Zusammenfassung der Merkmale des Arzneimittels - Ambrisentan Vivanta 10 mg Filmtabletten
Decentralised Procedure
Ambrisentan Vivanta 5 mg, 10 mg Filmtabletten
Procedure-Number: DE/H/6970/001–002/DC
Active Substance:
Ambrisentan
Dosage Form:
Film-coated tablet
Applicant:
Vivanta Generics s.r.o.
Publication
12.10.2023
This module reflects the scientific discussion for the approval of the above-mentioned procedure. The procedure was finalised at 13.09.2023.
V RECOMMENDED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT
V.1 Proposed list of recommendations not falling under Article 21a/22 of Directive
| Proposed name of the medicinal product in the RMS | Ambrisentan Vivanta 5 mg, 10 mg Filmtabletten |
| Name of the drug substance (INN name): | Ambrisentan |
| Pharmaco-therapeutic group (ATC Code): | C02KX02 |
| Pharmaceutical form(s) and strength(s): | Film-coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6970/001–002/DC |
| Reference Member State: | DE |
| Concerned Member States: | CY, ES |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Applicant (name and address) | Vivanta Generics s.r.o. Trtinova 260/1 196 00 Prague Czechia |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Pharmadox Healthcare Limited , KW20A Kordin Industrial Estate, Paola, PLA3000, Malta MSN Laboratories Europe Limited KW20A Corradino Park, Paola, PLA3000, Malta |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Ambrisentan Vivanta 5 mg, 10 mg Filmtabletten, in the
Treatment of patients with primary or secondary pulmonary arterial hypertension,
is approved.
II.1 Problem statement
This is a generic application.
II.2 About the product
Mode of action:
Ambrisentan antagonizes the endothelin A receptor (ETAR) which is a Gαq-coupled receptor and is activated by 21-amino acid peptides from the endothelin family. Ambrisentan counteracts endothelin-mediated vasoconstriction. Since the endothelin system plays an important role in the pathophysiology of pulmonary arterial hypertension, ambrisentan is indicated for the treatment of patients with primary or secondary pulmonary arterial hypertension.
Pharmacological classification:
Ambrisentan is classified under ATC code C02KX02 (antihypertensives for pulmonary arterial hypertension).
Claimed indication and recommendation for use and posology.
Claimed indication:
Ambrisentan Vivanta is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III, including use in combination treatment (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.
Posology and method of administration
Treatment must be initiated by a physician experienced in the treatment of PAH.
Ambrisentan monotherapy
Ambrisentan Vivanta is to be taken orally to begin at a dose of 5 mg once daily and may be increased to 10 mg daily depending upon clinical response and tolerability.
Ambrisentan in combination with tadalafil
When used in combination with tadalafil, Ambrisentan Vivanta should be titrated to 10 mg once daily.
In the AMBITION study, patients received 5 mg ambrisentan daily for the first 8 weeks before up titrating to 10 mg, dependent on tolerability (see section 5.1). When used in combination with tadalafil, patients were initiated with 5 mg ambrisentan and 20 mg tadalafil. Dependent on tolerability the dose of tadalafil was increased to 40 mg after 4 weeks and the dose of ambrisentan was increased to 10 mg after 8 weeks. More than 90% of patients achieved this. Doses could also be decreased depending on tolerability.
Limited data suggest that the abrupt discontinuation of ambrisentan is not associated with rebound worsening of PAH. When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once daily and the patient should be carefully monitored.
Special populations
Elderly patients
No dose adjustment is required in patients over the age of 65.
Patients with renal impairment
No dose adjustment is required in patients with renal impairment. There is limited experience with ambrisentan in individuals with severe renal impairment (creatinine clearance <30 ml/min); therapy should be initiated cautiously in this subgroup and particular care taken if the dose is increased to 10 mg ambrisentan.
Patients with hepatic impairment
Ambrisentan has not been studied in individuals with hepatic impairment (with or without cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment might be expected to increase exposure (Cmax and AUC) to ambrisentan. Therefore, ambrisentan must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).
Paediatric population
The safety and efficacy of ambrisentan in children and adolescents aged below 18 years has not been established. No clinical data are available.
Method of administration
It is recommended that the tablet is swallowed whole and it can be taken with or without food. It is recommended that the tablet should not be split, crushed or chewed.
II.3 General comments on the submitted dossier
This decentralised application is submitted in accordance with Article 10(1) of directive 2001/83/EC. With Germany as the Reference Member State in this decentralized procedure, the applicant is applying for the marketing authorisations for Ambrisentan Vivanta 5 mg and 10 mg Filmtabletten in CY and ES. The active substance is not considered a new active substance.
To support this application, the results of one bioequivalence study has been submitted:
A biowaiver is requested for the 5 mg strength.
European Reference Product (ERP)
The European reference product is Volibris® 5 mg and 10 mg film-coated tablets by GlaxoSmithKline (Ireland) Ltd., registered since 21 April 2008 (marketing authorization numbers: 5 mg: EU/1/08/451/001–002; 10 mg: EU/1/08/451/003–004).
The reference product for the bioequivalence study (10 mg strength) was purchased on the UK market.
The applicant has submitted an RMP for ambrisentan 5 mg and 10 mg film-coated tablets. No scientific advice was given to the applicant. The applicant followed the CHMP guidance documents (CPMP/QWP/EWP/1401/98 Rev. 1, January 2010 (bioequivalence guideline).
Sections 1.6.1–3 of the paediatric regulation EC No 1901/2006 are not applicable for a generic medicinal product. No PIP has been submitted.
Potential similarity with orphan medicinal productsHaving considered the arguments presented by the applicant and retrieved by the RMS, with reference to Article 8 of Regulation (EC) No 141/2000, Ambrisentan Vivanta is considered not similar (as defined in Article 3 of Commission Regulation (EC) No. 847/2000) to authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
GMPThe RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within and outside the Community the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
GMP active substanceRegarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
GCP/GLPA statement on the application of appropriate GCP standards in the submitted study has been provided in the study report.
Competent EU authorities have inspected the clinical and bioanalytical study site as well as the pharmacokinetic and statistical analysis site.
III.1 Quality aspects
Drug substanceThe drug substance Ambrisentan used for the manufacture of the drug product Ambrisentan 5 mg and 10 mg film-coated tablets is not monographed in the Ph. Eur..
The quality of the drug substances is confirmed by an ASMF.
Drug ProductThe aim of formulation development was to formulate Ambrisentan Film-coated tablets equivalent to Reference drug product Volibris® (Ambrisentan), film coated.
The active substance is indicated for treatment of pulmonary arterial hypertension (PAH) in adult patients.
The ingredients and the manufacturing process of the drug are considered suitable to produce a pharmaceutical product of the proposed quality.
All relevant quality characteristics of the drug substance and the drug product (release and shelf-life) are specified. The description of the analytical methods used to analyse the drug product are adequate, the validation results are plausible.
The proposed packaging materials are PVC/PVdC/ Al blister.
24 months shelf-life for 10 mg formulation is acceptable. 18 month stability for the 5 mg formulation is acceptable. Special storage conditions are not needed.
III.2 Non clinical aspects
From a toxicological point of view, the main aspects of endothelin receptor antagonists are hepatotoxicity and teratogenicity.
Some ERAs (e.g. sitaxsentan, bosentan) induce hepatotoxicity in humans. It has been discussed that these effects are mediated by an inhibition of the bile salt export pump (BSEP) which exports bile salts out of hepatocytes into the bile, inducing bile salt accumulation in liver cells and cytolysis. In December 2010, sitaxsentan (Thelin®) was withdrawn from the market due to its hepatotoxicity (EMA/CHMP/821121/2010). In chronic toxicity studies performed in mice, rats and dogs, high doses of ambrisentan induce hepatotoxicity (centrilobular hypertrophy, increases in ALT, AST and AP). It has been suggested that ambrisentan has a low risk of hepatotoxicity due to lower effect on bile transport compared to bosentan and macitentan, weak inhibition of the NTCP and OATP transporters and virtually no inhibition of BSEP (Aversa et al. 2015).
Ambrisentan is teratogenic in rats and rabbits (abnormalities of the lower jaw, tongue and palate). The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knockout mice indicate a class effect. As with other endothelin receptor antagonists, appropriate precautions must be taken for women of child-bearing potential.
For the Patient Reminder Card concerning the risks of hepatotoxicity and teratogenicity after administration of ambrisentan, please see the discussion in the Risk Management Plan.
III.3 Clinical aspects
PharmacokineticsTo support this application, the results of one bioequivalence study has been submitted:
Randomized, open-label, balanced, two-treatment, two-period, two-sequence single oral dose, two-way crossover, bioequivalence study of ambrisentan 10 mg film-coated with Volibris® 10 mg film-coated in healthy human male subjects under fasting conditions.
The study corresponds to the requirements of the EU bioequivalence guideline (CPMP/EWP/QWP/1401/98 Rev. 1/Corr**) and is adequate for an immediate release drug. Fasting conditions are acceptable, because ambrisentan “can be taken with or without food” (SmPC).
