Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Gilead Sciences Ireland UC, Carrigtohill, County Cork, T45 DP77, Ireland
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
HDV genotype 1 was predominant in the clinical trials population. It is not known whether HDV or HBV genotype affects the clinical efficacy of bulevirtide.
The pharmacokinetics, safety and efficacy of bulevirtide in patients with decompensated cirrhosis has not been established. The use in patients with decompensated liver disease is not recommended.
The underlying HBV infection should be simultaneously managed according to current treatment guidelines. In the clinical study of bulevirtide MYR202, only patients with signs of active hepatitis despite nucleoside/nucleotide analogue treatment were included; tenofovir disoproxil fumarate was coadministered with bulevirtide. Close monitoring of HBV-DNA levels is recommended.
Discontinuation of treatment with bulevirtide can lead to reactivation of the HDV and HBV infection and exacerbation of hepatitis. In case of treatment discontinuation, careful monitoring of liver function including transaminase levels, as well as HBV DNA and HDV RNA viral load should be performed.
Asymptomatic and dose-dependent elevation of serum bile salts has been very commonly observed with bulevirtide. This increase is reversible upon discontinuation of treatment. It can be expected in the majority of patients taking into account the mechanism of action of bulevirtide which, by inactivating the NTCP (sodium taurocholate co-transporter polypeptide) receptor, blocks the transport of bile acids from portal blood to hepatocytes. In patients with renal insufficiency, the increase in bile salts may be more pronounced.
There are no data available on the long-term impact (>48 weeks) of this bile salt increase induced by bulevirtide (see section 4.8).
Bulevirtide is intended for subcutaneous injection which is associated with risks for injection site reactions such as swelling, redness, irritation, itchiness, infection, hematoma and local pain. These local reactions are more likely to appear if the injection is accidentally misplaced or the solution accidentally misdirected to the soft tissue.
No data are available from HIV or HCV co-infected patients.
This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially “sodium-free”.
In vitro, it has been shown, that certain medicinal products can inhibit bulevirtide target sodiumtaurocholate co-transporting polypeptide (NTCP). The co-administration of such medicinal products (e.g. sulfasalazin, irbesartan, ezetimibe, ritonavir, and ciclosporin A) is not recommended.
As a precautionary measure, close clinical monitoring is warranted when NTCP substrates (e.g. estrone3-sulfate, fluvastatin, atorvastatin, pitavastatin, pravastatin, rosuvastatin, and thyroid hormones) are coadministered with bulevirtide. When possible, co-administration of these substrates should be avoided.
In vitro an inhibition of OATP1B1/3 transporters by bulevirtide was observed, albeit only at a concentration ≥0.5 µM, which is only reached in vivo after administration of high bulevirtide doses (10 mg subcutaneous). The clinical relevance of these findings is unknown. As a precautionary measure, close clinical monitoring is warranted when OATP1B1/3 substrates (e.g. atorvastatin, bosentan, docetaxel, fexofenadine, glecaprevir, glyburide (glibenclamide), grazoprevir, nateglinide, paclitaxel, paritaprevir, pitavastatin, pravastatin, repaglinide, rosuvastatin, simeprevir, simvastatin, olmesartan, telmisartan, valsartan, voxilaprevir) are co-administered. When possible, co-administration of these substrates should be avoided.
In a clinical study in healthy subjects, co-administration of tenofovir and bulevirtide revealed no impact on tenofovir pharmacokinetic.
No CYP inhibition by bulevirtide was observed in vitro at clinically relevant concentrations. However, in a clinical study, an approximately 40% increase in geometric mean of partial AUC2-4h values of coadministered midazolam (CYP3A4 substrate) was observed in combination of high dose bulevirtide (10 mg) and tenofovir (245 mg), whereas no significant influence on midazolam AUC2-4h was detected for tenofovir alone. As a precautionary measure, close clinical monitoring is warranted for co-administered narrow-therapeutic-index drugs which are sensitive CYP3A4 substrates (e.g. cyclosporine, carbamazepine, simvastatin, sirolimus, and tacrolimus).
There are no or limited amount of data from the use of bulevirtide in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
As a precautious measure, it is preferable to avoid the use of bulevirtide during pregnancy and in women of child-bearing age who do not use contraception.
It is unknown whether bulevirtide is excreted in human breast milk. Therefore, a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from treatment with bulevirtide, taking into account the benefit of breastfeeding for the child with regard to the benefit of treatment for the mother.
No human data on the effect of bulevirtide on fertility are available. In animal studies, no effects of bulevirtide on male or female mating and fertility were noted.
The product has minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with bulevirtide (see section 4.8).
The most frequently reported adverse reactions were asymptomatic, dose dependent and reversible (after discontinuation of treatment) increase in bile salts (very common) and injection site reactions (common) (see section 4.4).
The most frequently reported serious adverse reaction was an exacerbation of hepatitis after discontinuation of bulevirtide, possibly related to virologic rebound after discontinuation of treatment (see section 4.4).
Common and very common adverse reactions are listed below by system organ class and absolute frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100, <1/10).
| Med DRA System Organ Class | Adverse reactions | |
|---|---|---|
| Very common (≥1/10) | Common (≥1/100 to <1/10) | |
| Blood and lymphatic system disorders | Anaemia Eosinophilia Leukopenia Lymphopenia Neutropenia Reticulocytopenia Thrombocytopenia | |
| Nervous system disorders | Dizziness Headache Somnolence | |
| Cardiac disorders | Tachycardia | |
| Gastrointestinal disorders | Abdominal distention Nausea | |
| Skin and subcutaneous tissue disorders | Erythema Hyperhidrosis Pruritus Rash | |
| Musculoskeletal and connective tissue disorders | Arthralgia Muscle spasms | |
| Renal and urinary disorders | Haematuria | |
| General disorders and administration site conditions | Fatigue Influenza like illness Injection site erythema Injection site haematoma Injection site pruritus Injection site dermatitis Local reaction | |
| Investigations | Total bile salt increased | ALT increased Amylase increased AST increased Blood bilirubin increased Blood creatinine increased GGT increased Haemoglobin decreased INR increased Lipase increased Neutrophil count decreased |
Most ALT elevations were reported after treatment cessation and may be related to hepatitis exacerbation after withdrawal of antiviral treatment.
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.
This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.
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