An Investigation of Cefadroxil and Meropenem's Supply Chain and Estimation of the Health Economic Consequences in Sweden Due T

Independent project in Chemical Engineering Spring 2020 in cooperation with PLATINEA Supervisors: Enrico Balardi, Petter Forsberg and Simone Callegari Uppsala University contact: Gérman Salazar Alvarez Independent project number (Exjobbsnr.): MAT-VET 20007

An Investigation of Cefadroxil and Meropenem’s Supply Chain and Estimation of the Health Economic Consequences in Sweden due to Shortage

Christine Attemalm Jonathan Efverström Dania Elkhalifa Viktor Hansen Yasmine Sundelin Tjärnström

2020-06-24 Abstract

Sweden has been increasingly affected by drug shortage and the public healthcare system has iden- tiﬁed a large amount of antibiotics risking shortage. Drug shortage of antibiotics is a worldwide problem with complex causes and consequences affecting many countries healthcare systems. The aim of this study is to investigate the shortage of cefadroxil and meropenem. More speciﬁcally, to investigate risk factors in the supply chain contributing to their backorders as well as possible consequences for Swedish healthcare due to shortage.

To formulate the supply chain for cefadroxil and meropenem, the active pharmaceutical ingredient (API) manufacturers, final dosage form (FDF) holders and market authorization holders (MAHs) were identified. 4 active API manufactures, 18 active FDF holders and 4 MAHs were identified for cefadroxil and 4 active API manufactures, 32 FDF holders and 8 MAHs were identified for meropenem. In order to analyse the causes behind these antibiotic shortages, problems with the manufactures were researched using various sources. Since API production is the first step in the supply chain, problems connected to the API manufactures was the sole focus in this study. Re- search identified several problems with the API manufacturers for both antibiotics, indicating that the shortages can in fact be explained by issues in the supply chain.

In order to calculate and get an estimate of the health economic costs for society, a model based on direct and indirect costs was used. The direct costs were calculated by comparing the most suitable alternative treatment methods. For cefadroxil there were 5 alternatives in the case of shortage for the oral suspension from Mylan AB (the only product covered in this section of the report due to limited data), whereof 3 of the alternatives still were cefadroxil products. These 3 were cefadroxil dispersible tablets, cefadroxil capsules and Grüncef. The other 2 alternatives were Clindamycin and the combination antibiotic Trimethoprim/Sulfamethoxazol (Eusaprim R ). Meropenem had only one identiﬁed alternative drug called imipenem. In addition to comparing alternative treatments, the cost of extra labor hours spent on dealing with shortages as well as the increased risk of AMR was also also investigated closely. The indirect costs were based on loss of production due to patient care being longer and more demanding as a result of unforeseen side effects caused by the alternative treatments. This was analyzed qualitatively, in other words no deﬁnitive cost was calculated for loss of production.

Results showed that the exchange from Cefadroxil Mylan oral suspension to cefadroxil dispersible tablets would cost Sweden approximately +35 105 SEK/day. The exchange to cefadroxil capsules would cost -30 939 SEK/day and for Grüncef the cost would be +311 814 SEK/day. As for the other 2 antibiotics, the cost would be -23 103 SEK/day for Clindamycin and -53 084 SEK/day for Eusaprim R . When exchanging meropenem for imipenem, the direct cost was estimated to +343 299 SEK/day. Regarding the cost for extra labor hours spent on dealing with shortage, this was estimated to 1.6 MSEK per shortage, regardless of the antibiotic and shortage duration. The costs calculated for the replacement pharmaceuticals were based on worst case scenarios for when all MAHs had their products unavailable. If the calculated values are of any relevance for real life situations depends on the fragility of the supply chain. In other words, how big these health economic consequences are for Swedish healthcare is dependant on the risk of unavailability for these antibiotics which goes back to the fragility of the supply chain.

ii In regards to AMR, research showed that substituting cefadroxil for clindamycin and meropenem for imipenem increased the risk of AMR and as a consequence, the direct cost increased as well. The use of clindamycin to treat infections caused by Methicillin-Resistant Staphylococcus Aureus (MRSA) could lead to an additional cost of +3665 SEK/outpatient visit in the case of induced resistance against the antibiotic. Substituting meropenem for imipenem would result in an additional cost of +1160 SEK/day assuming that the bacteria behind the infection is ESBLcarba, an Enterobacteriaeac able to break down carbapenems (a class of antibiotics in which meropenem and imipenem reside). Using licensed drugs could minimize this risk but would however come at a cost for the patients health due to the extended lead time as a result of importation. This would in turn increase the indirect cost to society in the form of loss of production. Despite maybe lowering the risk of AMR, the calculated costs for shortage/day show that using licensed drugs would in fact increase the direct cost a great deal. The calculations for Grüncef and imipenem illustrate this as they proved to be much more costly than the other alternative treatments.

iii Abbreviations

AMR: Antimicrobial Resistance

API: Active Pharmaceutical Ingredient

CEP/COS: Certiﬁcation of suitability of European Pharmacopoeia monographs/Certiﬁcate Of Suit- ability

EDQM: European Directorate for the Quality of Medicines

EEA: European Economic Area

EMA: European Medicines Agency

ESBLcarba: Enterobacteriaceae producing extended Spectrum Beta Lactamase with the ability to break down carbapenems

EU: European Union

FASS: "Farmaceutiska Specialiteter i Sverige" (Pharmaceutical Specialities in Sweden)

FDA: U.S. Food and Drug Administration

FDF: Finished Dosage Form

GMP: Good Manufacturing Practice

MAH: Market Authorization Holders

MIC: Minimum Inhibitory Concentration

MRSA: Methicillin-Resistant Staphylococcus Aureus

PHAS: The Public Health Agency of Sweden

QALY: Quality Adjusted Life Years

Trim-Sulfa: Trimethoprim/Sulfamethoxazole

WHO: World Health Organisation

iv Contents

1 Introduction 1

2 Background 2 2.1 Supply Chains ...... 2 2.2 Backordering, Deregistrations, and ’Currently not provided’ Antibiotics ...... 3 2.3 Antibiotic Shortage and Consequences to Society ...... 4 2.4 Cefadroxil and Meropenem ...... 4

3 Method 5 3.1 Literature Study ...... 5 3.2 Models used to Calculate Health Economic Costs ...... 5

4 Research, Results and Discussion 6 4.1 Availability and Supply Chain ...... 6 4.1.1 Cefadroxil ...... 6 4.1.1.1 Availability ...... 6 4.1.1.2 Supply Chain ...... 8 4.1.1.3 Identiﬁed Problems with Manufacturers as Plausible Cause for Backorders ...... 9 4.1.2 Meropenem ...... 10 4.1.2.1 Availability ...... 10 4.1.2.2 Supply Chain ...... 12 4.1.2.3 Identiﬁed Problems with Manufacturers as Plausible Cause for Backorders ...... 13 4.2 Health Economic Evaluation and Consequences on Society ...... 14 4.2.1 Direct Cost ...... 14 4.2.1.1 Cefadroxil ...... 15 4.2.1.2 Meropenem ...... 21 4.2.2 Indirect Cost - Loss of Production due to Unforeseen Side Effects . . . . . 23 4.3 Limitations ...... 24 4.4 Improvements and development ...... 24

5 Conclusions 25

Bibliography 26

Appendices 33

v A List of FDF Holders (Secondary manufacturers) 34 A.1 Cefadroxil ...... 34 A.2 Meropenem ...... 35

B Companies Currently Manufacturing the FDF 37 B.1 Cefadroxil ...... 37

C MAHs in EEA 38 C.1 Cefadroxil ...... 38 C.2 Meropenem ...... 38

D Supporting Documents for Health Economic Calculations 39 D.1 Cefadroxil ...... 39 D.2 Meropenem ...... 40

E Calculations 42 E.1 Cefadroxil ...... 42 E.1.1 Conversion Between Volume and Mass ...... 42 E.1.2 Amount of Cefadroxil Capsules ...... 42 E.1.3 Amount of Clindamycin Capsules ...... 42 E.1.4 Amount of Eusaprim R ...... 43

vi Acknowledgements

Thank you to PLATINEA for giving us an interesting and important mission and thanks to our supervisors Enrico Baraldi, Petter Bertilsson Forsberg and Simone Callegari for providing us with information and assisting us with the thesis.

We would also like to thank Håkan Hanberger, infectious disease specialist at Linköping Univer- sity, for providing data used in this report regarding the direct cost of drug shortages in Sweden. Also, a big thanks to Magnus Munge, head of the pharmaceutical unit at region Kronoberg, for helping us by providing information regarding prices for meropenem products.

Thank you to Elin Svedlin at FASS for sharing general information about backorders and what it means for a drug to be currently not provided.

To Alberto Giannessi, Director of International Business Operations at ACS Dobfar S.p.A, thank you for providing us with information on the supply chains making it possible to draw some conclusions in this report.

Last but not least, we want to thank Thomas Grenholm Tängdén and Josef Järhult, medical doctors at Uppsala University and Fredrik Resman, infectious disease specialist at Lund University; for providing information regarding the alternative treatment methods to cefadroxil and meropenem. We must also, once again, thank Håkan Hanberger for assisting us with similar information regarding the alternative treatments.

vii 1. Introduction

Antibiotic shortage is a serious problem on a global scale and affects many factors in a healthcare system. It contributes to lower quality of healthcare for the individual patient, unnecessary strain of healthcare providers’ resources, and increasing risk for antibiotic resistance. The main reason behind the occurrence of antibiotic shortages is the economic aspect. This is caused by different factors such as longer and more complex supply chains and deﬁcient quality control of manufacturing methods. All these factors contribute to economic issues that can result in antibiotic shortage. One important factor in Sweden is its relatively small market of antibiotics. This leads to most antibiotics purchased by Sweden being foreign products, making the supply chain longer and less controllable. Consequences due to these longer supply chains are additional risk factors in terms of delays or accidents in production, increasing the risk of antibiotic shortage. [1]

Sweden has increasingly been affected by deficiencies in the availability of antibiotics. In 2017, the Public Health Agency identified a list of 34 essential antibiotics risking shortages in Sweden. In recent years, specific essential antibiotics from the Public Health Agency’s list have been backordered or deregistered, which has consequences for the Swedish healthcare. When mapping the supply chain of antibiotics, two major problems are the complexity of the network and classified information. PLATINEA is a collaboration platform with 15 partners from academia, authorities, industry and healthcare. The aim with the platform is to help preserve and enhance the value of existing antibiotics while also trying to secure access to those antibiotics that are risking shortage in Sweden. PLATINEA have in 2019 conducted a number of studies to understand why deficiencies in the availability of specific antibiotics occur and what types of general risk factors are underlying these shortcomings. PLATINEA now want to expand and further build on what they already know about antibiotic supply chains and consequences of unavailable antibiotics for Swedish healthcare. In order to have the ability to contribute with constructive solutions for the Swedish healthcare, they need a greater understanding of previously backordered antibiotics in the Swedish market.

