HEPCLUDEX 2mg powder for injection medication leaflet

HEPCLUDEX 2 mg powder for solution for injection

Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide.

For the full list of excipients, see section 6.1.

Powder for solution for injection (powder for injection).

The powder is white to off-white.

After reconstitution, solution with a pH of approximately 9.0 and osmolality of approximately300 mOsm/kg.

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

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

Bulevirtide should be administered once daily (every 24 hours ± 4 hours) by subcutaneous injection asmonotherapy or in co-administration with a nucleoside/nucleotide analogue for treatment ofunderlying 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 Tablebelow.

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

Body Weight (kg) Dosing of reconstituted Bulevirtide Daily Dosebulevirtide 2 mg powder forsolution for injection (ml)10 kg to < 25 kg 0.5 ml 1 mg25 kg to < 35 kg 0.75 ml 1.5 mg

Body Weight (kg) Dosing of reconstituted Bulevirtide Daily Dosebulevirtide 2 mg powder forsolution for injection (ml)35 kg and above 1 ml 2 mg

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

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

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

If an injection has been omitted and less than 4 hours have elapsed since the scheduled time, theinjection must be performed as soon as possible. The time of the next injection will not be calculatedfrom 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, thefollowing day.

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

The next injection will take place according to the usual schedule (injection of the prescribed dosewithout 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 nextadministration must take place in the usual way (i.e. in accordance with the original schedule).

No data is available in patients > 65 years.

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. Dueto renal excretion of bile salts, elevation of bile salts may be greater in patients with renal 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 beenestablished (see sections 4.4 and 5.2).

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

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 caregiversadministering 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 patientor 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 hasnot 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 treatmentguidelines. In the clinical study of bulevirtide MYR202, only patients with signs of active hepatitisdespite 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 andexacerbation of hepatitis. In case of treatment discontinuation, careful monitoring of liver functiontests including transaminase levels, as well as HBV DNA and HDV RNA viral load should beperformed.

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

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

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 thyroidhormones) are co-administered with bulevirtide. When possible, co-administration of these substratesshould be avoided.

In vitro an inhibition of OATP1B1/3 transporters by bulevirtide was observed, albeit only at aconcentration ≥ 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 precautionarymeasure, 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 noimpact 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 AUC2-4h values ofco-administered midazolam (CYP3A4 substrate) was observed in combination of high dosebulevirtide (10 mg) and tenofovir (245 mg), whereas no significant influence on midazolam AUC2-4hwas detected for tenofovir alone. As a precautionary measure, close clinical monitoring is warrantedfor 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 inwomen of child-bearing potential not using contraception.

It is unknown whether bulevirtide is excreted in human milk. Therefore, a decision must be madewhether 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.

No human data on the effect of bulevirtide on fertility are available. In animal studies, no effects ofbulevirtide 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 informedthat dizziness has been reported during treatment with bulevirtide (see section 4.8).

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 afterdiscontinuation of bulevirtide, possibly related to virologic rebound after discontinuation of treatment(see section 4.4).

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 asfollows: very common (≥ 1/10), common (≥ 1/100 to, < 1/10), uncommon (≥ 1/1,000 to < 1/100).

Frequency Adverse reaction

Common Eosinophilia

Uncommon Hypersensitivity, including anaphylactic reactiona

Very common Headache

Common Dizziness

Common Nausea

Very common Total bile salts increased

Very common Pruritus

Common Arthralgia

Very common Injection site reactionsb

Common Fatigue

Common Influenza like illnessa Adverse reaction identified through post-marketing surveillanceb Includes injection site erythema, injection site reaction, injection site pain, injection site induration, injection siteswelling, injection site rash, injection site haematoma, injection site pruritus and injection site dermatitis

Total Bile Salts Increased

Asymptomatic bile salt elevations, associated with the mechanism of action of bulevirtide, were verycommonly observed in clinical studies of bulevirtide; the bile salt elevations resolved upondiscontinuation of bulevirtide treatment.

