Hepcludex - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

HEPCLUDEX 2 mg powder for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains bulevirtide acetate equivalent to 2 mg bulevirtide.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for injection (powder for injection).

he powder is white to off-white.

After reconstitution, solution with a pH of approximately 9.0 and osmolality of approximately 300 mOsm/kg.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Hepcludex is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.

4.2 Posology and method of administration

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

Posology

Bulevirtide should be administered at 2 mg once daily (every 24 h ± 4 h) by subcutaneous injection as monotherapy or in co-administration with a nucleoside/nu­cleotide analogue for treatment of underlying HBV infection.

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

Duration of treatment

he 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 population

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. No data is available.

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 to minimise the risk of the injection site reactions.

The “Instructions for the User”, provided in the carton, must be followed carefully by the patient.

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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 hepatitis B virus (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 coadministered 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 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.

Increase of bile salts

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).

Administration site reactions

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.

Co-infection with human immunodeficiency virus and hepatitis C virus:

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

Excipients:

This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially „sodium-free“.

4.5 Interaction with other medicinal products and other forms of interaction

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. estrone-3-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 |aM, 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).

4.6 Fertility, pregnancy and lactation

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 age who do not use contraception.

Breastfeeding

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.

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.

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

Summary of the safety profile

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).

Tabulated list of adverse reactions

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).

Description of selected adverse reactions:

ALT elevations

Most ALT elevations were reported after treatment cessation and may be related to hepatitis exacerbation after withdrawal of antiviral treatment.

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.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 two Phase 2 studies. Patients with chronic HDV infection and active hepatitis were included. The population of both studies was mainly Caucasian, HDV genotype 1 was predominant.

MYR 202 study

A multicentre, open-label, randomised phase 2 clinical study evaluated the efficacy and safety of three doses of bulevirtide (2 mg/day, 5 mg/day and 10 mg/day) for 24 weeks in patients with chronic hepatitis D with liver cirrhosis, or who failed previous interferon therapy, or for whom such therapy was contraindicated (including history of interferon intolerance). Study participants received either daily subcutaneous injections of bulevirtide 2 mg/day, 5 mg/day and 10 mg/day on top of tenofovir (tablets), or tenofovir alone for 24 weeks. 50% of the study participants had liver cirrhosis at baseline. Participants had compensated liver disease, mean age was 40.2 (9.5) years, 66.9% were male, 85.6% were Caucasians, 13.6% Asians and 0.8% Black. Patients had active hepatitis with mean levels ALT of 115 (79.5) U/L. Patients with HIV and active HCV infection were excluded. Baseline characteristics were comparable between treatment arms. The primary endpoint of the study was undetectable HDV RNA or decrease by >2logio from baseline to week 24.

The table below summarises the efficacy results in mITT population at week 24:

ALT values <31 U/L for female and <41 U/L for male were considered normal

In this study, 25 participants developed anti-drug antibodies (ADA). No evidence of these ADA on the pharmacokinetics nor on the efficacy of Hepcludex was observed.

MYR 203 study

In study 203, 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 subjects developed virological breakthrough, possibly related to medication non-adherence.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Hepcludex in one or more subsets of the paediatric population for the treatment of chronic hepatitis D infection (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of bulevirtide were characterised after intravenous and subcutaneous administration. The exposure of bulevirtide increased disproportionally while the clearance and 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^M, 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 Cmax 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 t1/2 of 4–7 hours.

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

No data is available in patients younger than 18 years of age.

5.3 Preclinical safety data

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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Sodium carbonate anhydrous

Sodium hydrogen carbonate

Mannitol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

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

6.3 Shelf life

24 months.

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.

6.4 Special precautions for storage

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

6.5 Nature and contents of container

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

Pack-size of 30 vials.

6.6 Special precautions for disposal and other handling

Each vial is intended for single use only and the excess of unused product must be properly disposed of. Water for injections, syringes, 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 water for injection into the syringe. The syringe needle with the syringe containing the water for injection should then be inserted into the bulevirtide vial through the rubber stopper. The 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 complete content of the bulevirtide vial has to be extracted back into the same syringe with the same needle tip.

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 by 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.

7. MARKETING AUTHORISATION HOLDER

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/20/1446/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 31 July 2020

Date of latest renewal: 02 August 2021