Availability of essential medicines in the Czech Republic

March 15
th
, 2017
AVAILABILITY OF ESSENTIAL MEDICINES
IN THE CZECH REPUBLIC
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Publication date: March 15, 2017

Availability of Essential Medicines in the Czech Republic 2017
A R E T E - Z O E , L L C 1 3 3 4 E C h a n d l e r B l v d 5 A - 1 9 , P h o e n i x 8 5 0 4 8 A Z U S A Page 2
Executive Summary
This report analyzes availability of essential medicines as defined in the World Health Organization (WHO) Essential List
Medicines (Report of the WHO Expert Committee) in the Czech Republic. The WHO list of essential medicines contains most
effective and safe medicines needed to meet the most important needs in health systems, and is frequently used by countries
to create their own national lists. Without these drugs, some conditions will not be able to receive optimal therapy. Availability
gap represents serious public health concern.
Expert Committee of the World Health Organization selects Essential Medicines Lists in accordance with approved procedures.
The Committee evaluates the scientific evidence on the basis of the comparative effectiveness, safety and cost–effectiveness
of the medicines. Both lists (adult and pediatric) went through major revisions in 2015, as the Committee considered 77
applications, including 29 treatment regimens for cancer, hepatitis C and tuberculosis (The Selection And Use Of Essential
Medicines. Report Of The WHO Expert Committee, 2015)
1
Local availability is expressed as registration, in the form of total number of licensed products, and number of marketed
products, i.e. products that were on the market in Q3 2016. Of the total number of 13,256 individual registrations for essential
medicines, only 2,110 (14%) were actively marketed in Q3 2016. Total number of licensed and marketed product equals all
strengths, formulations and dosage forms counted separately. The dataset is current as of December 30, 2016. Any revisions to
the database made in the period between data download and publication of this report are not considered. Locally available
products were compared to the WHO list of essential medicines. The material is presented in graphs and summary tabulations
as listed in the table of contents.
The report provides overview of the situation in the Czech Republic. Essential medicines availability gap represents both public
health concern and risk of harm to individual patients. Substitute and second line therapies are often less effective, more toxic,
or more expensive. Improvisation and the use of less familiar medicines are more likely to lead to medication errors. Mitigation
of shortages and creation of shared contingency supplies puts additional strain on understaffed hospitals, in addition to human
toll inflicted by social stress. Drug shortages make it impossible to follow evidence-based practice guidelines, and force
decisions to prioritize certain group of people over another. Public health concerns arise due to inability to prevent and treat
contagious diseases such as tuberculosis. Significant resources have to be dedicated to overseeing and managing the situation
at government and supranational level.
Of the 427 essential medicines, 311 are registered. Of these, 292 essential medicines showed active marketing in Q3 2016 and
19 were registered but not marketed. 116 (27%) were not registered, and therefore not available, rather than in shortage
locally. Availability gap amounts to 135 (32%) essential medicines for both unregistered and not marketed essential medicines.
However, essential medicines that are not available locally significantly overlap with medicines that are in periodic or chronic
global shortage. Examples of the most significant global shortages of essential medicines are presented in the context of local
availability gap. The Czech Republic is a small market with complex regulatory environment and inconsistently applied and
enforced rules that often change in response to political demand. Alternative sources currently include parallel import from
other EU countries. Attempts to obtain essential medications from alternative sources provide opportunity for the introduction
of counterfeit, falsified and substandard drugs into clinical practice.
Of the 427 essential drugs, 311 are registered in the Czech Republic, 292 were registered and marketed
in Q3 2016, 19 were registered but not marketed, and 135 (32%) were unavailable. Most affected
classes are antibacterials, antituberculars, antiretrovirals, antiparasitics, and dermatologicals. Essential
medicines availability gap overlaps significantly with drugs that are in shortage globally.

SYNOPSIS
 Essential medicines are mainly generic formulations that are relatively inexpensive to
buy but not necessarily cheap to make.
 Problematic availability of essential medicines affects all countries around the globe,
not just the Czech Republic.
 Most affected drugs are parenteral nutrition components, sterile injectables, anti-
bacterials, anti-tuberculars, anti-retrovirals, tuberculin, vaccines, oncology drugs,
anesthetics, anti-malarial drugs, anti-parasitics and others.
 Most drugs in shortage are difficult or impossible to replace, and workaround solutions
are usually less effective, more toxic, and/or more costly.
 Main causes of drug shortages are consolidation of the industry, lack of competition,
low profit margin of some generic drugs, production issues, raw material availability,
business decisions and regulatory actions.
 Additional issues include sudden price hikes following acquisition and rebranding of old
generic products as well as for-profit adulteration (heparin).
 Counterfeit, falsified and substandard drugs reach both hospitals and individuals
through illegal supply chains. Common findings include cancer drugs, anti-retrovirals,
anti-malarials and anti-tuberculars.

About ARETE-ZOE
ARETE-ZOE, as a consultancy, provides solutions to complex problems in the high stakes and high consequence environment of
Global Pharmaceuticals, including clinical research, healthcare informatics, and public health. We blend established, Pharma
sector methodologies, innovation, and adaptations/transfers from other sectors to identify and resolve consequential practices
that pose risk and often result in avoidable patient casualty. However, we are specifically, not a patient advocacy group but
believe in optimizing organizational effectiveness and that smart business is agile, competitive and profitable, while
intrinsically safe, secure, and resilient.
We work within a global context because transnational interests influence national circumstances and choices at point of
prescription.
ARETE-ZOE provides full spectrum organizational and operational risk management consultancy. Our published materials
provide a glimpse of some aspects of our services to demonstrate both knowledge and ongoing participation within the
Pharmaceutical Industry. Our analysis and consultancy includes all channels of misuse, diversion, counterfeiting and illicit
exploitation of pharmaceuticals, medical devices, and precursor chemicals. Our advisement is to manufactures, jurisdictional
entities, insurers, legislators, litigators, patients, and health care providers.
This scope also frequently segues into the nexus of crime and terrorism as significant influencers that undermine sector
integrity differentiated from other criminal activity. Obviously, vulnerability assessment, information collection management
and intelligence production supporting decision-making for risk reduction and interventions are routinely within the scope of
our services as well as design and implementation of operational control measures.

TABLE OF CONTENTS
Executive Summary...........................................................................................................................................................................2
Synopsis.............................................................................................................................................................................................3
About ARETE-ZOE..............................................................................................................................................................................4
Table of Contents ..............................................................................................................................................................................5
I. Analysis and Interpretation..........................................................................................................................................................10
Relevance of unavailability of essential medicines for health care systems:..................................................................................13
II. Situation in the Czech Republic...................................................................................................................................................14
Alimentary tract and metabolism ...................................................................................................................................................14
Blood and blood forming organs.....................................................................................................................................................15
Cardiovascular system.....................................................................................................................................................................15
Dermatologicals...............................................................................................................................................................................16
Genito-urinary products and sex hormones ...................................................................................................................................16
Hormones for systemic use, excluding sex hormones and insulins ................................................................................................17
Antiinfectives for systemic use........................................................................................................................................................17
Antineoplastic products ..................................................................................................................................................................18
Musculoskeletal system ..................................................................................................................................................................19
Nervous system...............................................................................................................................................................................19
Antiparasitics...................................................................................................................................................................................19
Respiratory system..........................................................................................................................................................................20
Sensory organs ................................................................................................................................................................................20
Various ............................................................................................................................................................................................20
III. Significant global drug shortages ...............................................................................................................................................21
Parenteral nutrition components....................................................................................................................................................21
Sterile injectable drugs....................................................................................................................................................................21
Adulterated heparin........................................................................................................................................................................21
Sudden price spikes in off-patent prescription drugs .....................................................................................................................22
Antibacterials ..................................................................................................................................................................................22
Front-line tuberculosis therapy.......................................................................................................................................................23
Drugs for the treatment of HIV/AIDS and other antivirals..............................................................................................................23
Immune sera and immunoglobulins................................................................................................................................................24
Vaccines...........................................................................................................................................................................................24

