactions

“Frequencies of adverse reactions are based on all adverse events, regardless of investigator assessment of causality, excluding laboratory abnormalities reported as adverse events” (opens the prescribing information at this quote)

“Fatigue includes the preferred terms asthenia, fatigue, malaise, lethargy and sluggishness.” (opens the prescribing information at this quote)

“The following adverse reactions occurred in <3% of participants receiving HIBSAGO and are included because of a potential causal relationship:” (opens the prescribing information at this quote)

“Immune system disorders: Hypersensitivity” (opens the prescribing information at this quote)

“Skin and soft tissue disorders: Angioedema” (opens the prescribing information at this quote)

Injection site reactions in B-Well 1 and B-Well 2, weeks 1 to 36
Injection site reaction (all grades)Bepirovirsen, N = 1,223Placebo, N = 611
Any injection site reaction“57%”“15%”
Injection site erythema“32%”“2%”
Injection site pain“24%”“6%”
Injection site pruritus“19%”“1%”
Injection site bruising“19%”“6%”
Injection site induration/swelling“13%”“1%”
Injection site discoloration“8%”“<1%”
Injection site rash“6%”“<1%”
Injection site hematoma“4%”“1%”

“ISRs were the most common adverse reactions reported with HIBSAGO.” (opens the prescribing information at this quote)

“The frequency and severity of injection site reactions decreased over time, and 99% of injection site reactions reported in HIBSAGO recipients were mild to moderate in severity.” (opens the prescribing information at this quote)

Cutaneous vasculitis: biopsy-confirmed cases

“Adverse reactions of biopsy-confirmed vasculitis occurred in two participants treated with HIBSAGO.” (opens the prescribing information at this quote)

“leukocytoclastic vasculitis, and the events resolved with corticosteroid treatment after permanent discontinuation of HIBSAGO” (opens the prescribing information at this quote)

Laboratory abnormalities worsened from baseline in B-Well 1 and B-Well 2, weeks 1 to 36
Laboratory categoryBepirovirsen, N = 1,223Placebo, N = 611
ALT ≥3x to <5x ULN“10%”“<1%”
ALT ≥5x to <10x ULN“8%”“0”
ALT ≥10x to <20x ULN“4%”“0”
ALT ≥20x ULN“2%”“<1%”
AST ≥3x to <5x ULN“6%”“<1%”
AST ≥5x to <10x ULN“4%”“<1%”
AST ≥10x to <20x ULN“1%”“<1%”
AST ≥20x ULN“<1%”“0”
Total bilirubin ≥ULN to <1.5x ULN“8%”“11%”
Total bilirubin ≥1.5x to <2x ULN“2%”“2%”
Total bilirubin ≥2x ULN“<1%”“<1%”
Platelets ≥100 to <140 x 10^9/L“37%”“7%”
Platelets ≥75 to <100 x 10^9/L“8%”“<1%”
Platelets ≥50 to <75 x 10^9/L“2%”“<1%”
Platelets ≥25 to <50 x 10^9/L“<1%”“0”
Platelets <25 x 10^9/L“<1%”“0”
ANC ≥500 to <1,000 cells/mm3“8%”“3%”
ANC ≥100 to <500 cells/mm3“1%”“<1%”
ANC <100 cells/mm3“0”“0”
eGFR ≥15 to <30% decline from baseline“51%”“30%”
eGFR ≥30 to <50% decline from baseline“17%”“6%”
eGFR ≥50% decline from baseline“1%”“<1%”
uACR ≥0.3 mg/mg“2%”“1%”

“Each participant is only counted once per parameter with the laboratory value that represents their largest change from baseline in Weeks 1-36.” (opens the prescribing information at this quote)

“Information based on laboratory values reported from the central laboratory for B-Well 1 and B-Well 2 (local laboratory results were not included).” (opens the prescribing information at this quote)

Laboratory abnormalities: ALT increases leading to treatment pause or discontinuation

“During the first 24 weeks, <1% (n = 1) of HIBSAGO recipients had ALT ≥3x ULN with bilirubin ≥2x ULN (>35% direct bilirubin) and permanently discontinued treatment” (opens the prescribing information at this quote)

