Recent Findings and New Advances of Adverse Drug Reactions

#### **Chapter 2**

## Adverse Drug Reactions and Pharmacovigilance

*Md. Shah Amran*

#### **Abstract**

The discovery of a new drug usually takes 10-15 years. Within this time period, the candidate drug is thoroughly screened for its beneficial as well as side effects. But the side, adverse or toxic effects cannot be detected to a full scale due to some special reasons. The beneficial effects and toxicity of new drugs and vaccines are usually studied by "Clinical trials", which are divided into four categories ranging from clinical trial phases I to IV. During clinical trial phase-III, about 4,000-10,000 patients are involved and after passing this phase, the drug is allowed to enter into the global market. Then, billions of people, including those who were excluded in phase-III, may be administered with this drug. It is worthy to mention that these 4,000-10,000 patients may not show many of the side effects or toxic actions. The undetected adverse drug reactions (ADRs) are studied in clinical trial phase-IV, which is also known as post market surveillance. For this reason, the ADRs are compared with the tip of the iceberg, as it indicates the minor part of a major event. This phenomenon gave birth to a new branch of the pharmacology known as Pharmacovigilance.

**Keywords:** Adverse drug reaction, Drug safety, Pharmacovigilance, Phocomelia, Post market surveillance

#### **1. Introduction**

The discovery of a new drug can usually take 10-15 years [1, 2]. Within this time period, the candidate drug is screened for its beneficial as well as for its side effects (**Figure 1**). But the side, adverse or toxic effects cannot be detected to a full scale due to some special reasons.

Adverse Drug Reaction (ADR) is a damage or injury response caused due to intake of medication [3]. The ADRs may arise after administration of a single dose, or long-term administration of any drug or consequence of the administration of two or more drugs as a combination product or separately [4]. The study of ADRs has turned to be a separate field of science and is known as Pharmacovigilance (PV), which is defined by the World Health Organization (WHO) as, "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem" [5]. The Program for International Drug Monitoring (PIDM) was established by WHO in 1968 in response to the tragedy caused by thalidomide in 1961. The "Thalidomide Tragedy" was related to the birth of children with deformed limbs, also known as phocomelia [6], and it became one of the most known tragedies in the history of medical and pharmaceutical sciences. The WHO encourages, supports and promotes PV at

#### **Figure 1.**

*Steps of drug development and commercialization.*

the country level for its member countries, and offers collaboration through its Collaborating Centre for International Drug Monitoring in Uppsala, Sweden [7]. Until March 2019, the total number of member states which have enrolled in the WHO PIDM as a member corresponds to 142 and, additionally 29 associate members are expecting full membership [8].

To prevent tragedies such as the thalidomide disaster, governments all over the world took necessary ethical and legal actions and strengthened their drug regulatory authorities (DRAs) to keep alert and to ensure the marketing of relatively safe drugs.

#### **2. Adverse drug reaction**

An ADR can be defined as "any response to a drug which is noxious and unintended, and which occurs at doses used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function" [9].

#### **2.1 The importance of studying ADRs**

As we have mentioned earlier, the overall toxicity of a drug is clearly understood during the whole life cycle of a drug, while only a minor portion of these toxicities are unveiled during clinical trial phases. After global launching, the post market surveillance studies help to assess the information leading to drug withdrawals, safety alerts from regulatory authorities and changes in product labelling. This also triggers the advances in pharmacology and therapeutics. Directly or indirectly, reports of ADR studies have shaped much of the current drug regulatory framework and contributed significantly to drug regulatory decisions. Furthermore, some ADR reports have also proved to be valuable weapons in discoveries in pharmacology and in improving drug use [10]. Clinical trial phases [11] include a small number of population and many clinical trials usually exclude:


*Adverse Drug Reactions and Pharmacovigilance DOI: http://dx.doi.org/10.5772/intechopen.98583*

**Figure 2.** *The schematic diagram of an iceberg [12].*


During the development of a drug, only less than 50% of ADRs can usually be detected, with the remaining more than 50% being detected after global launching, during the whole life cycle of the product. This can be compared with tip of the iceberg, which indicates a minor part of a major problem (**Figure 2**).

That is why it is very important to study the ADRs after launching of a new drug or vaccine.

#### **3. Drug tragedies abroad and at home**

As will be mentioned and described below, the "Thalidomide-induced Phocomelia" led the drug regulatory authority to take rigorous actions, including regulatory actions against the drug and promulgation of regulatory guidelines, as well as legislation. This and other reports have helped to discover a number of major drug disasters, such as the Benoxaprofen (known to cause severe hepatotoxicity and a variety of cutaneous reactions), Torsadogenic Drugs (e.g., prenylamine, terfenadine, cisapride that caused QT prolongation), Practolol (known to cause exfoliative dermatitis, systemic lupus syndrome, drug eruption, psoriasiform eruptions, skin reactions with eye signs consisting of atypical conjunctival shrinkage and xerosis, and keratoconjunctivitis sicca) [10]. In Bangladesh, the "Paracetamol tragedy" led the Directorate General of Drug Administration (DGDA) to take strict regulatory actions in the manufacture and quality control of drugs by the manufacturers. A few examples of those drug tragedies that occurred abroad and in Bangladesh are discussed below.

#### **3.1 The thalidomide tragedy in Europe**

In December 1961, William McBride, an Australian obstetrician, alerted in a letter to the *Lancet* that he had seen "multiple severe abnormalities" in babies born from ladies who had been administered with 'thalidomide' at the time of their

pregnancy (**Figure 3**) [13]. Dr. McBride summarized his report by questioning if any of their readers had seen similar abnormalities in babies born from women who had taken this drug during pregnancy.

The letter the first printed and published suggestion from a medical doctor about the teratogenic effect of thalidomide in women and it was a brief publication containing only five sentences. Dr. McBride's apprehensions about the drug thalidomide were eventually settled by numerous babies who were born with birth defects [14, 15].

In 2016, a *BMJ* publication about a chronicled film, describing the lives of persons born with birth defects as a consequence of the administration of the medicines narrated, reported the following: "The thalidomide scandal stands as one of the worst ever medical disasters" [16, 17].

#### *3.1.1 Worldwide recognition*

William Griffith McBride was born on the 25th of May 1927 in Sydney, Australia. As his mother was sick, he had to spend much of his early living with an aunt on a dairy farm. He pursued his study of medical sciences at Sydney University Medical School.

Dr. McBride attained global recognition for his contribution to alert everyone worldwide about the danger of the drug thalidomide, which have caused defects in the development of the limbs of the fetus and, ultimately, gave rise to the birth of truncated babies. In Australia, his own country, Dr. McBride was praised as a national hero, and a radiance of honor fell over him over the next three decades. He had a blooming practice in Sydney, and he was awarded with both the 'Commander of the Order of the British Empire' in 1969 and the Order of Australia in 1977.

But a later part of McBride's life and work was not so pleasing. In 1993, when he was 65, McBride was found guilty of scientific deception by a medical court for the consciously publishing of erroneous and fallacious research. Consequently, his name was cut from the medical register [18–20].

**Figure 3.**

*The first page of the letter to the editor published in the scientific journal 'The Lancet', in 1961, on the adverse effects of thalidomide.*

#### **3.2 Sulfonamide tragedy in Chicago, USA**

An article reporting to the "Sulfanilamide Disaster" was published in June 1981 in an issue from the FDA Consumer magazine, and was entitled "Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident" [21]. The incident was described as: "By the 1930s it was widely recognized that the Food and Drugs Act of 1906 was obsolete, but bitter disagreement arose as to what should replace it. By 1937 most of the arguments had been resolved but Congressional action was stalled. Then came a shocking development: the deaths of more than 100 people after using a drug that was clearly unsafe. The incident hastened final enactment in 1938 of the Federal Food, Drug, and Cosmetic Act, the statute that today remains the basis for FDA regulation of these products".

Sulfanilamide is used to treat streptococcal infections due to its curative effects and, at that time, was available in the form of tablet and powder dosage. The demand for the liquid dosage form was raised by a salesman of the S.E. Massengill Co., in Bristol, Tenn., and the company's principal chemist and pharmacist, Harold Cole Watkins, who used diethylene glycol to dissolve sulfonamide and prepare an elixir. The quality control laboratory of the company analyzed the product for flavor, appearance and fragrance, and certified it as satisfactory. Instantly, the company considered it as a safe product, manufactured a certain quantity of it and sent product shipments to the whole country [21]. The new dosage form had not been analyzed for its toxicity and no pharmacological evaluation had been performed on the new sulfanilamide preparation. Watkins failed to record one feature of the elixir made by using diethylene glycol, which is applied as an antifreeze and is a lethal poison, causing renal damage followed by death [21].

#### **3.3 Tylenol tragedy**

Tylenol (Paracetamol) tragedy occurred in 1982 [22]. Tylenol was a product of of Johnson & Johnson and a trade-named drug intended for lessening pain, decreasing fever, and alleviating the symptoms of cough, cold, headache, allergies and influenza. The active pharmaceutical ingredient of this preparation is paracetamol (in the US it is known as acetaminophen), which is prescribed as an analgesic and antipyretic. The branded name (market name) Tylenol is accrued from a chemical name for the compound, N-acetyl-para-aminophenol (APAP). The branded name is possessed by McNeil Consumer Healthcare [22].

In 1982, in Chicago, US, Tylenol capsules laced with potassium cyanide caused the death of at least seven persons and raised a big concern about the safety of the marketed product. Potassium cyanide looks like normal table sugar, is water soluble but very toxic, being usually used for suicide (it is also known as suicide pills) [23].

This accident guided to the reforms in the packaging of over-the-counter drugs and to central anti-tampering laws. Johnson & Johnson took some necessary actions in their packaging and marketing policy that led to a reduction in the number of deaths and warned the public about potential poisoning risks. This action has been widely glorified as an exemplary public relation response to such a big crisis. Thus, Johnson & Johnson became able to regain their market share, which had been lost due to the Tylenol incident [22–24].

#### **3.4 Paracetamol tragedy in Bangladesh**

Two critical mishaps happened with paracetamol in Bangladesh. The first one occurred during 1990 to 1993, with the paracetamol produced by Adflame Pharmaceuticals Limited, and the second one took place during 2009 to 2010,

with the paracetamol manufactured by Rid Pharmaceuticals Limited. These two incidents are described below.

i.Adflame Pharmaceuticals Limited (1990 – 1993)

From 1990 to 1992, about 339 children developed renal failure in Bangladesh, and most of them died, after being given paracetamol (acetaminophen) solution using diethylene glycol [25]. The drug was manufactured by the "Adflame Pharmaceuticals Limited", Savar, Dhaka. The incident compelled the national government to forbid the trading of paracetamol preparations. Consequently, a decrease of 53% in the admission of victims with kidney failure and of 84% in admissions by unexplored kidney failure was observed in December 1992. This drug-related accident was reported in BMJ (**Figure 4**) in 1995 [25].

Three persons of the Adflame Pharmaceutical company were given 10-years of rigorous jail for producing a spurious drug which slaughtered 76 children in the 1990s. These convicted persons were Helena Pasha (Director), Mizanur Rahman (Manager) and Nigendra Nath Bala (production officer).

The prosecution against the manufacturing entity Adflame was only one of the four others also involved in this petition. Three other pharmaceutical producers were also accused of manufacturing the same contaminated liquid

#### **Figure 4.**

*Publication in BMJ on the 'paracetamol tragedy' in Bangladesh by Hanif et al., in 1995 [25].*

**20**

#### *Adverse Drug Reactions and Pharmacovigilance DOI: http://dx.doi.org/10.5772/intechopen.98583*

paracetamol, including Polychem Laboratories Ltd., BCI (Bangladesh) Ltd., and Rex Pharmaceuticals. The fifth pharmaceutical industry - City Chemical and Pharmaceutical Works Ltd., was also sued but not trialed.

ii.Rid Pharmaceuticals Limited, Brahmanbaria (2009–2010)

Once more, in 2009, 28 children died due to the diethylene glycol toxicity [26]. The national government started to constitute a probe committee which detected the presence of the toxic substance diethylene glycol in the liquid paracetamol of one pharmaceutical company, after investigating 300 samples of liquid paracetamol and liquid vitamins of 10 industries. This company was supposed to use propylene glycol, but instead used the toxic diethylene glycol, a component applied in tannery and battery industries. Consequently, its manufactory was completely sealed off and its goods were re-called from the market [26].

In 2016, the drug court (at Dhaka) decided to exonerate all five persons from the Rid Pharmaceutical Industry Ltd., in the case where a poisonous paracetamol was produced and authorized by this company, leading to the death of 28 children all over the country in 2009. The Dhaka drug court judge Mr. Atoar Rahman issued the order on a Monday afternoon. In the verdict, the judge slammed the drug authority for "their inefficiency in handling the case before the drug court". The judge said the prosecution had failed to demonstrate the charges due to the inability and inefficiency of the case investigation officer. Of the five officials, only Mizanur Rahman and his wife Sheuli were present during the delivery of the verdict. The rest of the accused persons are still absconding. The public prosecutor of this case, Dr. Nadim Miah, expressed his disappointment over the verdict by saying to the Dhaka Tribune: "We will decide on moving against the verdict after receiving the copy of the full verdict" [27]. Five prosecution witnesses gave depositions before the court during the trial, sources said. Twenty-eight children across Bangladesh died from renal failure during the period between June and August 2009, after consuming a paracetamol syrup manufactured by Rid Pharma. As the number of deaths was spread around the population, the government published notices in national daily newspapers warning people to not consume any drugs manufactured by this pharma company. A case was filed on August 10th, 2009, by the drug superintendent Shafiqul Islam with the Dhaka drug court against the five accused. Four more petitions were signed in Brahmanbaria, Comilla, Narayanganj and Sylhet. On July 22nd, 2009, the Directorate General of Drug Administration took steps to seal off the Rid Pharma's factory at Brahmanbaria. The national government also constituted a seven-member enquiry committee to probe the matter. On July 29th, 2009, the enquiry committee submitted its report, referring that a poisonous chemical named diethylene glycol was used to manufacture the paracetamol syrup. The report also said that Rid Pharma used diethylene glycol, mainly applied in tannery and rubber industries, as a cheaper substitute of propylene glycol, since diethylene glycol costed Tk. 200 per liter, while propylene glycol costed Tk. 1,100 [26–29].

#### **4. WHO's program on global patient safety challenge (also known as well-being program)**

The WHO has the responsibility to promote the health and hygiene of the people of its member countries. To perform this responsibility, WHO has taken a few programs. One of such programs is the Global Patient Safety Challenge. Till date, WHO has undertaken three Global Patient Safety Challenges, which are popularly known as '**Well-being Programs'**. These include [30]:


These programs are almost self-explanatory, and a detailed description is out of the scope of this chapter.

## **5. Pharmacovigilance (PV)**

According to WHO, PV can be defined as: "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem" [31]. The term PV has been accrued from the Greek word *Pharmakon* meaning *drug* and from the Latin term *vigilare* meaning *to keep aware or, vigilant/alert or, to keep watch* [31]. Vigilance usually indicates:


From the definition given above, we see that there are four pillars of PV. These include:

i.Detection


#### **5.1 Main aims**

The general aims of PV are to promote both patient care and patient safety with respect to the use of drugs and medical devices; and to bolster the public health programs (PHP) by giving reliable and equalized information for the productive estimation of the benefit–risk quotient of medicines [32].

The most important aims and purposes of PV are [32];

i.to alert people, not to scare them;


### **6. PV analytical tools**

It is well-known that PV is a risk management procedure for drugs. The process begins with identification of a possible danger, which is then assessed and investigated, ultimately resulting in actions that are taken to minimize those risks. The PV implementation requires the use of specific tools (**Figures 5** and **6**) that will help to communicate with the prescribers and end-users, and the last step should be an evaluation of the effectiveness of the process. The overall process of risk management is iterative due to new proofs that may emerge, or to certain measures taken that may be inadequate. A drug safety issue is rarely considered complete and the safety study goes on until the life cycle completion of the drug.

**Figure 5.** *PV tools to detect and assess the signals related to ADRs.*

#### **Figure 6.**

*Flow of information among PV centers and the global monitoring organizations by using PV analytical tools for ADRs analysis [33].*

The beginning of the process is normally a 'signal' which is not often a real hazard. Before that can occur, there is a necessity to detect the signal.

The term 'signal' is defined by WHO as a "reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely recorded previously" [34].

#### **6.1 VigiBase**

VigiBase is the starting point for the journey of Uppsala Monitoring Center (UMC) from data to wisdom regarding the safe use of drugs, as well as the sage therapeutic decisions in clinical practice. This is the motivating-force of the work of UMC and the WHO Program. The main aim of VigiBase is to make sure that initial signs of previously undetected, unknown, and unexplored drug-related safety problems are identified as quickly as possible.

VigiBase is one of the unique WHO global databases of individual case safety reports (ICSRs). This is the biggest database of its kind worldwide, with more than 20 million reported records of suspected adverse effects of drugs, which have been submitted since 1968 by member states of the WHO PIDM. VigiBase is continually updated with incoming reports from the member countries [35].

#### **6.2 VigiFlow**

VigiFlow stands as a management procedure for recording, processing, and sharing reports of ADRs. VigiFlow collects the domestic data and processes the ICSR, thus sharing the reports for instance with VigiBase. This allows maximum local control and gives effective ways for management review and data scanning coming from national sources [36].

#### **6.3 VigiLyze**

VigiLyze is a signal detection and management system using national, regional or global data as the launching point for quantitative signal detection. VigiLyze supports the overall signal management process, including the qualitative evaluation.

*Adverse Drug Reactions and Pharmacovigilance DOI: http://dx.doi.org/10.5772/intechopen.98583*

The major strengths of this signal detection tool are its capacity to re-estimate disproportionality based on any selected country or region background within seconds, and re-investigate those for certainty using different tools [37]. VigiLyze will enable the users to search for any drug or reaction that is shared with the program from UMC, other national centers, or their own centers.