The aim of this project is to identify the supply chain for the two essential antibiotics cefadroxil and meropenem, in order to investigate possible risk factors contributing to their backorders. In addition, this project will aim to predict the health economic consequences for Swedish healthcare due to shortages of these antibiotics. In this report the following questions will be addressed:

1. What does the supply chain look like for cefadroxil and meropenem?

2. Can the occurrence of backorders be explained by inefﬁciency in the supply chain?

3. What health economic consequences can be estimated to arise due to shortages of these two antibiotics?

1 2. Background

2.1 Supply Chains

Most European countries use outsourcing strategies since local manufacturing of APIs isn’t usually the most beneficial option. Outsourcing strategies entails that the suppliers chose to manufacture their APIs and FDFs outside the country in which they will be sold. In regards to Sweden, the more accurate term would be offshoring since Sweden (more specifically, the Swedish healthcare system) is considered to be a buyer and not a supplier. As a buyer, Sweden depends on other countries for most of its API and FDF production. Although outsourcing has brought benefits regarding costs, it has made the chain more complex and geographically widespread, making it more difficult to formulate. And confidentiality agreements between pharmaceutical companies has made the chain more diffuse for buyers, who as a result of this are unable to see potential issues resulting in shortage at their stage of the chain [2].

However, there are certain actors that exist in the typical supply chain for almost any pharmaceutical drug. The first actor being the API manufacturer. Most drugs have several API manufacturers which is beneficial in times of shortage. In general, API manufacturers are usually concentrated in a limited amount of countries and this leads to accessibility issues if any problems were to occur in any of the manufacturing sites. This means that the supply chain and it’s fragility is affected by the number of API manufacturers and their geographic location. The next important actor is the FDF holder. Production of the FDF includes additional chemical processes since it is here that the API is combined with excipients. Since this step includes a variety of processes dependant on the desired form of the FDF, the number of production sites often exceed the number of API manufacturing sites [3]. The FDF then reaches a MAH. The MAH is the company responsible for marketing the final product to hospitals and pharmacies where consumers of the drug gain access.

It is important to mention that some MAHs market drugs parallel imported from other countries. It is common between countries in the EEA, that drugs are marketed and sold in countries other than the one it was originally manufactured and released in. The driving force behind parallel importation of drugs is the economic benefit. Since medical prices vary depending on the country’s market conditions, companies can purchase a drug from a country with cheaper prices and then sell it for a higher price. In Sweden, parallel imported drugs must be repackaged by an approved Swedish re-packager and re-labelled with Swedish labelling before being sold on the Swedish market [4] [5]. Similar to the API manufacturers, a limited amount of MAHs confined to only a few countries can also lead to accessibility issues in the supply chain. After the product is marketed, the distribution process begins and the drug reaches a distribution center. The drug is then ready to be commercialized to hospitals and pharmacies. This commercialization is usually done through a wholesaler or retailer, which is a company selling the drug in larger quantities. These are the final actors in the typical drug supply chain [6].

2 Figure 2.1: The typical supply chain structure for a pharmaceutical drug,

Regarding end buyers and users, there are 21 decentralized political bodies in Sweden referred to as ’regions’ which are responsible for ﬁnancing and providing healthcare in their respective geographic regions. [7] The regions are the end-buyer in the supply chain of pharmaceuticals for inpatient care and negotiate pharmaceutical prices with MAHs. The pharmacies are the end-buyer for pharmaceuticals in outpatient care. The regions admit considerable leeway in operation which causes for substantial variation in terms of healthcare structure meaning that antibiotic purchase, storage, and usage may deviate from one region to another. In 2017, the Public Health Agency of Sweden conducted a report where storage and distribution methods of antibiotics were researched. The report concludes that antibiotics with a small degree of usage isn’t procured in large quantity by the regions. Neither are volume commitments made from the regions to MAHs, which makes it difﬁcult for MAHs to plan production. Consequently, these antibiotics are risking stock shortages in the long run if supply or demand rapidly changes. [8]

2.2 Backordering, Deregistrations, and ’Currently not provided’ Antibiotics

The backordering of a product means that the MAH stops delivering the product for a longer period of time. The problem can relate to several reason in the supply chain network. The reasons can be anything from manufacturing problems related to the API and FDF or unforeseen high demand of the product. From low accessibility, shortage in medicine arises if the backordered or unavailable drug is not easily replaced. [9] A drug’s low accessibility can also be a result of deregistration which means the complete cancellation of sales by the MAH. "Phasing out" is a concept recommended by the Swedish Medical Products Agency that guarantees this low accessibility prior to deregistration. This is to ensure that no product is left in the Swedish market once the deregistration date has been reached. The most common reason for deregistration of a medical product is low proﬁt. The Swedish Medical Products Agency is notiﬁed of all backorders and gives information regarding possible replacements [10]. In addition to backordering and deregistration, a drug can be ’currently not provided’ by the MAH. This status entails that the drug is no longer available for pharmacies or hospitals to order. Reasons for not providing a drug are most of the time related to the current market situation, according to Elin Svedlin from FASS. For example, if a drug is low on sales and the approval for deregistration is delayed, the status of a drug is changed to "currently not provided". This means that the remaining products left in stock is approved for sale, up until that approval has been ceased. It also happens that companies provide several similar products, therefore they list one product as "currently not provided" because an improved version is on it’s way to the market.

3 2.3 Antibiotic Shortage and Consequences to Society

When drug shortages occur, there are actions that the Swedish Medical Products Agency can take in order to salvage the situation. The ﬁrst response is usually to try and see if any replacement pharmaceuticals are available and if not, the agency tries to see if other drugs with similar effects can be prescribed. If both of these options don’t pan out and the agency cannot solve the drug shortage problem using drugs available in the Swedish market, dispensation or licensing is considered. Dispensation entails that an importer seeks approval from the agency to import the same drug from a foreign country while licensing means to seek permission to sell a drug not approved in Sweden. It is then up to the agency to approve or deny the request for dispensation or licensing. [11]

Despite these options that might seem like solutions, drug shortages is an issue for both hospitals and pharmacies in Sweden and the rest of Europe. Approximately 19% of the drug shortages occurring in Europe are antibiotics [12]. However this number covers not only antibiotics but also antiviral drugs and other antimicrobial agents. This issue of antibiotic shortage has put a strain on everyone working in the healthcare sector. Doctors and pharmacists must find a replacement for the antibiotic in shortage which can lead to delayed treatment for the patient, and the administrative staff must investigate the supply chain in order to identify possible disruptions [13]. Besides the fi- nancial consequences and additional labour hours, antibiotic shortage is a contributing factor to the rise of AMR since substituting antibiotics for sub-optimal alternatives can lead to resistance. AMR is a growing problem as it decreases the effectiveness of antibiotics leading to lingering infections possibly resulting in death for the patient. As a result of this, more time and money is spent on finding effective alternative treatments able to combat the bacteria that have developed resistance.

When estimating the cost of antibiotic shortage to society one can differentiate between the direct and indirect costs. Direct costs include additional fees due to the pricier alternative treatment methods, prolonged treatment time for the patient, extra labour hours spent dealing with shortage and increased risk for AMR. The indirect costs include loss of production for the patient due to absence from work, side effects arising from the alternative treatment methods and possible adjustments made to the treatment strategy [14].

2.4 Cefadroxil and Meropenem

Both cefadroxil and meropenem are broad-spectrum antibiotics used however for slightly different indications. Cefadroxil is often used to treat inﬂammations like tonsillitis and pharyngitis as well as infections such as urinary tract infections and post-surgical infections. Meropenem on the other hand is used to treat diseases such as sepsis, respiratory tract infections and bacillus infections [15] [16]. Cefadroxil is provided as tablets, dispersible tablets, capsules and powder for oral suspension while meropenem is provided solely as an intravenous injection. Cefadroxil is mostly utilized in outpatient care while meropenem is more common in inpatient care. These antibiotics belong to different classes, cefadroxil is a ﬁrst-generation semi synthetic cephalosporin meanwhile meropenem is a synthetic carbapenem. Both antibiotics possess beta lactam rings, making them

4 very similar to penicillin [17]. Unlike penicillin, these antibiotics target a larger group of bacteria. 3. Method

3.1 Literature Study

This literature study investigated why the antibiotics cefadroxil and meropenem received low accessibility in the Swedish healthcare system and what health economic consequences this has had for Sweden and Swedish healthcare providers. The study also attempted to identify risk factors in the supply chains, possibly causing the backorders. Attempts were made to gather as much information as possible from healthcare providers, and research studies were done to investigate the clinical and ﬁnancial effects of the shortages of cefadroxil and meropenem.

In order to gather information about API manufacturers and FDF holders, as well as their geograph- ical location www.pharmacompass.com was used. This website also granted insight into which API manufacturers had the necessary CEP/COS certificates granting them permission to reach the EU. Since this project is focused on Sweden, this information was relevant. Further research was then conducted with the help of www.edqm.eu/en/. EDQM and Pharmacompass provided similar information which was helpful when needing to confirm its accuracy. More specific information about the API manufacturers and FDF holders were found through their websites. Information on the MAHs located in Sweden was found through www.FASS.se and www.lakemedelsverket.se/, which is the Swedish Medical Products Agency’s database. The number of MAHs in the EEA were found through the European Medicines Agency’s website www.ema.europa.eu/en. These three databases, specifically the Swedish Medical Products Agency’s website, were also used to look into which specific products of cefadroxil and meropenem (tablets, capsules etc.) were backordered and their issue dates. Using these databases, a supply chain more specific to each antibiotic was constructed. When researching antibiotic shortage, articles written by multiple corporations were used. The Public Health Agency of Sweden provided data on the cost of antibiotic shortages and the cost of antibiotic consumption. Articles by the FDA provided additional information on drug shortages and possible strategies that can be utilized in order to gain economic stability after a shortage has occurred. Most of the articles and data specific to cefadroxil and meropenem was provided by Simone Callegari at Uppsala University and PLATINEA.

3.2 Models used to Calculate Health Economic Costs

To calculate the health economic costs for the shortages of cefadroxil and meropenem, models were used to calculate the direct and indirect cost for society. To calculate the direct costs, the prices of alternative treatment methods, meaning the prices for replacement pharmaceuticals, was investigated and compared to the original treatment method using cefadroxil and meropenem. This was done using data provided by PLATINEA that stated the number of units sold between the years of 2013-2018. Using this data while comparing the prices of cefadroxil and meropenem to their alternative treatmens, the direct cost was calculated. In addition, the cost of extra labour hours spent on dealing with shortage, the increased risk for AMR and its cost, as well as the possibility of prolonged treatment time for the patient was investigated. To estimate the indirect costs, loss of production was considered. In order to do this, side effects of the alternative drugs were researched

5 since they can lead to prolonged sickness resulting in the loss of production for society.

4. Research, Results and Discussion

4.1 Availability and Supply Chain

4.1.1 Cefadroxil

4.1.1.1 Availability

Regarding the powder for oral suspension, as early as 2012, the sales for Sandoz and Mylan began to alternate. This means that when sales were low for one, they were higher for the other. The low sales might have be due to temporary shortages, but at the start of 2017 both of these sales dropped. That both companies had a dip in sales at the same time indicates that the shortage was not caused by an unpredicted rise in sales. [18] There are 5 FDF holders currently manufacturing this ﬁnal dosage form (see appendix B.1).

