Decentralised Procedure. RMS Day 70 Preliminary Assessment Report. Paracetamol Pharmacin 1000mg, tablets (paracetamol) NL/H/2791/001/DC

Transcription

1 December 2011 CMDh/202/2005 Decentralised Procedure RMS Day 70 Preliminary Assessment Report NON-CLINICAL AND CLINICAL ASSESSMENT OF A GENERIC APPLICATION Paracetamol Pharmacin 1000mg, tablets (paracetamol) NL/H/2791/001/DC Applicant: Pharmacin B.V. Reference member state: The Netherlands Start of the procedure: 12 December 2012 Date of this report: 20 February 2013 (day 70) Deadline for comments: 22 March 2013 (day 100)

2 Table of content Page 1. INTRODUCTION NON-CLINICAL ASSESSMENT Critical evaluation of the Non-Clinical Overview and Summary Environmental Risk Assessment (ERA) Conclusions CLINICAL ASSESSMENT Introduction Clinical study reports BIOWAIVER PHARMACOKINETIC STUDY PHARMACODYNAMIC STUDIES ADDITIONAL DATA Post marketing experience Benefit-Risk assessment PHARMACOVIGILANCE Pharmacovigilance system Risk management plan LIST OF QUESTIONS AS PROPOSED BY THE RMS...17 Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 2/17

3 NON-CLINICAL AND CLINICAL ASSESSMENT Type of application: Reference product used in the bioequivalence studies: Original product: An abridged application, according to article 10(1) so called generic application N.A. Panadol 1000 mg, artrose tablets by GlaxoSmithKline Consumer Healthcare B.V 1. INTRODUCTION This decentralised application concerns a generic version of paracetamol, under three trade names. In this Assessment Report, the name Paracetamol Pharmacin 1000mg, tabletten is used. The originator product is Panadol 1000 mg, artrose tablets by GlaxoSmithKline Consumer Healthcare B.V., registered in RMS NL since 11 December With the Netherlands as the Reference Member State in this Decentralized Procedure, Pharmacin BV is applying for Marketing Authorisations for Paracetamol Pharmacin 1000 mg, tabletten in ES and PT. Paracetamol is an anilide derivative, with both analgesic and antipyretic effects. However, it does not have an anti-inflammatory effect. Paracetamol Pharmacin 1000 mg, tabletten are proposed to be indicated for mild to moderate pain or fever in adults and adolescents only. Proposed legal status is not subject to medical prescription, with supply through pharmacies only in the Netherlands. 2. NON-CLINICAL ASSESSMENT 2.1. Critical evaluation of the Non-Clinical Overview and Summary Pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol are well known. No further studies are required as paracetamol is a widely used, wellknown active substance. Therefore, the Applicant provided none. A non-clinical overview based on literature review is, thus, appropriate. The non-clinical overview has been written by TB Vree, Pharmacologist Ph.D. Nijmegen and Erik Dammers, Pharm D, DADA Consultancy, Nijmegen, The Netherlands and dated March The Report refers 58 publications up to year Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 3/17

4 The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. Assessor's comment: The non-clinical Overview is acceptable Environmental Risk Assessment (ERA) Since Paracetamol Pharmacin 1000 mg, tabletten is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary 2.3 Conclusions There are no objections to approval of Paracetamol Pharmacin 1000 mg, tabletten from a non-clinical point of view. 3. CLINICAL ASSESSMENT 3.1. Introduction This assessment report represents an evaluation of the key elements of the information provided by the company in the dossier. For more details, the reader should refer to the company's clinical overview and summary as well as to the clinical file. The clinical overview has been written TCM de Witte M.D. and Eric Dammer, Pharm. D., DADA Consultancy, Nijmegen, The Netherlands and is dated March Report refers to 64 publications up to year Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Concentration in plasma reaches a peak in 30 to 60 minutes. Paracetamol is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable. Excretion is almost exclusively renal, in the form of conjugated metabolites. Assessor's comment: The clinical overview on the clinical pharmacology, efficacy and safety is adequate Clinical study reports The Applicant did not perform a bioequivalence study and a BCS-based biowaiver is applied for. To support the application, a justification for a BCS-based biowaiver (written by the clinical expert E. Dammers, DADA Consultancy) was submitted BIOWAIVER Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 4/17