VigiLyze is accessible free of cost to national pharmacovigilance centers in all member states of the WHO Program for IDM. Under-reporting is a familiar matter in pharmacovigilance. By distributing the national reports of adverse events to the global database, individual nations can help increase all countries' understanding of achievable safety concerns.

VigiLyze provides a national, regional, and global aspects of the suspected adverse effects of a drug. This enormous collection of data enhances assessments of surfacing domestic issues. Through VigiLyze it is possible to obtain easy entrance to post-marketing safety information for medicines that are new to the national market, but that are already marketed in other parts of the globe [38].

It is important to mention that one of the major concerns of PV is the safety issue of the PHP [39], such as vaccination in the form of national immunization day, administration of anthelmintics, administration of vitamin A capsule, etc. In those cases, PV tools act as very essential weapons to analyze the situations or adverse effects arising from mass drug administration [40] to handle the pandemics.

#### **7. Bangladesh perspective of PV activities**

The Directorate General of Drug Administration (DGDA), under the ministry of Health and Family Welfare, is the national DRA of Bangladesh. The DGDA acts as the only PV center in Bangladesh. An Adverse Drug Reaction Monitoring (ADRM) cell has been set up under the DGDA in 1999 in Bangladesh [41]. The ADR reporting form was introduced in relevant medical institutions to collect information on ADRs. More recently, and under the ADRM, a PV cell was established to effectively monitor and collect the information on ADRs. However, PV is only one of the main components of effective medicine regulation by the national drug regulatory agencies. The vision of DGDA is to guarantee that effective, high-quality and safe drugs are available to the Bangladesh population. This can be achieved through

#### **Figure 7.**

*Interrelationship among the different health professionals (physicians, pharmacists, nurses and health technologists) and the patients [42].*

an effective dissemination of the PV cell activities all over the country, including all public and private medical institutes, hospitals, clinics, public and private practitioners, pharmacists, nurses, and other health professionals (**Figure 7**). However, it is very important to keep in mind that the patients should always remain at the center of all [41].

#### **8. Conclusions**

The main purpose of the PV study is to protect the future generations or the potential users from the harmful effects of a drug that has already launched in the market. Although the emergence of side effects resulting from the use of drugs are unavoidable, the incidence of morbidity and mortality caused by the occurrence of side effects can be reduced if proper measures are promptly adopted by the local, as well as by the global regulatory organizations. To this end, the main PV principles should be strictly followed by all the member countries of the WHO.

### **Acknowledgements**


#### **Conflict of interest**

The author declares no conflict of interest.

#### **Notes/Thanks/Other declarations**

Special thank goes to my wife Shirotaz Begum for her cooperation to complete this write up.

#### **Appendices and nomenclature**


*Adverse Drug Reactions and Pharmacovigilance DOI: http://dx.doi.org/10.5772/intechopen.98583*


### **Author details**

Md. Shah Amran Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Shahbag, Dhaka, Bangladesh

\*Address all correspondence to: amranms@du.ac.bd

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

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[3] Guideline for Good Clinical Practice. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. 10 June 1996. 2p.

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[5] https://www.who.int/teams/ regulation-prequalification/ pharmacovigilance (Accessed on 15-01- 2021)

[6] Neil Vargesson, Thalidomide-Induced Teratogenesis: History and Mechanisms, Birth Defects Research (Part C), 2015, 105:140-156.

[7] WHO Collaborating Centre for International Drug Monitoring, https://www.who.int/medicines/areas/ quality\_safety/safety\_efficacy/collabcentre-uppsala/en/ (Accessed on 15-01-2021)

[8] Members of the WHO Programme for International Drug Monitoring, Full and associate member countries of the WHO Programme and the year they joined. Full member countries (143), https://www.who-umc.org/globalpharmacovigilance/

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[9] Bangladesh National Formulary (BDNF), 2015, Volume 4, Pp759-768.

[10] Rashmi R. Shah, Importance of Publishing Adverse Drug Reaction Case Reports: Promoting Public Health and Advancing Pharmacology and Therapeutics, Drug Saf - Case Rep., 2017, 4:11 doi:10.1007/ s40800-017-0053-0.

[11] Chung Chow Chan, Herman Lam, Y. C. Lee, Xue-Ming Zhang, Analytical method validation and instrument performance verification, Wiley interscience, 2004, P1-11.

[12] https://penlighten.com/meaningorigin-of-idiom-tip-of-iceberg (accessed on 15-01-2021)

[13] W.G. McBride, THALIDOMIDE AND CONGENITAL ABNORMALITIES, The Lancet, 1961, Volume 278, Issue 7216, 1358p.

[14] Papers of William McBride, ca. 1953-1996, National Library of Australia, accessed 26 July 2010.

[15] Bara Fintel, Athena T. Samaras, Edson Carias, The Thalidomide Tragedy: Lessons for drug safety and regulation, Helix Magazine, Jul 28, 2009.

[16] Attacking the devil: the thalidomide story, BMJ 2016; 352 [BMJ 2016;352:i353]

[17] Md. Shah Amran and Md. Aktar Hossain, Pharmacovigilance and Bangladesh perspective, Bangla Academy Science Journal, 2019, 1:88-95.

[18] "Time Magazine" Archived 3 September 2009 at the Wayback Machine.

*Adverse Drug Reactions and Pharmacovigilance DOI: http://dx.doi.org/10.5772/intechopen.98583*

[19] Medical Tribunal of New South Wales Archived 20 September 2009 at the Wayback Machine.

[20] Dr. McBride hails end of the affair – "The Australian".

[21] Carol Ballentine, Sulfanilamide Disaster, FDA Consumer magazine, June 1981 Issue.

[22] West, Nancy. "History of Tylenol" (PDF). Nancy West Communications. Retrieved July 26, 2014*.*

[23] Dan Fletcher, A Brief History of the Tylenol Poisonings, The Time, Monday, Feb 09, 2009.

[24] Euromonitor International. "Acetaminophen benefits from concerns surrounding safety of analgesics". Market Research World. Retrieved July 26, 2014*.*

[25] Hanif, M., Mobarak, M.R., Ronan, A., Rahman, D., Donovan, J.J. and Bennish, M.L. 1995. Fatal renal failure caused by diethylene glycol in paracetamol elixir: the Bangladesh epidemic. Bri. Med. J.311, 88-91.

[26] The Daily Star, Three Adflame officials jailed for 10yrs, 03:56 PM, July 22, 2014 / LAST MODIFIED: 01:53 AM, March 08, 2015.

[27] The Dhaka Tribune, All acquitted in Rid Pharma paracetamol case, 12:25 pm November 28th, 2016.

[28] The Daily Star, Rid's syrup unauthorized, toxic element found, 11:00 PM, July 29, 2009 / LAST MODIFIED: 11:00 PM, July 29, 2009.

[29] The Daily Star, The unfortunate case of Rid Pharma, 12:00 AM, December 06, 2016 / LAST MODIFIED: 12:00 AM, December 06, 2016.

[30] https://www.who.int/patientsafety/ events/05/GPSC\_Launch\_ENGLISH\_ FINAL.pdf (Accessed on 01-12-2020)

[31] WHO / Pharmacovigilance (Accessed on 01-12-2020).

[32] WHO / Pharmacovigilance (Accessed on 16-06-2019).

[33] Maria Delaney, Improving pharmacovigilance through direct patient reporting, Cancerworld, March / April 2017. 77:28-32.

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[35] https://www.who-umc.org/vigibase/ vigibase/

[36] https://www.who-umc.org/globalpharmacovigilance/vigiflow/

[37] WHOcausality\_assessment.pdf (21-05-2021)

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[39] The SAFETY of MEDICINES IN PUBLIC HEALTH PROGRAMMES: Pharmacovigilance an essential tool, 2006, Pp 9.

[40] https://en.wikipedia.org/wiki/ Mass\_drug\_administration (Accessed on 17-01-2021)

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[42] Md. Shah Amran, Introduction to Pharmacy, Published by Krishnachura Publications, Central Road, Dhaka-1205, Dhaka, Bangladesh, 2nd edition, 2015, Pp-7.

#### **Chapter 3**

## Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy

*Vivekanandan Kalaiselvan, Shatrunajay Shukla, Santhanakrishnan Ramesh Kumar, Nikita Mishra, Pawan Kumar and Rajeev Singh Raghuvanshi*

#### **Abstract**

The pharmacovigilance has been evolved as a professional and ethical practice in ensuring the safety of medicines. The Adverse Drug Reactions (ADRs) associated with the use of medicines including Anti-Tuberculous Therapy (ATT) through a robust system of pharmacovigilance helps in promoting the safety of patients at large. The occurrence of ADRs associated with the use of ATT is expected, a large number of medicines are combined and used for prolonged duration. The suspected ADRs associated with first line ATT are well documented. However, the drugs used in second line or multidrug resistant to tuberculosis (TB), namely bedaquiline, reported to cause QT prolongation in electrocardiogram reading as one of the most common ADRs. Therefore, early identification and prevention of ADRs during ATT is essential for promoting the rational use and reduce the burden of anti-microbial resistance, besides achieving better treatment outcomes.

**Keywords:** Adverse Drug Reactions, Anti-Tuberculosis Therapy, Bedaquiline, Pharmacovigilance

#### **1. Introduction**

The unfortunate tragedy of thalidomide, in 1962, triggered the emergence and implementation of pharmacovigilance across the globe [1]. Thalidomide was introduced in Germany in 1957 and was widely prescribed for the treatment of morning sickness and nausea in pregnant women. Later it was found that babies were born with shortened or absence of limbs (medically known as phocomelia). In 1962, thalidomide was discontinued from the market due to the increased number of scientific reports describing numerous cases of phocomelia [2]. This tragedy led to the creation of the World Health Organization (WHO) pilot research project for International Drug Monitoring in 1968, with the purpose to develop a system and tools applicable internationally, for detecting previously unknown or poorly understood adverse drug reactions (ADRs) of medicines [3]. Currently, this network has been expanded to more than 140 developed, low- and middle-income countries. These 140 countries participated in the WHO programme for international drug monitoring as member states, and 31 countries have also joined as associate member states. These countries have established pharmacovigilance system at their capacity, to monitor the medication safety. WHO and its collaborating centres are continuously providing technical support for capacity building and strengthening of these pharmacovigilance systems [4].

As per WHO, Pharmacovigilance is defined as a "science of detection, assessment, understanding and prevention of ADRs or any other drug related problems" [5]. This enables the scope of clinical practice of monitoring & reporting of ADRs, analyses the information and sharing the learnings with healthcare providers for prevention of such ADRs, for better patient's safety and outcomes. Pharmacovigilance and its concepts are evolving as one of the most important components in contemporary clinical and regulatory practice. In clinical trials, most medicines will only be tested for short-term safety and efficacy on a limited number of carefully selected individuals (excluding pregnant women, children and elderly). In some cases, as few as 500, and rarely more than 5000, subjects receive the investigational new drug prior to its release [6]. It is not possible to identify and record many ADRs in such a shorter duration, protected environment and restricted population in trials. After stage three of clinical trial, the medicine is available to be launch in the market and is legally set free for consumption by the general population. Post market experience has shown that many adverse effects, interactions (i.e. with foods or other medicines), and risk factors may come to light even after several years of introducing the medicine into the market [7]. Moreover, many studies have shown that an ADR may result into a significantly decrease in the quality of life, increased hospitalizations, prolonged hospital stay and mortality [8]. Therefore, monitoring the safety of the medicines throughout its life period is pivotal, as most of the ADRs are usually reported during prolonged use.

The pharmacovigilance practice applies equally to medicines used in public health programs, including medicines used in Anti-Tubercular Therapy (ATT). As the management of tuberculosis (TB) involves longer duration of therapy and also multiple drugs, these arise as predisposing factors for the occurrence of ADRs [9]. Such ADRs pose a challenge in the management of TB. Though it is a prolonged treatment, medication must be continued in order to ensure the compliance, otherwise it will end with treatment failure or developing antimicrobial resistance [10]. Generally, patients discontinue the medication due to the emergence of ADRs resulting from the administration of first-line anti-TB drugs. During the course of TB treatment, there may be a risk of morbidity and mortality, particularly with drug-induced hepatitis. Therefore, there are public health program in various countries that systematically monitor, prevent and manage ADRs encountered during the treatment of TB, in order to achieve maximum treatment outcomes [11].

TB is a chronic infection caused primarily by *Mycobacterium tuberculosis*. The lung is generally the first affected organ, as the infection is usually due to inhalation of infected droplet nuclei. Approximately 80% of the TB cases are pulmonary TB [12]. Around 30% patients who are infected with Human Immune Deficiency Virus (HIV) will also develop active tuberculosis. Factors, such as HIV, Resistant TB, drug–drug interactions raise the complexity of problem. As per the WHO strategy, directly observed treatment short-course (DOTS) therapy for the duration of 6–8 months is one of the important components for the treatment of TB. The short-course therapy is usually performed in 2 phases: the initial phase (2 months) involves the concurrent use of at least 3 drugs to rapidly reduce the bacterial population and prevent emergence of drug-resistant bacteria. The second, continuation phase, (4–6 months) involves fewer drugs and is used to eliminate any remaining bacteria and prevent recurrence. Worldwide, HIV infection has been identified as an important predisposing factor of immune-suppression leading to TB [13]. It increases the susceptibility to primary infection and increases the reactivation rate


**Table 1.**

*Recommended drugs used to treat tuberculosis.*

of TB [14]. Although this regimen is effective in treating active TB, it is associated with many ADRs and poses a significant challenge to completion of treatment. Recommended treatment regimens for TB are given in **Table 1**.

#### **2. Importance of ADR reporting in tuberculosis**

Multiple types of drug therapy are given for TB, and even new TB patients (sensitive to first-line drugs), are receiving a treatment regimen with a combination of four drugs [15]. There is a chance for developing ADR either for one or the combination of drugs, and that has to be identified for ensuring a sustained treatment compliance, till the completion of ATT. When treatment is given to patients with TB-associated drug resistance, either ionized resistance, multidrug resistance or rifampicin resistance, pre-extensively drug resistance or extensively drug resistance TB, the number of drugs given could be higher, and it becomes imperative to identify the resulting/associated ADRs. In case any ADR takes place, the treatment management has to be done appropriately [16]. For TB patients having HIV co-infection, the treatment given for HIV infection, including the antiretroviral therapy, and/or the medication given for the associated conditions, may overlap with the ADR presented, and so it becomes very important to monitor this group of population for efficient management. In addition, also in TB patients with special medical conditions associated, like associated diabetes mellitus, liver, renal or seizure disorders, and psychosis, the treatment should be done cautiously, by closely observing the progress and monitoring all the ADRs encountered. Furthermore, when new drugs like Bedaquiline (BDQ ), Delamanid (DLM) and Pretomanid are initiated at TB programs, it is essential that the associated ADRs are captured promptly for effective management of TB [17].

#### **2.1 ADRs associated with first-line anti-TB drugs**

The ATT is expected to cause more ADRs, because it involves combination of several medicines and is used for a longer duration [9]. One of the most common ADRs observed with the administration of ATT is gastrointestinal symptoms, such as nausea, vomiting etc. These ADRs could be symptomatically managed without the need for a change in the dosage of drugs. The hepatotoxicity is also a risk associated with ATT, and its frequency can range from 2–39% in different countries [18]. As compared to Western population, Indian sub-population studies reported high incidence of hepatotoxicity with ATT [19].

#### *2.1.1 Isoniazid*

Isoniazid has been shown to be well tolerated at recommended dose. However, systemic or cutaneous hypersensitivity reactions can occasionally occur during the first weeks of treatment [15]. By daily supplementary dose of pyridoxine in vulnerable patients, the risk of peripheral neuropathy can be excluded. In the later stages of treatement, some susceptible patients can develop neurological disturbance, encompassing optic neuritis, toxic psychosis and generalized convulsions. This may require the discontinuation of isoniazid. An uncommon but potentially serious reaction is symptomatic hepatitis, which could be precluded by prompt withdrawal of treatment. Asymptomatic rise in serum concentrations of hepatic transaminases at the beginning of treatment has very low clinical significance. The same resolves spontaneously as the treatment carry on. Other rare adverse effects linked with isoniazid are lupus-like syndrome, pellagra, anemia, and arthralgias [20].

#### *2.1.2 Rifampicin*

At currently recommended doses, this drug has been shown to be well tolerated by most of the patients. Occasionally it may cause gastrointestinal reactions including abdominal pain, nausea, vomiting and pruritus with or without rash [21]. With an intermittent drug administration, adverse effects, such as fever, influenza-like syndrome and thrombocytopenia may occur. In HIV-positive TB patients, exfoliative dermatitis is more common. Patients taking the drug 3 times a week, adverse effects including temporary oliguria, dyspnoea and haemolytic anemia have been reported. If the regimen is changed to daily dosage these reactions usually subsided. In the beginning of treatment, moderate rises in serum concentrations of bilirubin and transaminases are common adverse effects are often transient and not clinical significant. A potentially fatal condition is dose-related hepatitis, it is therefore important to not exceed the maximum recommended daily dose of 600 mg.

#### *2.1.3 Pyrazinamide*

This drug has been reported to cause various skin reactions, like maculopapular rash, erythema multiforme, exfoliative dermatitis and drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Among the first-line drugs, pyrazinamide has shown to be the most common drug to cause cutaneous ADRs [22]. Pyrazinamide may cause gastrointestinal intolerance. Hypersensitivity reactions are rare, but have been reported in some patients with modest flushed skin. During the early phases of the treatment, moderate rises in serum transaminase concentrations

#### *Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy DOI: http://dx.doi.org/10.5772/intechopen.97246*

are common. A rare complication is severe hepatotoxicity. A degree of hyperuricaemia may also occur asymptomatically as a result of inhibition of renal tubular secretion [15]. The treatment may also result into gout, which can be treated with allopurinol. Arthralgia, especially of the shoulders, may occur which can be treated with simple analgesics (especially aspirin). By prescribing regimens with intermittent administration of pyrazinamide, hyperuricaemia and arthralgia may be eliminated. Sideroblastic anemia and photosensitive dermatitis are some of the rare ADRs associated with this drug [7, 8].

