Public Assessment Report Scientific discussion. Vancomycin Farmaplus Vancomycin hydrochloride SE/H/1158/01-02/MR

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1 Public Assessment Report Scientific discussion Vancomycin Farmaplus Vancomycin hydrochloride SE/H/1158/01-02/MR This module reflects the scientific discussion for the approval of Vancomycin Farmaplus 500 mg and 1000 mg powder for concentrate for solution for infusion. The procedure was finalised at For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version:

2 I. INTRODUCTION FarmaPlus AS has applied for a marketing authorisation for Vancomycin Farmaplus 500 mg and 1000 mg powder for concentrate for solution for infusion. The active substance is vancomycin hydrochloride. For approved indications, see the Summary of Product Characteristics. II. II.1 QUALITY ASPECTS Introduction Vancomycin FarmaPlus is presented in the form of powder for concentrate for solution for infusion containing mg or mg of vancomycin hydrochloride which corresponds to 500 mg or 1000 mg of the vancomycin. The excipients are sodium hydroxide and hydrochloric acid- The powder is filled in glass vials with rubber stopper and a flip off aluminium seal. II.2 Drug Substance Vancomycin hydrochloride has a monograph in the Ph Eur. Vancomycin hydrochloride is a white or almost white, hygroscopic powder which is freely soluble in water. The structure of vancomycin hydrochloride has been adequately proven and its physico-chemical properties sufficiently described. The route of synthesis has been adequately described and satisfactory specifications have been provided for starting materials, reagents and solvents. The active substance specification includes relevant tests and the limits for impurities/degradation products have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted and the data provided are sufficient to confirm the retest period. II.3 Medicinal Product Vancomycin FarmaPlus powder for concentrate for solution for infusion is formulated using excipients described in the current Ph Eur. All raw materials used in the product has demonstrated compliance with Commission Directive 2003/63/EC and the NfG on Minimising the risk of transmitting Animal Spongiform Encephalopathy Agents via human and veterinary medicinal products (EMEA/410/01). The product development has taken into consideration the physico-chemical characteristics of the active substance. 2/7

3 The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed and data presented support the shelf life and storage conditions claimed in the SPC. III. NON-CLINICAL ASPECTS The pharmacodynamic, pharmacokinetic and toxicological properties of vancomycin are well known. Pharmacology Vancomycin inhibits the synthesis of peptidoglycan, the major component of the cell wall of gram-positive bacteria by binding to precursors of the peptidoglycan. The effect is bactericidal. Pharmacokinetics The non-clinical pharmacokinetics of vancomycin are characterised by moderate protein binding, wide but variable tissue distribution and excretion primary in the unchanged form, in the urine. Oral absorption is limited vancomycin being a large glycopeptide. Toxicology The toxic profile of vancomycin is well known. Ototoxicity and nephrotoxicity are the most serious adverse effects of parenteral vancomycin therapy in the clinic. Correlations between serum vancomycin concentrations and ototoxicity and nephrotoxicity still remain to be clarified. Ototoxicity may be transient or permanent. Vancomycin may cause damage to the auditory branch of the eighth cranial nerve and permanent deafness has occurred. Rapid intravenous administration of vancomycin has resulted in a hypotensive reaction frequently referred to as the "red-man syndrome" or "red-neck syndrome". The reaction is characterized by a sudden decrease in blood pressure which can be severe and may be accompanied by flushing and/or a maculopapular or erythematous rash on the face, neck, chest, and upper extremities; the latter manifestations may also occur in the absence of hypotension. Rarely, cardiac arrest or seizures have occurred. Vancomycin-induced hypotension appears to result from a negative inotropic and vasodilating action produced in part by a release of histamine, which is directly related to the rate of infusion; the release of histamine also appears to be responsible for the usual manifestations (e.g., erythema, rash, pruritus) of the "red" characteasts and albumin in the urine. Fatal uremia has occurred. Rarely, the drug has been associated with acute interstitial nephritis. Vancomycin was not mutagenic in vitro in the mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNA synthesis assay or in vivo in the Chinese hamster sister chromatid exchange assay or the mouse micronucleus assay. The lack of an environmental risk assessment is justified since the product is a generic version of an already approved one and it is not likely to change the total market of vancomycin. 3/7