5 The Applicant discussed the characteristics related to the active substance and medicinal product in relation to the criteria for biowaiver according to Note for guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98). Assessor's comment: According to the current NfG on Investigation of Bioequivalence, the following issues should be addressed for biowaiving: BCS-based biowaiver are applicable for an immediate release drug product if: - the drug substance has been proven to exhibit high solubility and complete absorption (BCS-class I; for details see section III) and - either very rapid (> 85 % within 15 min) or similarly rapid (85 % within 30 min) in vitro dissolution characteristics of the test and reference product have been demonstrated considering specific requirements (see section IV.1) and - excipients that might affect bioavailability are qualitatively and quantitatively the same. In general, the use of the same excipients in similar amounts is preferred (see section IV.2). Generally, the risks of an inappropriate biowaiver decision should be more critically reviewed (e.g. site-specific absorption, risk for transport protein interactions at the absorption site, excipient composition and therapeutic risks) for products containing BCS class III than for BCS class I drug substances. A. Characteristics related to the active substance Risk of therapeutic failure or adverse drug reactions The Applicant stated that the non-critical therapeutic range of paracetamol is demonstrated by showing that paracetamol is not a narrow therapeutic index drug based on the available data on different dosing regimens for all age groups of patients [Drug facts and comparisons, 1988]. Further, the high first-pass effect of paracetamol and the hepatotoxicity were discussed. It was concluded that: Large variations in the first-pass metabolism lead to differences in the serum concentrations of paracetamol. Moreover, these serum levels are not clearly correlated to the analgesic effect. Furthermore, paracetamol appears to have a very wide therapeutic window. The difference between the maximum daily dose (4 g) and the minimal toxic dose (10 g) is at least a factor of 2.5 in adults. In children, the difference is even larger; the maximum daily dose is 50 mg/kg, compared to a minimal toxic dose of 150 mg/kg. Therefore, it may be inferred that there is no need for special precautions with respect to precision and accuracy of dosing of paracetamol. Assessor's comment: The risk of therapeutic failure is considered low for paracetamol formulations. Taking into account the high daily doses and the high interindividual variability in exposure due to the first-pass effect, the claim that paracetamol is not a critical therapeutic compound is agreed. Bioavailability Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 5/17

6 According to the Applicant, although the bioavailability of paracetamol as demonstrated by intact drug in plasma is approximately 80-90%, when one considers the metabolite and urinary data, absorption is close to 100%. Similarity in bioavailability with different formulations like tablets, effervescent tablets and powders based on the literature was also discussed and the Applicant drew the following conclusion: For paracetamol there are no indications that the type of oral dosage form affects the bioavailability. Similar values have been found for the bioavailability of solid oral dosage forms (tablets) and liquid oral dosage forms (effervescent tablets). Absorption as well as biotransformation is independent of the administered dose in the therapeutic range ( mg). Although paracetamol shows a considerable first-pass effect (30-40%), it has been demonstrated that the absorption of paracetamol is complete. Moreover, reported bioequivalence between orally administered aqueous and solid formulations of paracetamol is supportive, as it indicates that there are very little absorption limitations of a paracetamol formulation as long as it can be demonstrated that it disintegrates and dissolves rapidly. Assessor s comments: The pharmacokinetic properties of paracetamol are considered independent from the formulation administered and the dose given. Solubility Based on published literature on the solubility of paracetamol and dissolution data of test and reference product, the Applicant concluded that paracetamol has a high solubility. Paracetamol is very slightly soluble ( g/l) in cold water. However, it is very soluble in hot water [Merck Index (2006)]. Other sources claim a solubility of 1-5 g/l at 22ºC [Chemfinder (2004)] and 14 g/l at 25ºC [Yalkowsky et al (1992) in Chemfinder (2004)]. Other sources report a solubility of 14.7 mg/ml at 20ºC [Etman et al (1990) in Kalantzi (2006)], 14.3 mg/ml at 25ºC [Garekani et al (2003) in Kalantzi (2006)], and 23.7 mg/ml at 37ºC [Etman et al (1990) in in Kalantzi (2006)]. A solution of one dose of 1000 mg in 250 ml of water will lead to a concentration of 4.0 g/l. These data indicate that solubility of Paracetamol is still sufficient at a physiologic temperature of 37ºC. This is confirmed by the dissolution results of Paracetamol Pharmacin 1000 mg tablets. Assessor s comments: The argumentation of the Applicant that paracetamol is a highly soluble compound is agreed. Biopharmaceutical classification system (BCS) According to the BCS, drugs can be divided into four major categories based on their solubility and permeability. Class I: highly soluble and permeable Class II: poorly soluble but highly permeable Class III: highly soluble but poorly permeable Class IV: poorly soluble and poorly permeable Class I and III drugs are eligible for biowaivers. As a rule, a biowaiver is not appropriate for the Class II and IV drugs. Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 6/17

7 Initially, paracetamol had been classified as a BCS class III compound, however, following a technical report from the WHO expert committee on specifications for pharmaceutical preparations, it is classified as a BCS class I compound. When an API is absorbed to an extent of 85% or more, it is considered to be highly permeable. The permeability criterion was relaxed from 90% in the FDA Guidances to 85% in the WHO multisource document. One example of API now included in BCS class I that was previously considered to be Class III is paracetamol. Based on this information, the Applicant concluded that paracetamol has been shown to be highly soluble and completely absorbed and as in agreement with the WHO classification it can be classified as a BCS class I. Hence paracetamol meets the requirement of a BCS-based biowaiver. Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 7/17

8 Assessor s comments: WHO has a classification of several active substances, however the support of this is not well substantiated. This is also the case for paracetamol. The paracetamol monograph by Kalantzi et al. 1 indicates that paracetamol should be considered a BCS Class III drug based upon a criteria of > 90% bioavailability. It should be noted here that the EMA criteria is > 85% bioavailability, but as Kalantzi does not specifically indicate the cut-off value obtained in their research, it remains unclear that bioavailability/absorption after oral administration of tablets can be considered > 85%. Indeed, references indicate absolute bioavailabilities ranging from 62-89%, or urinary recovery data ranging from %. Rawlings et al. 2 studied the absolute bioavailability of paracetamol after administration of an i.v mg dose and a 500, 1000 and 2000 mg oral dose (Panadol tablets) in 6 healthy subjects. The results of this study is shown below in the figures and tables below. Table Table Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 8/17

9 These data indicate that the absolute bioavailability was 63% after the 500 mg oral dose, 89% after the 1000 mg oral dose and 87% after the 2000 mg oral dose. This is in line with the results obtained by Clements et al. 3 in which 5 subjects received a 5 and a 20 mg/kg oral and i.v. dose. Absolute bioavailability was about 80%. In addition, urinary excretion data showed that absorption was complete (see table below). The study showed also that after i.v. and oral dosing there was no clear impact on the sulphate conjugation, implying that sulphate conjugation occurs systemically and not in the intestine/gut wall. Table Table Further support is obtained from Eandi et al. 4 showing an absolute bioavailability of 60 70% and from Tukker et al. 5 showing an absolute bioavailability of 54 90%. In addition, Tukker et al. 5 showed also that excretion after oral administration was almost complete (88 100% of the dose; see table below). This was also indicated by Goicoechea et al. 6, however, the obtained values were a little lower (70 76% recovery). Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 9/17