#### *2.1.4 Streptomycin*

Streptomycin injections are painful, and rash, induration, or sterile abscesses can be formed at injection sites. Numbness and tingling around the mouth occur immediately after injection and cutaneous hypersensitivity reactions can occur. The incidence of ototoxicity associated with the use of ATT may be as high as 25% [23]. With currently recommended doses, the complications like impairment of vestibular function are uncommon. Vertigo is more common than hearing loss. Indications of injury at the 8th cranial (auditory) nerve include ringing in the ears, ataxia, vertigo and deafness. The damage is impermanent and can be reversed by reducing in dosage, or the stopping the treatment with this drug. This damage is commonly occurs within the first 2 months of treatment. More commonly, the other aminoglycoside antibiotics e.g. kanamycin, amikacin and capreomycin are more nephrotoxic than streptomycin. If urinary output falls, albuminuria occurs, or tubular casts are detected in the urine, streptomycin should be stopped, and renal function should be evaluated.

Though WHO's recommendation is not to use injectable streptomycin, we should take into consideration that other recommended treatments with aminoglycosides may cause similar types of ADRs [17].

#### *2.1.5 Ethambutol*

Dose-dependent optic neuritis caused by Ethambutol can result in impairment of visual acuity and color vision in one or both eyes. Early changes are usually reversible, but blindness can occur if treatment is not discontinued promptly. Ocular toxicity is rare when ethambutol is used for 2–3 months at recommended doses. Peripheral neuropathy has been reported in approximately 20% of patients treated with ethambutol. Other rare adverse events include generalized cutaneous reaction, arthralgia and, very rarely, hepatitis [24].

Several studies have reported that the drugs used to treat TB may cause ADRs. Management and prevention of such ADRs are important measures to be adopted to increase tolerance. Generally, with non-serious ADRs, the drugs do not need to be stopped, while with serious ADRs, the drugs often have to be stopped and a modified regimen has to be implemented [9].

#### *2.1.6 Capreomycin*

This drug is administered in combination with other first-line drugs. The common ADRs reported are hypersensitivity reactions, including urticaria and rashes, nephrotoxicity, electrolyte disturbance, hearing loss wit tinnitus and vertigo [11].

Grading of toxicity associated with drugs used for TB treatment and the ADRs associated with the anti-TB drugs used for therapy are given in **Tables 2** and **3**, respectively.


#### **Table 2.**

*Grades of toxicity resulting from TB treatment [25].*


#### **Table 3.**

*Most common ADRs associated with the use of anti-TB drugs.*

#### **2.2 ADRs associated with second-line anti-TB drugs**

Resistant -TB is usually treated with a combination of drugs that are more toxic than isoniazid and rifampicin. These drugs include fluoroquinolones, aminoglycosides, ethionamide, cycloserine, aminosalicyclic acid, linezolid and clofazimine, among others [26]. The main ADRs associated with the use of cycloserine are reported as neurological disorders, including headache, dizziness, vertigo, drowsiness, tremor, convulsions, confusion, psychosis, depression, rashes, allergic dermatitis, megaloblastic anemia, and changes in liver function tests [27]. Minor adverse

effects are relatively common, and they can be easily managed with symptomatic treatment. However, some adverse effects can be life-threatening, for example, nephrotoxicity due to aminoglycosides, cardiotoxicity due to fluoroquinolones, gastrointestinal toxicity due to ethionamide or para-amino-salicylic acid, central nervous system toxicity due to cycloserine, etc. [17].

#### **2.3 Multi Drug-resistant TB (MDR-TB)**

MDR-TB is caused by organisms that are resistant to isoniazid and rifampicin. As per the WHO reports, an estimated 480 000 worldwide patients developed MDR-TB in 2015, in addition to the 100 000 patients with rifampicin-resistant TB that were newly eligible for MDT-TB treatment [22]. Again, according to WHO, the second highest MDR-TB incident country in the world, China, accounted for 45% of the 580 000 cases, together with Indian and the Russian Federations, with 6.6% of new TB cases and 30% of previously treated cases having MDR/Rifampicin resistant TB.

The novel anti tubercular drugs, namely BDQ and DLM, now included in WHO second-line treatment [28], as well as in some countries, have received conditional approval for use in adults with MDR-TB. BDQ, a new anti TB- drug, has been given approval by the United States Food and Drug Administration in 2012 [29], and by the European Medicines Agency in 2014. In India, BDQ was introduced under the conditional access program in 2015. The safety profile and tolerability of a BDQcontaining treatment regimen used in India has been established. QT prolongation in electrocardiogram reading has been reported as one of the most common ADRs with the use of BDQ; the others include peripheral neuropathy, vomiting, breathlessness and thrombocytopenia [30].

#### **2.4 Prevalence of adverse events associated with second-line anti-TB drugs in children**

Children, especially those under 10 years old, can tolerate second-line combination of anti-TB drugs better than adults. In children, the higher rate of ADRs has been observed in those having HIV as comorbid infection, as compared to TB infection alone [14]. Several studies have also revealed that the majority of the adverse events found in children are mild to moderate, thus not requiring interruption or complete cessation of treatment. Moreover, even with the occurrence of few severe adverse events, permanent discontinuation of drugs is rarely necessary [14].

The second–line drugs are generally found to cause more ADRs, as compared to the first-line drugs [31]. The healthcare workers treating children should be aware of this fact and should thus be able to manage such ADRs. Healthcare workers, care givers or parents are required to be trained accordingly, because most of the children may not be able to report the drug-associated ADRs. The MDR-TB treatment outcomes in children are well achieved in many countries by using the currently available drugs [32, 33]. However, the improvement of the MDR-TB treatment programme can be achieved by: (1) implementing targeted or cohort event monitoring of adverse events, with the use of MDR-TB drugs in children; and (2) healthcare works training for a timely ADRs reporting, aiming to achieve the maximum treatment outcomes.

#### **2.5 Causality and severity assessment of anti-TB drugs-associated adverse events**

After determining the adverse events (suspected) of anti-TB drugs, the very next step is to establish the causal or temporal relationship between the drug and the

event, i.e., is the drug actually causing the event? It is possible that the administered drug and the occurrence of an adverse event may have a close temporal relationship, but still not be a reaction [34].

Having considered the parameters in assessing the temporal relationship, the next step is to address the following question: "Did these medicines actually cause the event?" In other words, "Is the event a reaction?" It is conceivable/acceptable that the administration of a medicine and the occurrence of an event may have a close relationship, but still not be a reaction, for example, death from myocardial infarction. In actual practice, the assessment of the relationship and causality frequently merge, particularly when an event is a well-known reaction and the relationship is close. The two phases occur without conscious deliberation, but should be there nevertheless. However, it is often necessary to gather other knowledge about the medicine, the patient and the event, in order to undertake a deliberate evaluation of these factors, which are actually external to the drug–event association that has occurred. Causality assessment is the methodological approach for evaluating a signal (identification of new safety alert) [35]. As per WHO, the causality assessment scale is the estimated strength of the relationship between the drug and the ADR can be classified as certain, probable, possible, unlikely, conditional/unclassified,


**Table 4.**

*WHO's scale for causality assessment [36].*


*Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy DOI: http://dx.doi.org/10.5772/intechopen.97246*

*a. Definite (>9).*

*b. Probable (5 to 8).*

*c. Possible (1 to 4).*

#### *d. Unlikely (< 0).*

#### **Table 5.**

*Naranjo's scale for causality assessment [37].*

unassessable/unclassifiable (**Table 4**). The Naranjo scale can also be applied for causality assessment, and is algorithm-based (**Table 5**) [38].

The severity assessment of ADRs can also be categorized in to into seven levels of severity level 1 and 2 are considered less severe or mild, levels 3 and 4 are moderate, and levels 5, 6 and 7 are classified as severe [39]. Severe level of ADRs includes all potentially life threatening ADRs, and the ones causing permanent damage or requiring intensive medical care. Even some other assessment scales classify severe and lethal.

#### **3. Conclusions**

The emergence of ADRs continues to remain an important public health issue worldwide, as it is among the ten leading causes of mortality. Early identification and prevention of ADRs during TB treatment will lead to the rational use of medicines and to a reduce burden of antimicrobial resistance. Better adherence within the target population will reassure that monitoring and good communication on risks and benefits provide favorable implications for decisions on medicine procurement. Safety monitoring of medicines is thus a vital and crucial element of any health system. As TB treatment relies on a multi-drug therapy for long duration, the emergence of ADRs is inevitable. Therefore, ADR reporting is essential as it will strengthen the evidence, maximize the benefits and minimize the risks.

## **Abbreviations**


### **Author details**

Vivekanandan Kalaiselvan1 \*, Shatrunajay Shukla1 , Santhanakrishnan Ramesh Kumar2 , Nikita Mishra1 , Pawan Kumar1 and Rajeev Singh Raghuvanshi1

1 Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Government of India, Ghaziabad, Uttar Pradesh, India

2 ICMR-National Institute for Research in Tuberculosis, Chennai, India

\*Address all correspondence to: vivekarts@gmail.com; kalaiselvan.ipc@gov.in

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Adverse Drug Reactions Associated with Anti-Tuberculosis Therapy DOI: http://dx.doi.org/10.5772/intechopen.97246*

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#### **Chapter 4**

## Prevalence and Significance of Antibiotic-Associated Adverse Reactions

*Tânia Magalhães Silva, Eva Rebelo Gomes, Inês Ribeiro-Vaz, Fátima Roque and Maria Teresa Herdeiro*

#### **Abstract**

The World Health Organization (WHO) defines Pharmacovigilance as the science and activities relating to the detection, assessment, understanding and prevention of adverse drug effects. The aim is to promote the safety and effective use of medicines through an early detection and evaluation of drug safety risks. The pharmacovigilance system is essentially based in spontaneous reports of Adverse Drug Reactions (ADR). ADR can be associated with severe outcomes and significant mortality, besides, most of them are deemed to be preventable events. Globally, antibiotics are among the most widely prescribed medications and their extensive use is linked to antibiotic-associated ADR. This chapter aims to summarize available epidemiological data concerning antibiotic use related ADR and analyze the reports received by the EudraVigilance system regarding the exclusive usage of antibiotics.

**Keywords:** Antibiotics, Adverse Drug Reactions, Pharmacovigilance System

#### **1. Introduction**

The history of antibiotics and its use can be dated back to the previous century [1]. According to the World Health Organization (WHO), antibiotics are "medicines used to prevent and treat bacterial infections" [2]. These powerful medicines are used to destroy specific bacteria, or to prevent their spread, thus not being suitable to treat, for instance, viral infections. Over the years, antibiotics have shown to effectively treat several previously life-threatening diseases caused by bacteria, being the first therapeutic approach in those clinical conditions [3, 4].

The appropriate use of antibiotics is safe, effective and has few adverse effects. However, when these medicines are improperly prescribed, bacterial resistance may arise. This problem, commonly known as antibiotic resistance (ABR), is one of the major public health threats of the 21st century worldwide [4, 5]. Globally, the annual predicted number of deaths caused by bacterial agents may increase from 700 thousand million deaths to 10 million by 2050, if no action is adopted [5]. A study based on data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) during 2015 estimated that, annually, around 670 thousand infections occur in the European Union (EU) due to antibiotic-resistant bacteria, with approximately 33 thousand people dying as a direct outcome of these types of infection [6]. The overall crude economic burden of ABR was estimated to be

at least 1.5 billion euros a year in the EU, the majority due to hospital costs [7]. Consequently, the fight against ABR stands as an extremely important public health target that should not be underestimated.

The appropriate use of antibiotics is essential to prevent ABR and reduce the risk of adverse reactions. Adverse drug reactions (ADR) are another public health problem, namely in terms of mortality, morbidity and healthcare costs, that requires maximum attention [8]. An ADR can be defined as "a noxious and unintended response to a medicinal product" [9], and can be caused by any drug class. Nevertheless, globally, antibiotics are among the leading drug classes responsible for the occurrence of ADR [10, 11].

Pharmacovigilance systems are essential to enhance patients' care and safety, being responsible for the monitoring of pre-market review and post-market surveillance processes. Moreover, they provide reliable and balanced information for an effective evaluation of the benefits and risks of available medical drugs [12].

The development of educational interventions to improve the awareness of health professionals, and the literacy of the population in general about the dangerous health implications of an inadequate antibiotics use is indispensable.

With this in mind, the aims of this chapter are:


#### **2. Antibiotics**

The global significance of antibiotics discovery in medical science is unquestionable. According to the Centers for Disease Control and Prevention (CDC), antibiotics can be described as "medicines that fight infections caused by bacteria in humans and animals, by either killing the bacteria or making it difficult for the bacteria to grow and multiply" [13]. Antibiotics can be of natural occurring origin or chemically synthesized, and have proven to be essential in fighting infectious diseases [14]. The discovery and development of these compounds has allowed the effective treatment of several bacterial infections, leading to an increased lifespan and to an improvement in the quality of life of millions of people [14].

Salvarsan, the first synthetic anti-infective drug reported, was synthesized and discovered by Paul Ehrlich, Alfred Bertheim and Sahachiro Hata in 1907. This antibiotic had its first clinical application in 1910 in syphilis treatment, and was shown to be highly effective and therapeutically safe, regardless of the side effects [1, 15, 16]. Afterwards, in 1932, Gerhard Domagk discovered Prontosil, a sulfonamide drug, which was further developed and commercially released in 1935 for public use by the pharmaceutical company Bayer. These were two of the first antibiotics of synthetic origin discovered [14–16]. On the other hand, penicillin

#### *Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

was the first naturally occurring antibiotic discovered in modern medicine, being observed in a petri dish in 1928 by Alexander Fleming. In 1941, Howard Florey, Norman Heatly and Ernst Chain pursued Fleming's studies and penicillin was finally produced in sufficient quantities to be used in clinical trials, allowing the treatment of uncountable soldiers during World War II. In 1945, the discovery of this unprecedent live-saving antibiotic led Fleming, Florey and Chain to won the Nobel prize [1, 14–16].

The discovery of these three antibacterial drug agents was remarkable and unveiled the future discovery, development and release of several new antibiotic classes during the so called "Golden Age" of antibiotics, a period between 1940s and middle 1960s [1, 15]. Interestingly, most of the antibiotics discovered during this era are still being currently used in the treatment of bacterial infections, once the pharmaceutical industry significantly reduced its investments in the production of new antibiotics due to the little benefit over existing treatments [3].

Antibiotics are classified in different classes. Some share similar chemical and pharmacological features and thus are used in the treatment of similar bacteria infections. These classes briefly comprise β-lactams, sulfonamides, aminoglycosides, tetracyclines, chloramphenicol, macrolides, glycopeptides, sulphonamides, ansamycins, polymyxins, quinolones, streptogramins, oxazolidinones and lipopeptides [16].

According to the Anatomical Therapeutic Chemical (ATC) Index 2020 from the WHO Collaborating Centre for Drug Statistics Methodology Norwegian Institute of Public Health, antibiotics are categorized as antibacterials for systemic use – J01 therapeutic subgroup, belong to the anti-infectives for systemic use (J anatomical group) and consist of the 10 different pharmacological subgroups displayed in **Table 1** [17]. Additionally, antibiotics can also be categorized as bactericidal or bacteriostatic, based on their mechanism of action (**Table 1**). The general assumption within the society for many years was that bactericidal antibiotics (agents that eliminate bacteria by causing cell death) were more powerful and effective than bacteriostatic antibiotics (agents that inhibit bacterial growth and reproduction). However, it became relevant to assess if this belief was indeed true and verified at a clinical level for several bacterial infections [18]. Several studies included in a systematic literature review on the topic have shown that for many invasive bacterial infections, such as pneumonia, skin and soft tissue infection, intraabdominal, genital and nonendocarditis bloodstream infections, there was no significant clinical differences in outcomes nor in mortality. Therefore, one can assume that this classification seems to be irrelevant when applied to these types of clinical infections [18].

#### **2.1 Main challenges with antibiotic use**

The discovery of new antibiotics allowed to save countless lives and revolutionize the future of medicine concerning, for instance, transplantation, surgery and chemotherapy, by preventing and treating bacterial infections in these patients. This has led to a significant decline in mortality and morbidity, and to an extended expected lifespan worldwide [19].

After this remarkable era, only a couple of new antibiotic classes were discovered, and the ones that were in clinical use started to become less effective, due to the rise of an emerging and global health threat, the ABR [7, 19].

The development of ABR is created by specific modifications in bacteria, namely mutations or acquisition of resistant genes by horizontal gene-transfer, allowing them to proliferate and survive in the presence of an antibiotic concentration that used to be enough to either prevent the growth or completely eliminate these


**J01E** Sulfonamides and Trimethoprim • Trimethoprim • Sulfanilamide • Sulfadiazine • Sulfadimethoxine • Combinations of Sulfonamides and Trimethoprim Bacteriostatic Folic acid synthesis inhibition **J01F** Macrolides, Lincosamides and Streptogramins • Macrolides: Erythromycin, Azythromycin • Lincosamides: Clindamycin, Lincomycin • Streptogramins: Pristinamycin, Quinupristin/Dalfopristin Bacteriostatic (Macrolides and Lincosamides) and Bactericidal (Streptogramins) Bacterial protein biosynthesis inhibition (50-S ribosomal subunit targeting)


#### **Table 1.**

*Classification of antibiotics based on the ATC index 2020.*

microorganisms [4]. The ABR phenomenon brought serious health and financial consequences to the society, particularly the increased risk in compromising the healthcare sector, together with a global economic impact, because the pharmaceutical companies no longer perceived both antibiotic discovery and development as lucrative investments [19]. Over the past 25 years, several economic, regulatory, and scientific barriers arose and led to a significant decline in the production of new antibiotics, with only two new classes entering the market and being applied into clinical therapy. Instead of generating new drug classes chemically different from the existent ones, the pharmaceutical industry chose to modify the already

existent antibiotics, particularly the naturally-occurring antibiotics, and to alert for its judicious use, aiming to increase their treatment efficiency and combat bacterial resistance on the long run [14, 20].

