Public Assessment Report. Scientific discussion. Vancocaps 250 mg hard capsules. (vancomycin hydrochloride) NL/H/3359/001/DC

Transcription

1 Public Assessment Report Scientific discussion Vancocaps 250 mg hard capsules (vancomycin hydrochloride) NL/H/3359/001/DC Date: 12 April 2017 This module reflects the scientific discussion for the approval of Vancocaps 250 mg hard capsules. The procedure was finalised on 4 October For information on changes after this date please refer to the steps taken after finalisation at the end of this PAR.

2 List of abbreviations C CEP CHMP CMD(h) CMS EDQM ERA ICH MAH Ph.Eur. PL RH RMP SmPC TSE Certificate of Suitability to the monographs of the European Pharmacopoeia Committee for Medicinal Products for Human Use Coordination group for Mutual recognition and Decentralised procedure for human medicinal products Concerned Member State European Directorate for the Quality of Medicines Environmental Risk Assessment International Conference of Harmonisation Marketing Authorisation Holder European Pharmacopoeia Package Leaflet Relative Humidity Risk Management Plan Summary of Product Characteristics Transmissible Spongiform Encephalopathy 2/11

3 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Vancocaps 250 mg hard capsules, from Eurocept B.V. Vancocaps is indicated for the treatment of staphylococcal enterocolitis and pseudomembranous colitis caused by Clostridium difficile due to antibiotic treatment. Oral vancomycin is not effective for other types of infections. Concurrent administration of oral vancomycin and an aminoglycoside is used to decontaminate the gastrointestinal tract of immunocompromised patients. Intravenous administration of vancomycin is not effective for the indications above. This is why vancomycin should be administered orally for these indications. The product is indicated for use in adults and children. Vancomycin should be reserved for cases where there is a specific indication, to minimise the chance of resistance emerging. Consideration should be given to official guidance on the appropriate use of antibiotics. A comprehensive description of the indications and posology is given in the SmPC. The product applied for is identical to Vancocaps CP 250 mg, capsules (NL License RVG 11984) which has been registered in the Netherlands through a national procedure by Eli Lilly Benelux in The Marketing Authorisation was transferred to Eurocept B.V. in July The concerned member states (CMS) involved in this procedure were Belgium and Luxembourg. The marketing authorisation has been granted pursuant to Article 10a of Directive 2001/83/EC, a so called bibliographic application based on the well-established medicinal use of vancomycin. II. QUALITY ASPECTS II.1 Introduction Vancocaps is a hard gelatin capsule which an opaque grey body, printed in red with 250, and an opaque dark blue cap. Each hard capsule contains mg of vancomycin hydrochloride, equivalent to 250 mg ( IU) of vancomycin activity, purified by chromatography. The hard capsules are packed in PVC/PE/Aclar-Al blisters. The excipients are: Capsule content - polyethylene glycol Capsule shell gelatin, indigo carmine (E132), black and red iron oxide (E172), and titanium dioxide (E171) II.2 Drug Substance The active substance is vancomycin hydrochloride, an established active substance described in the European Pharmacopoeia (Ph.Eur.). Vancomycin hydrochloride is a white or almost white powder freely soluble in water, slightly soluble in alcohol and insoluble in ether and chloroform. The drug substance does not exhibit polymorphism. The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological 3/11

4 quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the Ph.Eur. Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included. Quality control of drug substance The active substance specification is considered adequate to control the quality and meets the requirements of the monograph in the Ph.Eur. and CEP, with additional requirements for identification and drug product relevant parameters. Batch analytical data demonstrating compliance with this specification have been provided for five batches. Stability of drug substance The active substance is stable for 24 months when stored under the stated conditions. Assessment thereof was part of granting the CEP and has been granted by the EDQM. II.3 Medicinal Product Pharmaceutical development The product is an established pharmaceutical form and its development is adequately described in accordance with the relevant European guidelines. The choice of excipients is justified and their functions explained. The excipients are well known. The product is identical to and based on Vancocaps CP 250 mg, which is on the Dutch market since Therefore, additional development documentation is deemed unnecessary. The pharmaceutical development has been adequately performed. Manufacturing process The manufacturing process consists of four steps. The manufacturing process has been validated according to relevant European/ICH guidelines and described in sufficient detail. Process validation data on the product have been presented for three full scale batches in accordance with the relevant European guidelines. Control of excipients The excipients comply with Ph.Eur. or in-house requirements. These specifications are acceptable. Quality control of drug product The finished product specifications are adequate to control the relevant parameters for the dosage form. The specification includes tests for appearance, identity, microbial assay, assay, related substances, uniformity of mass, moisture content, dissolution, and microbial purity. The release and shelf-life requirements are identical. Limits in the specification have been justified and are considered appropriate for adequate quality control of the product. Satisfactory validation data for the analytical methods have been provided. Batch analytical data from three production scaled batches from the proposed production site have been provided, demonstrating compliance with the specification. Stability of drug product Stability data on the product have been provided for four commercial scale batches, stored at 25 C/60% RH (24 months). The long-term conditions used in the stability studies are according to the ICH stability guideline. The batches were stored in the proposed packaging. Not all parameters from the shelf-life specification have been evaluated as part of the stability studies. Based on the history of the product and the available long term stability data, the proposed shelf-life of six months is acceptable with the storage condition: Store below 25 C. Store in the original package in order to protect from moisture. 4/11