10 Table Almost complete excretion after oral dosing was confirmed by Lau 7. After an 20 mg/kg oral dose to 14 healthy subjects, urinary recovery was 94.2 ± 15.4%, of which paracetamol 5.6 ± 1.6%, glucuronide metabolite 54.8 ± 8.9% and sulphate metabolite 33.7 ± 8.0%. 1 Kalantzi et al. J Pharm Sci 95, 4-14 (2006) 2 Rawlings et al. European J. Clinical Pharmacology 11, (1977) 3 Clements et al. Britisch J. Clin. Pharmacology 18, (1984) 4 Eandi et al. Arzneim.Forsch/Drug Res. 34(II) 8, (1984) 5 Tukker et al. Pharmaceutisch Weekblad Scientific Edition 8, (1986) 6 Goicoechea et al. European J. Drug Metab. Pharmacokinet. 23, (1998) 7 Lau G., Metabolic Act. of drug and other xenobiotics in hepatocellular carcinoma, page 82. Chinese Universty Press ISBN (1997) Overall, the data showed that paracetamol has a high absolute bioavailability. Urinary recovery showed almost complete recovery of paracetamol and its metabolites. The latter were not formed in the intestine, but after absorption. Sufficient proof has been submitted that bioavailability of paracetamol after oral administration is more than 85%. Based on the available evidence, paracetamol is a BCS Class I drug, having a high permeability and high solubility. B. Characteristics related to the medicinal product In vitro dissolution Comparative in vitro dissolution testing between the Paracetamol 1000mg strength vs Panadol 1000mg (UK GSK) was performed at ph 1.2, 5.8, and 6.8 with the following conditions:. Dissolution test Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 10/17

11 Equipment: Paddle apparatus as described in BP edition in force Dissolution media: I. 0.1 M hydrochloric acid (ph = 1.0) II. phosphate buffer (ph = 6.8) III. phosphate buffer (ph = 5.8) Volume of dissolution: 900 ml Paddle speed: 50 rpm Temperature: 37 ± 0.5ºC. Sampling times: 5, 10, 15, 20, 25, 30 minutes Analysis: UV-Visible spectrophotometer Shimadzu (UV-2450) The results showed that Paracetamol Pharmacin 1000 mg tablets and Panadol Tablets 1 g released more than 85% of the paracetamol within 10 minutes in all dissolution media. The Applicant concluded that requirement of 85% release within 15 minutes for a biowaiver is met. Assessor's comment: Paracetamol 1000 mg tablet and the reference product Panadol 1000 mg tablet showed a solubility of more than 85% within 15 minutes in the different dissolution media (ph 1.2 in 0.1N HCl. ph 5.8 and 6.8 in phosphate buffer). However, a biowaiver cannot be granted. Similarity is not adequately demonstrated as dissolution data at the required physiologically relevant ph 4.5 in acetate buffer is lacking. This data should be provided. (PSRPH) See LoQ Excipients The composition of the test and reference product are shown below: Table Test product: Paracetamol 1000 mg tablets Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 11/17

12 The Applicant is of the opinion that the excipients included in the composition of the medicinal product are well-established and no interaction with the pharmacokinetics of the active substance is expected. As no atypically large amounts of known excipients or new excipients were used, no additional documentation has been submitted. Table Reference product, Panadol Tablets 1 g, GSK, UK DELETED Assessor s comments: According to the Guideline on the Investigation of Bioequivalence (Appendix III BCS-based Biowaiver), for BCS Class I drugs excipients should be well-established and applied in usual amounts in the formulation. Furthermore, excipients that might affect bioavailability should be qualitatively and quantitatively the same. It is agreed that the excipients are well-known and used in normal quantities. Moreover, no excipients are used in both Reference and Test that might affect bioavailability. Overall Conclusion A biowaiver can not be granted as similarity between the test and reference product has not been adequately demonstrated. Dissolution data at the physiologically relevant required ph 4.5 in acetate buffer is lacking. This is considered to be a PSRPH PHARMACOKINETIC STUDY N.A PHARMACODYNAMIC STUDIES N.A ADDITIONAL DATA N.A Post marketing experience No post-marketing data is available. The medicinal product has not been marketed in any country Benefit-Risk assessment Paracetamol is a long-standing drug and its safety/efficacy profile and use are wellestablished. In principle, a BCS-biowaiver is applicable to paracetamol based on the following: Paracetamol 1000 mg tablets are immediate release, solid pharmaceutical forms for oral administration and systemic action. Paracetamol is not a narrow therapeutic index drug Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 12/17