The global prevalence of bacteria resistance to antibiotics has been progressively growing. The major facilitating drivers of ABR are the overuse and misuse of these drugs, both in human and veterinary medicine and agriculture, as well as the inappropriate prescription of antibiotic therapy by health professionals. Additionally, ABR can also be triggered by the excessive and unrestricted consumption of antibiotics easily available at low price and over the counter for self-medication, in countries that lack antibiotic regulations, or by the free online acquisition of these medicines in countries where antibiotics are strictly regulated [4, 5, 19].

When an antibiotic successfully reaches its target with a certain required concentration, it causes the death or growth inhibition of pathogens. The resistance mechanisms frequently used by bacteria can be developed by the modification of the antibiotic main target or by the reduction of the antibiotic quantity able to reach the target. There are four key molecular mechanisms involved in bacteria resistance [21]:


#### **2.2 Epidemiological data**

A close link between excessive and inadequate antibiotic consumption and the associated ABR spread has been extensively reported in the literature as a public health hazard worldwide. Antibiotics overuse and misuse were shown to be two of the most critical ABR contributors [5, 19, 20].

The 2019 annual epidemiological report of antimicrobial consumption in the EU/European Economic Area (EEA) published by the ECDC disclosed that the average total consumption of antibacterials for systemic use (ATC group J01) from both primary care and hospital sectors in 2018 was of 19.4 defined daily doses (DDD) per 1000 inhabitants per day (ranging from 9.5 in the Netherlands to 34.1 in Greece). This surveillance report is based on antimicrobial consumption data reported by the 28 EU Member States, together with 2 EEA countries (namely, Iceland and Norway). Overall, a statistically significant decrease in the trend of antibiotics consumption over the 10-year period (2009–2019) was observed in the EU/EEA, with statistically significant differences (either a decrease or an increase) being noticed for particular countries. Apart from Slovakia, the antibiotic subgroup with the highest average consumption in all countries of the EU/EEA was β-lactam antibacterials – Penicillins (J01C) [22].

#### *Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

Approximately two-thirds of the world's population are living at the Asia Pacific region (APAC), one of the largest vulnerable regions to the serious problems posed by ABR. Countries belonging to the WHO South-East Asia region were acknowledged to display the greatest risk of ABR development and propagation comparing to all WHO regions [23]. The lack of a formal and efficient surveillance system, strictly dedicated to detecting and monitor human antibiotic consumption and resistance in APAC countries, makes it impossible to determine the overall burden and estimates of antibiotic use in this region. Nevertheless, there is a high demand for the adoption of successful strategies aiming to decrease the impact of this public health threat in Asia, as it is one of the most critical ABR epicenters worldwide [23].

Data on total antibiotic consumption in DDD per 1000 inhabitants per day are presented for 2 Asian and 1 African countries of the WHO Eastern Mediterranean Region, respectively the Islamic Republic of Iran with 38.8 (wholesalers data), and Jordan with 8.9 (import data, with the exception of locally produced medicines that would account for a significant fraction of the total antibiotic use), as well as Sudan with 35.3 (combined data from import and local manufacturers). The antibiotic subgroup most commonly used in Islamic Republic of Iran and Sudan was penicillin, respectively accounting for 33% and 41% of the total consumption, while in Jordan more than 50% of the antibiotics consumed were macrolides/lincosamides/ streptogramins (J01F), followed by penicillins and other β-lactam antibacterials (J01D) [24].

The same data is also available for 6 countries of the WHO Western Pacific Region, including Brunei Darussalam with 5.9 DDD per 1000 inhabitants per day, Japan with 14.2, Mongolia with 64.4, New Zealand with 22.7, Philippines with 8.2 and the Republic of Korea with 27.7. However, Brunei Darussalam and New Zealand only provided partial data, either of the public health care or community sectors, respectively [24]. Overall, within this region, approximately 33 to 50% of the antibiotics used were penicillins. The most commonly consumed antibiotic subgroups in Brunei Darussalam, Japan, Mongolia, New Zealand, Philippines and Republic of Korea were, respectively, β-lactam antibacterials (70%), macrolides/lincosamides/ streptogramins (32%) and other β-lactam antibacterials (32%), penicillins (33%), penicillins (44%), tetracyclines (J01A, 30%) and penicillins (30%) and other β-lactam antibacterials (33%) [24].

The WHO African Region only provided total antibiotic consumption data in DDD per 1000 inhabitants per day for 4 countries, specifically Burkina Faso with 13.8, Burundi with 4.4 (data restricted to the public sector), Côte d'Ivoire with 10.7 and, finally, the United Republic of Tanzania with 27.3 (data reports only from 2016). The pharmacological subgroup most commonly consumed in all these 4 countries was penicillin, accounting for about 40% of the total consumption in both Burkina Faso and Côte d'Ivoire, 78% in Burundi and 27% in United Republic of Tanzania [24].

The ABR threat greatly affects healthcare development, food production, and lifespan. To efficiently combat ABR, the 1st step is to prevent bacterial infections, the 2nd step is to restrict the resistant bacteria spread by improving an adequate antibiotic use and, finally, the 3rd step is to immediately interrupt the spread when the development has occurred [25].

According to the CDC's Antibiotic Resistance Threats in the United States (US) Report from 2019, which delivered the most recent national antibiotic resistanceassociated burden estimates, there are still over 2.8 million infections occurring in the US per year, yielding more than 350 thousand deaths. Although estimates have improved, particularly the death rate which decreased by 18% when compared to the same report from 2013, the high number of ABR-associated infections still remains an important challenge [25]. Moreover, 2016 CDC estimates revealed that

approximately 30% of all antibiotics prescribed in the US, which corresponds to about 47 million prescriptions per year, are still being inadequately used to treat diseases that do not require antibiotics [26].

Since ABR is a natural and irreversible phenomenon, it is crucial that countries around the world start adopting rigorous measures to slow down and inhibit the spread of bacterial resistance. In response to the emerging global public health threat posed by ABR, a number of national and international actions and initiatives have been developed in recent years to address this issue [27]. In 2015, WHO adopted a global action plan with several interventions that included strengthening health systems and surveillance, reducing the unnecessary use of antibiotics, as well as the prevention and control of ABR in humans, animals, agriculture, and the environment, highlighting the need for an efficient, indispensable and global "OneHealth" approach [27–29]. According to the CDC, the "OneHealth" approach is a "collaborative, multisectoral, and transdisciplinary approach—working at the local, regional, national, and global levels—with the goal of achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment" [30]. Subsequently, on June 29th, 2017, the European Commission adopted a similar integrated action plan, consisting of a series of global, rigorous and high priority strategies and measures, designed to restrict the development and spread of ABR in humans and animals, based on the "OneHealth" perspective [31]. Antibiotic resistance is indeed a One Health challenge, where people's and animal's health are linked together with the environment, that must be rapidly curbed.

The pointless or inadequate antibiotics usage is frequently determined by the knowledge, attitudes and beliefs of all the involved stakeholders on this relevant topic. In order to fight this threat, a couple of initiatives have been adopted by many countries worldwide. These have shown to effectively impact ABR and comprise bacterial infection regulatory programs to limit the transmission of resistant microorganisms, antibiotic stewardship courses based on the adherence to awareness guidelines and approaches to increase the judicious antibiotic prescription, educational interventions among health professionals to improve prudent antibiotic prescription and vaccination programs [20, 29, 32–35].

#### **3. Adverse drug reactions associated with antibiotics**

Pharmacovigilance is very important for monitoring the safety profile of authorized drugs [12, 36]. The ADR remain a challenge in medicine use and are regarded as a critical public health concern due to their potential harmful life-threatening effects [37].

According to the European Directive 2010/84/EU, an *adverse reaction* is defined as a "response to a medicinal product which is noxious and unintended". Moreover, these reactions may arise from the use of the medicinal product within or outside the terms of the marketing authorization (such as off-label use, overdose, misuse, abuse) or from occupational exposure. On the other hand, the definition of an *adverse effect* is given by the EU Directive 2001/20/EC as "any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment". One can then conclude that while an adverse effect is not necessarily triggered by the drug, as it is only temporally correlated with the drug use, an ADR is a form of adverse effect both temporally and causally associated with the drug [38, 39].

The classical or traditional pharmacological classification of ADR primarily adopted was only differentiating dose-related and non-dose-related

#### *Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

reactions, respectively as type A and type B, being solely characterized by properties of the drug (its well-known pharmacology and dose dependent effects). Subsequently, other 4 types of reactions were further established to facilitate the inclusion of adverse reactions that did not belong to type A or type B. Therefore, the modern ADR classification currently includes 6 types of reactions [40].

In 2003, to improve the drawbacks and oversimplifications of the traditional approach, an alternative and more accurate classification system was proposed by Aronson and Ferner, as it had been noticed that some ADR still did not fit well into just one of the classes described above. This classification scheme is known as DoTS and operates by taking into account 3 major parameters: the Dose responsiveness of the drug, the Time course of the reaction and the relevant Susceptibility factors of the patient (including genetic, pathological and other biological differences). Although this 3-dimensional approach is more precise and comprehensive when considering the diagnosis and prevention of ADR, it is also more complex for daily use, which prevented its extensive use in the clinic [41].

Globally, ADR have shown to cause significant morbidity and mortality across diverse populations, either in hospitalized or ambulatory patients, with a significant economic burden to the healthcare system. Adverse reactions affect the quality of life of patients, their confidence in the healthcare system and can significantly increase hospitalizations and the hospital stay period [42, 43].

Over the years, several studies have reported that on average, ADR are responsible for 5–10% of the hospitalizations worldwide, with 80% being frequently considered predictable and possibly avoidable reactions (type A). Moreover, it has also been shown that approximately one fourth of the ambulatory patients in primary care centers can also suffer an ADR reported as serious in 13% of the cases [42].

Studies from the US have shown that ADR were observed in over 1.2 million hospital stays (about 3.1% of all hospital stays) in 2004. In US hospitals, the incidence of serious and fatal ADR was extremely high, with evaluations of 6.7% and 0.32% respectively, making ADR between the 4th and 6th leading cause of death. In 2012, a management consulting firm estimated a profit of USD 115 billion for the prevention of 35 million adverse drug events. In United Kingdom, ADR incidence among admitted patients was found to be 6.5%, with admissions costing up to £466 million annually or 0.62% of annual health budget [44]. Within the EU, in 2008 the European Commission estimated that around 5% of all hospital admissions were triggered by ADR, with 5% of hospitalized patients experiencing an ADR during their hospital stay. Additionally, approximately 197 thousand deaths per year took place in the EU due to ADR [43].

These findings were undoubtedly one of the starting points for the implementation of a new EU pharmacovigilance regulatory framework in 2012, to reduce the ADR burden [43]. Currently, countless countries around the world already have well-established, active and robust national pharmacovigilance systems to safeguard patient's wellbeing.

Some medicines have been especially involved in hospital admissions due to ADR, including antibiotics. Inpatients are given at least one antibiotic in about 50% of the cases, with roughly 20–30% of these being considered unnecessary and accounting for 20–50% of drug costs in hospitals [10, 45]. Additionally, a previous study has reported that although antibiotics use seems to lead to a small incidence of adverse events, its widespread consumption accounts for 23% of all adverse events documented [10]. Between 2000 and 2010, developing countries were the major contributors to the global rise in antibiotics use and, consequently, in the risk of acquiring associated ADR [11].

There is a lack of studies assessing the incidence of ADR due to antibiotic consumption in the hospital sector, during patient's admission, stay and after discharge, as well as its incidence across all antibiotic classes. Nevertheless, the available literature has shown the clear contribution of antibiotics to 19% of ADR in the emergency department in the US between 2004 and 2006 (with allergic reactions accounting for 79%), 8% linked to hospital admissions in Greece in 2005, 6% in Spain between 2001 and 2006, 5% in The Netherlands in 2003, and 11% in India between 2002 and 2009, together with 10% of hospital-acquired ADR in the US and 22% in South Africa [11].

There are several mechanisms explaining different ADR, and the most wellknown include pharmacological causes, idiosyncrasies, hypersensitivity (allergic reactions), carcinogenesis and teratogenesis, direct toxicity, chronic exposure, drug-disease interaction and drug intolerance [46].

#### **3.1 ADR analysis in Europe: EudraVigilance**

EudraVigilance, the official EU pharmacovigilance database managing the collection and analysis of suspected ADR to authorized medical products in the EEA, was primarily launched in 2001, with a new format emerging in 2017. This new revised and enhanced version aimed to achieve an improved effective monitoring of the medicine safety, contributing to public health protection, and the communication of validated signals to the European Medicines Agency (EMA) and the national medicines regulatory authorities, in line with the legislative framework. By the end of 2017, submissions to EudraVigilance overcome the 12 million individual case safety reports (ICSR), referring to around 8 million individual cases, and making it one of the largest spontaneous reporting systems worldwide [47].

As previously mentioned, one of the drug classes most commonly prescribed and responsible for ADR, both in primary care and hospital sectors, are antibiotics. For Portugal, according to the data provided by the System of Information and Monitoring of the Portuguese National Health System (SIM@SNS) platform [48], developed by the shared services of the Health Ministry, the four antibacterials for systemic use mostly prescribed during the last couple of years (2018–2020) were: a combination of Amoxicillin and Clavulanic acid (**I**), Azithromycin (**II**), Amoxicillin (**III**) and Fosfomycin (**IV**) [49]. In particular, during the year of 2019, the total number of antibiotic packages prescribed within the public sector accounted for around 4.5 million, from which 1.27, 0.63, 0.52, and 0.35 million, respectively corresponded to I, II, III and IV. Data from 2018 revealed the same trend as 2019. Until August 2020, the only alteration observed was the increase in fosfomycin prescriptions over amoxicillin [49].

The individual safety reports stored at the VigiBase (for I) [50] and EudraVigilance (for II, III and IV) [51] databases at 14th November 2020 revealed that among all ADR reported, the most affected System Organ Classes (SOC) for each antibiotic were1 :

I.Combination of Amoxicillin and Clavulanic Acid (ICSR total = 140942): Skin and subcutaneous tissue disorders – **50.5%**, Gastrointestinal disorders – **24.9%**, and General disorders and administration site conditions – **11.9%**. Within all ADR reported for this combination, 24.6% were considered serious ADR;

<sup>1</sup> The antibiotic-associated ADR reported data are displayed in different ways, as they were retrieved from two different databases, VigiBase (for I) and EudraVigilance (for II, III and IV).


The most common ADR reported within each SOC caused by the consumption of these antibiotics include rash, urticaria and pruritus for skin and subcutaneous tissue disorders, diarrhea, nausea, vomiting and abdominal pain for gastrointestinal disorder and pyrexia, malaise, fatigue and asthenia for general disorders and administration condition sites.

The use of antibiotics can result in ADR, among which hypersensitivity reactions. One of the safest and more effective antibiotic subgroups is the β-lactam antibacterials. Within this subgroup, penicillin is one of the most prescribed antibiotics worldwide and is frequently associated with reported allergic reactions. Around 10% of the global population report an allergy to β-lactams, leading to an increased use of broad-spectrum antibiotics, promoting the risk for the development of resistant bacteria and adverse effects, together with an increased cost. Most reports of penicillin allergy describe an unknown or a mild cutaneous reaction. The estimated frequency of the more serious anaphylactic reactions to penicillin is roughly 0.02% to 0.04%, being rarer after oral or cutaneous exposure [52].

#### **3.2 Special populations: children, pregnant women and older adults**

ADR reporting system databases are of great utility in the early detection of medicine safety issues [8]. Most of the available data regarding ADR prevalence refer to adult populations within a hospital context [53]. Thereby, it is extremely important to increase our knowledge and perception on ADR incidence in special populations, such as the pediatric (0–18 years old), pregnant women and older adults (≥ 65 years old), as they may differ regarding the most frequently involved drugs and ADR manifestations, and may be at an increased risk due to their general exclusion from pre-marketing clinical assays.

#### *3.2.1 Children*

Antibiotics are among the most commonly prescribed drugs in children. Reports from a study conducted in the US during 2016 revealed that 47.4% of infants between 0 and 4 years old received at least one antibiotic prescription, when compared to 39.8% of the adult population. Although these drugs are very valuable for the treatment of severe infection diseases, its high and inadequate consumption can frequently lead to an increased bacterial resistance, as well as to the occurrence of adverse effects even if mild and spontaneously resolving [54]. Antibiotics have been repeatedly reported as the leading contributors to ADR in children. Children can be at an increased risk due to their anatomical and physiological characteristics, such

as their immature immune systems, especially in the first years of life. Moreover, there is a frequent abuse and misuse of these drugs in pediatric clinical practice due to lack of pharmacokinetics data or dose-finding studies, and many antibiotics are prescribed on an unlicensed or "off-label" basis as they were only tested and authorized for adults. Although many adverse events are equal in children and adults, with age not contributing to the frequency and severity of the ADR, there are a few number of antibiotic-associated ADR depending on the unique pharmacokinetic and pharmacodynamic features of the antibiotic that can differ significantly with age, particularly when administered to newborns and infants [54].

A systematic review [55] of ADR in pediatric patients reported that the overall rates of hospital admissions caused by ADR ranged from 0.4% to 10.3% of all children, while the ADR incidence rate varied between 0.6% and 16.8% among children exposed to a drug during hospital stay [8, 53]. Furthermore, a study performed between 2011 and 2015 in the US, based on 6542 surveillance cases, estimated that approximately 70 thousand annual emergency department visits were made for antibiotic-associated ADR among children. This review also showed that the antibiotic most commonly associated with ADR was, by far, the oral penicillin (55.7%), and the most typical clinical manifestations attributed to antibiotics were allergic reactions. Within the pediatric population, amoxicillin was found to be the antibiotic most frequently implicated among children under 10 years old [56]. The findings obtained from ADR reports of two studies conducted within the Portuguese pediatric population between 2003 and 2012 (age range 0–17 years old) and 2006 and 2016 (age range 10–18 years old) demonstrated that the most representative ADR identified involved the subsequent top 4 SOC: general disorders and administration site conditions, followed by skin and subcutaneous tissue reactions, nervous system disorders and gastrointestinal disorders. Antibacterials for systemic use were the second most represented group after vaccines [8, 53].