5 Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies For the gelatin capsules a certificate of suitability issued by the EDQM has been provided and compliance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via medicinal products has been satisfactorily demonstrated. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Vancocaps has a proven chemicalpharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. The following post-approval commitment was made: The MAH committed to place the first three production batches on formal stability studies according to ICH conditions. III. III.1 NON-CLINICAL ASPECTS Pharmacology Vancomycin is a well-known active substance with a well-known antibacterial spectrum. The antimicrobial spectrum of vancomycin includes only gram-positive bacteria. Resistance of Staphylococcus aureus and Clostridium difficile against vancomycin is low. The incidence of vancomycin-intermediate Staphylococcus aureus (VISA) is however increasing, in particular in highbacterial-load infections. III.2 Pharmacokinetics The actions of oral administered vancomycin are limited to the gastrointestinal tract, since oral vancomycin is poorly absorbed. The pharmacokinetic aspects of parentally administered vancomycin are not considered to be applicable for oral vancomycin. Vancomycin is a well-known compound with which there is sufficient clinical experience. It is not necessary to provide additional data. III.3 Toxicology No non-clinical data were provided regarding the toxicology of vancomycin. Vancomycin is a wellknown compound with which there is sufficient clinical experience. Systemic vancomycin may have an ototoxic or nephrotoxic effect. It is not necessary to provide additional data. III.4 Ecotoxicity/environmental risk assessment (ERA) In accordance to the guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00) an adequate justification for the absence of a complete ERA has been submitted. This justification includes the argument that the product is identical to the current oral presentation in the Netherlands (Vancocin CP 250 mg capsules). Vancocaps can be seen as a generic product that is intended to substitute that product. In addition, it is also intended as an alternative for the current oral use of powder presentations originally intended for parenteral use. In the Netherlands, the oral formulation is only a small fraction of vancomycin total use. The absence of a complete ERA is adequately justified. III.5 Discussion on the non-clinical aspects The application for Vancocaps 250 mg hard capsules is based on well-established use. This is endorsed, since vancomycin has been registered for this indication for a long time and the dose is not increased. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-to-date and adequate scientific literature. The overview justifies why 5/11

6 there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Vancomycin is a well-known active substance with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. IV.2 Pharmacokinetics Vancomycin should act gastro-intestinally. As such, it is shown that the drug is available in the gastrointestinal tract. Data on solubility showed that vancomycin is highly soluble. In addition, the dissolution data showed that vancomycin is readily available in the gastrointestinal tract. From the literature data it is not expected that vancomycin from the proposed formulation will be absorbed and will give sufficiently effective concentrations in the gastro-intestinal tract. Hence the only excipient added to the capsule content is polyethylene glycol (PEG or macrogol). This is a polymer of ethylene oxide and water. They are used for instance to increase the viscosity of a solution. Liquid macrogols, with a low molecular weight may be absorbed from the gastro-intestinal tract, but macrogols of high molecular weight are not significantly absorbed. Furthermore, PEG is not expected to influence vancomycin absorption and/or efficacy. This is supported by Lucas et al. (1987) comparing an oral solution of vancomycin in water versus a capsule formulation of vancomycin with PEG6000. No absorption of vancomycin and high faecal concentrations were observed. The data showed that the difference in formulation did not impacted absorption of vancomycin. IV.3 Pharmacodynamics Vancomycin is a tricyclic glycopeptide antibiotic obtained from Amycolatopsis orientalis. The in vitro bactericidal effect of vancomycin is based primarily on inhibition of cell wall synthesis. Vancomycin also affects the permeability of the bacterial cell membrane, while concurrently blocking RNA synthesis. The MAH has provided an overview of general pharmacodynamic properties of vancomycin. The pharmacodynamic section is considered sufficiently described. Acquired resistance to glycopeptides is most common in enterococci and is based on acquisition of various van gene complexes which modifies the D-alanyl-D-alanine target to D-alanyl-D-lactate or D- alanyl-d-serine which bind vancomycin poorly, because a critical site for hydrogen bonding is missing. This form of resistance is especially seen in Enterococcus faecium. In some countries, increasing cases of resistance are observed particularly in enterococci; multi-resistant strains of Enterococcus faecium are especially alarming. The prevalence of acquired resistance may vary geographically and with time for selected species. Local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. Cross-resistance with teicoplanin has been reported for some van genes. Van genes have rarely been found in Staphylococcus aureus, where changes in cell wall structure result in intermediate susceptibility, which is most commonly heterogeneous. Staphylococcus-strains with intermediate susceptibility for vancomycin (VISA) were reported. Also, methicillin-resistant staphylococcus aureus strains (MRSA) with reduced susceptibility for vancomycin were reported. The reduced susceptibility or resistance to vancomycin in Staphylococcus is not well understood. Several genetic elements and multiple mutations are required. There is no cross-resistance between vancomycin and other classes of antibiotics. 6/11

