Subchapter list

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2.3 Drug safety

It is necessary to focus on medications that the patient is already taking. It is also necessary to obtain information about which medicinal products are taken by the patient and if there is no risk of drug-drug interaction or related adverse drug reactions. In general, it is recommended to focus on the history of lifestyle, when various diets, smoking, alcohol, but also food supplements, can affect the effectiveness and safety of any currently used drugs. Over-the-counter drugs (OTCs) are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional. During taking the pharmacological history, it is also important to obtain information on OTCs.

2.3.1 Polypharmacy

Even a single drug that is not indicated for treatment can increase the risk of adverse drug reaction to the patient. Such a condition is called polypragmasy. The term polypragmasy should not be confused with the terms “polytherapy“ or ”polypharmacy“ which also refer to states when the patient is taking a number of drugs simultaneously. However, the difference is that in polygragmasy, not all drugs are indicated. There is a risk of misuse (e.g. missed dose, doubled dose, irregular use) in patients taking a large number of medicines at the same time. Polypragmasy can result in iatrogenia, reduced effectiveness of pharmacotherapy, severe adverse drug reactions, and an increase of healthcare costs. Therefore, this praxis should be avoided, especially in elderly and senile patients that are more prone to be subjected to polypragmasy. Innovative medicines that are polycomponent and contain multiple active ingredients in a single dosage form are intended to help solve this problem. These innovative medicines are intended to increase patient adherence and the safety of the medicines used. On the other hand, they have also caused frequent duplications, when the same active substance is prescribed to the patient separately and also in a polycomponent preparation for which the doctor does not realize that the same active compound is part of another preparation. This, in turn, increases the risk for the patient due to exceeding a single or daily dose.

When a single drug becomes redundant, the situation is referred to as polypragmasy and this condition is risky for the patient for various reasons:

This medicine can cause adverse drug reactions, alone or in combination with other treatments that the patient would not have suffered at all if he/she had not taken the medicine. The redundant drug may cause drug interactions, thereby affecting the efficacy or safety of other drugs.

2.3.2 Adverse drug reactions

An adverse drug reaction is an unintended or adverse response following the administration of one or more medicinal products under normal conditions of use, suspected to have arisen in correlation with the administration of the medicine. An adverse reaction may be a known adverse drug reaction of the treatment or it may involve a previously unknown adverse reaction.

An adverse drug reaction may occur even if lower than therapeutic dose has been used, e.g. a type I allergic reaction, when desensitizing with a penicillin antibiotic at a subtherapeutic dose. It should be noted that all drugs that have a pharmacological effect may cause adverse drug reactions.

Adverse drug reactions represent a very heterogeneous group of reactions and can be classified according to various criteria:

• expectedness,
• severity,
• preventability
• frequency of occurrence (Table 2.2)
• mechanism of origin (Table 2.3).

2.3.2.1 Expextedness

An unexpected adverse reaction is an adverse reaction whose nature, severity, or consequence is not listed in the SmPC. The expected adverse drug reactions are listed in the SmPC.

2.3.2.2 According to severity

A serious adverse reaction is whichever adverse drug reaction that results in:

• death of the patient;
• life-threatening condition of the patient;
• significant disability;
• permanent consequences;
• hospitalization or prolongation thereof;
• congenital anomaly in offspring;
• other serious consequences, which may include e.g. also incapacitation.

This applies to adverse reactions listed in SmPC and new adverse reactions not listed and previously unknown.

All but the above are considered to be non-serious adverse reactions.

2.3.2.3 Preventability

Preventability refers to the possibility of preventing the occurence of the adverse reaction in clinical practice. Preventability of an adverse reaction can be measured with the Schumock and Thornton criteria. The score has three sections: preventable, probably preventable and non-preventable. All the answers are categorized as “Yes” or “No”. Adverse drug reactions are considered “definitely preventable” if answer is “yes” to one or more questions in section A. If answers were all negative then we proceeded to section B. Adverse drug reactions are “probably preventable” if answer is “yes” to one or more questions in section B. If answers are all negative then we proceeded to section C, which means that the reaction is probably not preventable.

Schumock and Thornton criteria:

• Section A: Definitely preventable
  • Was there a history of allergy or previous reaction to the drug?
  • Was the drug involved inappropriate for the patient’s clinical condition?
  • Was the dose, route, or frequency of administration inappropriate for patient’s age, weight or disease state?
  • Was toxic serum drug concentration or lab monitoring test documented?
  • Was there a known treatment for adverse drug reactions?
• Section B: Probably preventable
  • Was therapeutic drug monitoring or another necessary lab test not performed?
  • Was the drug interaction involved in drug reaction?
  • Was poor compliance involved in drug reaction?
  • Were preventative measures not prescribed or administered to the patient?
• Section C: Non-preventable
  • If all the above criteria not fulfilled.

Please, note that many of previously explained concepts are taken into consideration in Schumock and Thornton criteria.

Preventability of adverse drug reactions can be used to assess and propose potential improvement measures that can be implemented at clinical center level to optimize patient´s safety and quality management. For instance, an increase of allergic preventable adverse drug reactions could trigger an evaluation of how alerts are evaluated in patient´s health records and how these alerts are considered upon prescription.

2.3.2.4 According to frequency of occurrence

Table 2.2: Adverse reactions (AR) according to frequency of occurrence

AR Frequency	Number of cases per patient
Very frequent	More than 1/10 patients
Frequent	More than 1/100 patients
Less frequent	1/100 to 1/1 000 patients
Rare	1/1 000 to 1/ 10 000 patients
Very rare	One for more than 10 000 patients

2.3.2.5 According to mechanism of origin

Table 2.3: According to mechanism of origin

Type		Description	Example
A – augmented	induced by the same mechanism as the therapeutic effects.		Insulin → hypoglyceamia Anticoagulants → bleeding
B – bizzare	they are caused by a genetic mechanism (idiosyncrasy) or an immunological mechanism (allergy).		Anaphylactic reaction to penicillin antibiotic administration pulmonary fibrosis during amiodarone therapy → allergic reaction type III
C – chronic	are caused by long-term use.		Prednison → iatrogenic Cushing's syndrome Laxatives → GIT dysfunction
D – delayed	manifest themselves after a long latency period.		Mutagenesis → cytostatics from the group of alkylating agents. Teratogenesis → thalidomide → focomelia Carcinogenesis → cyclophosphamide
E – end-of-use	discontinuation syndrome.		Tachycardia after discontinuation of beta-blockers. Adrenocortical insufficiency after discontinuation of glucocorticoids. Withdrawal syndrome after discontinuation of SSRIs.

Overall, monitoring adverse drug reactions involve several steps:

1. Identifying adverse drug reaction.
2. Assessing causality between drug and suspected reaction by using causality algorithms.
3. Documentation of adverse drug reaction in patient’s medical records.
4. Reporting serious adverse drug reaction to pharmacovigilance centers/regulatory authorities.

There are several causality algorithms. The most famous one is Naranjo´s algorithm. Other algorithms include Karsch and Lasagna, WHO-Uppsala. In addition, there are specific algorithms, such as Rumack´s algorithm for liver toxicity. All algorithm are based on these simple principles: chronology, previously published data/studies/case reports, reaction to discontinuation of medication, reaction to reintroduction of medication, alternative explanatory causes.

Act No. 378/2007 Coll., on Pharmaceuticals, obliges doctors and other healthcare professionals to report all unexpected and serious adverse drug reactions, even mere suspicions. In addition to the suspicion of serious or unexpected adverse drug reactions, other facts related to the use of the medicinal product that are serious for the health of patients must be reported. Other facts include, for example, cases of overdose, abuse or misuse, whether intentional or unintentional, and drug interactions. In such a case, it is necessary to gather as much information as possible in order to prevent the misuse of medicinal products and its consequences. It is also required to report the ineffectiveness of medicines in justified and serious cases, especially for vaccines and hormonal contraceptives. Facts to be reported include suspected defects in the quality of medicinal products which can cause an adverse drug reaction.

There are currently several ways to report adverse drug reaction to the State Institute for Drug Control. To report a suspected adverse drug reaction, use the CIOMS form, which can be downloaded at www.sukl.cz, the Medicines section, the Pharmacovigilance section, subsection Forms for reporting adverse reactions, or it can be sent to the State Institute for Drug Control, the Pharmacovigilance Department (pharmacovigilance@sukl.cz) or it is possible to report via an electronic form (on-line) or a paper form or contact the State Institute for Drug Control via phone.

The reporting includes the obligation for physicians to cooperate in verifying the facts related to the suspected adverse reaction and to make available to the State Institute for Drug Control, upon request, any relevant documentation, including documentation containing personal data.

Reports from healthcare professionals are referred to as spontaneous reports. Another type of reports that the State Institute for Drug Control receives and that are evaluated are reports from marketing authorization holders who are obliged to report the adverse drug reactions.

Reporting of suspected adverse drug reactions is one of the basic tools of pharmacovigilance.

The pharmacovigilance system consists of 3 consecutive steps:

1. Monitoring the use of medicinal products in daily clinical practice so that previously unrecognized adverse reactions or changes in the nature of adverse reactions can be identified.
2. Assessing the risk-benefit balance of medicinal products in order to decide what action, if any, is needed to make medicinal products safer to use.
3. Providing information to healthcare professionals and patients to improve safe and effective use of medicines.

Various sources of information are used to assess the risk and benefits of a particular drug:

• spontaneous reporting of adverse reactions from healthcare professionals and patients;
• clinical trials and epidemiological studies;
• published world medical literature;
• pharmaceutical companies;
• health and population statistics;
• information on consumption of medicinal products.

Pharmacovigilance combines all of the above in order to decide whether a medicinal product will be authorized or withdrawn from the market due to a lack of safety. The evaluation of pharmacovigilance results is followed by regulatory measures, which may be of a different nature due to the severity of the findings. They may include:

• modification of texts accompanying medicinal products (SmPC and package leaflet) –addition of warnings about adverse drug reactions and possibly of information about prevention options; introduction of patient cards, change of primary and secondary packaging;
• limitation of indications for use of the medicinal product;
• dosage change;
• change in dispensing (e.g. over-the-counter product to a prescription ‒ only product);
• withdrawal of the medicinal product and withdrawal of its marketing authorization (e.g. rofecoxib).

Pharmacovigilance is the only tool to ensure safe and effective medicinal products in clinical practice. Although medicinal products are rigorously evaluated for safety at all stages of clinical trials prior to marketing authorization, these data are limited. The conditions under which drugs are studied in clinical trials and the conditions under which patients are enrolled do not necessarily correspond to the way drugs are used in clinical practice after marketing approval. At the time of marketing authorization, a relatively small number of patients are exposed to the product for a limited time. This fact needs to be kept in mind whenever a new medicine is prescribed for which a marketing authorization has just been granted, and particular attention needs to be paid to monitoring of its safety profile in real clinical practice.

2.3.3 Drug interactions

See the corresponding chapter 3.

2.3.4 The role of a clinical pharmacologist or clinical pharmacist in a multidisciplinary team

In order to prevent adverse drug reactions and drug interactions and to minimize their impact on the patient, it is necessary to regularly review and re-evaluate the treatment settings, whether the patient still needs the medication and whether the pharmacotherapy has not entered a vicious circle when a single adverse drug reaction of one drug is solved by administering a second drug, which causes another adverse drug reaction, which is again solved by using a third drug, until neither the doctor nor the patient knows why the patient is taking these specific drugs. The aim should be to obtain complete information about all drugs and dietary supplements used by the patient and evaluate them, for example, in cooperation with a clinical pharmacist or pharmacologist, who can objectively assess the needs of all drugs and the risk of drug interactions, adverse drug reactions, etc.

The difference between a clinical pharmacist and a clinical pharmacologist is on the one hand in the type of university education, when the clinical pharmacist is a graduate of the Faculty of Pharmacy, while the clinical pharmacologist is a graduate of the Faculty of Medicine. Furthermore, there are differences in the rights where a clinical pharmacologist can issue prescriptions but a clinical pharmacist must not. A fundamental difference is also the setting of responsibilities, which is based on current legislation, where the physicians are responsible for treating the patients, while the pharmacists have an advisory role, are responsible for their recommendations, but not for the patient’s pharmacotherapy. There are no fundamental differences in the scope of work itself. The tasks of a clinical pharmacist/pharmacologist are:

• assessment of pharmacotherapy of the inpatients or outpatients from various perspectives:
  • indications, contraindications, duplication, selected doses,
  • risks of drug and food interactions and assessment of their clinical significance, prevention of adverse drug reactions and their monitoring,
  • Suitability of the administered drug because of the comorbidities of the patient, absence of the drug with respect to the comorbidities of the patient,
• consultation of the indication of medicines with the attending physician,
• monitoring the patient’s medication and assessing the causal relationship between changes during the course of the disease and current medication,
• proposals for dosage adjustments of selected drugs based on established plasma levels and pharmacokinetic parameters of the patient in cooperation with biochemists and microbiologists
• revision and optimization of recommended pharmacotherapeutic procedures and standards of inpatient wards, related to safe administration and use of drugs in inpatient wards,
• cooperation on drug policy. They can make a positive contribution to saving drug costs by using the principles of pharmacoeconomics in their daily work.

Application exercise:

Part 1: A 49-year-old female patient with a history of epilepsy was admitted for tremor, ataxia, headache, impaired perception, and increased convulsive activity. The patient has been taking phenytoin 300 mg daily, clonazepam 6 mg in the evening and imipramine 50 mg in the morning and evening for a long time. The treatment by the imipramine was initiated 14 days ago.

How would you treat this patient?

• Answer, solution

  This is probably a phenytoin toxicity as the described adverse drug reactions are correlated with an overdose. Therefore, the following steps should be taken:

  • Sampling for TDM to determine the current phenytoin level.
  • Temporary discontinuation of phenytoin.
  • Possible use of another anticonvulsant according to the clinical condition (e.g. levetiracetam, valproate), which immediately reaches therapeutic concentration.

What type of phenytoin adverse drug reaction is this – un/expected, non-/serious?

• Answer, solution

  Tremor, ataxia, headache, impaired perception and increased convulsive activity are adverse drug reactions described in the SmPC – i.e. expected but serious because they led to the patient’s hospitalization. For this reason, the adverse drug reactions should be reported to the State Institute for Drug Control.

What is the effect according to the mechanism of origin?

• Answer, solution

  A – Augmented – depending on the dose, exposure to the CNS.

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Part 2: The level of total phenytoin was 40 mg/L (the free fraction in this medical facility is not determined).

How would you interpret the TDM results?

• Answer, solution
  • The current level is outside the reference limits of the therapeutic level (10–20 mg/L).
  • The phenytoin level at the last visit (3 months ago) was 12 mg/L.
  • Ask the patient if she has taken more phenytoin.

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Part 3: The patient reports that she did not increase the dose or take the drug more often.

What is the reason for the increased phenytoin level?

• Answer, solution

  Most likely a drug interaction ‒ imipramine is an inhibitor of the hepatic CYP450 isoenzymes CYP2D6 and 2C19 and phenytoin is a substrate of CYP450 isoenzymes 2C9 and 2C19. Inhibition of phenytoin metabolism may increase plasma levels of phenytoin.

Where can I verify the cause of the drug interaction described above?

• Answer, solution
  1. I will contact a clinical pharmacist/pharmacologist.
  2. I will use an available trusted drug database ‒ Micromedex, Lexicomp, drugs.com, AISLP.
  3. I will check in a professional article.

  This statement is supported by clinical experience, where concomitant therapy of phenytoin and fluoxetine may result in a drug interaction within 1–42 days after concomitant administration. See Interaction between phenytoin and imipramine: here, or here, or here, or here.

Which preventive measures should be taken?

• Answer, solution
  • Advise the patient to contact the physician, neurologist and follow more frequent monitoring whenever pharmacotherapy is changed.
  • Avoid any food and beverage drug interactions with phenytoin:

  Phenytoin should be used on an empty stomach, alcohol should not be used during treatment.

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Part 4: Possible conclusion of the case report:

Phenytoin will be discontinued, the estimated length of withdrawal or the date of follow-up checks should be consulted with a clinical pharmacologist/pharmacist. Then phenytoin therapy is likely to continue at a reduced dose (not 300 mg/day, but quantified by interaction), with respect to non-linear pharmacokinetics but also a clinical pharmacologist/pharmacist cannot determine exactly, so repeated TDM samples are needed until stable concentration without fluctuation is reached.

Furthermore, with regard to apparently longer-term phenytoin therapy and age, prevention of osteoporosis by replacement of calcium and vitamin D can be recommended.

The choice of an antidepressant in the epileptic patient remains to be considered, due to the epileptogenic potential of imipramine. It is possible to suggest a change of the antidepressant to a drug with less interaction potential, e.g. from the group of SSRIs (citalopram). The question of switching from one antidepressant to another also arises here.

Note

Other interaction checkers for COVID-19 medications include, for instance: here.