The individual safety reports stored at the VigiBase (for I) [50] and EudraVigilance (for II, III and IV) [51] databases revealed that, among all ADR reported specifically for children, the percentage of antibiotic-associated ADR for the antibiotics mostly prescribed in Portugal between 2018 and 2020 was of **16.6%** for **I** (combination of amoxicillin and clavulanic acid), **17.1%** for **II** (azithromycin), **17.7%** for **III** (amoxicillin) and **4.2%** for **IV** (fosfomycin). Moreover, the most affected SOC were2 :


#### *3.2.2 Pregnant women*

People are aware about the existent lack of information concerning drug safety during pregnancy, mainly because pregnant women are often excluded from trials

<sup>2</sup> SOC data for the combination of amoxicillin and clavulanic acid (**I**) were not available at VigiBase.

#### *Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

throughout the clinical development of the drug. Since 1980, estimates indicate that only 10% of the authorized drugs have enough data involving child risk in pregnancy. Thus, there is a high need for epidemiological studies in pregnant women aiming to evaluate the incidence of ADR [57].

Since there are no reports of totally innocuous drugs commercially available, pregnant women must be cautious and try to avoid, as much as possible, the consumption of medicines, particularly during the first trimester, and only use them when the benefits to the mother outweigh the fetus risk [58]. Over the last years, it has been observed a rise in the number of women consuming drugs during pregnancy. Antibiotics are among one of the classes most commonly prescribed to treat infections in pregnant women, constituting nearly 80% of all drugs prescription, of which roughly 1 in every 4 women consume at least one antibiotic throughout their pregnancy course. However, its use must be prudent as the first concern is to protect the fetus from potential ADR resulting from antibiotic use [57, 58]. Urinary tract infections, sexually transmitted infections and upper respiratory tract infections represent 3 of the most typical infectious diseases found during pregnancy. When not treated, urinary tract and sexually transmitted infections represent an important risk to the fetus with consequences such as, as low birth weight, prematurity and spontaneous abortion. Moreover, the risk for short-term (congenital abnormalities) and long-term (changes in the gut microbiome, asthma, atopic disease) effects in the newborn, and physiological changes that usually take place during pregnancy, have also been related to antibiotic therapy [57].

Overall, there are several antibiotics that can be generally used during pregnancy without compromising safety, such as β-lactams (with penicillin and derivatives being the most prescribed drugs to pregnant women), vancomycin, macrolides, clindamycin, and fosfomycin, and others that must be mostly avoided, such as fluoroquinolones and tetracyclines [57]. In fact, penicillins have a long safety track record during pregnancy, but are usually substituted by macrolides as alternative for patients with penicillin allergies. Very recently, a cohort populationbased study from UK has shown that the prescription of macrolides instead of penicillin antibiotics led to an enhanced risk of major malformation, primarily those derived from the cardiovascular system, but only over the first pregnancy trimester. This study also reported an enhanced risk of genital malformations linked to macrolides prescription in any trimester, advertising for the careful use of this antibiotic subgroup in pregnant women [59]. Some studies have also indicated an increased asthma risk in early childhood, as well as an increased risk of childhood epilepsy and obesity linked to antibiotic use during pregnancy [58].

The use of 3 of the most prescribed antibiotics in Portugal over the last years, namely amoxicillin clavulanate, amoxicillin and fosfomycin, has been considered safe and well-tolerated during pregnancy, with no adverse effects being shown in the fetus or infant [57].

#### *3.2.3 Older adults*

Infectious diseases in the elderly population remains a public health concern because of the high mortality and morbidity outcomes. The geriatric population, regarded as a special population by the International Council for Harmonization (ICH), is more prone to develop ADR because they usually exhibit a combination of increased critical risk factors that can promote these reactions. These risk factors comprise multimorbidity, polypharmacy, changes in medication adherence, pharmacokinetics, greater vulnerability, aging-related physiological changes (changes in the body mass distribution, renal function, metabolic capacity and alteration in blood protein levels), deficit in the immune system, weakening cognition, in

addition to a clear lack on drug use information in the older people [60]. Research studies have estimated an ADR risk in older adults of four times higher than the rest of the population. Old age is also a critical factor for extended hospital stays, enhanced prevalence of complication and falls. The large majority of reported ADR in the older adults belong to type A, possibly avoidable and linked to commonly prescribed drugs. Common geriatric syndromes from older adults include delirium, falls, dizziness, urinary incontinence, which can sometimes be mistaken with typical manifestations from older people. Therefore, given their heterogeneity, to efficiently prevent the high ADR incidence in the older people, it is essential to focus on person-centered care intervention allied to good clinical practice [60].

Between 2007 and 2009, data from an US report on hospitalizations after emergency department visits for adverse events revealed that 3.8% of the total hospitalizations were due to the use of antimicrobial agents. In fact, these agents were the 5 th most common treatment class involved in hospitalizations. Data showed that the most frequent clinical adverse event manifestations arisen from antimicrobials use leading to hospitalizations were allergic reactions (36.2%), dyspnea and weakness (22.5%), gastrointestinal effects (20.5%), and neurologic effects (18.3%). Some of these adverse events, such as dyspnea, weakness, neurological adverse events, and effects on blood pressure may potentially promote significant negative implications in older patients, leading to altered mental status, falls, and hypotension [61].

The individual safety reports stored at the VigiBase (for I) [50] and EudraVigilance (for II, III and IV) [51] databases revealed that, among all ADR reported specifically for older adults (≥ 65 years old), the percentage of antibioticassociated ADR for the antibiotics mostly prescribed in Portugal between 2018 and 2020 was of **22.7%** for **I** (combination of amoxicillin and clavulanic acid), **20.7%** for **II** (azithromycin), **22.7%** for **III** (amoxicillin) and **31.5%** for **IV** (fosfomycin). Moreover, the most affected SOC were3 :


#### **4. Conclusions**

Overall, antibiotics are undoubtedly among the most successful drug agents in the world. They are attributed to having improved patient care and revolutionized modern medicine. However, the inappropariate prescribing of these agents has led to the development of one of the biggest public health concern: antimicrobial resistances [4, 5]. Therefore, it is vital to understand and overcome the main barriers and challenges resulting from antibiotics usage, aiming to design and develop educational interventions for increase awareness and knowledge within the society, and hopefully be able to change people's and prescribing physician's behavior.

<sup>3</sup> SOC data for the combination of amoxicillin and clavulanic acid (**I**) were not available at VigiBase.

*Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

Pharmacovigilance is a global top priority in healthcare systems. It provides instruments for monitoring the safety of medicines on the market through prevention, detection and assessment of adverse reactions, as well as invaluable information on the benefit/risk ratio of a health product throughout its life cycle [12, 36].

Currently, ADR are still ranked among the leading mortality causes in many countries and are recognize as hazards of drug therapy [42, 43]. Although ADR are prevalent in all ages, it is more difficult to predict the effect of the drugs among the special populations that do not take part in clinical trials. Post-marketing surveillance through pharmacovigilance centers is extremely important and the most efficient way to monitor ADR, especially for those groups [12, 42].

Although antibiotics are considered safe when rationally used for treatment and prophylaxis of several infectious diseases, with its prescription being generally high among all ages, these drugs can also substantially contribute to reported ADR, especially β-lactam antibacterials, and macrolides [10, 11, 45]. The most affected organ systems involved are the gastrointestinal system and the skin.

In sum, a visible reduction in global human mortality and morbidity, as well as in health costs, would certainly be noticed with the implementation of international and national campaigns alerting to both the rational use of antibiotics and the importance of reporting ADR, aiming to minimize patient's harm and significantly improve public health.

#### **Acknowledgements**

This research was funded by the project, PTDC/SAU-SER/31678/2017, supported by the operational program on competitiveness and internationalization (POCI) in its FEDER/FNR component, POCI-01-0145-FEDER-031678, and by the Foundation for Science and Technology in its state budget component (OE).

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Appendices and nomenclature**


### **Author details**

Tânia Magalhães Silva1 , Eva Rebelo Gomes2 , Inês Ribeiro-Vaz3,4, Fátima Roque5,6 and Maria Teresa Herdeiro1 \*

1 iBiMED - Institute of Biomedicine, Department of Medical Sciences, University of Aveiro, Aveiro, Portugal

2 Allergy and Clinical Immunology Service, University Hospital Center of Porto, Porto, Portugal

3 Porto Pharmacovigilance Centre, Faculty of Medicine of University of Porto, Porto, Portugal

4 Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine of University of Porto, Porto, Portugal

5 Research Unit for Inland Development, Guarda Polytechnic Institute (UDI-IPG), Guarda, Portugal

6 Health Sciences Research Centre, University of Beira Interior (CICS-UBI), Covilhã, Portugal

\*Address all correspondence to: teresaherdeiro@ua.pt

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Prevalence and Significance of Antibiotic-Associated Adverse Reactions DOI: http://dx.doi.org/10.5772/intechopen.98673*

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#### **Chapter 5**

## Evaluation of the Medication Safety of Chemotherapy Drugs

*Sayna Jabalpeikar*

#### **Abstract**

To evaluate the medication safety of chemotherapy drugs at a tertiary care hospital, with complete reporting of prescription errors, classifying prescription errors, complete detailing of watched medication administration errors (MAEs) by nurses, ordering watched MAEs, and figuring improvement methodologies. Likewise, in relation to side effects, how to overcome side effects, which antiemetic treatments to use, how to survey the appropriateness of requesting and apportioning. An imminent, observational, non-interventional contemplate study was driven at the Oncology Department, Baptist Hospital, Bangalore for half a year. All the data was collected from patient medical records according to case record structure. An aggregate of 70 patients tolerating chemotherapy were observed for information on a sort of side effects, prescription missteps and other relevant information like demographic findings, treatments, and drugs used to manage the adverse effects (AEs) collected from the patient's medical records. The data was characterized reliant on various parameters. The watched side effects according to different organ frameworks were orchestrated and appeared differently in relation to the distributed writing and bundle embeds. Among the 70 patients, 22 (31.4%) were males and 48 (68.57%) were females. Moreover, the age interval within these two groups was of 20–65. From the 70 patients, the number of chemotherapy cycles was of one for 14 (20%) patients, two for 16 (22.85%), three for 16 (22.85%), four for 5 (7.14%), five for 6 (8.57%), six for 9 (12.85%), and more than six for 4 (5.71%) patients, mostly due to maintenance chemotherapy. The evaluation of our information uncovered that the cancer with the most elevated predominance was breast cancer (24.28%), pursued by blood and bone marrow cancer (5.71%) in females, whereas in males were blood and bone marrow (4.28%), followed by lung cancer (2.85%), non-Hodgkin lymphoma (2.85%), and colon cancer (2.85%). The present study demonstrated that in both gender groups, the most influenced organ framework was gastro intestinal tract (GIT), trailed by skin and subcutaneous tissue, musculoskeletal, blood and nervous system. The most prescribed antiemetic drug was ondansetron (81.42%), and the normally endorsed chemotherapy agents in our setting were shown to be cisplatin (21.42%), carboplatin (17.14%), and paclitaxel (14.28%). The total percentage of errors on the 70 prescriptions was 24.28. Most of the errors were due to drug–drug interactions (10%). The total percentage of errors in drug administration performed by nurses was found to be 11.42%, out of which in 2.85% of the cases, it was used the wrong drug dose. The adverse impacts related with the usage of anticancer medication were surveyed for half a year. The AEs most commonly experienced suggest that for all intents and purposes, all the patients accepting cytotoxic drugs suffered at least one AE. The critical announced MAE rates on our hospital ward (0.04% of medication administration and 0.03% MAE/patient admission) send out an impression of being generally low due to the

utilization of current security rules. Emphasize on deep understanding of MAE at individual foundations, is likely going to result in important procedure changes, improved effectiveness of MAE detailing, and various focal points.

**Keywords:** medication safety, chemotherapy drugs, adverse effects, side effects, error in prescription, error in administration, emetogenic chemotherapy, antiemetic drugs, and comparison of antiemetic guidelines

#### **1. Introduction**

Medication safety has been recognized to be important in the provision of patient care for a long time. With the evidence pointing to medication errors (MEs) as one of the leading causes of avoidable complications and deaths, there is a pressing need for a better understanding of the nature and scope of MEs, and the will to improve the current clinical delivery systems. [1]

The chemotherapeutic agents are associated with severe adverse effects (AEs), leading to economic burden and decreased quality of life. [2]

The issue of medication safety in chemotherapy drugs is highly significant when anticancer therapy is used as a treatment modality due to the high hazards derived from these agents and the disease context in which they are used. [2]

The purpose of this chapter is to determine the error rate in prescribing, dispensing and administration of chemotherapy drugs and related agents used in the treatment of cancer, and to promote the prevention of MEs to improve patient safety.

The complexity of treatment regimens designed to achieve the maximal anticancer effect balanced against acceptable toxicity leaves limited margin for error. Overdosing can result in death due to treatment associated AEs, while under dosing can have significant implications for the management of the disease and to the patient outcome. [3]

MEs can occur for a number of reasons. Errors can occur when human and system factors interact with the complex process of prescribing, dispensing and administration drugs, to produce an unintended and potentially harmful outcome.

With an extreme move in the comprehension of medical errors through the production of the 1999 Institute of Medicine (IOM) report, To Err is Human, [4], the IOM board required a change in the manner health-care experts comprehend therapeutic error by standards ranging from subjective psychology to human factors, and investigation of human execution in workplaces.

The enhancements in aeronautics and other security-arranged businesses, for instance, chemical engineering, manufacturing, and nuclear power, showed that complex systems, instead of individual specialists, were the fundamental wellsprings of error and thus an objective for improvement openings through modifications, systematization, and innovation. Sentinel events in oncology, including the death of Betsy Lehman in 1994 at Boston's Dana-Farber Cancer Institute, conspicuously highlighted the open impression of medicinal error. Past research has seemed certain patients are at an extended danger of preventable damage, which is associated with their restricted Physiological Reserve, (physiological reserve is the capacity of an organ or body part to fulfill its physiological activity), which typically joins patients with intense ailments, comorbidities, different prescriptions, and harmful sickness. [5, 6]

Chemotherapeutic prescriptions have a constrained therapeutic index and the dosage expected to give an effective response is conventionally poisonous to the body's quickly multiplying cells. The typical tissues antagonistically affected by

#### *Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

the chemotherapy drugs are those, which are rapidly partitioning, like bone marrow, gastrointestinal tract and hair follicles. Chemotherapy drugs also have other organ explicit toxicities. Moreover, a couple of drugs that are usually associated with speedy adverse reactions are a consequence of their biochemical nature, rather than their activity against tumors. The use of some cancer chemotherapy drugs have been associated with a few AEs, usually going from mild nausea to fatal myelosuppression. [7]

During the most recent decade, various examinations have shown that medication inducing morbidity and mortality is one of the most significant general medical issues. [8]

Clinicians should be aware that chemotherapy induced nausea and vomiting (CINV) is one of the most complicated side effects of chemotherapy. With the correct use of antiemetics, CINV can be prevented in almost 70% up to 80% of the patients. [9]

The goal of each antiemetic treatment is to abrogate nausea and vomiting. Twenty years back, nausea and vomiting were typical AEs resulting from specific sorts of chemotherapy and which obliged up to 20% of the patients to postpone or decay possibly corrective treatments [10]. Clinical and major research over the span of ongoing years has provoked persistent enhancements in the control of CINV. [11]

The improvement of the serotonin receptor antagonists (5-HT3RAs) in the mid-1990s was a standout among the most imperative advances in the chemotherapy of cancer patients. [12, 13] Another group of antiemetics discovered, the neurokinin1 receptor antagonist (NK1RA), and the essential medication in this class, aprepitant, were consolidated into the refreshed antiemetic rules. [14, 15]

In 1998, the main Multinational Association of Supportive Care in Cancer (MASCC) antiemetic rules reliant on the outcomes of the Perugia understanding, were brought together and were distributed worldwide, trailed by the American Society of Clinical Oncology (ASCO) rules in 1999 [16]. The two guidelines, similarly as the National Comprehensive Cancer Network (NCCN) rules, invigorated [17, 18]. The audit of antiemetics, contrasts these three rules, regarding the utilization of antiemetics in chemotherapy settings.

#### **2. Medication error rate**

The ME rate was dictated by ascertaining the level of errors. The numerators in the proportion, is the absolute number of error. The numerator in the proportion is the complete number of error that they watch, the denominator is called "opportunities for errors" and incorporates every single watched dosage that is controlled, in addition to the portions requested but not directed. [19, 20]

$$\text{Mediation error rate} = \frac{\text{Number of errors observed}}{\text{Opportunities for errors}} \text{\textdegree 100} \tag{1}$$

Endorsing error happens at the time a prescriber orders a medication for a particular patient. The error might be due to dosage form, number of dosages, dose structure, course of association, and length of treatment. The MEs, including cancer chemotherapeutic administrators, may be particularly unsafe as these drugs have a limited helpful profile for which prescriptions have a confined association that may result in expanded toxicity and/or decreased tumor response. Furthermore, antineoplastic administrators are consistently coordinated to be

applied to more established patients with comorbidities and it is novel and complex treatment for nurses and medication assistants. Along these lines, antineoplastic masters are among the most outstanding reasons of ME. [1, 19, 20]

#### **3. Theoretical framework**

According to a study on MEs on a Community Hospital Oncology Ward, it was found that out of 141 medication administration errors (MAEs) detected amid the study period, the most persistent ones were administration errors, 41%, while 38% were either nurse or pharmacy dispensing errors, and 21% constituted order writing and transcribing errors. Out of these MAEs, only three errors resulted from adverse drug events. [20]

In another study based on the AEs.of.anticancer.drugs.in.an Oncology Centre of a Tertiary Care Hospital, from a total of 130 evaluated cases, 60 cases comprised males (46.2%), and 70 comprised females (53.8%). The most prevalent cancers among females were breast cancer and cervical cancer, whereas lung cancer and urinary bladder cancer were the most common among males. Nausea (48.5%), decreased appetite (39.2%), alopecia (37.7%), anemia (35.4%), vomiting (31.5%), and nail discoloration (30%) were the most frequently reported AEs. The commonly used pre medication were ondansetron, dexamethasone, aprepitant and proton pump inhibitors, individually or in combination. [21]

Moreover, a study regarding side effects of chemotherapy among cancer patients revealed that out of 99 patients, the majority had their age between 45–64 years (73.3%) and were females (93.3%). Nausea and vomiting were two of the most common side effects (83.3% and 78.9% respectively) reported.