Miltefosin ........................................................................................................................................................................................25
Oncology drugs................................................................................................................................................................................25
Central Nervous System..................................................................................................................................................................25
Antimalarial drugs ...........................................................................................................................................................................26
Pharma Bro: Daraprim (pyrimethamine) and the like.....................................................................................................................26
IV. Conclusion..................................................................................................................................................................................27
APPENDIX 1 Availability of essential medicines in the Czech Republic...........................................................................................28
TABLE 1 - Summary (table): Availability of essential medicines by organ class ..............................................................................28
GRAPH 1 – Summary (graph): Availability of essential medicines by organ class...........................................................................29
Alimentary Tract and Metabolism (A).............................................................................................................................................30
GRAPH 2 – Summary (graph): Availability of registered and marketed products (A) .....................................................................30
GRAPH 3 - Acid related disorders (A02), functional GIT disorders (A03), and antiemetics and antinauseants (A04) ....................31
GRAPH 4 - Constipation (A06), antidiarrheals (A07) and digestives incl. enzymes (A09) ...............................................................31
GRAPH 5 - Drugs used in diabetes (A10) .........................................................................................................................................32
GRAPH 6 - Vitamins (A11) and mineral supplements (A12)............................................................................................................33
Blood and Blood-forming organs (B)...............................................................................................................................................34
GRAPH 7 - Summary: Availability of registered and marketed products (B)...................................................................................34
GRAPH 8 - Anti-thrombotic agents (B01) ........................................................................................................................................35
GRAPH 9 – Anti-hemorrhagic agents (B02).....................................................................................................................................35
GRAPH 10 – Anti-anemic agents (B03)............................................................................................................................................36
GRAPH 11 - Blood substitutes and perfusion solutions (B05).........................................................................................................37
Cardiovascular system (C) ...............................................................................................................................................................38
GRAPH 12 – Summary (graph): Availability of registered and marketed products (C) ...................................................................38
GRAPH 13 - Cardiac therapy (C01) ..................................................................................................................................................39
GRAPH 14 - Diuretics (C02) and peripheral dilatators (C03) ...........................................................................................................40
GRAPH 15 - Beta-blockers (C07), Calcium-channel blockers (C08), renin-angiotensin system (C09) and lipid modifiers (C10).....40
Dermatologicals (D).........................................................................................................................................................................41
GRAPH 16 – Summary (graph): Availability of registered and marketed products (D)...................................................................41
GRAPH 17 - Antifungals (D01), emollients and protectives (D02)...................................................................................................42
GRAPH 18 - Antipsoriatics (D05), antibiotics (D06) and corticosteroids (D07) ...............................................................................42
GRAPH 19 - Antiseptics and disinfectants (D08), anti-acne preparations (D10).............................................................................43
Genito-urinary system and sex hormones (G) ................................................................................................................................44
GRAPH 20 – Summary (graph): Availability of registered and marketed products (G)...................................................................44
GRAPH 21 - Antiinfectives and antiseptics (G01), other gynecologicals (G02) ...............................................................................45

GRAPH 22 - Sex hormones and modulators of the genital system (G03) .......................................................................................46
Hormones for systemic use, excl. sex hormones and insulins (H) ..................................................................................................47
GRAPH 23 - Summary: Availability of registered and marketed products (H) ................................................................................47
Antiinfectives for systemic use (J) ...................................................................................................................................................48
GRAPH 24 - Antibacterials (J01): Summary: Availability of registered and marketed products (J01)............................................48
GRAPH 25 – Antibacterials (J01) - Tetracyclines (J01A), Amphenicols (J01B), Penicillins (J01C).....................................................49
GRAPH 26 – Antibacterials (J01) - Non-penicillin beta-lactams (J01D) ...........................................................................................49
GRAPH 27 – Antibacterials (J01) - Sulfonamides and Trimethoprim (J01E) and Macrolides, Lincosamides and Streptogramins
(J01F) ...............................................................................................................................................................................................50
GRAPH 28 – Antibacterials (J01) - Aminoglycosides (J01G) and Quinolones (J01M) ......................................................................50
GRAPH 29 – Antibacterials (J01) - Other antibacterials (J01X)........................................................................................................51
GRAPH 30 - Antifungals (J02) ..........................................................................................................................................................52
GRAPH 31 - Antimycobacterials (J04) – Summary (graph): Availability of registered and marketed products (J04) .....................53
GRAPH 32 - Antimycobacterials (J04) – Tuberculosis: Aminosalicylic acid and derivatives (J04AA), Antibiotics (J04AB),
Hydrazides (J04AC) and thiocarbamides (J04AD)............................................................................................................................54
GRAPH 33 - Antimycobacterials (J04) – Other antituberculars (J04AK) and combinations (J04AM), drugs for the treatment of
leprosy (J04B) ..................................................................................................................................................................................54
GRAPH 34 - Antivirals (J05) – Summary (graph): Availability of registered and marketed products (J05) .....................................55
GRAPH 35 - Antivirals (J05) – Nucleosides and nucleotides excl. reverse transcriptase inhibitors (J05AB) and Protease inhibitors
(J05AE).............................................................................................................................................................................................56
GRAPH 36 - Antivirals (J05) – Nucleoside and nucleotide reverse transcriptase inhibitors (J05AF), Non-nucleoside reverse
transcriptase inhibitors (J05AG) and Neuraminidase inhibitors (J05AH) ........................................................................................57
GRAPH 37 - Antivirals (J05) – Antivirals for treatment of HIV infections, combinations (J05AR) and other antivirals (J05AX) ......58
GRAPH 38 - Immune sera and immunoglobulins (J06)....................................................................................................................59
GRAPH 39 - Vaccines (J07) – Summary (graph): Availability of registered and marketed products (J07) ......................................60
GRAPH 40 - Vaccines (J07) – Bacterial vaccines (J07A) ...................................................................................................................61
GRAPH 41 - Vaccines (J07) – Viral vaccines (J07B) and combined viral and bacterial vaccines (J07C) ...........................................62
Antineoplastic and immunomodulating agents (L) .........................................................................................................................63
GRAPH 42 – Summary (graph): Availability of registered and marketed products (L)....................................................................63
GRAPH 43 - Antineoplastic agents (L01) - Alkylating agents (L01A)................................................................................................64
GRAPH 44 - Antineoplastic agents (L01) Antimetabolites (L01B)....................................................................................................64
GRAPH 45 - Antineoplastic agents (L01) Plant alkaloids and other natural products (L01C)..........................................................65
GRAPH 46 - Antineoplastic agents (L01) - Cytotoxic antibiotics (L01D) ..........................................................................................65
GRAPH 47 - Antineoplastic agents (L01) Other antineoplastic agents (L01X).................................................................................66
GRAPH 48 - Endocrine therapy (L02)...............................................................................................................................................67
GRAPH 49 - Immunostimulants (L03) and Immunosuppressants (L04) ..........................................................................................67

Musculo-skeletal system (M) ..........................................................................................................................................................68
GRAPH 50 – Musculoskeletal system..............................................................................................................................................68
Nervous system (N) .........................................................................................................................................................................69
GRAPH 51 – Summary (graph): Availability of registered and marketed products (L)....................................................................69
GRAPH 52 - General anesthetics (N01A), Local anesthetics (N01B)................................................................................................70
GRAPH 53 - Analgesics (N02A) and Antiepileptics (N03) ................................................................................................................70
GRAPH 54 - Anti-Parkinson drugs (N04) and Psycholeptics (N05) ..................................................................................................71
GRAPH 55 - Psychoanaleptics (N06) and Other nervous system drugs (N07).................................................................................71
Antiparasitic products, insecticides and repellents (P) ...................................................................................................................72
GRAPH 56 – Summary (graph): Availability of registered and marketed products (P) ...................................................................72
Respiratory system (R) ....................................................................................................................................................................73
GRAPH 57 – Summary (graph): Availability of registered and marketed products (R) ...................................................................73
Sensory organs (S)...........................................................................................................................................................................74
GRAPH 58 – Summary (graph): Availability of registered and marketed products (S)....................................................................74
Various (V).......................................................................................................................................................................................75
GRAPH 59 – Summary (graph): Availability of registered and marketed products (V) ...................................................................75
APPENDIX 2 Essential medicines unavailable in the Czech Republic ..............................................................................................76
TABLE 2 - Alimentary tract and metabolism (A)..............................................................................................................................76
TABLE 3 - Blood and blood forming organs (B) ...............................................................................................................................76
TABLE 4 - Cardiovascular system (C) ...............................................................................................................................................76
TABLE 5 - Dermatologicals (D).........................................................................................................................................................77
TABLE 6 - Genito-urinary system and sex hormones (G).................................................................................................................77
TABLE 7 - Systemic hormonal preparations, excl. sex hormones and insulins (H)..........................................................................77
TABLE 8 - Antiinfectives for systemic use (J) ...................................................................................................................................78
TABLE 9 - Antineoplastic and immunomodulating agents (L) .........................................................................................................79
TABLE 10 - Musculo-skeletal system (M) ........................................................................................................................................79
TABLE 11 - Nervous system (N) .......................................................................................................................................................79
TABLE 12 - Antiparasitic products, insecticides and repellents (P) .................................................................................................80
TABLE 13 - Respiratory system (R) ..................................................................................................................................................81
TABLE 14 - Sensory organs (S) .........................................................................................................................................................81
TABLE 15 - Various (V).....................................................................................................................................................................81
APPENDIX 3 Essential medicines unavailable in the Czech Republic: Global context.....................................................................82
TABLE 16 - Alimentary tract and metabolism (A)............................................................................................................................82
TABLE 17 - Blood and blood forming organs (B) .............................................................................................................................83