The capsules sold by Mylan that are now available, experienced a short backorder this year and in 2019. Both backorders in 2020 and 2019 lasted for approximately 3 months. [10] As of now, there are 15 FDF holders currently producing the 500 mg capsules (see appendix B.1). The tablets from Sandoz have recently been backordered according to the Swedish Medical Prod- ucts Agency but FASS states they are still "currently not provided" [19]. The tablets from Mylan are also "currently not provided" according to FASS. There are currently only 3 FDF holders manufacturing the 1 g tablets. Judging from the status of both the Mylan and Sandoz 1g tablets, as well as the powder for oral suspension, one can conclude that these dosage forms are completely unavailable in Sweden since equivalent products are not provided by any other MAHs.

The soluble tablets sold by PharmaSwiss which are currently available, haven’t always been. The drug experienced a short backorder in late 2019 lasting for approximately 3 months [20]. No information about FDF holders for the 1 g dispersible tablets were found suggesting that appendix A.1 and appendix B.1 are incomplete.

6 Table 4.1: List of cefadroxil products sold in Sweden and their availability as of May 20th 2020. [19] [20]

Product and Active Dosage Formula Availability MAH Ingredient Estimated backorder Cefadroxil Cefadroxil Powder for oral duration: 2017-08-24 to 100 mg/ml Mylan monohydrate suspension 2020-08-01 (updated: 2020-06-10) Cefadroxil Cefadroxil 1 g Tablet Currently not provided Mylan monohydrate Available. Backordered: Cefadroxil cefadroxil 500 mg Capsule 2020-01-13 to Mylan monohydrate 2020-04-23 Cefadroxil Cefadroxil Powder for oral 100 mg/ml Currently not provided Sandoz monohydrate suspension Currently not provided. Cefadroxil Cefadroxil Backordered: 1 g Tablet Sandoz monohydrate 2019-01-02 to 2020-04-22 Cefadroxil Cefadroxil 500 mg Capsule Available Sandoz monohydrate Available. Backordered Cefamox Cefadroxil Dispersible 1 g 2019-08-16 to PharmaSwiss anhydrous tablet 2019-11-18 Cefamox Ebb Medical AB, Cefadroxil Dispersible 1 g Available parallel imported anhydrous tablet from Poland

7 4.1.1.2 Supply Chain

Table 4.2: List of Cefadroxil API-manufacturers with CEP certiﬁcates. [27]

Geographic location Substance Certiﬁcate Holder (number of Issue Date Status manufacturing sites) Ranbaxy 2003-12-18 Cefadroxil Laboratories Withdrawn India (End Date: monohydrate Limited IN 110 019 by holder 2004-03-11) New Delhi China, Croatia, Czech Teva Republic, India (3), Cefadroxil Pharmaceuticals Israel (2), Italy (5), 2011-09-08 Valid monohydrate USA, Inc. US Hungary (2) & 65265 Mexico Mexico [21] Aurobindo Pharma Cefadroxil Multiple sites in Limited IN 500 038 2017-12-13 Valid monohydrate India [22] [23] Hyderabad Centrient China (2), India, Cefadroxil Pharmaceuticals Mexico, Netherlands 2019-03-21 Valid monohydrate Netherlands B.V. & Spain [24] NL 2613 AX Delft Cefadroxil ACS Dobfar S.p.A Italy (9) [25] 2019-08-16 Valid monohydrate IT 20067 Tribiano Orchid Pharma Cefadroxil Limited IN 600 034 India [26] 2016-06-30 Valid monohydrate Chennai

Since cefadroxil is an outsourced drug, primary manufacturing takes place in countries outside of Sweden. There are a total of ﬁve API manufacturers with CEP/COS certiﬁcates meaning that they are approved by EU medical guidelines (see table 4.2). Ranbaxy Laboratories CEP was withdrawn in 2004 so they are not considered relevant for this report. Teva API do not currently manufacture cefadroxil according to their website [28], this leaves 4 API manufacturers currently manufacturing cefadroxil; Aurobindo Pharma, Centrient Pharmaceuticals, ACS Dobfar and Orchid Pharma. Au- robindo Pharma has multiple factories in India and international subsidiaries. It is unclear which of them manufacture the API.

Secondary manufacturing includes the production of the FDF. Cefadroxil has 34 FDF holders with 2 of them located in Sweden (Mylan AB and Sandoz GmbH). The larger number of secondary manufacturing sites is expected since cefadroxil is sold in several ﬁnal dosage forms requiring different production equipment. The list with 34 FDF holders is incomplete because companies not listed on Pharmacompass have been conﬁrmed to make the FDF. All FDF holders can be found in appendix A.1. All FDF holders aren’t active, of all 34 FDF holders only 18 are active. Which companies that are active and what products they manufacture can be found in appendix B.1). Alberto Giannessi at ACS Dobfar S.p.A has shared some additional information for this report. According to Giannessi, the cefadroxil FDF was previously sold to the German company Salutas which is part of the Sandoz/Novartis group up until last year. Currently they sell their API to the German companies Steiner and Nextpharma. Nextpharma then goes on to sell the FDF to the Swedish

8 MAH, PharmaSwiss. This means that a connection between ACS Dobfar and the Swedish MAHs, PharmaSwiss and Sandoz, can be made. The ﬁrst depending on ACS Dobfar for their API and the latter for the FDF. As for Mylan, another Swedish MAH, they receive their 500 mg capsules and 1 g tablets from Teva Pharmaceuticals according to Teva generics website [29]. It is still unknown where Mylan receive their powder for oral suspension from.

Cefadroxil, being an outsourced drug, begins its distribution and commercialization in Sweden once the Swedish MAHs have received the FDF. There are a total of 16 MAHs in the EEA and 4 MAHs in Sweden (see table 4.1 for the speciﬁc Swedish MAHs & appendix C.1 for all geographic locations for MAH in EEA). Once these MAHs have marketed the drug, it is commercialized to hospitals and pharmacies through different distribution channels. Besides wholesalers and retailers, Mylan AB relies on direct contact with physicians through regular meetings when distributing their drugs. According to their website this is an important tool used to gain understanding of the demand and what they can do to supply it [30]. Ebb Medical AB, who sell multiple parallel imported drugs in Sweden for lower prices than the corresponding approved product, distribute all their products through Tamro. Tamro is the only distribution channel in Sweden working independently which means they do not own any pharmacies in which they distribute medical products to [31]. Speciﬁc distribution channels used by Sandoz GmbH and PharmaSwiss is not made apparent from their website.

Figure 4.1: A schematic picture of the supply chain for cefadroxil.

4.1.1.3 Identiﬁed Problems with Manufacturers as Plausible Cause for Backorders

As mentioned before Teva does not currently produce the API however, Mylan AB receive their FDF from Teva which produce 1 g tablets and 500 mg capsules. In 2015, when Teva made a deal to buy the pharmaceutical company Allergan generics [32], major cutbacks followed as a result of the pricey partnership. In an attempt to save 3 billion dollars by the end of 2019, Teva shut down a signiﬁcant amount of manufacturing sites, an API manufacturing site in Italy being one of the ef- fected. Teva also conﬁrmed that products would be discontinued in order to speed up the shutdown processes for their manufacturing sites [33] [34]. This could explain why Mylan, who receive their FDFs from Teva have “currently not provided” and recently backordered products. If Teva API can not produce the API then Teva generics, assuming they get their API from TEVA API, can not produce the FDF which in turn cuts off the supply to Mylan. TEVA does not manufacture powder

9 for oral suspension so this do not explain why the powder is backordered.

In 2016 an article was released stating that 16 manufacturing sites located in India and China were guilty of spreading drug resistant bacteria as result of their poor handling of pharmaceutical waste. These sites belonged to Aurobindo Pharma, Orchid Chemicals and Asiatic Drugs and Pharmaceu- ticals. Aurobindo Pharma and Orchid Chemicals are two out of the four active API manufacturers of cefadroxil. The bacteria’s were found to be resistant to cephalosporines, carbapenems and fluo- roquinolones [35]. According to an article from 2019, problems with Aurobindo’s manufacturing sites has been an ongoing concern for the FDA [36]. In 2019 a warning letter was issued by the FDA to Aurobindo Pharma. The letter cited many concerns regarding the company’s deviations from current GMP (CGMP) for their APIs. According to this letter, the EDQM voiced similar concerns because the API batches they received showed a level of contamination exceeding the acceptable limit [37]. If these issues put a halt in these companies’ API production is unclear but one can make this assumption since spreading drug resistant bacteria is a serious problem. With antibiotic shortage already being a global issue, making sure that we don’t contribute to it being less effective is crucial. One could speculate that the issues regarding Aurobindo might have been solved had the public been able to see which specific products are being ill-produced. But lack of transparency due to confidentiality makes it easier to not address the issues at hand.

Centrient Pharmaceuticals and ACS Dobfar have no API manufacturing issues that stand out however ACS stopped selling its FDF to Sandoz as of last year. The tablets backorder started early 2019 and if ACS Dobfar stop selling to Sandoz that same year, the backorder started too early for that to be the underlying cause. This could however be the cause behind the powder for oral suspension being “currently not provided” since the speciﬁc duration for this is unclear. There are only 5 companies that produce the 100 mg/ml oral suspension, 15 companies that manufacture the 500 mg capsules and only 3 that manufacture 1 g tablets B.1. ACS Dobfar S.p.A manufacturers all 3 of these and they don’t sell to Sandoz leaving them with one less company to buy their FDFs from. The low amount of FDF holders for the oral suspension and the tablet might be a contributing factor for the current backorders Sandoz is facing. Lack of actors in the different stages of a supply chain does make the chain more fragile, increasing the risk for low availability.

4.1.2 Meropenem

4.1.2.1 Availability

The meropenem products sold in Sweden along with their MAH as of April 20th 2020 can be seen in table 4.3, including one newly deregistered product that is relevant to the backorders. The dosages corresponds to the API which is meropenem trihydrate, formulated as a powder. The product also contains sodium, completing the FDF. The powder is later put in a liquid to be ad- ministrated for intravenous injection. Unlike the remaining products, vaborem also contains the antibiotic vaborbactam. [38]

In the rest of EEA there are other MAHs. These could be useful if there’s a meropenem shortage in Sweden, and license alternatives have to be imported. [10]. The number of companies and the location of their headquarter that are a MAH in the EEA, can be found in appendix C.2 [39].

10 According to the Swedish Medical Product Agency there are no ongoing backorders as of April 20th 2020, but there are four closed backorders of meropenem in the last few years, seen in table 4.3. There are also three antibiotics that are currently not provided.

Table 4.3: List of meropenem products sold in Sweden and their availability.

Product MAH Dosage Availability Meropenem Bradex 1 g Available FrostPharma 500 mg Available Meropenem 1 g Available Fresenius Kabi Fresenius Kabi 500 mg Available Meropenem STADA 1 g Available STADA Nordic 500 mg Available Meropenem SUN 1 g Available SUN Pharmaceuticals 500 mg Available Available. Backordered Meronem 1 g 2018-11-08 to Pfizer 2019-02-01. Available. Backordered 500 mg 2018-11-20 to 2019-02-01. Meropenem Accord 1 g Currently not provided Accord Healthcare AB 500 mg Currently not provided Meropenem Ebb 1 g Currently not provided Ebb Medical 500 mg Currently not provided Menarini International Vaborem 1 g Currently not provided Operations Deregistered 2019-05-29. Meropenem Pfizer 1 g Backordered 2016-11-24 Pfizer to 2019-03-21. Deregistered 2019-05-29. 500 mg Backordered 2016-09-01 to 2019-03-21.