Other common side effects were hair loss and loss of appetite. Also 6.7% of patients experienced peripheral neuropathy symptoms. [22]

#### **3.1 Chemotherapy-induced emesis**

With respect to the emetogenicity potential, the chemotherapy agents can be classified into four emetic risk groups: [23].

**High** (≥90% of patients experienced nausea and vomiting when no prophylactic antiemetic protection was provided);

**Moderate** (30–90% of patients experienced nausea and vomiting when no prophylactic antiemetic protection was provided);

**Low** (10–30% of patients experienced nausea and vomiting when no prophylactic antiemetic protection was provided);

**Minimal** (≤10% of patients, experienced nausea and vomiting when no prophylactic antiemetic protection was provided), as suggested by all three guidelines. [17, 18, 23, 24]. Hence, antiemetic prophylaxis is directly proportional to the emetogenic potential of the chemotherapy.

The emetogenic potential of the drugs is different in each guideline. In the MASCC guideline in particular, the emetogenic potential of oral chemotherapeutic agents is different from intravenous chemotherapeutic agents. In MASCC and NCCN guidelines, intravenous etoposide is labeled as having low emetogenic potential. However, oral etoposide is usually classified as having moderate emetogenic potential, implying that there is a 30%–90% incidence of emesis [24].

In a recently published study by Einhorn *et al*, [25] oral etoposide indeed seemed to have only low emetogenic potential. Additionally, althought imatinib is classified by the MASCC and NCCN guidelines as a moderate emetogenic agent, the daily use of antiemetics is not recommended in the special case of imatinib by the NCCN.

The ASCO guidelines do not implicate any of the oral chemotherapeutic agents in their classification system [23].

#### **3.2 Patient-related risk factors inducing emesis**

Patient-related risk factors, including age (young age usually experience more nausea and vomiting), gender (females generally experience more nausea and vomiting compared to males), a history of alcohol intake, a history of an emesis experience amid pregnancy, impaired quality of life, and also a history of previous chemotherapy, are known to increase the risk for CINV. [23, 26, 27]

#### **3.3 Antiemetic agents**

#### *3.3.1 5-hydroxytryptamine receptor antagonists (5-HT3RAs)*

These are the most effective antiemetic agents in the prophylaxis of acute CINV. [28]

The different 5-HT3RAs, namely dolasetron, granisetron, ondansetron, palonosetron and, tropisetron appear to be interchangeable. The lowest fully effective single dose for each agent should be use. The oral and intravenous routes are similarly effective. These statements are supported by all three guidelines. [29]


#### *3.3.2 Steroids*

Steroids are commonly used in the treatment of several cancers, such as lymphoma and leukemia as they help to destroy cancer cells and render chemotherapy more effective reduce allergy reaction to certain drugs, and also protect the patient from having nausea and vomiting after a round of chemotherapy. Steroids used in chemotherapy include prednisolone, methyl prednisolone, and dexamethasone. [33, 34]

**Dexamethasone:** Although not approved as an antiemetic, dexamethasone plays a major role in the prevention of acute and delayed CINV and is an integral component of almost all antiemetic regimens [33, 34].All three guidelines recommend the use of dexamethasone for the acute prevention of highly, moderately, and low emetogenic chemotherapy.

According to the three guidelines, for the prevention of delayed emesis, dexamethasone is recommended in combination with aprepitant for highly emetogenic chemotherapy (MASCC, ASCO, NCCN), but not for moderately emetogenic chemotherapy (MASCC, ASCO). Only the NCCN guidelines suggest dexamethasone as a possible combination partner for aprepitant with moderately emetogenic chemotherapy.

This recommendation of the MASCC and ASCO expert panel is mostly drive by the study of Warr *et al*. [35] in patients receiving moderately emetogenic chemotherapy. In this study, aprepitant is given as monotherapy for the prevention of delayed CINV, and a complete response rate of 55%, in comparison with 49% for ondansetron, was achieved in the delayed phase.

This result might suggest that the combination of dexamethasone and aprepitant in the delayed phase would have greater antiemetic efficacy. Thus this might be the reason why the NCCN panel was recommending this combination in the moderately emetogenic setting in the delayed phase.

Further studies are warranted to clarify this clinically important question. When combined with aprepitant, dose reduction of dexamethasone (dexamethasone is a sensitive substrate of the cytochrome P450 [CYP450] 3A4 enzyme) has to be undertaken. For the prevention of acute CINV, the dose of choice should be 20 mg of dexamethasone (12 mg when co administered with aprepitant). For highly emetogenic chemotherapy a single dose of 8 mg dexamethasone (12 mg in the NCCN guidelines) is enough. For moderately emetogenic chemotherapy, these dose recommendations were largely driven by studies from the Italian Group for Antiemetic Research [36, 37].

#### *3.3.3 Neurokinin 1 receptor antagonists (NK1RAs)*

NK1 receptor antagonists are in a class of drugs used to treat nausea and vomiting associated with chemotherapy. Aprepitant, casopitant, fosaprepitant, and rolapitant are some examples of NK1 drugs.

**Aprepitant:** Is the first representative of this new group that blocks the NK1 receptor in the brainstem emetic center and gastrointestinal tract [38]. So far, it is only available for oral use and should be administered as 125 mg on day one, and 80 mg on day two and day three as recommended by all three guidelines. Published studies have shown that the addition of NK1RAs to standard antiemetic therapy (5HT3RA plus dexamethasone) appears to have a significant effect in controlling cisplatin-induced acute as well as delayed emesis.

In all studies the aprepitant regimen was more pronounced in the delayed phase of CINV [38–40]. The use of aprepitant is suggested for both highly and moderately emetogenic chemotherapy by all three guidelines.

In the moderately emetogenic setting, one study has been published and, formed the basis for the recommendation of aprepitant for anthracycline and

#### *Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

cyclophosphamide– based emetogenic chemotherapy. In this study [35], the triple combination of ondansetron, dexamethasone, and aprepitant used in the first 24 hours, followed by aprepitant monotherapy for another 2 days, proved to be superior to the whole 5-day study period (51% *vs* 42%). However, no significant differences were observed in the delayed period (49% *vs* 55%), possibly because only patients receiving an anthracycline and cyclophosphamide– based regimen were included in this study.

The MASCC and ASCO guidelines restricted the recommendation of the triple combination in the moderately emetogenic setting due to this "high-risk" chemotherapeutic regimen.

The NCCN guidelines, however, recommended aprepitant in the moderately emetogenic setting in selected patients based on the emetogenic potential of the chemotherapy.

In the MASCC guidelines, it was noted that no trials have compared so far, the combination of aprepitant with dexamethasone for delayed emesis with the previous standard of dexamethasone combined with a 5-HT3RA in highly emetogenic chemotherapy. [16] In the meantime, a study addressing this question [40] showed that the effect obtained from the combination of aprepitant with dexamethasone was superior to one resulting from the combination of ondansetron and dexamethasone in the delayed phase.

Aprepitant is a moderate inhibitor of CYP3A4; therefore, the dexamethasone dose has to be reduced, as discussed before. Theoretical concerns that aprepitant might interact with chemotherapeutic agents could not be demonstrated in preclinical and clinical studies so far [16, 40, 41].

#### *3.3.4 Metoclopramide*

Metoclopramide was part of the former MASCC, ASCO, and NCCN guidelines and was suggested for the prevention of delayed emesis [16, 20]. Although metoclopramide has proved to be as effective as 5-HT3RA when combined with steroids in the prevention of delayed CINV [42, 43] it is not recommended in the new guidelines in this setting. However, because 5-HT3RAs are recommended as an alternative to dexamethasone in the delayed phase for moderately emetogenic chemotherapy, metoclopramide might also be an adequate alternative, although not recommended by the guidelines.

#### *3.3.5 Cannabinoids*

The MASCC guidelines state that cannabinoids can be considered for refractory nausea and vomiting and as a rescue antiemetic. However, due to the weak antiemetic efficacy with potentially high side effects including, sedation, euphoria, dysphoria, dizziness, and hallucination, cannabinoids are not recommended as first-line treatment for the prevention of CINV.

In the ASCO and NCCN guidelines, cannabinoids are advised in patients intolerant or refractory to 5-HT3RAs or steroids and aprepitant.

Interestingly, a systematic review addressing the efficacy of oral cannabinoids in the prevention of nausea and vomiting revealed, that cannabinoids were slightly more efficient than conventional anti emetics (e.g., metoclopramide, phenothiazines, haloperidol.). However, their usefulness was generally limited by the high incidence of toxic effects, such as dizziness, dysphoria, and hallucinations. [44–46]

#### *3.3.6 Benzodiazepines*

Benzodiazepines can be useful in controlling anxiety and reduction of anticipatory CINV or in patients with refractory and breakthrough emesis, as suggested by all three guidelines. [47]

#### *3.3.7 Antihistamines*

The most common antihistamines used are diphenhydramine and hydroxyzine. Nevertheless, the available studies have not shown any significant antiemetic activity in these agents. [48]

#### *3.3.8 Olanzapine*

Olanzapine is an atypical antipsychotic drug with, antiemetic potential due to its action at multiple receptor sites implicated in the control of nausea and vomiting. [49] In a phase II trial where olanzapine was used in combination with granisetron and dexamethasone for the prevention of CINV, the combination therapy proved to be highly effective in controlling acute and delayed CINV in patients receiving highly and moderately emetogenic chemotherapy. [50] The latest phase II study published by Navari *et al*. [51] showed exceptionally high complete protection rates from both acute and delayed CINV when using a combination of palonosetron (day 1), dexamethasone (day 1), and olanzapine (days 1–4) in patients receiving highly or moderately emetogenic chemotherapy. Consequently, olanzapine is mentioned by the MASCC and NCCN guidelines for the treatment of refractory and breakthrough emesis with a suggested dose of 2.5–5 mg.

#### **3.4 Classification of CINV based on the guidelines**

According to the guidelines CINV can be differentiated into five categories: [52].


#### **3.5 Prevention of CINV**

*3.5.1 Regimens linked to a high incidence of nausea and vomiting are referred as highly emetogenic chemotherapy (*≥*90%)*

**Acute CINV:** All three guidelines suggest the combination of a 5-HT3RA, dexamethasone, and aprepitant within the first 24 hours of chemotherapy.

**Delayed CINV:** All three guidelines suggest the combination of dexamethasone and aprepitant for delayed CINV. Trials have indicated that from 60% to nearly 90% of patients receiving cisplatin will experience delayed emesis if not given preventive anti emetics. Therefore, appropriate prophylaxis is necessary [17, 52, 53].

#### *3.5.2 Regimens linked to a moderate incidence of nausea and vomiting are referred as moderately emetogenic chemotherapy (30–90%)*

**Acute CINV:** All three guidelines recommend the combination of a 5-HT3RA plus dexamethasone with or without aprepitant for acute CINV. However, the key question in this setting is whether aprepitant should be part of the antiemetic prophylaxis or not. The ASCO and MASCC guidelines recommend the triple combination (a 5HT3RA, dexamethasone, and aprepitant) for patients receiving the combination of an anthracycline and cyclophosphamide–based regimen. The NCCN guidelines, however, broadened the spectrum of the use and suggest using the triple combination in patients receiving other chemotherapy agents of moderately emetogenic risk like carboplatin, epirubicin, ifosfamide, or irinotecan [17, 52, 53].

**Delayed CINV:** Dexamethasone is the preferred agent to be used for delayed CINV. Nonetheless, when aprepitant is used for the prevention of acute CINV then it should also be used for the prophylaxis of delayed CINV as mono therapy, as stated by the MASCC and ASCO guidelines. As discussed before, the NCCN guidelines suggest aprepitant with or without dexamethasone in this situation. A 5-HT3RA can be used as an alternative, although their therapeutic role in the delayed phase is rather limited [34]. In contrast to all three previously published guidelines, metoclopramide is not reflected in the new guidelines as an alternative option [17, 52, 53].

#### *3.5.3 Regimens linked to a low incidence of nausea and vomiting are referred as low emetogenic chemotherapy (10–30%)*

The MASCC and ASCO guidelines in unison recommend the use of a steroid alone in the first 24 hours and no prophylaxis beyond 24 hours for acute CINV. The NCCN guidelines recommend prochlorperazine or metoclopramide as well, as alternative drugs to dexamethasone [17, 52, 53].

*3.5.4 Regimens linked to a minimal incidence of nausea and vomiting are referred to as minimally emetogenic chemotherapy (*≤*10%)*

All three guidelines suggest that, for patients treated with agents of low emetic risk, no antiemetic drugs should be routinely administered before chemotherapy [17, 52, 53].

*3.5.5 Regimens linked to an incidence of nausea and vomiting in case of anticipatory, breakthrough or refractory chemotherapy*

#### **Anticipatory, breakthrough and refractory CINV:**

Anticipatory CINV is mostly seen in patients with anxiety or patients who did not receive adequate antiemetic prophylaxis in the previous cycle [17, 52, 53].

Breakthrough CINV is defined as an event that happens in spite of optimal preventive treatment.

Refractory CINV is nausea and vomiting that recurs in subsequent cycles of therapy when all previous preventive and rescue treatments fail.

If optimal treatment has been given as prophylaxis, repeated dosing of the same agents is unlikely to be successful; the addition of dopamine-receptor antagonists

(for instance, metoclopramide) might be useful, or the addition of other agents such as benzodiazepines or neuroleptics. Olanzapine, an atypical neuroleptic, could also be considered, as suggested by the MASCC and NCCN guidelines. [16]

#### *3.5.6 Regimens, linked to CINV in case of receiving chemotherapy more than one day in a cycle*

**Multiple-Day chemotherapy:** for patients receiving multiple day chemotherapy like, for instance with cisplatin, the MASCC guidelines recommend the use of a 5-HT3RA in combination with dexamethasone for acute CINV and dexamethasone alone for delayed CINV. The use of NK1RAs remains to be defined, as stated by the MASCC guidelines. However, the NCCN guidelines advise the application of aprepitant for at least the first 3 days, in analogy to highly emetogenic chemotherapy. Furthermore, the NCCN guidelines clearly mention the use of palonosetron in this setting [17, 52, 53].

#### **4. MEs involving antineoplastic agents**

MEs involving cancer chemotherapy agents may be particularly harmful as these drugs have a narrow therapeutic index for which incorrect dosing or administration may result in increased toxicity and/or decreased tumor response. In addition, antineoplastic agents are often administered to older patients with comorbidities and may be part of novel and complex treatment protocols less familiar to nurses and pharmacists. As a result, antineoplastic agents are among the most common causes of ME-related deaths. These concerns have led to an update of national guidelines, including recommendations for a systems approach consisting of multidisciplinary monitoring of medication use, prescribing guidelines, preparation and dispensing methods, and medication administration. [54]

#### **5. Materials and methods**

An imminent, observational, non-interventional study was led at the Oncology Department, Baptist Hospital, Bangalore for half a year. All patient related- data was gathered according to case record structure. During a 6 months period, I directed an imminent report on the Oncology Ward in a Tertiary Care Hospital, with the following objectives:


*Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

A survey review of a self-assertively picked test of 70 chemotherapy solicitations to assess the appropriateness of mentioning and administering was conducted. An aggregate of 70 patients getting chemotherapy met for information on sort of side effects, MEs and other pertinent relevant information like, diagnosis, treatment, drugs utilized, and arrangement with the AEs were assembled from the patient's medical records. The data was arranged reliant on various parameters.

The MAEs are described as a preventable oversight in medicine association due to error beginning in requesting, apportioning, or overseeing. It includes association of (1) wrong prescription, (2) wrong dose, (3) wrong route, (4) wrong time, (5) a medication to which the patient has a known sensitivity, as well as, (6) a prescription with multiple drugs cooperation with another prescription. The patients accepting investigation included patients with affirmed malignancies who confessed that go chemotherapy in oncology wards.

As we expect to survey the resulting side effects a 6 month examination period was arranged. The number of patients getting chemotherapy in oncology ward for a half-year time span were utilized to appraise the sample measure.

#### **6. Results and discussion**

#### **6.1 Demographic details**

#### **Age and sex:**

Among the 70 patients, 22(31.4%) were males and 48(68.57%) were females. A further order dependent on the age uncovered that in the majority of the patients, both males and females were in the age range of 20–65 years. (**Table 1**).

#### **Number of chemotherapy cycles:**

Among the 70 patients, 14(20%) had only one chemotherapy cycle. 16(22.85%) had two chemotherapy cycles, 16(22.85%) had three chemotherapy cycles, 5(7.14%) had four chemotherapy cycles, 6(8.57%) had five chemotherapy cycles, 9(12.85%) had six chemotherapy cycles and, 4(5.71%) had more than six cycles of chemotherapy, mostly due to maintenance chemotherapy.

#### **6.2 Chemotherapy agents**

The most common endorsed chemotherapy agents in our setting.were.cisplatin (21.42%), carboplatin (17.14%), paclitaxel (14.28%), oxaliplatin.(12.85%), doxorubicin.(11.42%), and docetaxel.(11.42%), as it can be observed in **Table 2** and **Figure 1**.

#### **6.3 Clinical diagnosis of the patients**

The sub-classification based on the gender, revealed that breast (24.28%), blood and bone marrow (5.71%), cervical (2.85%), ovarian (2.85%), lung (2.85), non-Hodgkin lymphoma (2.85%), colon (2.85%), stomach (2.85%), and esophageal (2.85%) cancers


**Table 1.**

*Cancer patient's distribution according to the age groups.*

#### *New Insights into the Future of Pharmacoepidemiology and Drug Safety*


#### **Table 2.**

*Chemotherapy agents used in the setting.*

*Prevalence of the chemotherapy agents used in the setting according to number of prescriptions.*


#### *Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

#### **Table 3.**

*Cancer prevalence among the study patients.*

were the most prevalent types of cancer in females. On the other hand, blood and bone marrow (4.28%), lung (2.85%), non-Hodgkin lymphoma (2.85%), colon (2.85%), and oral (2.85%) cancers were the most prevalent in males as it can be seen in **Table 3**.