7 IV.4 Clinical efficacy No new clinical or preclinical studies were conducted, which is acceptable given that the application has been submitted under Article 10a of Directive 2001/83/EC. In order to demonstrate the efficacy of a dose of vancomycin the MAH has provided numerous publications. From the results of these studies, vancomycin proved to be an efficacious and safe medicine in the treatment of staphylococcal enterocolitis. Moreover, staphylococcal resistance to vancomycin remained very low, especially when compared to other antibiotic treatment options (Wallace et al. 1965, Kahn and Hall 1966, Cook and Farrar 1978, Konishi et al. 1997, Schiller et al 1998, Lin et al. 2010). Vancomycin also proved to be efficacious and safe in the treatment of pseudomembranous colitis caused by Clostridium difficile (Keighley et al. 1978, Fekety 1997, Wenish et al. 1996, Brook 2005, Halsey 2008, Nelson 2011, Kee 2012, Leifeld 2012, Rineh et al. 2014). IV.5 Clinical safety Oral vancomycin has long been considered as a safe drug with only two major and six minor adverse events reported from 1956 to 1985 (Matzke et al, 1986). The clinical studies used to describe the clinical efficacy likewise fail to report any consistently occurring side effect. Only case reports could be traced as sources of adverse events of oral vancomycin. The following undesirable effects have been reported in patients using oral vancomycin (Table 1). The frequency of each undesirable effect is given in brackets using the following categories: very common ( 1/10), common ( 1/100, <1/10), uncommon (>1/1,000, <1/100), rare ( 1/10,000, <1/1,000) and very rare (<1/10,000). Table 1. Reported undesirable effects in patients using oral vancomycin Infections and infestations Bacterial infection; fungal infection (common) Immune system disorders Anaphylactic reaction (rare) Hypersensitivity (rare) Ear and labyrinth disorders Deafness (uncommon) Tinnitus (rare) Vascular disorders Decreased blood pressure (rare) Flushing (rare) Gastrointestinal disorders Nausea (uncommon) Skin and subcutaneous tissue disorders Pruritus (uncommon) Rash (uncommon) Red man syndrome (redness (erythema) on the head, neck, chest and back. Uncommonly associated with pruritus, decreased blood pressure, gasping or wheezing respiration and breathlessness (dyspnoea)) (rare) Exfoliative dermatitis (rare) Urticaria (rare) Stevens-Johnson syndrome (very rare) Toxic epidermal necrolysis (very rare) Renal and urinary disorders Interstitial nephritis (rare) General disorders and administration Pyrexia (uncommon) site conditions One isolated case of hepatic toxicity after administration of oral vancomycin was published (Cadle et al, 2006). Ototoxicity and nephrotoxicity, which are known side effects of intravenous vancomycin, have not been reported for oral vancomycin. More recently a more extensive safety profile for oral vancomycin was presented as the result of its comparison with a new macrocyclic antibiotic fidaxomicin which included 1147 patients of which 564 were treated with fidaxomicin and 583 patients were treated with vancomycin (Weiss et al, 2012). This vancomycin patient-cohort is by far the largest ever to be reported in the literature although this report deals with the safety aspects of vancomycin only. Since the studies included in this comparison were performed recently the methodology was far more sophisticated than the earlier clinical studies as performed with vancomycin and therefore it is not surprising that this comparison unveils a number of 7/11