Results of the clinical study:
Table 1. PK parameters (non-transformed; arithmetic mean ± SD, tmax median, range) for ambrisentan (n=21)
| Pharmacokinetic Parameter | Arithmetic Means (±SD) | |
| Test Product | Reference Product | |
| AUC0-t | 8516.6829 ± 1927.47397 | 8260.8032 ± 1837.40894 |
| Cmax | 1243.2657 ± 239.94265 | 1286.4558 ± 253.49600 |
| Tmax | 1.500 (0.750, 4.000) | 1.500 (0.750, 5.000) |
| AUC0-inf | 8969.1588 ± 2001.14842 | 8713.6568 ± 1910.48047 |
| T1/2 | 10.3453 ± 3.46343 | 10.8554 ± 2.95429 |
| Kel | 0.0742 ± 0.02561 | 0.0689 ± 0.02019 |
| AUC%Extrap | 4.8395 ± 2.15428 | 5.0927 ± 1.30725 |
Table 2. Pharmacokinetic parameters (geometric least square means; Test/Reference ratio and 90% confidence limits) for ambrisentan (n=21)
| Pharmacokinetic arameter | Geometric Mean Ratio Test/Ref | Confidence Intervals | CV% |
| AUC 0-t (ng.hr/mL) | 102.87 | 99.65%, 106.20% | 5.97% |
| C max (ng/mL) | 96.49 | 88.36%, 105.38% | 16.60% |
Figure 1. Linear (A) and semilogarithmic (B) profile of mean plasma concentrations vs. time for ambrisentan (n=21) for up to 72 h post-dosing. Red: Reference product; Blue: Test product
The difference of AUC0-∞ and AUC0–72h was <20% in all subjects. No pre-dose concentration was detected.
Tmax was never observed at the first sample time. All plasma levels were within the validated range.
^ The Bioequivalence was shown appropriately for the 10 mg strength.
Biowaiver Request and in vitro release experiments:
The composition of the 5 mg tablet is quantitatively proportional to the composition of the 10 mg tablet used in the bioequivalence study. The applicant has demonstrated similarity of the 5 mg and the 10 mg tablet by providing in vitro release data according to the conditions specified in the EU bioequivalence guideline. Thus, a biowaiver can be granted.
Summary Pharmacovigilance systemThe Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
Risk Management Plan
The applicant has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Ambrisentan 5 mg and 10 mg film-coated tablets.
Safety specification
| Important identified risks | Teratogenicity Decrease haemoglobin/haematocrit, anaemia, including anaemia requiring transfusion Hepatotoxicity |
| Important potential risks | Testicular tubular atrophy/Male infertility |
| Missing information | None |
Pharmacovigilance Plan
Routine pharmacovigilance activities are proposed.
Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Targeted follow-up questionnaires for risks of teratogenicity, hepatotoxicity and decrease of haemoglobin/haematocrit, anaemia, including anaemia requiring transfusion.
Risk minimisation measures
| Safety concern | Risk minimisation measures | Pharmacovigilance activities |
| Important Identified Risks | ||
| Teratogenicity | Routine risk minimization measures: Listed in SmPC section 4.3, 4.4, 4.6 and 5.3. Listed in PL section 2. Additional risk minimization measures: Patient Reminder Card | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Targeted follow-up questionnaires. Additional pharmacovigilance activities: None |
| Decrease of haemoglobin/ haematocrit, anaemia, including anaemia requiring transfusion | Routine risk minimization measures: Listed in SmPC section 4.4, and 4.8. Listed in PL section 2 and 4. Additional risk minimisation measures: None | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Targeted follow-up questionnaires. Additional pharmacovigilance activities: None |
| Hepatotoxicity | Routine risk minimization measures: Listed in SmPC section 4.2, 4.3, 4.4, 4.8, 5.1 and 5.2. Listed in PL section 2 and 4. Additional risk minimization measures: Patient Reminder Card | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: Targeted follow-up questionnaires. Additional pharmacovigilance activities: None |
| Important Potential Risks | ||
| Testicular tubular atrophy/Male infertility | Routine risk minimization measures: Listed in SmPC section 4.6 and 5.3. Listed in PL section 2. Additional risk minimization measures: None | Routine pharmacovigilance activities beyond adverse reactions reporting and signal detection: None Additional pharmacovigilance |
activities: None
Missing information
None
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
Periodic Safety Update Report (PSUR)With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.Common Renewal DateThe common renewal date is 13.09.2028.
Legal StatusMedicinal product subject to medical prescription.
User TestingThe user testing of the applicant’s generic ambrisentan product is considered acceptable.
Quality
From pharmaceutical point of view approval is possible.
Clinical
Bioequivalence was demonstrated for the 10 mg strength, and the biowaiver for the 5 mg strength can be granted. From a clinical perspective, benefit/risk is considered positive.
The application is approved. For intermediate amendments, see the current product information.