Furthermore, the most common type of cancer in the age group of 0–20 years was blood and bone marrow cancer (4.28%), while within the age group 20–65 years was breast cancer (24.28%) in females and oral cancer (2.85%) in males. In addition, in adults over 65 years breast cancer (2.85%) was the most prevalent in females. While in men there was not any significant type, as the occurrence of all the cancer types were shown to be equal (**Figure 2**).

#### **6.4 Side effects**

According to **Table 4**, the most influenced organ framework in both females and males was gastro intestinal tract (GIT), trailed by skin and subcutaneous tissue, musculoskeletal, blood, and nervous systems. Most of the patients have suffered the side

#### **Figure 2.**

*Cancer prevalence among the study patients according to gender.*



**Table 4.**

*Side-effects prevalence and distribution depending on the organ system.*

effects related to GIT, such as nausea, vomiting, diarrhea and decreased appetite. The majority of the patients experienced pain all over the body, especially in the muscle and joints and most of the patients experienced alopecia (temporary hair loss).

There are many side effects resulting from the use of chemotherapeutic agents, and rapidly developing cells have been shown to be highly affected by these agents. Hair follicles, skin, and the cells that line the GIT are some examples of the fastest growing cells in the human body, and therefore are more sensitive to the effects of chemotherapy. For this reason patients may experience hair loss, rashes, and diarrhea, respectively.

#### **6.5 Antiemetics**

#### *6.5.1 Antiemetic therapy*

Our analysis showed that all of the patients have used anti emetics in their treatment. The antiemetic used, was either a single anti emetic or a combination of antiemetics. Ondansetron was prescribed for 81.42% of the patients and used at doses of 8 mg and 16 mg, of which 8 mg was most commonly prescribed in patients recommended with a single antiemetic treatment, while the utilization of 16 mg was applied in medications containing more than one antiemetic. Dexamethasone was endorsed in 44.28% of the patients with a range of 4mg - 20 mg. Among these, 8 mg was the most normally utilized dose separately, as well as in combination with other agents. The other antiemetic, aprepitant represented 24.28% of the medications. Palonosetron was also recommended in this setting.

Aside from the antiemetics, other premedication utilized were Pantoprazole 20 mg and 40 mg, Ranitidine 150 mg and Rabeprazole 20 mg. Of these Pantoprazole, 40 mg was the most commonly used, representing 72.85% of the total prescriptions.

#### *6.5.2 Emetogenicity and antiemetics*

The utilization of more up to date antiemetic agents has profoundly diminished the occurrence of nausea and vomiting in patients receiving chemotherapy, although these symptoms were not completely forestalled. All of the patients got an antiemetic medication preceding the chemotherapy.

A 5-HT3RA like Ondansetron, Palonosetron, and a steroid drug such as dexamethasone and Aprepitant were the normally endorsed premedication in our setting, either separately or in combination. The main high hazard associated emetogenic tranquilizer used in chemotherapy in our investigation was Cisplatin. The premedication generally recommended for this setting was Ondansetron 16 mg and Dexamethasone 8 mg either separately or in combination. Cyclophosphamide, Carboplatin, Doxorubicin, Epirubicin, Oxaliplatin, Cytarabine and Ifosfamide were the drugs used in cases of moderate emetogenicity. In this study, the premedication used by the patients were Ondansetron with 8 mg and 16 mg doses, Dexamethasone with 4 mg, 8 mg, 16 mg, and 20 mg doses, Palonosetron with 0.25 mg dose and Aprepitant with 125 mg dose.

#### **6.6 Medication errors**

In this project, the error percentage in the prescription as well as in the administration of chemotherapy drugs in an oncology ward was also established.

#### *6.6.1 Prescription error*

The total error percentage reported in relation to the total number of prescriptions (70) was of 24.28%.

#### *Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

From these total error percentage 10% were due to drug–drug interaction, 2.8% to an unclear read, 2.8% of to lack of patient's age,2.8% to poorly written medication order, 1.42% to lack of date, and 1.4% to a bad hand writing, making it difficult to read. A complete list of errors and their associated percentage is presented in **Table 5**.

#### *6.6.2 Administration error*

Drug administration is performed by nurses. The total error percentage reported in administration of chemotherapy drugs in all the 70 patients under study was of 11.42%, out of which 2.85% were due to wrong administration dose, 2.85% to drug administration outside the guidelines, 1.42% to errors related to the speed in drug administration, and 1.45% to wrong administration technique. A complete error list is displayed in **Table 6**.

#### *6.6.3 Prevention of medication errors*

Currently, there are no sufficient strategies for estimating ME rates, and an assortment of self- reporting and non- self-reporting approaches should be utilized. The repeat of declared MEs, made the health care system to check carefully the


#### **Table 5.**

*Types of medication error possible to occur in drug prescription.*

#### *New Insights into the Future of Pharmacoepidemiology and Drug Safety*


#### **Table 6.**

*Types of medication errors possible to occur in drug administration.*

quality with which MEs are looked for, the procedure used, the patient populace, and the importance of errors.

We have concluded that a nurse is the perfect single individual to detect a ME. Firstly, by routinely surveying the suitability of the medication and differentiating the substituted drug to the doctor-composed request. Although, the nurse may be accused of assessing the whole procedure between request composing and apportioning and afterwards, the association system.

Secondly, nurse ME declaration is the transcendent strategy in many, if not most restorative centers, give it ponder for understanding and improving the medical caretaker, revealing procedure of progressively summed up application.

Thirdly, although disliking, everyone should clearly promote a ME presentation/reduction. The ME aversion is an essential activity and a fundamental piece of significant worth in nursing. As O'Shea has noted, a nurse is accountable and responsible for the drug administration and ME anticipation is currently considered as a national nursing basic. [20]

Taking into account the jobs of drug specialists and nurses in MAE revealing cover, the benefit of including the drug store, at any foundation, would be conversely related to the adequacy of nurse reporting. Considering our decreased *Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

rate of reporting late organizations, our MAE rates are presumably similar to those detailed from different programs with compelling interception systems in place. In total, the prescribed current benchmarks displayed error rates of about 5% for association plus intercepted MEs, and roughly 0.1% to 0.2% for MAEs. These numbers appear to be commonly autonomous of patient age and chemotherapy *versus* non-chemotherapy solutions. For organization plus captured MEs, type 1 errors have been commonly typical. [a type I error is when a researcher rejects the null hypothesis that is actually true in reality. In other words, a type I error is a false positive or the conclusion that a treatment does have an effect, when in reality it does not have].

Our investigation shows that the MAE may fundamentally move toward nurse dispensing and organization. Our outcomes propose that in order to improve the formulation of MAE prevention strategies, each therapeutic center should initially be aware of where in the process of mentioning, apportioning, and overseeing medicines, the overwhelming number of MAEs starts.

#### **6.7 Adverse effects**

The overall AEs observed in both genders were practically identical. Nevertheless, the effects on gastro intestinal tract and musculoskeletal system were higher in females, which may be explained by a higher affectability of this gender by these particular effects. Iron deficiency is seen as a moderately basic condition in patients with disease, particularly those with solid tumors, lymphomas and receiving myeloid suppressive chemotherapy. Treatment for chemotherapy-induced anemia (CIA) started when the hemoglobin level fell beneath 12 mg/dl with oral or intravenous iron enhancements. Blood transfusions were picked in serious cases. In our setting, the specialists generally recommended ferrous sulfate, folic acid and Vitamin B12 prophylactic estimates, for example, great oral hygiene, avoidance of spicy food, and utilization of mild-flavored toothpaste and saline peroxide mouthwashes 3 or 4 times per day, ingrained where appropriate for limiting oral mucositis.

#### **7. Conclusions**

The AEs related with the utilization of anticancer drugs were assessed during half a year. The AE prevalence encountered and experienced suggests that all patients getting cytotoxic medication may endure at any rate one AE. Nausea, vomiting, decline appetite, alopecia, anemia, nail discoloration and anorexia were the most prevalent AEs detected. Correlation of the AEs observed with the group of individuals to achieve larger purpose did not show some new AEs. The frequency of AEs has shown to be extensively high and arouse from the utilization of existing premedication. Given the disclosures of the examination, the attempts to confine the AEs related with the anticancer medicines ought to be centered around. Expanding the mindfulness through informative intercession, actualize proper usage of premedication and non- pharmacological treatment are essential for improved personal satisfaction. Treatment rules are noteworthy in light of the fact that they outfit clinicians with a movement of proposition made from the international expert's dependent on their elucidation of the latest clinical trial data. In spite of certain qualifications among the MASCC, ASCO, and NCCN rules, all gave invigorated references and proposals to direct the perfect use of

antiemetics. Nevertheless, the necessity for a progressively and reasonable usage of treatment rules is critical to improve the nature of thoughts of cancer patients. Significant detailed MAE rates on our hospital ward (0.04% of medication organizations and 0.03 MAEs/patient admission.) have all the earmarks of being generally low due to the use of current security rules. An accentuation on contemplating MAEs at individual foundations is probably going to result in significant technique changes, improved effectiveness of MAE revealing, and various other advantages.

#### **8. Limitation**

The major limitation of the study was the inability to distinguish between immediate and delayed AEs due to the difficulty of the patients in recall the AE's.

#### **Acknowledgements**


### **In Memory of My Grandfather Fathollah Namjoo Kerman**

*But* grandpa's *not truly gone. Because his memory lives on. In all of us who loved him.*

#### **Acronyms and Abbreviations**


*Evaluation of the Medication Safety of Chemotherapy Drugs DOI: http://dx.doi.org/10.5772/intechopen.96758*

### **Author details**

Sayna Jabalpeikar Department of Pharmacy Practice, Karnataka College of Pharmacy, Bengaluru, India

\*Address all correspondence to: sainaj30h2@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 6**

## Small Molecule/HLA Complexes Alter the Cellular Proteomic Content

*Gia-Gia Toni Hò, Wiebke Hiemisch, Andreas Pich, Michelle Matern, Lareen Sophi Gräser, Rainer Blasczyk, Christina Bade-Doeding and Gwendolin Sabrina Simper*

#### **Abstract**

A medical product usually undergoes several clinical trials, including the testing of volunteers. Nevertheless, genomic variances in the patients cannot be considered comprehensively and adverse drug reactions (ADRs) are missed or misinterpreted during trials. Despite the relation between ADRs and human leukocyte antigen (HLA) molecules being known for several years, the fundamental molecular mechanisms leading to the development of such an ADR often remains only vaguely solved. The analysis of the peptidome can reveal changes in peptide presentation post-drug treatment and explain, for example, the severe cutaneous ADR in HLA-B\*57:01-positive patients treated with the antiretroviral drug abacavir in anti-HIV therapy. However, as seen in the biophysical features of HLA-A\*31:01-presented peptides, treatment with the anticonvulsant carbamazepine only induces minor changes. Since the binding of a drug to a certain HLA allelic variant is extremely distinct, the influence of the small molecule/protein complex on the proteomic content of a cell becomes clear. A sophisticated methodology elucidating the impact of drug treatment on cells is a full proteome analysis. The principal component analysis of abacavir, carbamazepine or carbamazepine-10,11-epoxid treated cells reveals clear clustering of the drug-treated and the untreated samples that express the respective HLA molecule. Following drug treatment, several proteins were shown to be significantly up- or downregulated. Proteomics and peptidomics are valuable tools to differential clinical outcomes of patients with the same HLA phenotype.

**Keywords:** Adverse drug reaction, human leukocyte antigen, abacavir, carbamazepine, proteome

#### **1. Introduction**

Since treatment with drugs can trigger harmful adverse events, several tests have to be performed before the approval of new drugs. In preclinical trials, the substance is tested in cell culture or animal experiments in order to ascertain its pharmacokinetics, the pharmacodynamics and to exclude any toxic effects. Clinical trials are designed for the examination of the efficacy and safety of a drug under

defined parameters; they are differentiated into different stages [1]. Clinical trials can be randomized, masked, placebo-controlled or crossover studies. Therefore, they are favored towards non-interventional case–control studies [2].

Phase 0 studies are first-in-human-studies using subtherapeutic dosage of the tested drug in a small group of fewer than 15 healthy volunteers to asses pharmacokinetics and pharmacodynamics [3]. In phase I studies therapeutic dosages of the drug are tested in healthy volunteers to examine its tolerability and safety [4]. They are not randomized trials, making them susceptible for selection bias [5]. Phase II studies are more broadly conceived, and the drug is tested in sick individuals for spotting its efficacy, optimal doses and tolerability, including potential side effects. This same occurs in phase III studies where several thousands of volunteers are tested in order to prove a significant therapeutic effect of the drug under study. After drug's approval, the pharmacovigilance can still be monitored in the so-called post-marketing surveillance trials or phase IV studies [3].

Despite these different stages of testing, genomic variances in the patients cannot be considered completely. While differences in metabolism are easier to spot, there are other genes not being taken into account, thus leading to the lack of some adverse drug reactions (ADRs) in clinical trials [6].

#### **2. Adverse drug reactions (ADRs)**

#### **2.1 ADRs as an underestimated factor in the health care system**

If harm is occurring during treatment with a drug, it can be termed as an adverse event (AE), regardless of a causal link between the drug usage and the symptoms. However, adverse drug events (ADEs) are caused by the drug application [7–9]. This includes harm triggered by the substance itself, as well as harm induced by inappropriate dosages or premature discontinuation of the medication [7, 10]. For example, the overdose of a drug is an ADE. Depending on the drug, the probability of occurring an ADE differs, being very low in patients treated with for instance with antimitotics, and very high in patients under immunosuppressive medication [11]. This is explicable by the mode of action of the drug, for instance the antimitotic nystatin attaches to the cell membrane of fungal cells causing their disruption, but does not disrupt human cells. Contrarily, immunosuppressive medication may led a patients to be more prone to infections and cancer, since the whole immune system is suppressed [10].

Despite a correct dosage and application, unintended and harmful reactions to drugs can still occur [12]. Such ADRs are distinguished from side effects that comprise positive, negative and irrelevant unintended effects [7, 10, 11].

ADRs can be classified into dose-dependent and predictable type A and dose-independent idiosyncratic type B [13] (see **Figure 1**). Most ADRs are type A reactions (>80%), explicable by the pharmacological activity of the drug [13, 14]. Therefore, they can occur in nearly all patients [14]. Type A ADRs are rarely fatal, and the symptoms are drug-specific [13–15]. These ADRs are affected by drug pharmacokinetics, comorbidities and drug–drug-interactions [14]. In contrast to type B ADRs, the emergence of type A ADRs are comprehensible [10]. At the first appearance, type B ADRs seem to be idiosyncratic, but the immune system is often involved and, in these cases, they are called drug hypersensitivity reactions [10]. The clinical picture can involve a single organ or be systemic [16]. Despite their less frequent occurrence, type B ADRs are characterized by an increased mortality rate [13, 14].

Type B ADRs can be subclassified depending on the drug's mode of action with immune cells into allergic, pharmacologic and pseudoallergic reactions [14]. *Small Molecule/HLA Complexes Alter the Cellular Proteomic Content DOI: http://dx.doi.org/10.5772/intechopen.97373*

**Figure 1.**

*Classification of ADRs. ADRs are ADEs that occur despite a proper dosage and application, and are mainly subclassified into type A and rare type B reactions.*

Hereby, allergic reactions are mediated by both the innate, as well as by the adaptive immune systems and include, for instance, the IgE-mediated penicillin allergy or contact dermatitis. Pseudoallergic reactions manifest, for example, as urticaria/ anaphylaxis bronchospasm. Pharmacologic reactions are T cell-mediated. Other possible classifications are relative to the time point of the first symptoms, or to their type of immune mechanism or type of drug [14].

The ADRs have often arisen as an underestimated factor in the health care system, due to their underreporting and underdiagnosis [15, 17–20].

#### **2.2 Type B ADRs manifest as different clinical pictures**

Type B ADRs can be systemic or affect certain organs, with skin, liver and blood cells being the most impacted [16]. Cutaneous forms of ADRs include, for example, maculopapular exanthema (MPE), acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [10].

The MPE is relatively mild, forming rashes with macules or erythematous and maculopapular lesions [21, 22].

AGEP is known to have an acute onset characterized by fever, large erythema and sterile, non-follicular pinhead-sized rapidly appearing pustules with desquamation starting from four to ten days later [10, 23]. The mucosa is barely involved; other organs are free of symptoms. Several drugs are shown to induce AGEP, among which we can find aminopenicillins, quinolones and pristinamycine [10, 23].

The DRESS, also known as drug-induced delayed multiple organ hypersensitivity syndrome (DIDMOHS), drug-induced hypersensitivity syndrome (DIHS), drug hypersensitivity syndrome (DHS) or hypersensitivity syndrome (HSS), is characterized by a cutaneous exanthema spread for over more than half of the body and other organ's involvement, such as hepatitis, eosinophilia, arthralgia or lymphadenopathy [10, 24]. DRESS can be triggered by anticonvulsants (carbamazepine (CBZ), oxcarbazepine, lamotrigine, phenytoin and phenobarbital), sulfonamides and uricostatic drugs (allopurinol) [24].

Although overall SJS and TEN may be fatal in 20–25% of all cases, in TEN the mortality may increase up to 48% and, in the elderly, TEN can be fatal in 70% [24, 25]. Typically, SJS/TEN manifest with skin blisters and bullae, detachment of the skin and erosions of mucous membranes [26]. In SJS, up to 10% of the body surface area is affected, while in TEN at least 30% is affected; if between 10% and 30% of the body surface area are affected a transitional form is diagnosed [25].

Additionally, complications with the lungs, fever and hypovolemia may occur [25]. It has been shown that apoptotic signal-associated cytokine levels are increased in SJS/TEN [27]. Patients suffering from SJS/TEN are positive for Nikolsky's sign, yet specific laboratory parameters are still lacking [28].