11 4.1.2.2 Supply Chain

Table 4.4: List of meropenem API manufacturers with CEP certiﬁcates. [27]

Geographic location Issue Date Substance Certiﬁcate Holder (number of API Status (CEP/COS) manufacturing sites) Shenzhen Haibin Meropenem Pharmaceutical Co., Ltd. China (1) [40] 2019-11-29 Valid trihydrate CN 518 081 Shenzhen city Sun Pharmaceutical India (9), USA (1), Meropenem Industries Limited In Australia (2), Israel 2018-01-12 Valid trihydrate 400 063 Mumbai (1), Hungary (1) [41] Meropenem ACS Dobfar S.p.A IT Italy (9) [25] 2019-07-09 Valid trihydrate 20067 Tribiano Shandong Anhong Meropenem Pharmaceutical Co., Ltd. N/A 2020-01-23 Valid trihydrate CN 251 500 Dezhou City 2014-05-20 Meropenem Daewoong Bio Inc. KR Withdrawn N/A (End date: trihydrate 445-938 Hwaseong-Si by holder 2018-10-31) Kyongbo 2014-04-07 Meropenem Withdrawn Pharmaceutical Co., Ltd N/A (End date: trihydrate by holder KR 336-020 Asan-Si 2018-10-22) Unimark Remedies 2018-08-23 Meropenem Limited In 400-099 N/A (End date: Suspended trihydrate Mumbai 2018-09-10)

It’s suggested that all meropenem products that are or have been unavailable in table 4.3 are outsourced. The reason for this is that none of the MAHs has site in Sweden that produces Meropenem. Pﬁzer has a marketing and production site in Sweden, but doesn’t make antibiotics. Ebb Medical is a Swedish brand that sells parallel imported drugs at a lower price, and do not have their own manufacturing. [31]. Menarini, an Italian company, perform both research and manufacturing. The same goes for Accord Healthcare which is an Indian company. Menarini has a site in Sweden but makes diabetes products rather than antibiotics. [42]. Accord Healthcare also has a site in Sweden, but doesn’t produce meropenem. [43].

A production line was found for Meronem through FASS from September 2019, which was after the backorders ended. However, it is likely that the production line was the same during the backorder. Meronem, being the only available product today had a given production line while similar information was not found for the other products that are unavailable [38]. FASS stated three companies for Meronem’s production line, the ﬁrst being Corden Pharma in Copanago Italy. Cor- den Pharma is a pharmaceutical company specialized in the manufacturing of sterile liquid dosage forms for injection, which is the FDF for all meropenem products. [44]. It is therefore very likely that Corden Pharma produces the FDF for Meronem. The second company listed on FASS was As- traZeneca and their production site in Macclesﬁeld UK. This production site is AtraZeneca’s centre for packaging in Europe [45]. AtraZeneca used to be in charge of packaging Meronem before and

12 at least 18 months after the acquisition, and it is likely that they still did during its backorder. [46]. The third and final company listed on FASS was Pfizer in Zaventem, Belgium. Pfizer is a logistic center and the main distributor of Pfizer products in Europe [47]. Excluding the API suppliers, the production line for Meronem can be summarized to Corden Pharma manufacturing the FDF, AstraZeneca making the packaging and Pfizer distributing the product.

Meronem and Meropenem Pfizer are both from the company Pfizer. It’s reasonable they would’ve had a similar supply chain when they were both available. However, Meronem used to belong to AstraZeneca but their rights were sold to Pfizer on December 23rd 2016. [46]. AstraZeneca is still involved in its supply chain, suggesting that wasn’t the case for Meropenem Pfizer. The other products that don’t have a clear supply chain, can get their API and FDF from any of the API manufacturers and FDF holders.

There are many manufacturers for the API, but only seven that have or had a CEP/COS certiﬁcate. Those can be be seen in table 4.4. However, only four of them are valid. All 32 FDF holders for meropenem products are listed in Appendix A.2. Corden Pharma Caponago which is the suspected FDF holder for Meronem isn’t on the list, but it’s possible that they are covered in AstraZeneca because it’s an AstraZeneca legacy company. [46]

Figure 4.2: A schematic picture of the supply chain for meropenem.

4.1.2.3 Identiﬁed Problems with Manufacturers as Plausible Cause for Backorders

Meropenem Pﬁzer was backordered about a month before the acquisition of the business of Meronem. It’s possible that Pﬁzer phased out their own product to make room for a new one.

Considering the fact that Vaborem also contains Vaborbactam, there’s a possibility that other API and FDF suppliers are involved. Problems with those manufacturers could be the reason for unavailability. This was however not researched considering the focus of this report is meropenem.

Sun Pharmaceuticals Industries Ltd. have had manufacturing issues since 2014 on their plant in Halol in India, where they manufacture FDF rather than API. The expectations of GMP from FDA

13 weren’t met. Even though it doesn’t say anything about EMA it’s reasonable that they have similar standards. Not meeting the requirements can lead to companies having to import the FDF from another source, which might put the product on hold for a while. [48].

Shandong Anhong Pharmaceutical Co ltd. is listed as an meropenem trihydrate supplier at pharmacompass (issued January 23rd 2020). Shandong Anhong refers to a location in China but the company cannot be found using standard search engines.

In 2017, The Guardian reported about an explosion at a Chinese factory that produced raw materi- als for Piperacillin/Tazobactam (trade name Tazocin) leading to a global shortage of the antibiotic. Due to the lack of Tazocin, the global demand for meropenem as an alternative medication increased. [49]. A rapid increase in demand in a short period of time can lead to the suppliers not meeting the necessary capacity, further leading to drug shortage. This doesn’t really line up with the backorder dates, but it’s possible that the effects are extended.

In March 2019 a processes going into 2020 was started, where jobs in the packing department at the AstraZeneca Macclesﬁeld site were going to be cut. [50]. It’s possible that this affected the packing capacity for a period a time. It’s possible that this caused a backorder until the site adjusted.

On November 5th 2018 Corden Pharma Copanago opened a new and bigger manufacturing plant for sterile injectable drugs. [51]. The backorders of Meronem were also conducted in the beginning of November. If it’s true that Corden Pharma manufactures the FDF for Meronem, this could be a cause for the backorders. One reason could be that they moved the production to the new plant.

4.2 Health Economic Evaluation and Consequences on Society

4.2.1 Direct Cost

Håkan Hanberger, infectious disease specialist at Linköping University shared some information regarding 2 backorders for 2 different antibiotics in 2019, where they calculated the cost for extra hours spent on handling these two shortages. The staff taken into consideration were doctors, pharmacists and other workers in the medical ﬁeld. In order to reach a speciﬁc sum, the number of hours spent on dealing with these 2 shortages and the cost per hour was estimated for the region Östergötland. It was estimated that doctors, medical consultants, pharmacists and other hospital staff put in an extra 60 hours of work on weekdays and 20 hours on weekends, bringing the total up to 80 hours to handle each shortage. The cost per hour was estimated to 1000 SEK bringing the direct cost for extra labor hours to:

80 extra labor hours · 1000 SEK/hour = 80000 SEK f or each antibiotic shortage

In order to take consideration to all regions in Sweden, the sum was multiplied by 20 since region Östergötland is only 5% of Sweden. The conclusion was that the extra administrative time spent on dealing with shortage was equivalent to 1.6 MSEK per shortage (assuming that all products are unavailable), regardless of the antibiotic. For this report we assume that handling the shortage of all backordered cefadroxil and meropenem products will also cost society 1.6 MSEK each in extra administrative staff hours. This sum spent on handling a shortage can be seen as a huge economic

14 consequence since the cost is spent no matter how long the shortage lasts. For a shortage lasting no longer than a couple of months, 1,6 MSEK can seem rather large. And for a shortage lasting years, the cost can amplify if multiple initiatives need to be taken along the way to handle the shortage.

In the coming two sections, the direct costs for replacement pharmaceuticals have been calculated using estimated national volume demand and estimated prices per unit of pharmaceutical sold. The raw data for volumes was provided by PLATINEA and won’t be presented in this report due to secrecy. Which alternative treatments are often used instead of cefadroxil and meropenem were provided by Fredrik Resman, infectious disease specialist at Lunds university and Simone Callegari from Uppsala University and PLATINEA. The information provided by Fredrik Resman regarding replacement pharmaceuticals was also confirmed by medical doctors Thomas Grenholm Tängdén, Håkan Hanberger and Josef Järhult. Additional information provided by these healthcare workers stated that meropenem is used more in Swedish healthcare while cefadroxil is only used in a handful of cases. In addition to alternative treatment methods, prolonged sickness is considered as a direct cost to society as well as the increased risk of AMR. The direct cost due to AMR is presented through data collected by the Public Health Agency of Sweden in their report "Uppskat- tning av framtida sjukvårdskostnader till följd av antibiotikaresistens, bilaga 2" [52]. The agency did a study where they calculated the direct cost that would arise as a result of treating infections caused by specific bacteria prone to antibiotic resistance. The estimated costs were based on extra healthcare expenses. The agency took into consideration both outpatient and inpatient care. As previously mentioned, cefadroxil is assumed for the first and meropenem for the latter. However, prolonged sickness will not be represented as an exact calculation in this report.

4.2.1.1 Cefadroxil

Cefadroxil oral suspension is rarely used in inpatient care [18] so for the sake of this report we will assume that cefadroxil is solely used in outpatient care. PLATINEA only provided sales data about the oral suspension from Mylan so that is what we will cover in this report. When this dosage form is in shortage it can be exchanged for different products that are sold in Sweden. For this report, the cost of the backorder will be calculated based on the market situation today (May 17th 2020), so products that are backordered or currently not provided will not be considered as replacements. The complete list of which products that are currently backordered or currently not provided can be found in table 4.1.

To estimate the cost of a backorder, an estimate of how many units sold per year must be made. The 60 ml units dropped in sales in 2017 so when calculating the amount of units sold, the sales data between 2013 and 2016 was used to give a more accurate representation of how much cefadroxil is usually sold. According to the provided data, around 95 439 units of the 60 ml cefadroxil oral suspension are sold per year (Standard deviation = 17 957, CV = 18.1%). The amount of 100 ml units sold were also calculated using data between 2013 and 2016 as sales dropped in 2017. Calcu- lations showed that 114 885 units of the 100 ml oral suspension are usually sold per year (Standard deviation = 51 165, CV = 44.53%). All prices used in the calculations are found in appendix D.1. All the prices for the cefadroxil products were found on May 15th 2020 and the rest were found on May 17th 2020. FASS was used as the primary source when researching prices for the different alternatives.

15 In this report, the cost for 5 different replacements will be calculated, amongst them are other cefadroxil products:

1. 1 g dispersible tablets as they can be given to most patients.

2. 500 mg capsules for the same reason, that it easily can be given to most patients.

3. The licensed drug Grüncef which also is a oral suspension.

4. Clindamycin, it is another antibiotic than can be used as a replacement when there is shortage of cefadroxil.

5. Trimethoprim/Sulfamethoxazole (Trim-Sulfa) is a combination of 2 different antibiotics that also can be used as a replacement when there is a cefadroxil shortage.

For alternative treatments 1, 2 and 3, an assumption is made stating that all patients are adults without kidney problems requiring the max dosage of 1 g cefadroxil, twice a day. The assumption that max dosage is taken twice a day is irrelevant in the calculations because each patient previously taking Cefadroxil Mylan’s oral suspension, took 2 units a day as well. Calculations done for alternative treatments 4 and 5 are based upon the same assumption, that max dosage is required. Because the oral suspension is 100 mg/ml, a 60 ml unit is equal to 6 g cefadroxil and 100 ml is equal to 10 g (Calculation Appendix E.1.1).

1. Cefadroxil, dispersible tablets Each 60 ml unit of cefadroxil can be exchanged for 6 dispersible tablets and each 100 ml unit for 10 tablets, as the tablets are 1 g each. The tablets are only sold in packs of 10 so no matter the amount required, a unit oral suspension is exchanged for one pack consisting of 10 tablets. The price for the dispersible tablets from PharmaSwiss and Ebb medical are the same at 215.26 SEK for one pack of 10 x 1 g tablets. As stated earlier the 60 ml units from Mylan cost 120.59 SEK/unit and the 100 ml cost 182.30 SEK/unit. There were 95 439 units of the 60 ml oral suspension sold per year and 114 885 units of the 100 ml sold per year.

Replacement of the 60 ml Cefadroxil Mylan units:

95 439 units/year · (215.26 SEK/unit − 120.59 SEK/unit) = +9 035 210 SEK/year ≈ +9.0352 MSEK/year

Replacement of the 100 ml Cefadroxil Mylan units:

114 885 units/year · (215.26 SEK/unit − 182.30 SEK/unit) = +3 786 610 SEK/year ≈ +3.7866 MSEK/year

Total estimated cost:

3.7866 MSEK/year + 9.0352 MSEK/year = +12.822 MSEK/year = +35 105 SEK/day

The dispersible tablets can be a good replacement, they are more expensive but the easy administration makes them more comfortable for patients. The problem is that the dispersible tablets can not easily be given to children.

16 2. Cefadroxil, capsules The capsules from Sandoz and Mylan are also currently available and can be used as a replacement pharmaceuticals. The capsules only contain 500 mg API, this means that a 60 ml unit can be exchanged for 12 capsules and a 100 ml unit can be replaced by 20 capsules (Calculation Appendix E.1.2). Since a patient consumes 2 units per day, a treatment with 2x60 ml units would be replaced with 24 capsules and treatment with 2x100 ml units by 40 capsules. Mylan and Sandoz normally sell their capsules in packages of 14, 20, 30 & 100 but Sandoz’s packages with 14 capsules are currently not available (as of May 14th 2020). Pharmacists try to minimize the amount of capsules given to patients so if the treatment plan consisted of 24 capsules preferably 2 packages with 14 capsules would be given. Cefadroxil Mylan 60 ml units would thus be exchanged by their one package of 14 capsules (from Mylan as Sandoz 14 packs are unavailable) with a price of 92,40 SEK. The treatment plan to replace 2x100 ml units would be to sell 2 packs with 20 capsules, one unit of 100 ml is thus exchanged for a pack of 20 capsules. Cefadroxil Mylan’s pack of 20 capsules costs 109.09 SEK. These prices show that these replacement drugs actually cost less than the oral suspension.

Replacement of the 60 ml Cefadroxil Mylan units: 95 439 units/year · (92.40 SEK/unit − 120.59 SEK/unit) = −2 690 425 SEK/year ≈ −2.6904 MSEK/year Replacement of the 100 ml Cefadroxil Mylan units: 114 885 units/year · (109.09 SEK/unit − 182.30 SEK/unit) = −8 410 731 SEK/year ≈ −8.4107 MSEK/year Total estimated cost: −2.6904 MSEK/year − 8.4107 MSEK/year = −11.101 MSEK/year = −30 393 SEK/day Even if the capsules are less expensive than the oral suspension, the comfort for the patient needs to be considered. There are patients that feel discomfort when taking capsules so for them having dispersible tablets that can be dissolved in water is a necessity. Another limitation is that these capsules can not be given to children. This is not conﬁrmed by healthcare workers but there is an argument to be made that only the patients that need the oral suspension get it prescribed, the patients that don’t need it might get the less expensive alternative like the capsules. If we consider that, capsules are not a good alternative as a replacement for the oral suspension.

3. Grüncef, oral suspension Grüncef is a licensed drug with cefadroxil as it’s API, meaning it is a generic alternative [53]. Since other cefadroxil alternatives not requiring licensing exists, it is more likely that they are cho- sen before Grüncef. Grüncef is also a 100 mg/ml solution only sold in units of 60 ml costing 450 SEK. Since both Grüncef and the oral suspension share the same concentration, exchanging units between them can be done easily.

Replacement for 60 ml Cefadroxil Mylan units: With around 95 439 units of the 60 ml oral suspension being sold per year, this means that using Grüncef’s 60 ml solution instead of Cefadroxil Mylan’s would cost: 95 439 units/year · (450 SEK/unit − 120.59 SEK/unit) = 31 438 561 ≈ +31.439 MSEK/year

17 Replacement for 100 ml Cefadroxil Mylan units: Since Grüncef is only sold as a 60 ml unit, a 100 ml of the oral suspension needs to be replaced by 2x60 ml of Grüncef. There are 114 885 units of the 100 ml sold per year so the cost for the exchange would be:

114 885 units/year · (450 SEK/unit · 2 − 182.30 SEK/unit) = 82 452 965 ≈ +82.453 MSEK/year

Total estimated cost:

31.439 MSEK/year + 82.453 MSEK/year = +113.89 MSEK/year = +311 814 SEK/day

In the case of exchanging Cefadroxil Mylan for Grüncef, a four day lead-time takes place. This means that it takes four days for the ordered Grüncef products to actually arrive and be of use. What this entails is that this alternative drug can cause prolonged sickness for the patient as they can be without antibiotics for a period of four days. In this report a cost for the lead time will not be considered but it is worth mentioning since it indicates that the cost of this exchange would be higher than calculated.

Using Grüncef as an alternative is very expensive but it is the only formulation that can be given to everyone as it is easy to decide a dose that is suitable for the individual patient. The only disadvan- tage with Grüncef is the four day lead-period which could lead to the patient being dealt inferior drugs resulting in unforeseen side effects. This alternative would be ﬁtting if no other cefadroxil drug with an appropriate administration for the patient could be found.

4. Clindamycin, capsules In this calculation Clindamycin Actavis is used because it is the least expensive relevant product found on FASS. Clindamycin Actavis’s API is clindamycin but it can be used instead of cefadroxil according to Fredrik Resman. The max dosage is 4 capsules a day, no time period was stated on FASS but antibiotic cures are often a maximum of 10 days so that will be assumed as the maximum treatment time in this case. In appendix E.1.3 it was calculated that 2 units of 100 ml cefadroxil can be exchanged for 40 capsules of clindamycin and 2 units of 60 ml cefadroxil can be exchanged for 24 capsules.

Replacement for 60 ml Cefadroxil Mylan units: 24 capsules covers both units Cefadroxil used per day. To come close to 24 capsules, one pack of 32 capsules costing 145,75 SEK is used. To cover the fact that the one pack of 32 capsules covers 2 units of cefadroxil, the amount of units sold will be divided in half. The cost for the 60 ml unit is 120.59 SEK so the cost of the exchange becomes: 145.75 95 439 units/year · ( SEK/unit − 120.59SEK/unit) = −4 553 871 SEK/year ≈ −4.5539 MSEK/year 2 Replacement for 100 ml Cefadroxil Mylan units: 40 capsules are sold as 2 packs of 20. A normal cure with Cefadroxil Mylan’s oral suspension requires 2 units so each unit of oral suspension can be exchanged for a pack of 20 capsules which costs 148.49 SEK. 100 ml cefadroxil costs 182.30 SEK and 114 885 units Cefadroxil are sold per year. Using this information the cost for the exchange becomes:

114 885 units/year · (148.49 SEK/unit − 182.30 SEK/unit) = −3 884 262 SEK/year ≈ −3.8843 MSEK/year

18 Total cost of exchange:

−4.5539 MSEK/year − 3.8843 MSEK/year = −8.4382 MSEK/year = −23 103 SEK/day

5. Trimethoprim/Sulfamethoxazole, oral suspension In this report Eusaprim R will be used as it is the least expensive Trim-Sulfa product. It is also an oral suspension which is good in this case because it shares the same formulation as the Ce- fadroxil Mylan product these calculations are based on. The recommended dosage stated in FASS is a 20 ml suspension taken twice a day for a maximum of 7 days. In appendix E.1.4 the amount of Eusaprim R needed for the exchange is calculated. 2x100 ml units of Cefadroxil Mylan would be exchanged for 280 ml of Eusaprim R and 2x60 ml units of Cefadroxil Mylan would be exchanged for 168 ml of Eusaprim R . This alternative product is only sold in 100 ml units so 2x100 ml cefadroxil would be exchanged for 3x100 ml Eusaprim R and 2x60 ml cefadroxil would be exchanged for 2x100 ml Eusaprim R .

Replacement for 60 ml Cefadroxil Mylan units: As mentioned above, 2x60 ml units of cefadroxil can be exchanged for 2x100 ml units of Eusaprim R . So each 60 ml cefadroxil unit can be replaced by a 100 ml unit of Eusaprim R .

95 439 units/year · (48.79 SEK/unit − 120.59 SEK/unit) = −6 852 520 SEK/year ≈ −6.8525 MSEK/year

Replacement for 100 ml Cefadroxil Mylan units: 3 units of Eusaprim R are required for the same dose as 2 units of cefadroxil, meaning that each unit cefadroxil is equivalent to 1.5 units Eusaprim R . This can be considered in calculation by multiplying the units cefadroxil sold with 1.5:

114 885 units/year · (48.79 SEK/unit · 1.5 − 182.30 SEK/unit) = −12 535 677SEK/year ≈ −12.536 MSEK/year

Total cost of exchange:

−6.8525 MSEK/year − 12.536 MSEK/year = −19.389 MSEK/year = −53 084 SEK/day

Clindamycin Actavis and Eusaprim R are two other kind of antibiotics, they are less expensive alternatives but they are not preferred over cefadroxil in the cases where cefadroxil can be used. Considering the costs and the comfort of the patients, a good alternative is to use a combination of the dispersible tablets and Grüncef. The dispersible tablets can be used for the patient where it is applicable since the price difference from the oral suspension is small. Grüncef, being the more expensive option, can be used when it is required, like for children.

According to Fredrik Resman, other antibiotics within the penicillin group can also be used as an alternative to cefadroxil. No cost was calculated in this report since there are many penicillin-like antibiotics and no speciﬁc option was given. Therefore the focus was placed on other more speciﬁc replacement pharmaceuticals. However worth mentioning is that penicillins usually are preferred over clindamycin and trim-sulfa, as these two antibiotics are mostly used once patients prove to be hypersensitive to penicillin.

All these calculations assume that both Mylan and Sandoz have their oral suspension unavailable. In most cases, Cefadroxil Mylan oral suspension is simply exchanged for Cefadroxil Sandoz oral

19 suspension. Both these companies depend on 4 active API manufacturers and 5 FDF holders for the oral suspension. The fragility in the supply chain decides how likely it is for both these products to be unavailable at the same time which would in turn lead to alternatives being used. In other words, cefadroxil would be less prone to shortage if more actors were involved in each step of the supply chain. The increased stability would then lower the economic consequences due to shortage since cefadroxil products of the same FDF would be interchangeable resulting in fewer alternatives being used. Cefadroxil is prone to shortage according to the reports conducted by PLATINEA last year which increases the likely-hood of these costs actually occurring [54] [55] [56].

Regarding the alternative treatments for cefadroxil, Grüncef’s API is also cefadroxil. This indicates that the switch from Cefadroxil Mylan to Grüncef isn’t affected by AMR since bacteria resistant to Grüncef would be resistant to Cefadroxil Mylan as well. In regards to Clindamycin, sulfamethoxazole & trimethoprim, they are all in different antibiotic classes than cefadroxil. For this reason AMR needs to be taken into consideration. According to FASS, clindamycin is used for similar indications as cefadroxil but for patients with extra sensitivity to pencillins and cephalosprins. Re- search showed that clindamycin is commonly used to treat MRSA infections. MRSA, also known as the "super bug", is a bacteria that causes a variety of infections such as skin infections, lung infections and post-surgical infections. MRSA infections are more difﬁcult to treat since the bacteria is resistant to most antibiotics, including penicillins and cephalosporins [57]. Therefore one can say that clindamycin is used when patients are extra sensitive to cephalosprines and penicillins and when the infections they have, are caused by bacteria resistant to these types of antibiotics. In other words, clindamycin is actually used when trying to avoid AMR but this has changed over the years.

There is a growing concern regarding clindamycin since inducible resistance by S.aureus has been detected, in both in vivo and in vitro testing [58]. Therefore, close monitoring is advised when treating patients with clindamycin for S.aureus infections, since induced resistance can lead to unnecessary clindamycin treatment. However, treatment for non S.aureus related infections is both safe and effective with clindamycin [59]. This is why it is recommended that microbiology laboratories perform regular testing for inducible clindamycin resistance in S.aureus and report all ﬁndings. This way, clinics are informed and can limit their use of the drug when necessary. This is important so that material is not wasted on patients with resistance when it could be given to patients actually susceptible to the antibiotic. Not to mention the consequences it would have on patients wanting and needing to be treated with something effective.

Since clindamycin is used for MRSA infections which could then lead to an induced resistance by S.aureus, the AMR cost of MRSA resistance is used. This is the most realistic choice since no direct cost for S.aureus resistance has been calculated by the Public Health Agency of Sweden. The PHAS report estimates that the direct cost for outpatient care due to MRSA resistance would be +3665 SEK/visit with an additional 310 SEK for necessary treatment adjustments per patient case. These estimations show that using clindamycin as a result of cefadroxil shortage, can in fact increase the direct cost to society. Since switching to clindamycin can lead to induced resistance which in turn highers healthcare costs. Regarding Eusaprim R , it is a combination antibiotic meaning that the chances of it increasing the risk of AMR is low. Since it is not likely that a bacteria resistant to sulfametoxazol, is also resistant to trimetoprim and vice versa. Recent studies even indicate that antibiotic combination therapy is the new solution to AMR [60].

20 4.2.1.2 Meropenem

Meropenem shortage can be solved either by importing meropenem generics or other types of antibiotics as alternatives. Meropenem-Rotexmedica is a generic license alternatives according to Apoteket and imipenem is an alternative antibiotic suggested by Region Östergötland [61], as well as Thomas Grenholm Tängdén, Håkan Hanberger, Josef Järhult and Fredrik Resman. In this report the imipenem as alternative antibiotic will be evaluated since it would be the go-to option according to the medical doctors listed above. Imipenem is similar to meropenem also being a carbapenem [62].

Data of sold units between 2013 and 2018 for 7 different MAHs was provided by PLATINEA, while 8 MAHs are found in table 4.3. Every meropenem MAH in the data provide dosages of 500 mg or 1 g where one package contains 10x1 vials per unit, suggesting that the missing MAH is Menarini that only manufacturers one dosage of 1 g. The MAH for imipenem is Fresenius Kabi with their product Imipenem Fresenius Kabi 500 mg / 500 mg provided in 10x20 ml units per unit. Imipenem Fresenius Kabi contains 500 mg imipenem and 500 mg cilastatin in 20 ml infusion. Cilastatin isn’t an antibiotic but an inhibitor of dehydropeptidase, slowing down metabolism of imipenem [63].

For the calculation of direct costs. First, the sum of all units sold per dosage (independent of MAH) each year were calculated to estimate Sweden’s total demand. According to the data provided, Sweden’s annual consumption average are 191 957 units of meropenem 500 mg (SD = 20 481, CV = 10.3 %) and 211 174 units of meropenem 1 g (SD = 30 189, CV = 14.3 %). Then, the price for meropenem and imipenem was estimated by collecting and summarizing procurement data from each region that had this available on their website. This resulted in meropenem 500 mg being priced for 227.20 SEK (SD = 52.28 SEK, CV = 23 %), meropenem 1 g priced 407.00 SEK (SD = 71.04 SEK, CV = 17.5 %), and imipenem 500 mg priced 415.00 SEK (SD = 21.21 SEK, CV = 5.11 %). See appendix D.2 for data of prices and sources. Last, the direct cost for replacing meropenem with imipenem was calculated comparing estimated volume and price for both antibiotics. The dosage difference between meropenem and imipenem was assumed as 1:1 as Fredrik Resman witnessed that dosages of meropenem and imipenem in most cases are interchangable.

Meropenem 500 mg 191 957 units/year · 227.20 SEK/unit = 43 574 239 SEK/year Meropenem 1 g 211 174 units/year · 407.00 SEK/unit = 85 947 818 SEK/year Imipenem 500 mg (191 957 + 211 174 · 2) units/year · 415.00 SEK/year = 254 936 575 SEK/year Direct costs 254 936 575 SEK/year − (43 574 239 + 85 947 818) SEK/year ≈ 125.39 MSEK/year = +343 299 SEK/day

The direct cost estimate should be considered as an indicator of the degree of economic inﬂuences meropenem shortages are capable of causing. The calculated cost is however based on a worst case

21 scenario. In order to experience this scenario, all products from the 7 MAHs must be unavailable simultaneously for an entire year, excluding Vaborem. This was never the case, there was always a few meropenem products available. It’s likely that any other brand of meropenem available in Sweden was used instead of imipenem. That would result in a different price in the calculations. Even though it would be more relevant to calculate the cost of the found backordered and unavail- ble products, it’s not possible with this method. In the data given, the MAHs are anonymous. That means that we cannot guarantee that the data is matched to the right MAH. There are blanks in the data, suggesting that no products have been sold, which could be a backorder. It’s however difﬁcult to match the right product, considering there’s no issue dates for the products that aren’t currently available. Even if that would be possible, there’s still no way to calculate how many alternative products were sold instead, because there’s no data for comparison.

The risk of all meropenem products to become unavailable at the same time depends on the number of steps and actors from API to FDF, along with the current market status where the MAHs are active. Meropenem have four API producers, 32 FDF holders, and the MAH are active in a stable and reliable market relative to global standards. However, since the supply chain can’t be fully deﬁned in detail, the case can be that several MAHs depends on the same API producer or FDF holder meaning that issues at either of these could cause issues for several MAHs. Major issues caused at the manufacturing of FDF appears unlikely due to the high number of actors. However, issues at the API producers appears more likely. Especially considering the risks with Shandong Anhong Pharma and Sun Pharma as discussed in 4.1.2.3. If one API manufacturer fails to deliver and oth- ers aren’t able to rapidly enough readjust their supply volume for the new demand, an antibiotic shortage could be experienced in Sweden. A shortage seems especially likely when considering the low procurement and lack of volume commitments made by the Swedish regions to the MAHs. However, this scenario would likely not result in as high of a direct cost as previously calculated because all brands of the antibiotic wouldn’t be affected.

There is a reason that Meropenem is a ﬁrst choice of treatment, and it might be that other antibiotics might be more prone to develop a resistance with the bacteria. Imipenem is broader when it comes to gram-positive bacteria, leading to it affecting other bacteria which might not be necessary. Although carbapenems are the go-to drug for multiresistant bacteria, there are exceptions [62]. En- terobacteriaceae can produce carbapenemase making them resistant. For some of these bacteria the minimum inhibitory concentration, MIC, is always elevated for imipenem. This means that the lowest concentration of imipenem required to prevent growth of bacteria is higher than for other carbapenems, suggesting that meropenem is more effective and should be used instead. [64]. This concludes that there’s a higher risk of AMR when switching to imipenem.

ESBLcarba is a speciﬁc type of Enterobacteriaceae with the difference being that they produce extended spectrum beta-lactamase which in turn are able to break down carbapenems. Since imipenem can be used to treat infections caused by this bacteria, the direct cost arising as a result of the bacteria’s resistance against carbapenems is used. The PHAS report estimates that the direct cost for inpatient care due to ESBLcarba resistance would be +1160 SEK/day when treated for inva- sive infections. In addition, the cost of adjusting the antibiotic treatment due to ESBL/ESBLcarba resistance was estimated at +609 SEK per patient case. This shows that the switch to imipenem can increase the direct cost since using the antibiotic against Enterobacteriaceae infections can lead to resistance resulting in higher healthcare costs to counteract the issue.

22 4.2.2 Indirect Cost - Loss of Production due to Unforeseen Side Effects

Substituting antibiotics with other alternative drugs or generics can lead to unpredictable side effects which in turn can extend the time a patient is sick. The most common side effects that can occur when using all cefadroxil products in Sweden are nausea, vomiting, diarrhea, irritation in the digestive tract, stomach pain and rashes on the skin. Similar side effects are observed when using Grüncef, since it has the same API. The alternatives Clindamycin Actavis and Eusaprim R are two other kinds of antibiotics, they are less expensive alternatives but include other side effects than cefadroxil, side effects such as abnormal liver values for clindamycin and candida infections for Eusaprim R . Most common side effect of meropenem are diarrhea, skin irritation, nausea and inﬂammation on the injection site. [65] Comparing this to imipenem side effects that might be caused by imipenem are nausea, diarrhea, vomit, skin irritation, hypertension, cramps, dizziness, pruritus, hives and somnolence. [66] There is a signiﬁcant difference in potential side effects between meropenem and imipenem. Imipenem have more side effects that might be riskful to patients with other conditions.

Prolonged sickness possibly caused by these side effects could result in a patient taking longer time off work which for society entails production loss. This loss in production could contribute to shortage in resources and a decrease in wealth for society. The severity of production loss depends on the friction period, which is the time it takes to replace an employee on sick leave. When investigating the indirect cost of shortages to society, there is a constant battle regarding what should be considered more valuable, production loss due to prolonged sick leave or the years of perfect health gained by the patient [67]. In many cases when employees are sick they can be replaced. The loss of production is then not dependant on the patients absence, but more so on the replacement. If the position that is now vacant can be filled by someone experienced in the field, perhaps a co-worker, society endures minimal losses since no time is spent training new personnel. However this argument only holds up in the cases where the absentee is easily replaced resulting in not too long of a friction period. In these cases one can argue that the loss of production would cost the individual out of work more than it would cost the work place. In the cases where a replacement is harder to find and the friction period is then extended, society suffers greater loss since work places will be forced to either have existing employees working overtime, or they will need to place new hires. Regardless of which route they decide to take, higher costs will arise as a consequence.