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

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

Injection Site Reactions

Bulevirtide is intended for subcutaneous injection which is associated with risks for injection sitereactions including swelling, redness, irritation, itchiness, infection, haematoma, rash, induration andlocal pain. These local reactions are more likely to appear if the injection is accidentally misplaced orthe 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-relatedlaboratory abnormalities.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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.

The clinical efficacy and safety of bulevirtide was investigated in one Phase 3 study and two Phase 2studies. Patients with chronic HDV infection and active hepatitis were included. The population ofthese 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 immediatetreatment 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 41years; 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 thepatients 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 interferonexperienced. During the study (through Week 48), 63% of these patients, received concomitanttherapy according to the standard care for their underlying HBV infection: the most commonconcomitant 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 withbulevirtide 2 mg once daily and delayed treatment at Week 48.

Week 48a

Bulevirtide 2 mg Delayed Treatment(Immediate Treatment) (N=51)(N=49)

Undetectableb HDV RNA or decrease in

HDV RNA by ≥ 2 log10 IU/mL and ALT 45%d 2%normalisationc

Undetectableb HDV RNA or decrease in e

HDV RNA by ≥ 2 log10 IU/mL 71% 4%

ALT normalisationc 51% e 12%

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 othersites, ≤ 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 whowere interferon experienced, had a contraindication to interferon, or were cirrhotic, were randomisedto receive bulevirtide 2 mg + TDF (N=28) or TDF alone (N=28) for 24 weeks. At Week 24, 21% ofpatients in the bulevirtide 2 mg + TDF group achieved a combined response, 54% achievedundetectable HDV RNA (defined as < limit of detection [LOD], where LOD was 14 IU/mL) ordecrease 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/Lfor 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 thislimited dataset, the efficacy and safety profiles were not substantially different than for patients treatedfor 24 weeks. Two patients developed virological breakthrough, possibly related to medication non-adherence.

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

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

See section 4.2 and 5.2 for information on paediatric use.

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

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

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. Noactive 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 effluxtransporters (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 aniontransporting polypeptides, OATP1B1 and OATP1B3 with IC50 values of 0.5 and 8.7 µM, respectively.

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 werereduced compared to values estimated after the first dose. Accumulation ratios for 2 mg dose for Cmaxand AUC were approximately 2-fold. Steady state is assumed to be achieved within the first weeks ofadministration. After reaching peak concentrations, plasma levels declined with t1/2 of 4-7 hours.

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

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

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

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 arebased on exposure matching the paediatric bulevirtide concentration to concentrations observed inadults with HDV infection treated with bulevirtide 2 mg once daily. Simulated steady-state plasmaexposures of bulevirtide weight-based dosing (see section 4.2) once daily by subcutaneous injection inpaediatric patients are predicted to be within the safe and efficacious exposures associated with 2 mgbulevirtide once daily by subcutaneous injection in adults.

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

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

A pre and post-natal development study (PPND) has been completed in rats and did not show anybulevirtide-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 insection 6.6.

2 years

After reconstitution, chemical and physical in-use stability has been demonstrated for 2 hours at roomtemperature (up to 25°C). From a microbiological point of view, it is recommended that the productshould 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 disposedof. Sterile water for injections, syringes (with necessary graduations according to the dose to beadministered), needle tips and alcohol wipes should be provided to the patient.

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 thesyringe head in order to extract 1 ml of sterile water for injection into the syringe. The syringe needlewith the syringe containing the sterile water for injection should then be inserted into the bulevirtidevial through the rubber stopper. The sterile water for injection inside the syringe will then be injectedinto the bulevirtide vial and the bulevirtide vial has to be carefully swayed until a clear solution isobtained. The required content for the dose to be administered from the bulevirtide vial has to beextracted back into the same syringe with the same needle tip (See Table below).

Required dose volumes to be extracted for administration of bulevirtide

Bulevirtide Dose Required volume of reconstituted bulevirtideto be extracted1 mg 0.5 ml1.5 mg 0.75 ml2 mg 1 ml

The needle tip has then to be detached from the syringe. To this syringe, a needle tip for subcutaneousinjection has to be attached and any remaining air bubbles have to be removed from the syringe priorto 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 localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/20/1446/001

Date of first authorisation: 31 July 2020

Date of latest renewal: 17 July 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.