The algorithm of drug causality for epidermal necrolysis algorithm (ALDEN) is designed to ascertain the correct diagnosis [29]. SJS/TEN can be triggered not only by anticonvulsive medication (CBZ, lamotrigine, phenytoin and phenobarbital), sulfonamides and uricostatic drugs (allopurinol), but also by oxicam-NSAIDs, sulfasalazine and antiretroviral medication (nevirapine) [30].

#### **3. Associations of human leukocyte antigen (HLA) alleles with type B ADRs**

Associations of certain alleles of the human leukocyte antigen (HLA) system with type B ADRs have been previously reported [31]. The HLA molecules are cell surface glycoproteins that present peptides to immune cells exerting their crucial function in the recognition of self/non-self. By varying in their function and structure, HLA class I and II molecules can be differentiated. Whereas HLA class II molecules are composed of two membrane-anchored chains α and β, HLA class I molecules are composed of the invariant light chain β2-microglobulin (β2m) non-covalently linked to the membrane-anchored heavy α-chain [32]. The peptidebinding groove of the HLA class I molecules is formed by the α1 and α2 domains, where a peptide with a length of eight to ten amino acids is presented. Contrarily, HLA class II molecules present longer peptides, since their peptide-binding groove formed by the α1 and the ß1 domains is open in both ends. HLA class I molecules interact with CD8<sup>+</sup> T cells and present peptides of intracellular origin, whereby HLA class II molecules display peptides derived from the extracellular space or from vesicles to interact with CD4<sup>+</sup> T cells [33]. As part of the adaptive immune system, T cells are able to scan cells for the presence of antigens inducing the death of the respective cells, or releasing of cytokines leading to the activation of other immune cells. Some differences can also be found in the expression patterns of HLA molecules. While HLA class I is expressed by all nucleated cells and platelets, HLA class II expression is limited to immune cells, such as antigen presenting cells, macrophages and B cells [32, 34].

The HLA molecules are characterized by an exceptional polygenism and polymorphism [35]. The HLA genes are encoded in a 220-genes-encompassing region organized in HLA class I, class II and class III genes, whereby class III genes are immune system-related [32, 35, 36]. Among the currently known 28,786 alleles, 20,597 are HLA class I alleles and 7,723 are HLA class II alleles, making it impossible to consider allelic variants in clinical trials [35]. Therefore, HLA-mediated ADRs are inevitably overlooked before the approval of the drug.

As such, the association of abacavir (ABC) hypersensitivity with HLA-B\*57:01 is the best known [37]. About 5% of HIV patients that are treated with ABC show symptoms [38, 39]. Other examples are the association of CBZ hypersensitivity with two alleles, HLA-A\*31:01 and HLA-B\*15:02, and of allopurinol hypersensitivity with HLA-B\*58:01 [22, 40, 41]. In Han Chinese, all patients developing CBZ hypersensitivity were positive for HLA-B\*15:02 [41]. In Northern Europeans, in the presence of the allele HLA-A\*31:01, the risk for an ADR increases from 5–26%, whereas in its absence it decreases to 3.8% [22]. Moreover, the association of ticlopidine, nevirapine and/or dapsone hypersensitivity with the alleles HLA-A\*33:03, HLA-DRB1\*01:01 and HLA-B\*13:01 has also been described [42–44] (see **Figure 2**). In general, ADRs can occur in about 15% of the patients during hospitalization [52].

*Small Molecule/HLA Complexes Alter the Cellular Proteomic Content DOI: http://dx.doi.org/10.5772/intechopen.97373*

#### **Figure 2.**

*Depiction of some HLA-associated ADRs. Each example box includes the name of the drug, the associated HLA allele, the author of the first publication, the journal and year of the publication, the syndromes and adverse reactions (SJS/TEN in orange, MPE and DRESS in yellow, hepatotoxicity/drug-induced liver toxicity in green, mixed symptoms in light orange) and the population where the association was observed. Among others the following drugs were shown to be associated with ADRs: Abacavir [37, 45], carbamazepine [41, 46], allopurinol [40], nevirapine [44], phenytoin [47], sulfamethoxazole [48], ticlopidine [42], flucloxacillin [49], lamotrigine [50], oxcarbazepine [51], dapsone [43].*

#### **3.1 Peptide loading of HLA class I molecules**

Peptide loading occurs in the endoplasmic reticulum after biosynthesis and folding of the nascent HLA class I heavy chain. The interaction with the chaperone calnexin stabilizes the association of the HLA class I heavy chain with the light chain β2m [53]. The peptide loading complex (PLC) is also composed of the chaperone calreticulin, the transmembrane glycoprotein tapasin and the thiol oxidoreductase endoplasmic reticulum resident protein 57, which ensure the correct glycosylation, folding and peptide loading [54].

Peptides presented by HLA class I molecules derive from the cytosol. In the cytosol, ubiquitinylated proteins are degraded via proteasomes into short peptides with a length of 3–22 amino acids [32, 55]. The transporter associated with antigen processing subserves ATP-dependent translocation of cytosolic peptides into the lumen of the endoplasmic reticulum, where they are loaded onto the HLA class I molecule [32]. Ubiquitinylated proteins are composed of misfolded and aged proteins, together with defective ribosomal products, that comprise up to 30% of the newly synthesized proteins [56, 57]. Thereby, a rapid CD8<sup>+</sup> T cell reaction is enabled in infections [58].

#### **3.2 Peptide presentation by HLA class I molecules**

As already described above, the peptide binding region (PBR) is shaped by the α1 and α2 regions of HLA class I molecules, and the α1 and ß1 regions of HLA class II molecules. What they have in common is the basic structure composed of a β-sheet at the ground of the PBR, and two α-helices that form the sidewise boundaries [32].

Solely those peptides with a certain amino acid sequence fit into the PBR of an HLA allele. HLA alleles mostly differ in the PBR region, which gives them a unique peptide binding motif, since alterations in the shape of the PBR lead to the presentation of an altered set of peptides. The PBR of HLA class I molecules is partitioned into pockets A-F, with pocket A binding residue 1 of a given peptide, pocket B binding residue 2 and so on [36, 59–61]. Typically, a peptide binding motif is defined by a N- and a C-terminal anchor, the amino acids at p2 and pΩ binding to pocket B and F [32, 61]. The side chains of the presented peptide can bind either into the pockets or point outwards. This complex of the peptide and HLA molecule is scanned by T cells that are able to recognize foreign peptides in the complex of self HLA.

#### **4. Activation of the adaptive immune system by drugs**

During the maturation of T cells, positive and negative selection assure the generation of an HLA-restricted, but self-tolerant, T cell receptor (TCR) repertoire. Therefore, viral, bacterial or stress-related peptides present in case of infection are recognized by the immune system when CD8+ and CD4+ T cells scan the HLA molecules. The TCR is composed of two chains, α and β, with each obtaining three complementarity determining regions (CDRs) named CDR1, CDR2 and CDR3. These are extremely variable loops able to recognize both the combination of the HLA molecule and the peptide [32].

For the activation of CD8<sup>+</sup> T cells, not only the interaction of the TCR is necessary, but also the interaction of the CD8 co-receptor with the HLA molecule, leading to the phosphorylation of the immunoreceptor tyrosine-based activation motifs [62, 63]. As a second signal, the CD28 molecules on naïve T cells need to interact with a receptor of the B7 family on the target cell, aiming to ensure their survival. Finally, cytokines initiate the third signal by triggering the clonal expansion and differentiation into effector cells. The activated cytotoxic T cell can cause the apoptosis of the target cell through the release of granules with perforin, granzymes, and a scaffold protein triggering the activation of the caspase 3 [64].

Synthetical drugs usually only have a size of less than one kDa, making them invisible to the immune system. Nevertheless, they can induce a reaction within the immune system through their binding to a carrier protein (hapten), or after metabolization of the drug (prohapten) [21]. This hapten-protein complex can trigger several immune reactions, from type I to IV, according to Gell and Coombs [14]. The binding of IgE antibodies to the complex activates mastcells and basophils in type I reactions [14, 21]. This can be seen, for example, in allergy caused by β-lactam antibiotics manifesting as urticarial and anaphylaxis [14]. Type II reactions are mediated by IgG and IgM antibody-dependent cell-mediated cytotoxicity, and are seen in aminopyrine hypersensitivity leading to leukopenia. On the other hand, type III reactions are characterized by IgG-driven immune-complexes that are deposited or cleared by complement activation [10, 14, 21]. A type III reaction example is the minocycline-mediated DRESS [10]. Delayed type IV reactions are generally triggered by T cells.

T cells have been isolated from the blister fluid of patients suffering from cutaneous ADRs [65, 66]. Three models (1, 2 and 3) tend to explain the involvement of cytotoxic T cells in HLA class I-associated ADRs.


#### **5. Analysis of the peptidome in HLA-associated ADRs**

The drug ABC is a guanosine-analogue indicated for HIV therapy. ABC hypersensitivity manifests as a systemic disease, striking up 11 days upon start of the treatment [37]. Fever, rash, constitutional symptoms, and gastrointestinal symptoms, such as nausea, vomiting, diarrhea, or abdominal pain, characterize the clinical picture of ABC hypersensitivity [37, 39]. In 2002, its association with

HLA-B\*57:01 has been published [37, 45] and in 2008, the testing for the presence of HLA-B\*57:01 in patients was recommended to reduce the risk of ABC hypersensitivity [39].

In order to prove or disprove the altered repertoire model, analysis of the peptidome has been performed. Furthermore, it is also possible to unravel the structure of the drug bound to the HLA molecule, by using a peptide found in the analysis of the peptidome. In ABC hypersensitivity, both experiments were performed. The crystal structure of ABC bound to the F pocket of HLA-B\*57:01 has shown that this position is already occupied by the drug, thus leading to an alteration in the peptidome [83]. Typically, peptides presented by HLA-B\*57:01 are anchored by a C-terminal tryptophan, tyrosine or phenylalanine [83, 84]. The alteration in the chemical properties of the PBR enables binding of a new repertoire of endogenous self-peptides [83, 84]. These peptides will then trigger the activation of ABCspecific cytotoxic T cells, resulting in ABC hypersensitivity [83].

The drug CBZ is a tricyclic anticonvulsant usually used in the therapy of bipolar disorders, as well as in nerve pain [21, 85–88]. Certain patients treated with CBZ can develop severe SJS/TEN, DRESS or MPE, as recognized soon after the approval of the drug [86, 89]. Later on, the association of CBZ-mediated SJS/TEN with HLA-B\*15:02 became evident, primarily in South East Asian populations [41, 90–92]. Interestingly, in Caucasians and some Asian populations, milder symptoms, such as DRESS and MPE, were found to be associated with HLA-A\*31:01 [22, 81, 93, 94]. As the allele HLA-B\*15:02 is mostly found in South Asia, being nearly absent in Europe [95], this may explain why the HLA-B\*15:02 is not found in Caucasians with CBZ hypersensitivity [96]. Contrarily, the allele HLA-A\*31:01 has been shown to be distributed worldwide [95]. Despite clearly differing in their sequence in the PBR, both alleles are associated with CBZ hypersensitivity [21]. However, research has shown that CBZ hypersensitivity is presented as two distinct diseases forms with differing mechanisms of action [21], consistent with the different clinical pictures and median onset of HLA-B\*15:02- and HLA-A\*31:01-associated CBZ hypersensitivity [24, 95].

The altered repertoire model has been discussed for the association of HLA-B\*15:02 with CBZ-mediated SJS/TEN, but no clear alterations in the peptidome, after treatment with CBZ, were found [83, 97, 98]. Additionally, derivates of CBZ have been shown to bind soluble immobilized HLA-B\*15:02 [99]. Later published studies have revealed that the main metabolite CBZ-10,11-epoxide (EPX) was binding to the F pocket, so that the nonpolar aromatic pΩ anchor was no longer able to bind that position [81]. These findings are in agreement with those where a polymorphism in the epoxide hydroxylase 1 was influencing the risk of SJS/TEN in the Han Chinese population [100]. Nevertheless, this does not explain the activation of CBZ-specific T cells *in vitro* [99, 101].

In HLA-A\*31:01-associated CBZ-mediated ADRs, no clear alterations in the peptide binding motif post CBZ and EPX treatment have been found [21].

#### **6. Analysis of the proteome in HLA-associated ADRs**

The field of proteomics greatly contributes to a comprehensive profiling of the immune response. To enable side effect predictions for uncharacterized drugs, and to prevent the delay in the licensing process, one widely used action is the analysis of drug (small molecule)-protein interactions [102].

Small molecules-targeted proteins [103] are clearly disturbed or even enabled on their protein–protein-interaction networks. The ability of a protein to initiate the onset of expression, regulation, and/or function of its cognate interaction

*Small Molecule/HLA Complexes Alter the Cellular Proteomic Content DOI: http://dx.doi.org/10.5772/intechopen.97373*

partner, highly depends on its structural integrity. Drugs are not only physically, but also functionally, involved with many other proteins and cellular components, as both drugs and proteins are embedded in cellular pathways and networks [103]. The identification of regulated proteins following drug treatment provides insight into the regulatory impact of drugs on target cells (see **Figure 3**). The classical HLA-Ia molecules, one of the molecular interaction partners of small molecules, are genetically very polymorphic and structurally highly variable. This variability is attributed to the peptide repertoire that can be intracellularly selected and extracellularly presented by the distinct HLA-Ia molecules. This structural variability

#### **Figure 3.**

*Workflow of protein drug profiling. Comprehensive analysis of protein abundance in drug-treated cells compared to control cells. After drug treatment, the cells were lysed, and proteins extracted from the sample. Proteins were digested into peptides and analyzed by liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). Significant regulated proteins were determined and analyzed via pathway analysis.*

makes molecular and bioinformatical analyses of drug-HLA interaction calculations impossible. Unfortunately, the binding of a drug to an HLA-Ia molecule has a profound impact on certain HLA-allele carriers [97]. To somehow enable bioinformatic calculations, experimental achievements in the analysis of small molecule-protein interactions showed broad alterations in the proteome repertoire of targeted cells [21]. Proteomic analysis provides information on protein expression, and mass spectrometry (MS)-based protein drug profiling, improves the understanding of presentable peptides and identification of HLA-bound ligands [104].

ABC-mediated ADRs in HLA-B\*57:01 positive individuals are unique in their rapid emergence [105]. Although it could be possible to demonstrate that ABC alters the chemical properties of the PBR, and elicits immune responses through ABC-specific T cells, not all HLA-B\*57:01 positive individuals develop ABC-induced hypersensitivity reactions [39]. It becomes obvious that not only the HLA type, but also further individual patient-specific factors, may contribute to ABC-mediated ADRs. The proteome analysis of ABC-treated cells provides insights into the regulatory impact of ABC in the HLA-B\*57:01-expressing cells (see **Figure 4**). ABC treatment resulted in an increased apoptosis rate; proteins that generally lead to decreased viral replication were differentially regulated, such as PML and TNPO3. Furthermore, ABC treatment provided hints towards an increased proteasomal degradation activity that would enlarge the pool of presentable peptides. The proteomic drug profiling of ABC-treated cells allowed to enlarge the knowledge about ABC-dependent cellular changes.

CBZ-mediated ADRs are associated with HLA-A\*31:01 and HLA-B\*15:02. A recent study about HLA-B\*15:02-restricted CBZ-induced ADRs revealed that EPX, as the main metabolite, might be responsible for severe reactions in HLA-B\*15:02 positive individuals [81, 99]. To increase the understanding of differential clinical courses, proteome analysis of CBZ- and EPX-treated cells has been performed [21]. CBZ treatment of HLA-A\*31:01-positive cells provided evidence towards an increased ubiquitination activity, but with a stable cellular viability. On the other hand, EPX treatment of HLA-B\*15:02-positive cells resulted in increased cytokine

#### **Figure 4.**

*Mass spectrometric analysis of the proteome of Abacavir (ABC) treated and non-treated cells. A) Protein abundance after ABC treatment. Significantly upregulated proteins are shown in green and downregulated proteins are shown in red. B) Network analysis for up- and downregulated protein groups following ABC treatment. Upregulated proteins are illustrated in red, downregulated proteins are illustrated in green; noncolored proteins were added by the IPA algorithm. High confident interactions are represented by a continuous line; medium confident interactions are represented by a dashed line.*

*Small Molecule/HLA Complexes Alter the Cellular Proteomic Content DOI: http://dx.doi.org/10.5772/intechopen.97373*

release [21]. The proteomic analyses of CBZ and EPX-treated cells provided the first perceptions into the potential protein regulation and involvement of cellular pathways. Furthermore, proteomic profiling has also shown to contribute to the comprehensive understanding of CBZ-induced ADRs in the context of HLA specificity.

A deep knowledge over the spectrum of proteins that are influenced by drug/ protein complexes clearly plays an important role in drug safety, and offers the possibility to identify potential toxicity targets. The emerging role of proteomics improves personalization of immunotherapy treatment in HLA- associated diseases, since detail target analysis supports the understanding of enigmatic HLAassociated ADRs.

#### **7. Conclusions**

The proteomic repertoire is a real time view on the health status of a cell, and can be altered through the medical condition of the illness after treatment with the respective drug. Therefore, the knowledge of the proteomic repertoire of a healthy cell pre- and post-treatment with a given drug is indispensable and should not be underestimated.

#### **Acknowledgements**

We would like to thank Karsten Heidrich and Ulrike Schrameck for their excellent technical assistance in the mass spectrometry analysis.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Gia-Gia Toni Hò1 , Wiebke Hiemisch1 , Andreas Pich<sup>2</sup> , Michelle Matern1 , Lareen Sophi Gräser1 , Rainer Blasczyk1 , Christina Bade-Doeding1 and Gwendolin Sabrina Simper1 \*

1 Institute for Transfusion Medicine and Transplant Engineering, Medical School Hannover, Hannover, Germany

2 Institute for Toxicology, Medical School Hannover, Hannover, Germany

\*Address all correspondence to: simper.gwendolin@mh-hannover.de

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 3