When trying to quantify the economic value of health outcomes, QALY is a tool used by the medical ﬁeld to measure how many years of perfect health are gained as a result of treatment [68]. However, criticism has risen regarding the use of QALY in indirect cost analysis. According to some studies, when calculating indirect cost as loss of production, the addition of QALY will lead to "double counting" since the factor of health will be counted twice. Health plays a role in both loss of production and QALY. The state of health affects loss of production since it decides how long an employee is absent. As for QALY, this tool is built on the extended time a patient is healthy after treatment so 12 months of perfect health is equal to 1 QALY [68]. This implies that the effect of health is being counted two times, once in loss of production and again in QALY, hence the double counting [67]. Despite the criticism QALY has faced, no other model for health economic outcomes has managed to replace it [68].

23 4.3 Limitations

Due to the current Covid-19 situation, contact with Swedish healthcare workers was very limited. Interviews could not be executed as planned and this lack of insight into the Swedish healthcare system lead to additional assumptions being made when writing the report. However, a simple questionnaire sent out to multiple doctors and healthcare workers helped give some perspective into which alternative treatments were actually used in practice.

This study is limited to only investigating Swedish government run healthcare actors. And since Sweden is in the center of this project, only the API manufacturers with CEP/COS certiﬁcates are taken into consideration.

When researching risk factors in the supply chain, this study was limited to researching API manufacturing problems. Due to the narrow scope of this project and its time restrictions, additional problems in other aspects of the supply chain were not be explored. Limited time is also the reason for why a list over active FDF holder for meropenem, like the one for cefadroxil (appendix B.1), was not constructed. The fact that such a table wasn’t investigated indicates that the amount of FDF holders stated in this report is exaggerated. For cefadroxil only about half of all FDF holders were active, there is no evidence that this is the case for meropenem but it is a possibility.

The sales data used to calculate the direct cost of cefadroxil shortage to society, only covered the powder for oral suspension from Mylan. There are many other recently backordered products whose cost couldn’t be calculated as a result of this limitation. All calculations for cefadroxil are also calculated using theoretical cures that might not be used. This means the the cost might be lower than calculated in the report. In addition, all treatments were based on theoretical doses since real doses were not provided by healthcare workers nor conﬁrmed using various sources.

4.4 Improvements and development

While working on this report time was a restriction, therefore only a handful of sources were used when researching the supply chains. In the future with more time at hand, it would be beneficial to compare several sources when doing this in order to confirm the accuracy of certain information. This would be beneficial since while researching for this report, sources proved to be contradictory at times. And as mentioned before, only risk factors in the API manufacturing step of the supply chain was investigated. However if this project was to be expanded, researching additional actors would be interesting. That way a more accurate assumption as to why these backorders occurred can be found.

In this report, for the sake of simplicity in the calculations, the cost of the backorders was calculated per year. It would however be more accurate to calculate the exact cost of the identiﬁed cefadroxil and meropenem backorders. In addition, to calculating more deﬁnite direct costs, interviews with doctors and healthcare workers should be carried out. This way one would know from early on, which alternative treatments are relevant to look into as well as what other costs to society might

24 arise due to shortage. 5. Conclusions

There is a pattern for both cefadroxil and meropenem that there is a low number of API manufacturers and MAHs in Sweden in comparison to the relatively large number of FDF holders. This would mean that the supply chains are more vulnerable at the API manufacturers and MAHs than the FDF holders. Therefore one can conclude that the occurrence of backorders can in fact be explained by deficiencies in the supply chain. Problems starting already at the top of the chain with the API manufacturers for both cefadroxil and meropenem were identified as possible causes for the backorders. Transparency in the supply chain is extremely important. Suppliers, buyers, consumers and other actors in the supply chain should be able to easily trace a products journey from start to finish. Transparency like this would hopefully make suppliers more careful of their manufacturing conditions. This would also make it easier to identify the specific cracks in a drug’s supply chain causing its low availability. Since meropenem has double the number of MAHs as cefadroxil, it’s classified as medium risk for unavailability. Cefadroxil is however at high risk due the low number of MAHs and API manufacturing issues both contributing to it’s unavailability. How big the risk for a backorder is can lead to bigger or smaller health economic consequences for the Swedish Healthcare system. Since a bigger risk increases the chances of additional measurements being taken in order to deal with the shortage, the economic consequences would rise as a result.

The absolute cost for antibiotic shortage was estimated to start at 1.6 MSEK in administrative costs per shortage, regardless of its duration. Followed by the direct cost for cefadroxil alternatives at -53 084 SEK up to +311 814 SEK per day and +343 299 SEK per day for the meropenem alternative, imipenem. In addition to these costs, the lead time for Grüncef as an alternative to cefadroxil indicates prolonged sickness and hospitalization time for the patient increasing the direct cost as well. These calculated costs show just how costly these shortages are for Swedish healthcare. Even though the shortage of both cefadroxil and meropenem would cost around 300 000 SEK per day at most, the shortage of meropenem would have a bigger impact on Swedish healthcare considering it’s used to a larger extent than cefadroxil. In regards to AMR, substituting these antibiotics with imipenem or clindamycin proved to increase the risk of AMR, increasing the direct cost due to higher healthcare expenses and treatment adjustments. The switch to clindamycin to treat MRSA infections would cost +3665 SEK/outpatient visit, assuming that the MRSA developed an induced resistance against the antibiotic. And substituting meropenem for imipenem to treat Enterobacte- riaceae infections would cost +1160 SEK/day, assuming that the bacteria has built up a resistance against imipenem.

In order to lower this risk, using licensed drugs should be the ﬁrst line of response during times of shortage. This will however be more expensive and take more time to import increasing the direct cost as seen by the calculations for Grüncef and imipenem. The use of licensed drugs would in turn leave the patient sick for an extended period of time. This can also have an even bigger effect on society due to patients experiencing more adverse side effects, being away from work longer, and lessening the tax-revenue. This domino effect would therefore in turn increase the indirect costs as well.

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[66] FASS. Bieffekter - imipenem/cilastatin fresenius kabi. Cited May 14th 2020. Avail- able at: https://www.fass.se/LIF/product?userType=0&nplId=20071211000015# side-effects.

[67] Marc A. Koopmanschap and Frans F. H. Rutten. Indirect costs: The consequence of production loss or increased costs of production. Medical Care, 34(12):DS59–DS68, 1996. Available at: http://www.jstor.org/stable/3766353.

[68] Luis Prieto and José A Sacristán. Problems and solutions in calculating quality-adjusted life years (qalys). PubMed Central, pages DS59–DS68, 2003. Available at: https://www.ncbi. nlm.nih.gov/pmc/articles/PMC317370/.

[69] Pharmacompass. Fdf holders cefadroxil - pharmacompass; cited: April 10th 2020. available at: https://www.pharmacompass.com/ fdf-licensing-available-formulations-dossiers/cefadroxil.

[70] Pharmacompass. Meropenem dossiers. Cited April 20th 2020. Available at https://www.pharmacompass.com/active-pharmaceutical-ingredients/meropenem/ﬁnished- dosage-forms/dossiers.

[71] nmrc. Products - aspen pharmacare; cited: April 19th 2020; available at: http://www.nmrc. com.na/product_register.

[72] Aurobindo USA. Products - aurobindo usa; cited: April 19th 2020; available at: https: //www.aurobindousa.com/product-catalog/.

[73] Devats. Products - devats; cited: April 19th 2020; available at: https://www. pharmacompass.com/pdf-document/dossiers/devats-india/cefadroxil.

[74] Pharmacompass. Zeiss pharma products. Last cited May 11th 2020. Available at: https: //www.pharmacompass.com/pdf-document/dossiers/zeiss-pharma/cefadroxil.

[75] Region Kronoberg. Upphandlade läkemedel i Region Kronoberg, från 2020-05-01. 2020-05-01. Available at: https://www. folkhalsomyndigheten.se/contentassets/488c4abcf0ff4f2b9d72a6a17de3cae1/ future-costs-antibiotic-resistance-18010.pdf.

[76] Region Stockholm. Upphandlade läkemedel i Region Stockholm, från 2020. 2020-05- 13. Available at: https://contracts.tendsign.com/Attachment/Download/1579312/ 8964537.

[77] Region Västerbotten. Upphandlade läkemedel i Region Västerbotten. 2020-05-01. Avail- able at: https://www.regionvasterbotten.se/VLL/Filer/Upphandl%20rekv%20lm_ Norrlandst%2020200501.xls.

31 [78] Region Blekinge. Upphandlade läkemedel i Region Blekinge. 2020-05-01. Avail- able at: https://regionblekinge.se/download/18.49156cbe171df91ec6aa6fd/ 1588847567227/Upphandlade%20l%C3%A4kemedel%20Region%20Blekinge%20200505. xlsx.

[79] Region Skåne. Upphandlade läkemedel i Region Skåne. 2020-05-01. Available at: https: //contracts.opic.com/Contract/Details/1562576.

[80] Region Sörmnland. Upphandlade läkemedel i Region Sörmland. 2019. Available at: https://samverkan.regionsormland.se/siteassets/halsa-och-vard/ lakemedelskommitten/upphandlingsarbete/kopia-av-sammanstalld_ produktlista_sov_201902.xlsx.

32 Appendices

33 A. List of FDF Holders (Secondary manufacturers)

A.1 Cefadroxil

• ACS Dobfar S.p.A (also API manufacturer)

• Amn life science

• Ani pharma inc

• Antibiotice sa Romania

• Apotex inc

• Apothecon lc

• Aspen pharmacare holdings

• Aurobindo pharma limited (also API manufacturer)

• Bernofarm pharmaceutical company

• Bio labs

• Bristol laboratories ltd

• Cspc ouyl pharmaceutical co.,ltd

• Devats india

• Globela pharma

• Hikma pharmaceuticals PLC

• IVAX pharmaceuticals inc

• Jodas expoim pvt. Ltd

• Lupin ltd

• MS pharma

• Mylan AB (has site in Sweden)

• Nectar lifesciences limited

• Orchid chemicals & pharmaceuticals ltd (also API manufacturer)

• Pro doc limitee

• Purepac pharm

34 • Ranbaxy laboratories limited

• Sandoz inc (has site in Sweden)

• Sun pharmaceuticals industries limited

• Teva pharmaceutical (also API manufacturer)

• Umedica laboratories

• Warner chilcott company, llc

• Xepa-soul pattinson m sdn bhd

• Xl laboratories private limited

• Zeiss oharma

• Zim laboratories

Found at pharmacompass [69]

A.2 Meropenem

• Pﬁzer Inc.

• Hospira Inc.

• ACS Dobfar S.p.A (also API manufacturer)

• Adock Ingram Healthcare

• Amneal Pharmaceuticals

• Antibiotice SA Romania

• AstraZeneca PLC

• Aurobindo Pharma Limited

• B. Braun Medical Inc.

• Bernofarm Pharmaceutical Company

• Brooks laboratories Limited

• Daewoong (also API manufacturer)

• Fresenius Kabi Austria

• GLAND PHARMA LIMITED

• Hanlim Pharmaceuticals Inc.