8 adverse effects hitherto unidentified for vancomycin. The table below summarises the numerical details of this comparison for the various adverse events reported. Table 2. Adverse events of fidaxomicin and vancomycin obtained from direct comparisons in 1147 patients Adverse event Vancomycin (%) Fidaxomicin (%) Discontinuation of study due to an adverse event 7 6 Vomiting Gastrointestinal bleeding* 3 4 Anaemia 2 2 Leukopenia # 1 3 Infections ECG changes 0 0 Abnormal liver tests 3 3 Death 6 6 * All events deemed unrelated to the drug # Nearly all reports in subjects with malignancies and related treatments The vast majority of all events were not related to the study drug. Vancomycin can be administered to pregnant women and children, and its long-term administration as a therapy for recurrent C. difficile infections has not been linked to any significant safety issues. This profile is confirmed by the latest PSUR covering the period of September 2004 to January 2012 without one single adverse event reported. The safety of oral vancomycin is properly discussed with recent literature and is considered acceptable. IV.6 Risk Management Plan The MAH 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 Vancocaps 250 mg hard capsules. Summary table of safety concerns as approved in RMP: Important identified risks Ototoxicity Nephrotoxicity Important potential risks Use of vancomycin during pregnancy and/or breastfeeding Development of resistance Missing information None The member states agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information. IV.7 Discussion on the clinical aspects Vancocaps 250 mg is considered widely established. For this authorisation, reference is made to clinical studies and experience with vancomycin. Vancomycin has been shown to be effective in the treatment of staphylococcal enterocolitis and pseudomembranous colitis caused by Clostridium difficile due to antibiotic treatment. The provided clinical overview is sufficient. No new clinical studies were conducted. This is accepted. V. USER CONSULTATION 8/11

9 The package leaflet (PL) has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test consisted of a pilot test, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. The results show that the PL meets the criteria for readability as set out in the Guideline on the readability of the label and PL of medicinal products for human use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Vancocaps 250 mg hard capsules has a proven chemical-pharmaceutical quality. Vancocaps is an effective drug, which is considered widely established. The benefit/risk balance is considered positive. The Board followed the advice of the assessors. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Vancocaps with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 4 October /11

10 VII. REFERENCES C Brook I (2005) Pseudomembranous colitis in children. J Gastroent Hepat 20, 182 Cadle RM et al (2006) Vancomycin-induced elevation of liver enzyme levels. Annals Pharmacother 40, 1186 Cook FV and Farrar WE (1978) Vancomycin revisited. Ann Int Med 88, 813 Fekety R (1997) Guidelines for the diagnosis and management of Clostridium difficile associated diarrhea and colitis. Am J Gastroenterol. 92, Halsey J (2008) Current and future treatment modalities for Clostridium difficile associated disease. Am J Health Syst Pharm, Kee VR (2012) Clostridium difficile infection in older adults: a review and update on its management. Am J Geriatr Pharmacother 10, 14 Keighley MRB et al (1978) Randomized controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhea. Br Med J 2, 1667 Konishi T et al (1997) Oral vancomycin hydrochloride therapy for post-operative methicillin-cephemresistant S. aureus enteritis. Jpn J Sur 27, 826 Leifeld L and Kruis W (2012) Management des toxischen Megakolons. Z Gastroenterol 50, 316 Lin Z et al (2010) Staphylococcal enterocolitis: forgotten but not gone? Dig Dis Sci 55, 1200 Lucas RA et al (1987) Disposition of vancomycin in healthy volunteers from oral solution and semisolid matrix capsules. J Clin Pharm Ther 12, 27 Nelson RL et al (2011) Antibiotic treatment for Clostridium difficile associated diarrhea in adults Review. Cochrane Library 11, 1 Rineh a et al (2014) Clostridium difficile infection: molecular pathogenesis and novel therapeutics. Expert Rev Anti Infect Ther 12, 131 Schiller BF et al (1998) Methicillin-resistant staphylococcal enterocolitis. Am J Med 105, 164 Wallace JF et al (1965) Oral administration of vancomycin in the treatment of staphylococcal enterocolitis. New Eng J Med 272, 1014 Weiss K et al (2012) Safety analysis of fidaxomicin in comparison with oral vancomycin for C. difficile infections. Clin Infect Dis 55 (Suppl 2), /11

11 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE SUMMARY Scope Procedure number Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached 11/11