TABLE 18 - Cardiovascular system (C) .............................................................................................................................................83
TABLE 19 - Dermatologicals (D).......................................................................................................................................................84
TABLE 20 - Genito-urinary system and sex hormones (G)...............................................................................................................85
TABLE 21 - Systemic hormonal preparations, excl. sex hormones and insulins (H)........................................................................85
TABLE 22 - Antiinfectives for systemic use (J) .................................................................................................................................86
Antibacterials ..................................................................................................................................................................................86
Antifungals ......................................................................................................................................................................................86
Antimycobacterials..........................................................................................................................................................................87
Antivirals..........................................................................................................................................................................................88
Immune sera and immunoglobulins................................................................................................................................................89
Vaccines...........................................................................................................................................................................................89
TABLE 23 - Antineoplastic and immunomodulating agents (L) .......................................................................................................90
TABLE 24 - Musculo-skeletal system (L)..........................................................................................................................................90
TABLE 25 - Nervous system (N) .......................................................................................................................................................91
TABLE 26 - Antiparasitic products, insecticides and repellents (P) .................................................................................................92
TABLE 27 - Respiratory system (R) ..................................................................................................................................................94
TABLE 28 - Sensory organs (S) .........................................................................................................................................................94
TABLE 29 - Various (V).....................................................................................................................................................................95
TABLE 30 – Essential medicines unavailable in the Czech Republic: alternative sources ...............................................................96
APPENDIX 4 - Essential medicines available in the Czech Republic: Registration and marketing................................................ 102
GRAPH – 60 – Essential medicines available in the Czech Republic: Share of products marketed in Q3 2016 ........................... 102
GRAPH – 61 – Essential medicines available in the Czech Republic: Share of products marketed in Q3 2016 by organ class.... 103
GRAPH – 62 – Essential medicines available in the Czech Republic: Availability gap .................................................................. 104
GRAPH – 63 – Essential medicines available in the Czech Republic: Availability gap by organ class........................................... 105
References.................................................................................................................................................................................... 106

I. Analysis and Interpretation
Of the 427 essential medicines, 311 are registered in the Czech Republic. Of these, 292 (68%) essential medicines showed
active marketing in Q3 2016 and 19 (5%) were registered but not marketed. 116 (27%) were not registered, and therefore not
available, rather than in shortage locally. Availability gap amounts to 135 (32%) essential medicines for both unregistered and
not marketed essential medicines. Of the total number of 13,256 registrations for essential medicines, only 2,110 (14%)
showed active marketing in Q3 2016.
However, essential medicines that are not available locally significantly overlap with medicines that are in periodic or chronic
global shortage. Examples of the most significant global shortages of essential medicines are presented in the context of local
availability gap. The Czech Republic is a small market with complex regulatory environment and inconsistently applied and
enforced rules that often change in response to political demand. Alternative sources currently include parallel import from
other EU countries. Attempts to obtain essential medications from alternative sources provide opportunity for the introduction
of counterfeit, falsified and substandard drugs into clinical practice.
The Czech Republic is a small market with complex regulatory environment and inconsistently applied and enforced rules that
often change in response to political demand. Most essential drugs that are not available in the Czech Republic were not
registered, and therefore not available, rather than in shortage. Essential medicines that are not available in the Czech
Republic significantly overlap with drugs that have been experiencing chronic or periodic shortages worldwide.
 Of the 427 essential drugs, 311 are registered in the Czech Republic, 292 were marketed in Q3 2016,
and 135 (32%) are unavailable. Detailed breakdown of registered, marketed and unavailable
essential medicines can be found in Summary table and Summary graph in Appendix 1.
 Of the 13,256 registrations for essential medicines, only 2,110 (14%) showed active marketing.
 Most affected classes are antiparasitic medications, dermatologicals, drugs against tuberculosis and
HIV/AIDS, and antibacterials. Full breakdown of registered and marketed essential medications can
be found in Appendix 1. The dataset is presented as a summary and then in detail by organ class
and ATC subclass, as relevant/appropriate.
 Majority of essential medicines that are not available in the Czech Republic are not registered
locally. Several essential medicines are registered but not marketed. For list of essential medicines,
that are unavailable in the Czech Republic, refer to Appendix 2.
 Unavailable essential medicines overlap significantly with drugs that are in shortage globally. For
essential medicines that are unavailable in the Czech Republic, and additional information on global
shortages of these drugs, refer to Appendix 3.
Global concern: Drug shortages of essential medicines have existed for more than a decade. The issue affects all countries
around the globe, developed and developing alike, not just the Czech Republic. Essential medicines, with a few exceptions, are
off-patent generic formulations that are relatively inexpensive to buy but not necessarily easy to make. Generic status of these
medicines leaves them open to competition and reduces return on investment. In manufacturing practice, inexpensive generic
formulations are less likely to be emphasized because of competition over equipment and prioritization of products that
provide higher return on investment. Market prices are pushed down further by hospital procurement systems that have to
prioritize low cost over any other criteria at all times. In clinical practice, essential medicines are difficult or impossible to
replace. Proprietary solutions are usually less effective, more toxic, and/or more costly.

Pharmaceutical industry has experienced profound change since the 1980s. The current geography of pharmaceutical
manufacturing and markets is the result of long-term trends: industry consolidation through acquisition and mergers,
globalization, and outsourcing of key operations to low cost regions. Physical location of manufacturing does not necessarily
correlate with corporate headquarters; in fact, many raw materials are now produced solely in Asia.
Essential medicines most affected by global shortages are parenteral nutrition components, sterile injectable drugs,
antibacterials, and front line tuberculosis therapy, drugs for the treatment of HIV/AIDS, immune sera and immunoglobulins,
tuberculin, vaccines, oncology drugs, anesthetics, sedatives, anti-malarial drugs, and anti-parasitic medications. Additional
concerns include sudden price hikes following acquisition and rebranding of generic products, as well as for profit adulteration
(heparin).
Local impact: In addition to limited global availability of these drugs, it may be difficult for the Czech Republic to find a supplier
for other reasons as well. The main reasons are low profit margin, low price level for pharmaceuticals due to authorized
reimbursement rates as cost controls, and monetary inducements to prescribe more expensive medicines. Reduced incident
rate for demand as originally developed, however, is relevant for contemporary combination therapies, which makes
unavailability more problematic. Pharmaceutical manufacturers tend to prioritize bigger markets where detailed contractual
obligations apply. Complex regulatory environment, inconsistent and unpredictable enforcement, administration
overresponsive to political pressures, and complicated procurement compound the problem. Some essential medicines are
available in other EU countries from which they could be obtained through parallel import (See Table 30 in Appendix 4).Only
two essential medicines, IMPLANON (etonorgestrel) and OKRIDO (prednisolone) are available through the EU centralized
registration process
2
., which means all the other unavailable essential medicines have to be acquired through a more
byzantine acquisition path. EudraPharm
3
database has been established to fulfil Articles 57(1)(l) and 57(2) of Regulation (EC)
No 726/2004. EudraPharm is intended to be a source of information on all medicinal products for human or veterinary use that
have been authorised in the European Union (EU) and the European Economic Area (EEA) and information on clinical trials. The
database, however only includes data entered by Portugal and the European Commission.
Root causes: Main causes of global drug shortages are consolidation of the industry, lack of competition due to suppliers
exiting the market, and monopolization. Additional causes identified in various industry analyses are low profit margin,
production issues, and raw material availability. In addition, regulatory actions against manufacturers that fail to comply with
good manufacturing practice and occasional import bans may force significant investment in modernization of production or
business decision to exit the market. Business decisions to discontinue products for which there is low or unpredictable
demand and reallocation of resources to prioritize products with higher return on investment compound the problem. This
creates conditions that are exploited by counterfeiters.
U.S. Government Accountability Office (GAO) Report to Congress (2016) highlighted the fact that many manufacturers had a
long history of manufacturing compliance failures, and that declining number of suppliers was more likely to lead to shortage
of drugs on the market. In addition, due to low profit margins of generic drugs, and especially sterile injectable formulations,
manufacturers were less likely to increase production to meet market demand (U.S. Government Accountability Office)
4
. Due
to the fact that natural market forces are unlikely to reduce the shortfall, government intervention may be necessary to ensure
supply availability.
Canadian report on drug shortages identified additional causes of increased demand: new indication for a generic drug,
changes in guidelines, or disease outbreaks often result in inability of production to keep pace, especially if the manufacturing
process is lengthy and complicated by multiple sourcing of raw materials. Business decisions to discontinue certain drugs or
reallocation of resources and production capacity have the same effect. Regulatory requirements, import bans and expenses
required to remedy them are another common cause of drug shortages and discontinuations. Additional problems include the
fact that many manufacturers are located in countries that have less stringently enforced safety and regulatory standards.