4 IV. IV.1 CLINICAL ASPECTS Introduction IV.2 Pharmacokinetics Vancomycin has been clinically used for decades. The pharmacokinetics of vancomycin has been extensively studied and is shortly summarized below. Absorption Vancomycin is not appreciably absorbed orally. The mean plasma levels after intravenous infusion of 1 g vancomycin over 60 minutes were approximately 63 mg/l at the end of infusion, approximately 23 mg/l after 2 hours, and approximately 8 mg/l after 11 hours. If vancomycin is administered during a peritonealdialysis intraperitoneally, approximately 60% reach the systemic cycle during the first 6 hours. After intraperitoneal administration of 30 mg/kg serum levels of approximately 10 mg/l are reached. Distribution After intravenous administration vancomycin is distributed in nearly all tissues. In pleura, pericard, ascites and synovia liquid as well as in heart muscle and in heart valve concentrations similar to those in blood plasma are achieved. The apparent distribution volume in the steady state is named to be 0.43 (up to 0.9) l/kg. In case of non-inflammatory meninges only small quantities of vancomycin pass into the cerebrospinal fluid. Vancomycin is bound to plasma proteins to 55%. Metabolism Vancomycin is metabolised only to a small extent. Elimination After parenteral administration vancomycin is excreted renally via glomerular filtration, nearly completely as the microbiologcally active substance (approximately 70-80% within 24 h). Biliar excretion has low relevance (less than 5% of a dose). The serum half life in adult patients with normal renal functions is about 4-6 hours. The clearance of vancomycin from the plasma correlates approximately with the glomerular filtration rate. Special populations Renal impairment Impaired renal function can prolong the elimination (half-life 7.5 days). In patients with impaired renal function the dosage has to be adapted to the excretion rate. Hepatic impairment There is no evidence that the dose has to be reduced in patients with hepatic insufficiency. 4/7

5 Elderly The natural decrease of the glomerular filtration rate with higher age can result in an increased vancomycin serum concentration if dosage is not adapted according to renal function. Children The serum half life in children with normal renal function is hours. Children below 12 years of age are given a usual dose of 40 mg/kg body weight per day (usually divided into 4 doses, i e 10 mg/kg every 6 hours). In newborns and infants the recommendation is giving an initial dose of 15 mg/kg body weight followed by maintenance doses of 10 mg/kg every 12 hours during the first week after birth, and then every 8 hours during the first month of age. It may be necessary to monitor serum levels. Interactions The current SPC describes pharmacodynamic interactions with other potentially oto- or nephrotoxic medicinal products, anestetics and muscle relaxants. IV.3 Pharmacodynamics Vancomycin is a tricyclic glycopeptide antibiotic that inhibits the syntesis of the cell wall in Gram-positive bacteria by binding with high affinity to the D-alanyl-D-alanine terminus of cell wall precursor units. The drug is bactericidal for dividing microorganisms. Vancomycin displays concentration-independent activity with the area under the concentration curve (AUC) divided by the the minimum inhibitory concentration (MIC) of the target organism as the primary predictive parameter for efficacy. On basis of in vitro, animal and limited human data, an AUC/MIC ratio of 400 has been established as a PK/PD target to achieve clinical effectiveness with vancomycin. To achieve this target when MICs are > 0.5 mg/l, dosing in the upper range and high trough serum concentrations (15-20 mg/l) are required. IV.4 Clinical efficacy and safety As the product was initially approved for more than 25 years, the scientific documentation for clinical efficacy and safety that was the basis for approval at that time is not according to current standards. However, extensive clinical experience in EU and world-wide in seriously ill patients and numerous large modern clinical studies where vancomycin have been used as a comparator, as well as current international treatment guidelines, provides sufficient reassurance for the efficacy and safety of parenteral vancomycin in the approved indications No new efficacy or safety data have been submitted and none are required for this product. IV.5 Discussion on the clinical aspects Significant discrepancies between the SmPC for Vancomycin FarmaPlus and that for other vancomycin products previously approved in other member states, were identified during the assessment procedure, in particular with regard to approved indications. Therefore, the MAH has committed to submit a type II variation to update the SmPC in accordance with current guideline and recommendations within 6 months at latest. 5/7

6 V. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Due to significant discrepancies in previously approved indications for vancomycin products, the MAH has committed to submit a type II variation to update the SmPC in accordance with current guideline and recommendations within 6 months at latest. User consultation A user consultation with target patient groups on the package information leaflet (PIL) has been performed on the basis of a bridging report making reference to Vancomycin CNP, SE/H/974/01-02/DC and Layout of Carboplatin FarmaPlus NO/H/0179/001/DC. The bridging report submitted by the applicant has been found acceptable in type 1B variation 2121:2011/ The risk/benefit ratio is considered positive and Vancomycin FarmaPlus 500 mg and 1000 mg powder for concentrate for solution for infusion is recommended for approval. VI. APPROVAL The Mutual recognition Vancomycin Farmaplus 500 mg and 1000 mg powder for concentrate for solution for infusion was successfully finalised on /7

7 Public Assessment Report Update Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) Postadress/Postal address: P.O. Box 26, SE Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0) Fax: +46 (0) Internet: Template version: