HEPCLUDEX Powder for solution for injection Ref.[11023] Active ingredients: Bulevirtide

HDV and HBV genotype

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.

Decompensated liver disease

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.

Co-infection with HBV

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 co-administered with bulevirtide. Close monitoring of HBV-DNA levels is recommended.

Hepatitis exacerbations after treatment cessation

Discontinuation of treatment with bulevirtide can lead to reactivation of HDV and HBV infections and exacerbation of hepatitis. In case of treatment discontinuation, careful monitoring of liver function tests including transaminase levels, as well as HBV DNA and HDV RNA viral load should be performed.

Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV)

No data are available from HIV or HCV co-infected patients.

Excipients

This medicine contains less than 1 mmol of 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 sodium-taurocholate 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. estrone-3-sulfate, fluvastatin, atorvastatin, pitavastatin, pravastatin, rosuvastatin, and thyroid hormones) are co-administered 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 pharmacokinetics.

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 AUC_2-4h values of co-administered midazolam (CYP3A4 substrate) was observed in combination of high dose bulevirtide (10 mg) and tenofovir (245 mg), whereas no significant influence on midazolam AUC_2-4h 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).

Pregnancy

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 potential not using contraception.

Breastfeeding

It is unknown whether bulevirtide is excreted in human breast milk. Therefore, a It is unknown whether bulevirtide is excreted in human milk. Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from treatment with bulevirtide, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

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).

Summary of the safety profile

The most frequently reported adverse reactions are increase in bile salts (very common), headache (very common), pruritus (very common) and injection site reactions (very common). Increases in bile salts were usually asymptomatic and reversible upon treatment discontinuation.

The most frequently reported serious adverse reaction is an exacerbation of hepatitis after discontinuation of bulevirtide, possibly related to virologic rebound after discontinuation of treatment (see section 4.4).

Tabulated list of adverse reactions

The following adverse reactions are based on pooled data from clinical studies in adults and post-marketing experience. Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100).

^a Adverse reaction identified through post-marketing surveillance
^b Includes injection site erythema, injection site reaction, injection site pain, injection site induration, injection site swelling, injection site rash, injection site haematoma, injection site pruritus and injection site dermatitis

Description of selected adverse reactions

Total Bile Salts Increased

Asymptomatic bile salt elevations, associated with the mechanism of action of bulevirtide, were very commonly observed in clinical studies of bulevirtide; the bile salt elevations resolved upon discontinuation of bulevirtide treatment.

Due to renal excretion of bile salts, elevation of bile salts may be greater in patients with renal impairment.

There are no data available on the long-term impact (>96 weeks) of this bile salt increase induced by bulevirtide.

Injection Site Reactions

Bulevirtide is intended for subcutaneous injection which is associated with risks for injection site reactions including swelling, redness, irritation, itchiness, infection, haematoma, rash, induration and local pain. These local reactions are more likely to appear if the injection is accidentally misplaced or the solution is accidentally misdirected to the soft tissue.

Eosinophilia

Increases in eosinophil counts were commonly observed in patients receiving bulevirtide treatment; there were no associated clinical sequelae, hepatic adverse reactions, or significant liver-related laboratory abnormalities.

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.

This medicinal product must not be mixed with other medicinal products, except those mentioned in section 6.6.