Quality controls become more challenging because raw materials may be imported from a third party. Finally, communication
of upcoming shortages is essential to mitigate their impact (Multi-Stakeholder Steering Committee on Drug Shortages)
5
.
Major drug producing countries like China are not spared, either. According to survey conducted in Shaanxi province, 8
traditional Chinese medicines and 87 types of biologicals and chemicals were reported to be in short supply, most of them
essential medicines. The main determinants identified by the authors were low prices, low market demand, Good
Manufacturing Practice (GMP) issues, materials issues, and regulatory hurdles for imported drugs (Yang et al.)
6
.
Counterfeit, falsified and substandard medications: Whilst producers of counterfeit products mainly focus on lifestyle drugs
and common drugs of abuse that are easy to sell through illicit channels, such as erectile dysfunction medications,
benzodiazepines, steroids or anti-obesity drugs, essential medicines are now also increasingly found on the black market
(Newsweek)
7
. Europol in its 2016 report on counterfeiting in the European Union considers fake pharmaceuticals a major
hazard (Europol)
8
. The most common findings are cancer drugs, anti-infectives such as treatments for HIV/AIDS
(SafeMedicines)
9
, tuberculosis, or common antibiotics, and anti-malarials (Kelesidis and Falagas)
10
, but also diabetes
medications and others. Although counterfeit anti-infective and anti-parasitic drugs are traditionally a problem in Africa and
Asia (Almuzaini, Choonara and Sammons)
11
, they are now reaching Europe as well. Security and integrity of pharmaceutical
supply chain in Europe made significant progress due to Falsified Medicines Directive and obligatory safety features on
pharmaceutical packaging. However, many of these measures have yet to be implemented (European Medicines Agency)
12
.
Currently, the main concerns in U.S. and European hospital supply chains are cancer drugs (Europol)
13
and (CatalystPhrma)
14
. In
2012, counterfeit bevacizumab reached U.S. cancer patients (Food and Drug Administration)
15
, and in 2014, EMA warned
against counterfeit Herceptin (European Medicines Agency)
16
Consequences: Essential medicines availability gap represents both public health degradation and risk of harm to individual
patients. Substitutions and second line therapies are often less effective, more toxic, or more expensive. Improvisation and the
use of less familiar medicines lead to medication errors. Mitigation of shortages and creation of shared contingency supplies
puts additional strain on understaffed hospitals. However, unavailability inflicts social stress from patients’ and physicians’
frustration, anger and feeling of helplessness. Drug unavailability makes it impossible to follow evidence-based practice
guidelines, and force consequential decisions to prioritize certain group of people over another. Public health concerns arise
due to inability to prevent and treat contagious diseases such as tuberculosis. Significant resources have to be dedicated to
overseeing and managing the situation at government and supranational level. Legal importation is often bureaucratic and
burdensome, and unresponsive to therapeutic necessity. Procurement rules forced by state budgetary practices such as just-
in-time supply chain compound vulnerability to interruptions. Attempts to obtain essential medications from alternative
sources provide opportunity for the introduction of counterfeit, falsified and substandard drugs into clinical practice. Natural
market dynamics will not make essential medicines available without specific regulatory intervention or concerted advocacy by
caregivers and patients.

Relevance of unavailability of essential medicines for health care systems:
Clinical
Practitioners
 Inability to follow evidence-based guidelines forces the
use of alternatives.
 Alternative and second line therapies are often less
effective, more toxic, or more expensive.
 Improvisation and use of less familiar products leads to
medication errors.
 Off-label use of familiar drugs affects treatment outcome,
and introduces additional liabilities.
 Frustration, anger, feeling of helplessness strains
professional relationships and stalls collaboration.
 Consequential decisions have to be made to prioritize
certain group of people over another.
Hospital
administration
 Mitigation of shortages and creation of contingency plans
is labor intensive and puts additional strain on staff
 Triage guidelines institutionalize discrimination, often in
favor of vulnerable groups.
 Contingency plans and alternative treatment options are
often less effective, more toxic and more expensive.
 Search for legal import options is bureaucratic and labor
intensive, and often to slow
 Counterfeit, substandard and falsified products are a
concern when less familiar distributors have to be used.
Pharmacists
 Mitigation of shortages and communication with hospitals
and practitioners adds to staff workload
 Not all products can be adequately replaced
 Search for legal import options is bureaucratic and labor
intensive, slow, and labor intensive
 Expensive and rarely used alternative treatment options
introduce additional potential liabilities
Public
officials
and
State
Administration
 Unavailability of essential medicines represents public
health issue and poses risk for individual patients.
 Mitigation of shortages leads to trade-offs between GMP
and other requirements and ensuring access.
 Inability to prevent and treat contagious diseases forces
introduction of unpopular measures such as isolation
 Cost of treatment of certain diseases can increase
dramatically
 Supranational organizations and joint task forces may
have to be established to mitigate the situation
successfully
 Significant dedicated resources including external
consultants and diversion of staff from other tasks.
Individual
Patients
 Postponed non-emergency surgeries and procedures,
affecting quality of life and ability to work
 Adverse outcomes caused by improvisation, errors, and
efficacy/toxicity of alternative treatments
 Direct treatment costs, indirect costs caused by prolonged
treatment, disability and time off work
 Isolation due to major public health threats (tuberculosis)
 Self-medication with drugs from illicit sources may lead to
deleterious health consequences.

II. Situation in the Czech Republic
Focus of the following analysis is on essential medicines that are not available in the Czech Republic, and evaluation of the
situation in the context of global drug shortages. Czech Republic, as a small market with low prices levels, may have difficulty
securing access to essential medicines that are in short supply globally. The World Health Organization (WHO) considers 427
drugs essential for health systems. Of these, 311 are registered in the Czech Republic, 292 were on the market in Q3 2016, and
135 (32%) are currently unavailable. Availability gap in the Czech Republic amounts to 135 (32%) essential medicines for both
unregistered and not marketed essential medicines. Worst affected groups include anti-parasitic drugs and antiinfectives,
especially drugs for the treatment of tuberculosis and HIV/AIDS, and dermatologicals. The data is presented in detail in
appendices.
 Appendix 1 – Availability of essential medicines in the Czech Republic shows summary table and summary graph of
total number of essential medicines by their generic names and their availability in the Czech Republic by organ class.
The series of graphs shows detailed breakdown of all system organ classes by availability of essential drugs.
 Appendix 2 – Essential medicines unavailable in the Czech Republic lists all essential medicines not available in the
Czech Republic, organized by organ class. The table includes information about number of registrations and number of
marketed products.
 Appendix 3 – Essential medicines unavailable in the Czech Republic: Global context lists all essential drugs
unavailable in the Czech Republic in a summary table by organ class, adds information on patent status of the drug
and main indication, and makes mention of major shortages of the products worldwide.
 Appendix 4 – Essential medicines available in the Czech Republic: Registration and marketing compares the share of
actively marketed products and products that are registered but not marketed.
Alimentary tract and metabolism
There are 34 medicines listed on the World Health Organization (WHO) list of essential drugs, of which 25 are currently
approved for marketing and available to patients. As of December 29, 2016, 9 (26%) were unavailable in the Czech Republic.
The highest share of approved and marketed drugs was found for glucose lowering agent metformin (657 approvals/54
marketed), gastric ulcer medication omeprazole (430/52), fast-acting insulin (153/17) and oral hypoglycemic agent gliclazide
(144/13).
Unavailable medications include motion sickness drug hyoscine (scopolamine) hydrobromide, docusate sodium – drug for the
treatment of constipation, intestinal anti-infective paromomycin, ready to use formulations of oral rehydration therapy salts,
hydrocortisone for topical rectal use, vitamins nicotinamide and riboflavin, zinc sulfate and sodium fluoride. Significant
number of medicines for the treatment of alimentary ailments is only available in very limited number of registrations, making
the system vulnerable to disruption: calcium gluconate (1/1), pyridoxine (2/2), thiamine (2/2), glibenclamide (2/1), atropine
(2/2), retinol (3/3), sulfasalazine (3/3) and others.
Most of these products are subject to continuing or periodically emerging global shortages that affect many off-patent drugs
and especially sterile injectables and parenteral nutrition components. None of the essential medicines is available through
European centralized procedure. With the exception of paromomycin, Portugal is the only EU country, where these essential
medicines are currently obtainable.
For details, see Graphs 2 to 6 in Appendix 1; Table 2 in Appendix 2 and Table 16 in Appendix 3.