“Three other participants also permanently discontinued treatment because of ALT ≥10 x ULN for 4 or more weeks, and 53 (4%) paused treatment due to ALT increases.” (opens the prescribing information at this quote)

Laboratory abnormalities: platelet count decreases

“During the first 24 weeks, two participants treated with HIBSAGO had serious adverse reactions of thrombocytopenia, with platelet counts <50 × 10⁹/L.” (opens the prescribing information at this quote)

“This participant was assessed as having immune thrombocytopenia. Both participants recovered with corticosteroid treatment and permanent discontinuation of HIBSAGO” (opens the prescribing information at this quote)

“In total, 8 (<1%) participants met permanent discontinuation criteria, and 114 (9%) participants paused treatment due to platelet declines.” (opens the prescribing information at this quote)

“In the pivotal clinical trials, the maximum change from baseline in platelet count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -68 x 109/L (40.7) or -28.1% (13.79), from a baseline of 233 x 109/L. The mean platelet count in the HIBSAGO group recovered to within 5% of baseline values by Week 60 (36 weeks after last dose of HIBSAGO).” (opens the prescribing information at this quote)

Laboratory abnormalities: neutrophil count decreases

“During the first 24 weeks, 27 (2%) of participants had neutrophil counts <1,000 cells/mm3 at 2 or more consecutive visits. No participant had a value <500 cells/mm3 at 2 or more consecutive visits. The decline in neutrophil count was not associated with adverse events that indicated increased risk of infection.” (opens the prescribing information at this quote)

“In the pivotal clinical trials, the maximum change from baseline in absolute neutrophil count in the HIBSAGO group occurred at Week 24, with a mean (SD) change from baseline of -0.795 x 109/L (1.0969) or -20.36% (29.40), from a baseline of 3.33 x 109/L.” (opens the prescribing information at this quote)

Laboratory abnormalities: eGFR decreases

“During the first 24 weeks, in participants treated with HIBSAGO, 4% had an eGFR decrease >30% of pretreatment levels for 2 or more consecutive readings and <1% (one participant) experienced such declines more than 24 weeks after completion of HIBSAGO treatment” (opens the prescribing information at this quote)

“No participant met criteria for permanent discontinuation of HIBSAGO treatment based on decreased renal function, but 28 (2%) participants paused treatment because of decreased renal function.” (opens the prescribing information at this quote)

“In the pivotal clinical trials, the maximum change from baseline in eGFR in the HIBSAGO group occurred at Week 25, with a mean (SD) change from baseline of -10 mL/min/1.73 m2 (9.96) or -10% (10.28), from a baseline of 100.8 mL/min/1.73m2. The mean eGFR in the HIBSAGO group recovered to within 5% of baseline values by Week 36 (12 weeks after last dose of HIBSAGO).” (opens the prescribing information at this quote)

Pooled adverse events, serious adverse events, and grade 3 or higher adverse events

“In a pooled analysis at 72 weeks, adverse events were reported in 91% of the patients in the bepirovirsen groups and in 73% of those in the placebo groups; serious adverse events were reported in 7% and 4% of the patients, respectively. During the treatment period, adverse events of grade 3 or higher were reported in 16% of the patients who received bepirovirsen and in 3% of those who received placebo; increases in the alanine aminotransferase level were the most common grade 3 adverse events with bepirovirsen (in 6% of the patients).” (opens the original PubMed page at this quote in a new tab)View highlighted excerpt for this quote

Immunogenicity: anti-drug antibodies

“In the Phase 3 B-Well trials, 43% (517/1,203) of participants treated with HIBSAGO tested positive for ADAs. The presence of ADAs resulted in a 26.6% lower systemic clearance of bepirovirsen. The development of these antibodies did not appear to be associated with a reduced treatment response or differences in the safety profile.” (opens the prescribing information at this quote)

Overdosage

“Single doses of HIBSAGO 600 mg (2 times the recommended dose) were administered subcutaneously in a clinical trial to 5 healthy adults. Two participants developed tolerability issues at this dose, with symptoms including headache, nausea, vomiting, myalgia, and dizziness which lasted 24 to 48 hours despite symptomatic treatment.” (opens the prescribing information at this quote)

“There is no specific treatment for an overdose with HIBSAGO. If overdose occurs, the patient should be treated supportively with appropriate monitoring.” (opens the prescribing information at this quote)