• HQ SPCLT PHARMA

35 • Ind Swift Laboratories Limited

• Jeil Pharmaceutical Co., Ltd.

• Jodas Expoim Pvt. Ltd

• Kaliberr Labs

• Macter International Limited

• Melinta Therapeutics

• Nishchem International Pvt. Ltd.

• RANBAXY LABORATORIES LIMITED

• Reyoung pharmaceutical

• Sandoz Inc.

• Savoir LifeTec Corperation

• Shenzhen Haibin Pharmaceutical Co. ltd (also API manufacturer)

• Sun Pharmaceuticals Industries ltd. (also API manufacturer)

• SWISS PARENTALS LTD

• Umedica Laboratories

• Zeiss Pharma

Found at pharmacompass [70]

36 B. Companies Currently Manufacturing the FDF

B.1 Cefadroxil

Powder for oral suspension Capsule Tablet Company Concentration Company Concentration Company Concentration ACS Dobfar ACS Dobfar ACS Dobfar 250 mg/5 ml 250 mg 1 g S.p.A S.p.A S.p.A ACS Dobfar ACS Dobfar Amn Life 500 mg/ 5 ml 500 mg 500 mg S.p.A S.p.A Science Aspen Amn life 250 mg/ 5 ml 500 mg Devats 500 mg Pharmacare science Aspen Antibiotice sa 500 mg/ 5 ml 500 mg Devats 250 mg Pharmacare Romania Aurobindo 500 mg/ 5 ml Apotex 500 mg Hikma 1 g (USA) Aurobindo Aspen 250 mg/ 5 ml 500 mg Teva 1 g (USA) Pharmacare Bernofarm pharmaceuti- Aurobindo 125 mg 250 mg/ 5 ml 500 mg Zeiss Pharma cal (USA) (Dispersible) company Bernofarm Bernofarm pharmaceuti- pharmaceuti- 250 mg 125 mg/ 5 ml 500 mg Zeiss Pharma cal cal (Dispersible) company company Bio Labs 125 mg/ 5 ml Bio Labs 500 mg Zeiss Pharma 500 mg Bio Labs 250 mg/ 5 ml Hikma 500 mg - - Hikma 250 mg/ 5 ml Lupin 500 mg - - Hikma 500 mg/ 5 ml MS pharma 500 mg - - Lupin 250 mg/ 5 ml Sandoz 500 mg - - Lupin 500 mg/ 5 ml Teva 500 mg - - Umedica Zeiss Pharma 125 mg 250 mg - - Laboratories Umedica Zeiss Pharma 250 mg 500 mg - - Laboratories - - Xepa Soul 500 mg - - Table updated: April 19th 2020. Information taken from the companies own website except: Aspen pharmacare was found at "Namibia Medicines Regulatory Council" website [71], Aurobindo was taken from their American website [72] & Devats and Zeiss Pharmaproducts were taken from a pdf uploaded at pharmacompass [73] [74]. No information about Nectar lifesciences limited or Cspc onyl pharmaceutical co. ltd.was found.

37 C. MAHs in EEA

C.1 Cefadroxil

Table C.1: Number of MAHs of cefadroxil products in the EEA and their geographic location of HQ

Number of MAHs in the EEA Geographic location (including Sweden) Sweden (4), Germany (3), Slovenia (1), Spain (3), 16 Romania (1), Cyprus (1), Portugal (1), France (2)

C.2 Meropenem

Table C.2: Number of MAHs of meropenem products in the EEA and the geographic location of HQ

Number of MAHs in the EEA Geographic location (including Sweden) United States (2), Sweden (1), India (4), Cyprus (6), Switzerland (1), Ireland (2), Greece (9), Romania (2), Slovenia (1), France (3), Spain (3), 59 Germany (8), Poland (3), Netherlands (2), Portugal (2), United Kingdom (2), Lithuania (1), Italy (2), Bulgaria (2), Luxembourg (1), Iceland (1), Czech Republic (1)

38 D. Supporting Documents for Health Economic Cal- culations

D.1 Cefadroxil

Table D.1: Prices for different cefadroxil products, all prices are taken from FASS

Product Package size Price Cefadroxil Mylan, powder for oral 60 ml 120.59 SEK suspension, 100 mg/ml Cefadroxil Mylan, powder for oral 100 ml 182.30 SEK suspension, 100 mg/ml Cefadroxil Mylan, 14 capsules 92.40 SEK capsules, 500 mg Cefadroxil Mylan, 20 capsules 109.09 SEK capsules, 500 mg Cefadroxil Mylan, 30 capsules 180.43 SEK capsules, 500 mg Currently Cefadroxil Sandoz, 14 capsules not capsules, 500 mg available Cefadroxil Sandoz, 20 capsules 109.28 SEK capsules, 500 mg Cefadroxil Sandoz, 30 capsules 180.43 SEK capsules, 500 mg Cefamox löslig, dispersible tablet (Ebb 10 tablets 215.26 SEK medical), 1 g Cefamox löslig, dispersible tablet 10 tablets 215.26 SEK (PharmaSwiss), 1 g Clindamycin Actavis, 20 capsules 148.49 SEK capsules (Teva), 300 mg Clindamycin Actavis, 32 capsules 145.75 SEK capsules (Teva), 300 mg Eusaprim R , oral suspension (Aspen 100 ml 48.79 SEK Nordic), 8 mg/ml + 40 mg/ml

39 All prices on cefadroxil products are from May 15th 2020 and Clindamycin Actavis and Eusaprim R is from May 17th 2020

D.2 Meropenem

Table D.2: Retrieved prices of meropenem products in different regions (as of May 13th 2020).

Package Region Product Price size Stockholm / Gotland / Meropenem Fresenius 10x20 ml 450.00 SEK Västerbotten Kabi 1 g Stockholm / Gotland / Meropenem Fresenius 10x20 ml 250.00 SEK Västerbotten Kabi 500 mg Uppsala None there found Södermanland Meronem 1 g 10x1 374.00 SEK Södermanland Meronem 500 mg 10x1 189.00 SEK Södermanland Meropenem Hospira 1 g 10x1 374.00 SEK Meropenem Hospira 500 Södermanland 10x1 189.00 SEK mg Kronoberg Meropenem Bradex 1 g 10x1 369.00 SEK Meropenem Bradex 500 Kronoberg 10x1 227.00 SEK mg Blekinge Meropenem Stada 1 g 10x1 369.00 SEK Meropenem Stada 500 Blekinge 10x1 203.00 SEK mg Skåne Meropenem SUN 1 g 10x1 549.00 SEK Meropenem SUN 500 Skåne 10x1 328.00 SEK mg Örebro None there found

Meropenem Meropenem 1 g 500 mg Average price 407.00 SEK 227.20 SEK SD 71.04 SEK 52.28 SEK CV 17 % 23 %

Table of retrieved prices of meropenem products in different regions. Including average price, standard deviation (SD), and coefﬁcient of variation (CV). Prices can be found at respective regions website. [75] [76] [77] [78] [79] [80]

40 Table D.3: Retrieved prices of imipenem products in different regions (as of May 13th 2020).

Package Region Product Price size Imipenem/Cilastatin Stockholm / Gotland / Fresenius Kabi 500 10x20 ml 445.00 SEK Västerbotten mg/500 mg Uppsala None there found Imipenem/Cilastatin Södermanland Fresenius Kabi 500 10x20 ml 400.00 SEK mg/500 mg Kronoberg None there found Imipenem/Cilastatin Blekinge Fresenius Kabi 500 10x1 550.00 SEK mg/500 mg (Excluded) Skåne None there found Imipenem/Cilastatin Örebro Fresenius Kabi 500 10x20 ml 400.00 SEK mg/500 mg

Imipenem/Cilastatin 500 mg/500 mg Average price 415.00 SEK SD 21.21 SEK CV 5 %

Table of retrieved prices of imipenem products in different regions. Including average price, standard deviation (SD), and coefﬁcient of variation (CV). Prices can be found at respective regions website. The product sold in Blekinge is excluded due to the dosage form being solid and can therefor not be directly compared to infusion dosage forms. [75] [76] [77] [78] [80]

41 E. Calculations

E.1 Cefadroxil

E.1.1 Conversion Between Volume and Mass

The oral suspension has the concentration 100 mg/ml meaning there is 100 mg API per ml suspension. To calculate the amount of API (m), the volume (V) is simply multiplied with concentration (C).

C ·V = m

For 60 ml units:

100 mg/ml · 60 ml = 6000 mg = 6 g

For 100 ml units:

100 mg/ml · 100 ml = 10000 mg = 10 g

E.1.2 Amount of Cefadroxil Capsules

There is 6 g API in a 60 ml unit of oral suspension and 10 g in a 100 ml unit. The amount of API must be the same so the amount of capsules needed to receive the same dose can be calculating by dividing the amount of API in the oral suspension with the amount of API in a capsule (500 mg). 60 ml unit: 6 g 6000 mg = = 12 capsules 500 mg/capsule 500 mg/capsule

100 ml unit: 10 g 10000 mg = = 20 capsules 500 mg/capsule 500 mg/capsule

E.1.3 Amount of Clindamycin Capsules

The max dosage of cefadroxil is 10 g API 2 times a day, this is 2x100 ml units of Cefadroxil. The max dosage for Clindamycin Actavis is 4 capsules a day but it isn’t stated on FASS for how many days the cure is. For this report it is assumed that the cure is 10 days because that is the "standard" for antibiotics. 4 capsules a day for 10 days is 40 capsules per cure. So when treating a patient, the max dosage of 2x100 ml units of cefadroxil can be exchanged for 40 capsules of clindamycin. To calculate how many capsules that are needed to replace a 60 ml cefadroxil unit the data calculated in appendix E.1.1 can be used. Each 60 ml unit contain 6 g API and each 100 ml unit contain

42 10 g API. Each patient uses 2 units so 12 g API is used if the patient has 60 ml units and 20 g API if they use 100 ml units. By dividing 12 g with 20 g the dose can be calculated in %: 12 g = 0.6 = 60 % 20 g So if 2x60 ml units are used it is only 60 % of the max dosage. This percentage can be used to calculate the amount of capsules needed to exchange a dose of 2x60 ml cefadroxil by simply multiplying the max dosage of 40 capsules with 0.6 (60 %).

40 capsules · 0.6 = 24 capsules

So 2x100 ml units of cefadroxil can be exchanged for 40 capsules of Clindamycin Actavis and 2x60 ml units with 24 capsules.

E.1.4 Amount of Eusaprim R

This calculation is similar to the one in appendix E.1.3. The dosage stated on FASS is 20 ml twice a day for a maximum of 7 days, for a max dose of 280 ml. These values are for acute infections but in this report we assume that is the dose used in this case as well because no doctor could be interviewed for exact dosages. 280 ml is then the replacement for a max dosage of cefadroxil. According to FASS, for acute infections all adults take 20 ml twice a day. For this report it is assumed that they can take a lower dose to compensate for taking 2x60 ml units of cefadroxil. Using that a dose of 2x60 ml units only is 60 % of the max dosage (appendix E.1.3) how much Eusaprim R is needed to compensate can be calculated:

280 ml · 0.6 = 168 ml

So 2x100 ml units of cefadroxil can be exchanged for 280 ml of Eusaprim R and 2x60 ml units can be exchanged for 168 ml.