13 Paracetamol is a BCS Class I drug, i.e. high permeability and high solubility The excipients used in the tablet formulation are partly comparable to the excipients used in the Reference formulation. The other excipients are used in normal quantities and are considered not to affect bioavailability. However, dissolution data at the physiologically relevant required ph 4.5 in acetate buffer is lacking. Hence, a biowaiver can not be granted as similarity between the test and reference product has not been adequately demonstrated. This is considered a PSRPH. 4. PHARMACOVIGILANCE 4.1. Pharmacovigilance system 4.2. Risk management plan PART I PRODUCT OVERVIEW The Applicant submitted a risk management plan, dated November 2012, version 1.0., which follows the format of the guideline on GVP Module V Risk Managemnet Systems. As this concerns an application under Article 10(1) of Directive 2001/83/EC, RMP Modules SI-SVII are not required. Assessor s comments: Agreed PART II - SAFETY SPECIFICATION Module SVIII Summary of the safety concerns The Applicant refers to the SmPC and PIL of the product, which have been aligned with approved SmPC and PIL of other paracetamol 1000 mg tablets products that are registered in the Netherlands in 2010 and Furthermore, the Applicant indicates that if and when any new safety concerns for Paracetamol 1000 mg tablets, requiring action other than labeling changes, are made publicly available, the RMP needs to be revised to include them under this subsection. Assessor s comments: A summary of the main safety concerns is mandatory. The following considerations should be taken into account for a summary of the main safety concerns: - The core RMP for paracetamol solution for infusion products - The current knowledge on safety issues for paracetamol - The product s strength (1000 mg instead of the common 500 mg) - The indication which is for adults and adolescents only, weighing 43 kg - The proposed supply status in the Netherlands which is supply by pharmacies only Taking these considerations into account, the safety concerns stated in table below should be included in the RMP Table Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 13/17

14 Important identified risks Important potential risks Hepatotoxicity/ abnormal liver function (Patients with pre-existing liver disease, chronic alcoholism, malnutrition, dehydration, underweight adults) Overdose (non-intentional and intentional) Interaction with anticoagulants Interaction with enzyme inducers Medication overuse headache Important missing information Off-label use (patients younger than 12 years of age, adolesents with small body weight) Medication errors In case the Applicant wishes to include further important risks, a thorough scientific justification should be submitted. See LoQ PART III PHARMACOVIGILANCE PLAN The Applicant states that other than the need for 3 yearly PSUR for the reference listed drug no additional pharmacovigilance activities recommended for the same are available in the public domain. As per the PSUR synchronization list of September 2012, routine PSURs for this product need to be submitted. The data lock point for this product is May 1st 2012 and the PSUR will be submitted before 90 days of the next data lock point. Assessor s comment: It is agreed that routine pharmacovigilance is currently considered sufficient for paracetamol 1000 mg tablet formulations as for the reference product no additional pharmacovigilance measures are in place. It should be noted that 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 on the EURD list. As indicated by the current EURD list published October 2012, no routine PSURs need to be submitted for paracetamol (non IV formulations). However, this should not refrain the company from performing other routine pharmacovigilance measures such as screening of the literature, signal detection etc. The Applicant is asked to update part III of the RMP accordingly. See LoQ PART IV PLANS FOR POST- AUTHORISATION EFFICACY STUDIES The Applicant indicates that the information as to whether efficacy studies have been imposed as a condition, if recommended for Paracetamol 1000 mg tablets, is not available in the public domain and hence currently no information is provided in this section. If and when the additional efficacy studies for Paracetamol 1000 mg Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 14/17

