HEPCLUDEX 2 mg powder for solution for injection

Hepcludex is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult and paediatric patients 3 years of age and older weighing at least 10 kg with compensated liver disease.

Treatment should be initiated only by a physician experienced in the treatment of patients with HDV infection.

Posology

Bulevirtide should be administered once daily (every 24 hours ± 4 hours) by subcutaneous injection as monotherapy or in co-administration with a nucleoside/nucleotide analogue for treatment of underlying hepatitis B virus (HBV) infection.

The recommended dose of bulevirtide in adult patients is 2 mg once daily.

The recommended dose of bulevirtide in paediatric patients is based on weight as detailed in the Table below.

Dosing for paediatric patients using bulevirtide 2 mg powder for solution for injection

Concerning co-administration with nucleoside/nucleotide analogues for treatment of HBV infection, refer to section 4.4.

Duration of treatment

The optimal treatment duration is unknown. Treatment should be continued as long as associated with clinical benefit.

Consideration to discontinue the treatment should be given in case of sustained (6 months) HBsAg seroconversion or loss of virological and biochemical response.

Missed doses

If an injection has been omitted and less than 4 hours have elapsed since the scheduled time, the injection must be performed as soon as possible. The time of the next injection will not be calculated from the time of the "rescue" injection, but according to the injection schedule previously established. It is, therefore, necessary to return to the usual pattern of administration, at the appointed time, the following day.

If an injection has been missed and more than 4 hours have elapsed since the scheduled time, the missed dose should not be administered.

The next injection will take place according to the usual schedule (injection of the prescribed dose without doubling), at the appointed time the next day.

If the injection has been made by mistake more than 4 hours after the scheduled time, the next administration must take place in the usual way (i.e. in accordance with the original schedule).

Special populations

Elderly

No data is available in patients > 65 years.

Renal impairment

No studies have been conducted with bulevirtide in patients with renal impairment.

Renal function should be carefully monitored. Elevation of bile salts may occur during treatment. Due to renal excretion of bile salts, elevation of bile salts may be greater in patients with renal impairment.

Hepatic impairment

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh-Turcotte class A). The safety and efficacy of bulevirtide in patients with decompensated cirrhosis have not been established (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of bulevirtide in patients younger than 18 years of age have not been established in clinical studies. The recommended dosage of bulevirtide for paediatric patients 3 years of age and older weighing at least 10 kg with compensated liver disease is based on population pharmacokinetic/pharmacodynamic modelling and simulation (see section 5.2).

Method of administration

For subcutaneous use only. Bulevirtide may be injected into sites such as the upper thigh, or abdomen.

Appropriate training should be given to the patients self-administering the product or to the caregivers administering the product to minimise the risk of the injection site reactions.

The “Step-by-step injection guide”, provided in the carton, must be followed carefully by the patient or the caregiver.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 may lead to reactivation of HDV and HBV infections and severe acute exacerbations of hepatitis, especially in patients with cirrhosis who may be at increased risk of more severe flares or progression to hepatic decompensation. In case of treatment discontinuation, careful monitoring of hepatic function with both clinical and laboratory follow-up should be performed for at least 6 months after discontinuation, including monitoring transaminase levels, as well as HBV DNA and HDV-RNA viral load. In certain circumstances, resumption of antiviral therapy may be warranted.

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.

Breast-feeding

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.

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There are no data on human overdose with bulevirtide. If overdose occurs, the patient must be monitored for evidence of toxicity and given standard supportive treatment as necessary.

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals. ATC code: J05AX28

Mechanism of action

Bulevirtide blocks the entry of HBV and HDV into hepatocytes by binding to and inactivating NTCP, a bile salt liver transporter serving as essential HBV/HDV entry receptor.

Clinical efficacy and safety

The clinical efficacy and safety of bulevirtide was investigated in one Phase 3 study and two Phase 2 studies. Patients with chronic HDV infection and active hepatitis were included. The population of these three studies was mainly Caucasian, HDV genotype 1 was predominant.

MYR301 study

In Study 301, 100 of 150 patients with chronic HDV infection were randomised to receive immediate treatment with once daily bulevirtide 2 mg (N=49) or to have treatment delayed for 48 weeks (N=51). Randomisation was stratified by the presence or absence of compensated cirrhosis.

Of the 49 patients in the immediate treatment group, mean age was 44 years; 61% were male, 84% were White, and 16% were Asian. Of the 51 patients in the delayed treatment group, mean age was 41 years; 51% were male, 78% were White and 22% were Asian. All 100 patients had infection with HDV genotype 1.

Baseline characteristics were balanced among the immediate and delayed treatment groups. Of the patients who received 2 mg bulevirtide at baseline, mean plasma HDV RNA was 5.1 log₁₀ IU/mL, mean ALT was 108 U/L, 47% of patients had a history of cirrhosis, and 53% were interferon experienced. During the study (through Week 48), 63% of these patients, received concomitant therapy according to the standard care for their underlying HBV infection: the most common concomitant medications were tenofovir disoproxil fumarate-containing or tenofovir alafenamide-containing products (49%) and entecavir (14%).

The table below presents the virologic and biochemical outcomes for immediate treatment with bulevirtide 2 mg once daily and delayed treatment at Week 48.

a. For the first endpoint, for missing values, the last observation carrying forward (LOCF) was used if COVID-19 related; otherwise, missing = failure; for the second and third endpoints, missing = failure.

b. < lower limit of quantification LLOQ (target not detected)

c. Defined as an ALT value within the normal range: Russian sites, ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites, ≤ 34 U/L for females and ≤ 49 U/L for males.

d. p-value < 0.0001.

e. Not multiplicity controlled.

MYR202 study

In Study MYR202, 56 of 118 patients with chronic HDV infection and ongoing viral replication who were interferon experienced, had a contraindication to interferon, or were cirrhotic, were randomised to receive bulevirtide 2 mg + TDF (N=28) or TDF alone (N=28) for 24 weeks. At Week 24, 21% of patients in the bulevirtide 2 mg + TDF group achieved a combined response, 54% achieved undetectable HDV RNA (defined as < limit of detection [LOD], where LOD was 14 IU/mL) or decrease by ≥ 2 log₁₀ IU/mL, and 43% achieved ALT normalisation. At Week 24, no patients in the TDF group achieved a combined response, 4% achieved undetectable HDV RNA or decrease in HDV RNA by ≥ 2 log₁₀ IU/mL, and 7% achieved ALT normalisation (normal ALT was defined as ≤ 31 U/L for females and ≤ 41 U/L for males).

MYR203 study

In Study MYR203, a total of 15 patients were treated with bulevirtide 2 mg daily for 48 weeks. In this limited dataset, the efficacy and safety profiles were not substantially different than for patients treated for 24 weeks. Two patients developed virological breakthrough, possibly related to medication non-adherence.

Immunogenicity

Bulevirtide has the potential to induce antidrug antibodies (ADA), as detected in clinical studies using an enzyme-linked immunosorbent assay (ELISA). In Studies MYR203 and MYR301, a total of 64 patients who were treated with bulevirtide 2 mg monotherapy for 48 weeks were eligible for assessment of ADA prevalence; 18 of these patients (28.1%) were positive for ADA prevalence, of which 3 patients (4.7%) were positive for ADA at baseline.

There is no evidence that the pharmacokinetics, safety, or effectiveness of bulevirtide were altered in these patients.

Paediatric population

See section 4.2 and 5.2 for information on paediatric use.

The pharmacokinetic properties of bulevirtide were characterised after intravenous and subcutaneous administration. The exposure of bulevirtide increased disproportionally while the apparent clearance and apparent volume of distribution decreased with higher doses.

Distribution

The estimated volume of distribution is smaller than total body water. In vitro plasma protein binding is high with > 99% of bulevirtide bound to plasma proteins.

Biotransformation

No biotransformation study was performed for bulevirtide. Bulevirtide is a linear peptide consisting of L-amino acids, and it is expected to be degraded to smaller peptides and individual amino acids. No active metabolites are expected.

Based on the results of in vitro interaction studies, bulevirtide did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

No in vitro induction of CYP1A2, CYP2B6 or CYP3A4 by bulevirtide was observed.

Based on the in vitro studies, no clinically relevant interaction is expected for most common efflux transporters (MDR1, BCRP, BSEP, MATE1 and MATE2K) and uptake transporters (OATP2B1, OAT1, OAT3, OCT1 and OCT2). A specific in vitro interaction was identified with the organic anion transporting polypeptides, OATP1B1 and OATP1B3 with IC₅₀ values of 0.5 and 8.7 µM, respectively.

Elimination

No bulevirtide excretion into urine was detected in healthy volunteers. Elimination via target (NTCP) binding is assumed to be the main route. Both distribution and elimination after multiple dosing were reduced compared to values estimated after the first dose. Accumulation ratios for 2 mg dose for C_max and AUC were approximately 2-fold. Steady state is assumed to be achieved within the first weeks of administration. After reaching peak concentrations, plasma levels declined with t_1/2 of 4-7 hours.

Other special populations

Renal impairment

No studies have been conducted with bulevirtide in patients with renal impairment.

Hepatic impairment

No studies have been conducted with bulevirtide in patients with moderate and severe hepatic impairment.

Elderly

No data is available in patients older than 65 years of age.

Paediatric population

The pharmacokinetics of bulevirtide in paediatric patients have not been evaluated in a clinical study. Dosing recommendations for paediatric patients 3 years of age and older weighing at least 10 kg are based on exposure matching the paediatric bulevirtide concentration to concentrations observed in adults with HDV infection treated with bulevirtide 2 mg once daily. Simulated steady-state plasma exposures of bulevirtide weight-based dosing (see section 4.2) once daily by subcutaneous injection in paediatric patients are predicted to be within the safe and efficacious exposures associated with 2 mg bulevirtide once daily by subcutaneous injection in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, and toxicity to reproduction and development.

No genotoxicity and carcinogenicity studies were conducted due to the nature and mechanism of action of the product.

A pre- and post-natal development study (PPND) has been completed in rats and did not show any bulevirtide-related toxicity.

Sodium carbonate anhydrous

Sodium hydrogen carbonate

Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

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

3 years

After reconstitution, chemical and physical in-use stability has been demonstrated for 2 hours at room temperature (up to 25°C). From a microbiological point of view, it is recommended that the product should be used immediately.

Store in a refrigerator (2°C -8°C). In order to protect from light, keep the vials in the outer carton.

Colourless glass vial with bromobutyl or chlorobutyl rubber stopper, sealed with a flip off cap (aluminium with plastic disc).

Pack-size of 30 vials.

Each vial is intended for single use only and the excess of unused product must be properly disposed of. Sterile water for injections, syringes (with necessary graduations according to the dose to be administered), needle tips and alcohol wipes should be provided to the patient.

Instructions for use

The bulevirtide vial should be taken from the refrigerator shortly before the injection and the blue flip-off cap has to be removed. A single-use syringe should be taken and a needle tip attached to the syringe head in order to extract 1 ml of sterile water for injection into the syringe. The syringe needle with the syringe containing the sterile water for injection should then be inserted into the bulevirtide vial through the rubber stopper. The sterile water for injection inside the syringe will then be injected into the bulevirtide vial and the bulevirtide vial has to be carefully swayed until a clear solution is obtained. The required content for the dose to be administered from the bulevirtide vial has to be extracted back into the same syringe with the same needle tip (See Table below).

Required dose volumes to be extracted for administration of bulevirtide

The needle tip has then to be detached from the syringe. To this syringe, a needle tip for subcutaneous injection has to be attached and any remaining air bubbles have to be removed from the syringe prior to injection. The content of the bulevirtide vial will then be administered subcutaneously.

Disposal of medicinal product and auxiliary components

All used components/ waste should be handled according to the current regulation.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.