Blood and blood forming organs
The World Health Organization (WHO) lists 30 medicines as essential, of which 23 are currently approved for marketing and
available to Czech patients. The highest number of registered and marketed products is available for electrolytes (409/74),
carbohydrates for intravenous nutrition (259/39), electrolytes with carbohydrates (109/19), platelet concentrates and whole
blood (97/24), and coagulation factor VIII (95/17).
As of December 29, 2016, 7 (23%) hematological products were unavailable in the Czech Republic: low-molecular weight
heparin dalteparin, streptokinase, hydroxycobalmin, dextran, red blood cells, fresh frozen plasma and magnesium sulfate. In
addition to drugs that are currently unavailable, others may become vulnerable to disruption due to very limited number of
registrations: heparin (1/1), phytomenadione (2/2), trenexamis acid (2/2) and others.
Shortage of sterile injectable drug formulations and parenteral nutrition components are a major problem globally, so
unavailability of magnesium sulfate, hydroxycobalamin and dextran does not come as a surprise. Heparins are another group
of products subject to periodic global shortages. Heparin is produced almost exclusively in China and any disruptions are likely
to result in global shortage. Import bans imposed by the FDA and other regulators create window of opportunity to transfer
rejected supplies to less regulated markets and jurisdictions with gaps in detection of adulterated products and inconsistent
enforcement. Unavailability of packed red blood cells and fresh frozen plasma is likely related to local incentives for blood
donors (TnNova)
17
. Utilization of the same donor pool by commercial producers compounds the problem.
None of the essential medicines is available through European centralized procedure. However, according to EudraPharm,
registrations for dalteparin, streptokinase and dextran are available in Portugal. Several i.v. formulations of hydroxycobalamin
are registered in Portugal. In addition, hydroxycobalamin powder for solution for infusion is also available due to registration
by the European Commission.
Cardiovascular system
The World Health Organization (WHO) considers 25 cardiovascular drugs essential. Most of them are available to patients in
the Czech Republic. Cardiovascular drugs are generally well represented: the highest share of national registrations is available
for amlodipine (454/47), metoprolol (234/42), bisoprolol (193/37), simvastatin (250/34), atenolol (36/21), carvedilol (253/20),
enalapril (51/19), verapamil (49/19) and furosemide (35/15).
As of December 29, 2016, the only three unavailable drugs are injectable vasodilatator hydrazaline, medication for
hypertensive crises nitroprusside and potassium-conserving diuretic amiloride. Drugs vulnerable to disruption due to low
number of registrations include propranolol (1/1), hydrochlorthiazide (1/1), methyldopa (1/1), ephedrine (1/1), lidocaine (2/1)
and others.
The main issues in this therapeutic group are problems relating to other old, off-patent sterile injectable drugs. In addition,
some older off-patent drugs such as nitroprusside have become hard to reach due to sudden sharp increase in price. In the
U.S., nitroprusside is considered the standard of care, which means that the drug must be available in limited situations when
needed. The drug’s price increased significantly upon acquisition by Valeant (RAPS)
18
.
None of these unavailable essential medicines can be obtained through European centralized procedure. According to
EudraPharm, hydrazaline and nitroprusside are not available elsewhere in Europe, either. Amiloride is registered in Portugal as
oral formulation in combination with hydrochlorthiazide.

Dermatologicals
The World Health Organization (WHO) lists 21 dermatologicals as essential for health systems. In this group, 10 are registered
in the Czech Republic. However, only nine were available to patients in the last quarter (Q3 2016). The highest number of
registrations in this group is available for povidone-iodine (40/23), antipsoriatics for topical use (26/9), bethametasone (24/6)
and terbinafine (24/4). Five products are available only in one or two registrations, making the system vulnerable to disruption:
carbamide (2/2), podophyllotoxin (2/1), nystatin (1/1), hydrocortisone (1/1) and muciprocin (1/0).
Twelve essential dermatologicals (57%) are currently unavailable in the Czech Republic: antifungal miconazole, medication for
the removal of warts salicylic acid, antiseborrhoic agent selenium sulfide, antifungal griseofulvin, antiinfective and astringent
topical formulations with zinc, and topical antibiotic silver sulfadiazine. In addition, the list includes disinfectant and antiseptic
products chlorhexidine, chloroxylenol, isopropanol and ethanol, and potassium permanganate, essential component of many
first aid and survival kits used for wound cleaning, athletes foot and trench foot. Muciprocin, topical antibiotic used for the
treatment of impetigo and folliculitis, is registered but was not marketed in the last quarter.
Internationally significant shortages of dermatologicals due occasionally occur, mainly due to manufacturing delays and low
demand. Examples of such shortages are chlorhexidine (Therapeutic Goods Administration)
19
and muciprocin (Food and Drug
Administration)
20
. None of the reports suggests a major global long-term problem. Shortage of isopropanol (rubbing alcohol) in
Europe is a long-term problem caused by major increase in price and relatively low demand (ICIS)
21
.
None of the essential medicines not registered in the Czech Republic is available through European centralized procedure.
According to EudraPharm, some of these products are registered in Portugal. Multiple topical and oral formulations are
available for miconazole. Topical products containing salicylic acid, zinc and chlorhexidine are available alone and in
combinations with other medications. Selenium sulfide is available in the form of a shampoo, silver sulfadiazine as a cream,
and chloroxylenol as cutaneous solution. No registrations were found for griseofulvin, isopropanol, potassium permanganate
and ethanol.
Genito-urinary products and sex hormones
Out of 19 essential products, 7 (37%) are not registered in the Czech Republic. The highest number of registrations is available
for levonorgestrel and ethinylestradiol (50/13), testosterone (41/5) and progesterone (19/7).
Unavailable medications include ergometrine, mainly used as uterotonic for prevention of bleeding after childbirth,
contraceptives norethisterone, etonorgestrel, combination of norethisterone and ethinylestradiol, and plastic intra-uterine
device with copper, medication for the treatment of menopausal symptoms medroxyprogesterone and estrogen, and
emergency contraceptive levonorgestrel.
Of these medications, current shortage of norethisterone has been reported from Australia (Therapeutic Goods
Administration)
22
. In addition, shortage of oxytocine and ergometrine has been a chronic problem in Pakistan (The News
International)
23
.
Of these products, only etonorgestrel is registered centrally as Implanon (European Commission)
24
. Registrations available
nationally in Portugal include ergometrine, combination of norethisterone and ethinyestradiol in the form of oral formulations
and transdermal patches, oral combination of estrogen and medroxyprogesterone, oral formulation of norethisterone, and
levonorgestrel as oral formulation and intra-uterine device. According to EudraPharm, prednisolone is registered in Portugal as
oral formulation and as powder for solution for infusion.

Hormones for systemic use, excluding sex hormones and insulins
The World Health Organization (WHO) considers 11 hormones essential for health systems. In this group, 10 are registered and
available in the Czech Republic. The only unavailable product is prednisolone. The highest number of registrations is available
for levothyroxine (90/17), dexamethasone (58/2), methylprednisolon (52/17), desmopressin (25/6), and hydrocortisone (16/2).
Drugs vulnerable to disruption due to low number of registrations include oxytocin (2/2), propylthiouracil (2/1), iodine (2/1),
fludracortisone (1/1) and glucagon (1/1). Occasional shortages of prednisolone did not reach global proportions. Prednisolone
is available through centralized registration as Okrido (European Commission)
25
. For details, see Graph 23 in Appendix 1; Table
7 in Appendix 2 and Table 21 in Appendix 3.
Antiinfectives for systemic use
World Health Organization (WHO) considers 119 systemic anti-infectives essential for health systems. Of these, 90 are
registered in the Czech Republic. However, only 80 were available to patients in the last quarter (Q3 2016). From this group,
full 39 (33%) are either not registered or not marketed. The highest number of registrations is available for amoxicillin -
clavulanate (372/24), fluconazole (252/22), linezolid (188/10), and clarithromycin (168/22). Drugs most vulnerable to shortages
due to low number of registrations include numerous antibiotics and antimycobacterials, anti-retrovirals, vaccines and
immunoglobulins. The group is divided into 6 subgroups: systemic antibacterials (J01), antimycotics (J02), antimycobacterials
(J04), antivirals (J05), Immune sera and immunoglobulins (J06) and vaccines (J07). For overview, refer to Graph 24 in Appendix
1; Table 8 in Appendix 2 and Table 22 in Appendix 3.
Of the 36 essential anti-bacterial drugs (J01), 7 are not available in the Czech Republic because of no registration: beta-lactams
cloxacillin and cefalexin, sulfonamide sulfadiazine, macrolide erythromycin, aminoglycosides streptomycin and kanamycin,
and spectinomycin. Anti-bacterials vulnerable to disruption due to low number of registrations include chloramphenicol (2/1),
benzathin penicillin (1/1), trimethoprim (3/1) and nitrofurantoin (1/1). None of the essential antibacterials not registered in
the Czech Republic is available through European centralized procedure. According to EudraPharm, sulfadiazine (oral
formulation), erythromycin (oral formulation and powder for solution for infusion), and streptomycin (powder for solution for
injection) are registered in Portugal. Cloxacillin, cephalexin, kanamycin and spectinomycin are not listed in either of these
databases. For details, see Graphs 24 to 29 in Appendix 1; Table 8 in Appendix 2 and Table 22 in Appendix 3.
WHO lists three antimycotics (J02) as essential drugs: amphotericin B, fluconazole, and flucytosin. Fluconasol is available in the
form of 252 registrations (22 marketed). Amphotericin B (2/1) qualifies as drug vulnerable to disruption due to low number of
licenses. Flucytosine is not registered in the Czech Republic. Flucytosine is not available through European centralized
procedure and is not listed in EudraPharm, either. For details, see Graph 30 in Appendix 1; Table 8 in Appendix 2 and Table 22
in Appendix 3.
Another subgroup, antimycobacterials (J04), lists 18 drugs for the treatment of tuberculosis and 2 for the treatment of leprosy.
The Czech Republic has currently available only 6 essential antitubercular drugs: rifambicin (3/2), isoniazid (2/1), rifabutin
(1/1), capreomycin (1/1), pyrazinamide (1/1) and ethambutol (1/1). Additional four drugs are registered but not marketed:
delamanid (4/0), bedaquiline (2/0), p-aminosalicylic acid (1/0) and cycloserine (1/0). Unavailable essential antituberculars
include rifapentine, protionamide, ethionamide, terizidone, and combinations: rifampicin+isoniazid, ethambutol+isoniazid,
rifampicin+pyrazinamide+isoniazid, and rifampicin+pyrazinamide+ethambutol+isoniazid. Essential antileprosy agents include
clofazimine (2/1) and dapsone (unavailable). None of the essential antimycobacterials not registered in the Czech Republic is
available through European centralized procedure. Combination antitubercular drugs rifampicin+pyrazinamide+isoniazid and
rifampicin+isoniazid are registered in Portugal, along with antileprosy medication dapsone. For details, see Graphs 31 to 33 in
Appendix 1; Table 8 in Appendix 2 and Table 22 in Appendix 3.
Antivirals (J05) are a numerous group scarcely represented in the Czech Republic. Out of 29 essential antivirals, 5 are not
registered and another 4 are registered but not marketed. In addition to valganciclovir, the unavailable antivirals include

combinations: lamivudine + nevirapine + zidovudine, lamivudine + nevirapine + stavudine, lopinavir + ritonavir and
ombitasvir + paritaprevir + ritonavir. Additional antivirals, such as nevirapine, stavudine, saquinavir and combination product
with efavirenz + emtricitabine + tenofovir are registered but not marketed.
Most other essential antivirals are available in very limited number of licenses. None of the essential antivirals not registered in
the Czech Republic is available through European centralized procedure. According to EudraPharm, valganciclovir is registered
in Portugal, combination of lopinavir and ritonavir in Portugal and by the European Commission, and combination ombitasvir +
paritaprevir + ritonavir by the European Commission. For details, see Graphs 34 to 37 in Appendix 1; Table 8 in Appendix 2 and
Table 22 in Appendix 3.
Essential medicines in subgroup J06 include immune sera (J06A) and immunoglobulins (J06B). Imunoglobulins are generally
well-represented on the Czech market, both for intravascular (65/21) and extravascular (39/10) use. Anti-D immunoglobulin
(6/4) and tetanus immunoglobulin (2/1) are also available. Snake venom antisera are registered but not marketed. Two
products in this group are not registered in the Czech Republic: diphtheria antitoxin and rabies immunoglobulin. These two
products are not available through European centralized procedure and are not listed in EudraPharm, either. For details, see
Graph 38 in Appendix 1; Table 8 in Appendix 2 and Table 22 in Appendix 3.
The last subgroup (J07) is reserved for vaccines. 24 products in this subgroup are considered essential. The highest number of
registrations is available for combined bacterial and viral vaccines (80/4), hepatitis B (39/4), tick-borne encephalitis (38/5),
varicella zoster (29/2) and meningococcal vaccines (27/4). Five products have no registration in the Czech Republic: rubella
vaccine, measles vaccine, live attenuated tuberculosis, and pertussis vaccine and diphtheria toxoid. Mumps vaccine is
registered but not marketed. Several more products are registered in very low numbers, making their availability vulnerable to
disruption: cholera vaccine (3/1), poliomyelitis vaccine (3/1), Haemophillus influenza B (2/1), Japanese encephalitis (2/1) and
purified antigen of pneumococcus (1/1). These listed products are not available through European centralized procedure and
are not listed in EudraPharm, either. Most vaccines are available in combinations, so the only vaccine that is truly unavailable is
live attenuated tuberculosis. For details, see Graphs 39 to 41 in Appendix 1; Table 8 in Appendix 2 and Table 22 in Appendix 3.
Anti-infectives have been in short supply for more than a decade, and the availability, or lack thereof, on the Czech market, is
consistent with availability of these drugs globally. Global shortages affect namely old off-patent injectable broad-spectrum
anti-bacterials, anti-tubercular drugs including first line therapy, and antiretroviral drugs for the treatment of HIV/AIDS.
Lack of availability of immune sera against rabies and diphtheria antitoxin, as well as snake antivenom against most species are
also a global problem. Global shortages were also reported for numerous vaccines, namely diphtheria toxoid and tetanus
toxoid, as well as Bacille Calmette–Guérin (BCG).
Antineoplastic products
WHO lists 45 essential antineoplastic products (L). In the Czech Republic, 40 of them are registered, and all but one have been
on the market in Q3 2016. The highest number of registrations is available for methotrexate (598/13), imatinib (358/4),
bicalutamide (204/14), anastrozole (181/19), capecitabine (143/16) and filgrastim (100/10).
Six products from this group are unavailable. Five products have no registration in the Czech Republic: tretinoin, miltefosine,
procarbazine, daunorubicin and dactinomycin. Asparaginase is registered but is not marketed. Another nine drugs are
vulnerable to disruption due to limited alternatives: ifosfamide (3/3), tioguanine (3/1), vincristine (3/2), trastuzumab (3/2),
mercaptopurine (2/1), bevacizumab (2/2), chlorambucil (1/1), vinblastine (1/1) and bleomycin (1/1). These listed products are
not available through European centralized procedure. According to EudraPharm, daunorubicin and tretinoin are approved in
Portugal.
Shortages and limited availability of generic injectable oncology products have been an ongoing problem for more than a
decade. Additional concern relates to counterfeit and falsified cancer products in legitimate supply chain. Drugs in shortage are

particularly likely to become the target of counterfeiters due to attempts of hospitals to obtain them from less familiar sources.
Efforts to push the costs as much down as possible and procurement and sourcing policies compound the issue.
Musculoskeletal system
WHO considers 6 drugs from this group (M) essential. In the Czech Republic, 5 of these drugs are registered and marketed. One
product, vecuronium, is unavailable. The highest number of registrations is available for ibuprofen (557/58), followed by
allopurinol (56/9). Furthermore, atracuronium (3/1) and penicillamine (2/2) are vulnerable to disruption due to low number of
registrations. Vecuronium is not available through European centralized procedure. According to EudraPharm, vecuronium is
approved in Portugal.
In the U.S., vecuronium is currently in short supply due to manufacturing delays experienced by Pfizer. In December 2013,
Pfizer sold Vecuronium injection to Mylan, and in 2014, Ben Venue has stopped production in Ohio. Teva and Sagent are not
actively marketing the drug (ASHP)
26
.
For details, see Graph 50 in Appendix 1; Table 10 in Appendix 2 and Table 24 in Appendix 3.
Nervous system
WHO lists 37 nervous system drugs (N) as essential. In the Czech Republic, 35 of them are registered and 33 are marketed. The
highest number of registrations is available for oxycodone (653/18), risperidone (255/42), paracetamol (226/27), nicotine
(182/23), valproic acid (90/33), hydromorphone (88/9), hydromorphone (88/9) and others.
Four products are unavailable: halothane (0/0), lorazepam (0/0), lidocaine combinations (2/0), methadone (6/0). Numerous
other drugs such as clomipramine (3/2), amitriptyline (3/1), neostigmine (3/2), phenytoin (2/2), ethosuximide (2/1), biperiden
(2/1), fluphenazine (2/1), caffeine citrate (2/1), pyridostigmine (2/1), ketamine (1/1), chlorpromazine (1/1) and lithium (1/1)
are vulnerable to disruption due to low number of registrations.
Halothane and lorazepam are not available through European centralized procedure. According to EudraPharm, lorazepam is
Both halothane and lorazepam are drugs that have been in short supply around the world. Halothane was unavailable in Malta
(Times of Malta)
27
for more than two years and shortages of lorazepam occur regularly as well.
Antiparasitics
WHO considers 36 antiparasitic drugs (P) essential. In the Czech Republic, only 9 of them are registered and 6 are marketed, 30
(83%) are unavailable. The highest number of registrations is available for permethrin (7/1). Numerous other drugs such as
metronidazole (1/1), hydroxychloroquine (1/1), primaquine (1/1), quinine (1/1), meglumine antimoniate (1/0), pentamidine
isethionate (1/0), praziquantel (1/0) and mebendazol (1/1) are vulnerable to disruption due to low number of registrations.
Essential antiparasitics not registered in the Czech Republic include diloxanide, chloroquine, amodiaquine, proguanil,
mefloquine, pyrimethamine alone and in combinations, artemether alone and in combination with lumefantrine, artesunate
– alone and in combinations with mefloquine and with amodiaquine, sodium stibogluconate, nifurtimox, melarsoprol,
suramin sodium, eflorinthine, oxamniquine, triclabendazole, diethylcarbamazine, pyrantel, levamisole, ivermectin,
niclosamide and benzyl benzoate.

None of the drugs not registered in the Czech Republic is available through European centralized procedure. According to
EudraPharm, eflornithine cream is registered through the European Commission and Portugal and chloroquine, mefloquine,
pyrimethamine, artemether + lumefantrine, artesunate + mefloquine, albendazole and benzyl benzoate cutaneous solution are
Availability of antiparasitic medications is a serious global concern. Especially antimalarial medications are in short supply due
to reliance on plant Artemisia that needs to be grown, harvested and processed. Demand increased greatly after in 2004-5
following WHO recommendation to switch to artemisin-based products as first-line treatment. In the U.S. Turing’s Daraprim
(pyrimethamine) recently became the most recognizable antiparasitic medication of all times due to massive price hike.
Acquisition and rebranding of old generic products became another concern that limits availability of certain drugs in
developed markets.
For details, see Graph 56 in Appendix 1; Table 12 in Appendix 2 and Table 26 in Appendix 3.
Respiratory system
WHO considers essential 10 respiratory system drugs (R). In the Czech Republic, 9 of them are registered and marketed. The
highest number of registrations is available for loratidine (45/17) and xylometazoline (32/17). Drugs vulnerable to disruption
due to low number of registrations include ipratropium bromide (3/2) and lung surfactants (2/1). Cyclizine is not registered.
Cyclizine is not available through European centralized procedure or elsewhere in Europe. For details, see Graph 57 in
Appendix 1; Table 13 in Appendix 2 and Table 27 in Appendix 3.
Sensory organs
WHO lists 13 drugs as essential for the treatment of sensory organs (S). In the Czech Republic, 9 of them are registered and
marketed, 4 are unavailable. The highest number of registrations is available for latanoprost (45/16) and timolol (19/11). Drugs
vulnerable to disruption due to low number of registrations include tropicamide (3/1), gentamicin (1/1), acyclovir (1/1),
prednisolone (1/1), acetazolamide (1/1), atropine (1/1) and fluorescein (1/1).
Four drugs for the treatment of sensory organs are not registered in the Czech Republic: tetracycline, epinephrine, pilocarpine,
and tetracaine. None of these four drugs is available through European centralized procedure. Epinephrine and tetracaine are
not available elsewhere in Europe, either. Ophthalmic formulations of tetracycline and pilocarpine are available in Portugal.
Shortages of ophthalmic formulations of generic drugs occur occasionally elsewhere in the world, too. For details, see Graph
58 in Appendix 1; Table 14 in Appendix 2 and Table 28 in Appendix 3.
Various
In category Various (V), WHO lists 21 drugs as essential. In the Czech Republic, 12 of them are registered and 10 marketed; 11
are unavailable. The highest number of registrations is available for oxygen (545/57), water for injection (61/20), calcium
folinate (34/6) and iohexol (24/9). Drugs vulnerable to disruption include methylene blue (3/0), barium sulfate with suspending
agents (3/2), deferoxamine (2/1), thiosulfate (1/0), protamine (1/1), naloxone (1/1), Prussian blue (1/1) and mesna (1/1).
No registration is available for edentates, sodium nitrite, dimercaprol, acetylcysteine, fomepizole, tuberculin, technical
disinfectants, diatrizoic acid and iotroxic acid. None of these nine drugs is available through European centralized procedure.
Acetylcysteine and tuberculin are registered in Portugal.
Shortage of tuberculin is a global concern. For details, see Graph 59 in Appendix 1; Table 15 in Appendix 2 and Table 29 in
Appendix 3.

III. Significant global drug shortages
According to University of Utah Drug Information Service, the total number of drugs in shortage in the U.S. culminated in 2011
when the total all-year average reached 267 drugs. Figures by quarter for the period from Q1 2010 to Q2 2015 show
fluctuation in the range from 150 to 320 per quarter (University of Utah Drug Information Service)
28
. These shortages are so
common in the U.S. and UK hospitals that they forced some creative solutions how to overcome them in emergency settings
(SCCM)
29
. Recent classes of drugs in shortage cover the whole spectrum and include anticonvulsants, sedatives, anesthetics
and pain medications, antiarrhythmics, beta-blockers, beta-adrenergics, calcium-channel blockers, dopamine and dobutamine,
nitroglycerine injection, lidocaine, fluid replacement therapy, diuretics, antinauseants, calcium gluconate, dextrose and normal
saline. According to American Society of Health System Pharmacists (ASHP), annual or quarterly reviews do not fully reflect the
fluid nature of ongoing drug shortages. However, the shortages have been going on for so long that by now everyone has some
kind of contingency plan in place (Pharmacy Practice News)
30
. According to survey conducted among European pharmacists in
summer 2013, 45% indicated that they experienced shortage of life-sustaining and life-preserving drugs such as oncology
drugs. More than 30% of respondents stated that these shortages were associated with increased hospital costs. Half of them
only received information about shortage from the distributor or wholesaler at time of no delivery rather than from the
government (Pauwels et al.)
31
. In some countries, such as Iran, other factors such as sanctions contribute to the shortage of
medicines (Sogol et al)
32
.
Parenteral nutrition components
In June 2015, American Society of Health System Pharmacists (ASHP)
33
published shortage alert stating that the two
manufacturers, Hospira and American Regent, were unable to supply the drug due to manufacturing delays. Previous instances
of shortage of the same drug (2013) were solved by temporary importation from a French manufacturer (Food and Drug
Administration)
34
. Injectable zinc sulfate is mainly used as a component in parenteral nutrition. However, zinc sulfate is not the
only component in shortage: other affected components include calcium gluconate, cyanocobalamin, dextrose, magnesium
sulfate, multivitamin infusions, injectable phosphate, potassium chloride, selenium injection, sodium chloride 23.4%, sodium
phosphate, sterile water for injection (McGuff Company)
35
, and trace elements for adult, pediatric and neonatal use (ASPEN)
36
.
Sterile injectable drugs
The U.S. Food and Drug Administration (FDA) received numerous alerts of upcoming shortages (Food and Drug
Administration)
37
, having managed to avert many of them. Significant portion of these shortages involve older sterile injectable
drugs, including cancer drugs, surgical anesthetics, as well as drugs needed for emergency medicine, and electrolytes for
patients on parenteral nutrition (Food and Drug Administration)
38
. According to OsoBio analysis from 2013, there were 204
reported drug shortages the previous year. Compared to 2006, the total number of drugs in shortage tripled. Of the portion of
reported shortages that were closely examined by the FDA, 80% involved sterile injectable drugs, from oncology to antibiotics
and electrolytes and parenteral nutrition. The leading reasons for shortages were operational problems at manufacturing
facilities (43%), delays in manufacturing or shipping (15%), and shortages in active pharmaceutical ingredients (10%). Sterile
injectable drugs face unique market features: the top three manufacturers hold >70% of the market volume and most clients
rely on just one manufacturer to produce 90% or more of their drug. Plant closings, shutdowns, and disruptions of raw
materials further compound the problem. Low price due to reimbursement policies further lowers the return on investment
and contributes to manufacturers exiting the market (Osobio)
39
.
Adulterated heparin
In winter 2007-2008, the FDA started receiving reports of deaths of patients on hemodialysis from all-over the country. Soon
the investigation led to suspicions that the contamination may have been intentional rather than accidental: firm Changzhou

SPL, a Chinese subsidiary of Scientific Protein Laboratories, sold oversulfated chondroitin sulfate (OSCS) as heparin to their
customer Baxter International. The motive for this adulteration was purely financial, since a pound of OSCS costs about $9
compared to $900 for heparin(The New York Times)
40
. The total death toll in the U.S. climbed to 149 (RAPS)
41
. The scandal led
to many changes in oversight of the manufacturing process, including implementation of more sensitive tests that were able to
detect the contaminant(RAPS)
42
. In July 2014, the FDA put Beijing company Shunxin Meihua Bio-technical on its import alert
list after it barred the inspectors from accessing some of its facilities. The reason was that the firm was getting some of its
supplies of heparin from suspect suppliers (FiercePharma)
43
. In 2016, several members of the House Committee on Energy &
Commerce raised new concerns over the investigation. The reason for these concerns was lack of communication within the
FDA itself that led to four-year delay in imposing import bans on more than 20 Chinese heparin producers. French regulators
recently found that another manufacturer, from Dongying City, had very weak control over the origin of their crude heparin
supply chain. Concerns over quality of heparin products are ongoing.
Sudden price spikes in off-patent prescription drugs
In December 2016, Special Committee on Aging, United States Senate, published report Sudden Price Spikes in Off-Patent
Prescription Drugs: The Monopoly Business Model that Harms Patients, Taxpayers, and the U.S. Health Care System (U.S.
Senate)
44
. In November 2015, Chairman Susan Collins (R-Maine) and Ranking Member Claire McCaskill (D-Missouri) launched
special investigation into abrupt and dramatic price increases of prescription drugs. The Committee’s investigation centered on
four companies – Turing Pharmaceuticals, Retrophin, Inc., Valeant Pharmaceuticals International, and Rodelis Therapeutics.
These firms acquired decades old off-patent affordable medicines and then suddenly raised their prices astronomically. The
Committee closely examined a business model that these four companies used, provided case studies, explored the influence
of investors, assessed the impact of price hikes on patients, payers, providers, hospitals and governments, and discussed
potential responses. The business model involved acquisition of off-patent sole-source drugs over which they could exercise de
facto monopoly pricing power, and then impose and protect astronomical price increases. The central elements of this
business model are the acquisition of a sole-source drug, for which there is only one manufacturer and therefore there is no
immediate competition, and the fact that the drug is considered the gold standard so physicians cannot stop prescribing it.
Additional elements of this business model identified by the report were small market, not attractive to competition and
dependent population incapable of organizing effective opposition. Closed distribution through specialty pharmacies were
intended to prevent competition from entering the market. Lastly, the companies engaged in price gouging not justified by
R&D or other costs. Of the case studies included in this report, two involved essential medicines: Turing’s Daraprim
(pyrimethamine) (Slate)
45
for the treatment of toxoplasmosis, and Valeant’s Nitropress (nitroprusside) used for acute
hypertensive crises in emergency medicine. Other major price increases, unrelated to these firms under investigation, involved
insulin and opiate antidote naloxone.
Antibacterials
Shortages of antibiotics increased dramatically after 2007. Farha Quadri et al. (2015) reviewed shortages on antibacterial drugs
in the U.S. and concluded that nearly half of the drugs in shortage were needed for the treatment of multidrug-resistant
infections and high-risk pathogens such as Clostridium difficile, carbapenem resistant Enterobacteria, methicillin-resistant
Staphylococcus aureus, Pseudomonas aeruginosa and leprosy. Tuberculosis drugs were excluded. The authors analyzed data
from 2001 to 2013 and found out that 148 antibiotics were in shortage at some point during this period. Over the course of the
study period, 148 antibacterial drugs went on shortage. Most of the shortages involved generics, broad-spectrum antibiotics,
many of them gold-standard therapies. Common reasons for shortage were listed as having no alternative production source,
manufacturing delays, supply and demand issues, shortage of raw materials, regulatory problems, import ban, business
decisions and even natural disaster. In many instances the cause of the shortage of unknown. More importantly, shortages are
rarely distributed evenly throughout the whole region and often involve limited availability rather than complete
discontinuation (Quadri et al)
46
Major antibacterial shortages in the U.S. involved essential drugs cefotaxime, cephalexin,

trimethoprim-sulphametoxazole, azithromycin, clindamycin, gentamycin, ciprofloxacin and vancomycin (Medscape)
47
.
Shortage of antimicrobials affects other parts of the world the same way: in Australia, the main concerns as of December 2016
were shortage of vancomycine, metronidazole, and numerous antivirals (DailyMail)
48
. Antibacterial shortages affect
ophthalmologic (ASHP)
49
and otic (ASHP)
50
formulations in the same manner.
Front-line tuberculosis therapy
Most tuberculosiss require a regimen of several drugs taken for 6-9 months. In the U.S., 10 drugs are approved for the
treatment of tuberculosis. Four of them, all on the WHO list of essential drugs, form the core of first-line treatment: isoniazid,
rifampin, ethambutol and pyrazinamide. In 2012, the U.S. experienced severe shortage of isoniazid. In January 2013, a survey
by the National Tuberculosis Controllers Association (NTCA) indicated that the isoniazid shortage was interfering with patient
care and could contribute to TB transmission in the United States. Although there were occasional shortages of second-line
antituberculars before 2012, the situation after November 2012 became critical due to sustained generalized interruption of
first-line anti-tuberculosis medication. Despite notification obligation imposed by presidential executive order Reducing
Prescription Drug Shortages, the shortage of isoniazid came without warning (CDC)
51
. Isoniazid shortage was eventually
resolved in June 2013 (Medscape)
52
. Most common causes of shortage are problems with manufacturing, especially of
injectable drugs. This may include non-specific discoloration of product, glass shards, metal filings, fungal or other
contaminants. Other causes are delays in manufacturing or shipping, shortage of raw materials, single manufacturer,
regulatory action, price increase, and increasing demand that outpaces supply. Supply interruptions involved other
antituberculars, too, namely kanamycin, amikacin, streptomycin, capreomycin, cycloserine, ethionamide, linezolid and
rifapentine (CDC)
53
and recently also emerged: tuberculin (LiveScience)
54
. In 2014, Treatment Action Group (TAG) conducted
analysis of reasons for supply interruptions of antituberculars. The main reasons for unstable supply are the small number of
manufacturers of these products, and exclusive production for the U.S. market, which is fragmented due to reliance on
uncoordinated procurement from dozens of local and state tuberculosis programs. The cure, according to TAG, involves the
creation of strategic reserve of antituberculars, which would have a set supply of six months’ worth of stock should an issue
arise, and to pool demand domestically and internationally through Global Drug Facility (GDF)
55
. Shortage of tuberculosis
drugs is a global problem that affects developed countries with occasional and rare occurrence of the disease as much as
countries like India (The Wall Street Journal)
56
or South Africa (Médecins Sans Frontières)
57
.
Drugs for the treatment of HIV/AIDS and other antivirals
In the developed world, the most relevant shortage of antivirals is periodic problem with supply of influenza drug Tamiflu
(Drugs)
58
. However, the rest of the word has a different problem: HIV/AIDS. The United Nations set ambitious goals of ending
the AIDS epidemic by 2030, goals that depend on steady supply of affordable medicines in regions of interest. First-line HIV
therapy is based on long-term use of combination of zidovudine, lamivudine and nevirapine, which keeps the virus count down
and prevents infection. Major population of HIV positive people lives in India, sub-Saharan Africa, Russia and Eastern Europe,
but also Latin America and other regions. For example in India, free anti-retroviral drugs are dispensed to about 800,000
people. Of these, most are on second-line therapy, some are on first-line drugs. More than 40 companies make antiretrovirals
in India, both domestic and multinationals. Aurobindo, Cipla and Hetero drugs account for 70% of the global generic market
with HIV drugs. Indian produced generics for pediatric antiretrovirals and some portions of the adult HIV market (nucleoside
and non-nucleoside reverse transcriptase inhibitors accounted for about 90% of the global purchase volumes. In India,
antiretrovirals are procured by government run hospitals from Hetero, Mylan, Cipla and Ranbaxy. The National Programme for
AIDS (NACO) provides 15 antiretrovirals used in first line, second line, and pediatric combination regimen. In mid-2015, NACO
effectively run out of stock for all but one of these medications due to delayed payments to manufacturers. In an effort to
decrease prices, India recently abolished customs import duties for drugs and test kits (The Pharma Letter)
59
. The same
problem – inability to pay for essential medicines and consequent shortage, affects other countries like Venezuela (USA
Today)
60
, Cameroon (VOA News)
61
, Uganda (VOA News)
62
, Nigeria (PunchNG)
63
and South Africa. Ironically, only a minority of

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