15 tablets tablets is made publicly available, the RMP needs to be revised to include them under this section, if required. Assessor's comment: The reference medicinal product does not have any efficacy studies imposed as a condition of the marketing authorisation, hence this section may be omitted as indicated in Module V of the guideline on GVP PART V - RISK MINIMISATION MEASURES With respect to routine risk minimisation measures the Applicant refers to the following: - The SmPC, which should be and remain in line with reference texts. - The PIL, which should be user tested. - Braille texts on the carton packaging to minimise risk in visually impaired patients - Blister packaging of tablets in 18, 20, 30, 40 and 100 tablets. Any new packs proposed in future need to be evaluated as to whether any special risk minimization measures are required for them. - Legal status of supply of not subject to medical prescription. There are no other conditions or restrictions with regard to the safe and effective use for this product. No additional risk minimisation activities are in place for other paracetamol 1000 mg tablets, hence no additional risk minimization activities are required for the current product. No format of the risk minimisation plan is included. The evaluation of effectiveness of risk minimization activities is currently not applicable since this is the first version of the RMP. Summary of risk minimisation measures: Keeping the SmPC & PIL in line with the reference texts. Ensuring that the proposed pack sizes are acceptable as per dosing regimen. Maintaining the legal basis of the product in line with that of reference drug product. Assessor s comment: It should be noted in part V of the RMP that paracetamol 1000mg tablets are only allowed to be sold by pharmacies without a prescription. Hence, this is a restriction to the not subject to medical prescription status. See LoQ It should be noted that this section of the RMP, particularly the format of the risk management plan, should be amended to include the important identified and potential risks as well as important missing information as indicated above with respect to the safety specification. See LoQ PART VI: SUMMARY OF ACTIVITIES IN THE RISK MANAGEMENT PLAN BY MEDICINAL PRODUCT RMP part VI section Format and content of the summary of the RMP Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 15/17

16 The Applicant proposes the safety concerns as summarizes in table Table The Appicant indicates that further details in this section are to be written after requirements and formats are published on EMA s website. Assessor s comment: It should be noted that for some subsections of RMP part VI, Module V of the guideline on GVP does include adequate guidance. Of note, currently this section does not include any safety concerns. This section should be amended to include the safety concerns as indicated above at the safety specification. See LoQ Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 16/17

17 5. LIST OF QUESTIONS AS PROPOSED BY THE RMS Non-clinical aspects Potential Serious Risks to Public Health Not applicable. Points for Clarification Not applicable. Clinical aspects Potential Serious Risks to Public Health 1. Similarity between the test and reference product has not been adequately demonstrated as dissolution data at the physiologically relevant required ph 4.5 in acetate buffer is lacking. This data should be provided. Points for Clarification 1. The following safety concerns should be included in the RMP: Important identified risks Important potential risks Hepatotoxicity/ abnormal liver function (Patients with pre-existing liver disease, chronic alcoholism, malnutrition, dehydration, underweight adults) Overdose (non-intentional and intentional) Interaction with anticoagulants Interaction with enzyme inducers Medication overuse headache Important missing information Off-label use (patients younger than 12 years of age, adolesents with small body weight) Medication errors Part II, V and part VI of the RMP should be amended to include the listed safety concerns. 2. As indicated by the current EURD list published in October 2012, no routine PSURs need to be submitted for paracetamol (non IV formulations) medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC. However, the company should perform other routine pharmacovigilance measures such as screening of the literature, signal detection etc. The Applicant is asked to update part III of the RMP accordingly. 3. Part V of the RMP should be updated to include the restriction to the status not subject to medical prescription which in the Netherlands limits Paracetamol Pharmacin 1000mg tabletten only to be sold by pharmacies without a prescription, as per current practise. Paracetamol Pharmacin, NL/H/2791/001/DC Day 70 PrAR-NC+C Page 17/17