Adverse Drug Reactions

Introduction

One common question that we encountered at work is if this drug has any adverse effects? Or rather, as a pharmacist, we should warn the patients on the potential adverse effects of a newly started drugs (especially those very common or needs urgent medical attention).

NOTE: Clinical decision is often a judgement between potential benefits and harms of a treatment.



Adverse Drug Reactions

The World Health Organization (WHO) defines an adverse drug reaction (ADR) as 'a drug-related event that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function'. However, this definition does not consider the following scenarios, all of which can also cause ADRs.

  • Overdose (including prescribing or administration errors)
  • Therapeutic failure
  • Drug interactions
  • Drug withdrawal

NOTE:

  • All adverse reactions are adverse drug event, but that not all adverse drug events will be adverse drug reactions.
  • Adverse effects can be difficult to differentiate from background events occurring commonly in the population.



Frequency

Although adverse drug reactions are listed in product leaflet, it does not necessarily occur to the patient. Rather, terms such as 'common' and 'uncommon' are often used in product leaflets to describe levels of risk of ADRs.

  • To avoid misunderstanding of public on the level of risk, we should avoid using verbal descriptors such as 'common', but to use frequencies in patient counselling - e.g. 1 person in every 1000.

Frequency of ADRs



Classification of Adverse Drug Reactions

Adverse reactions can be classified as

  • Type A, which are most common and related to the drug's pharmacological effect
    • Are often dose dependent and may often be managed by dose reduction.
    • If they are anticipated, measures may be taken to ameliorate or prevent the problem.
Examples of Adverse Drug Reactions
  • Type B, which are rare and unpredictable,

although other classes of reaction can be identified.

Extended Rawlins-Thompson Classification of ADRs

In other words, there are adverse drug reactions that we can predict based on pharmacological action, but there are also unpredictable one.

In contrast with Rawlins-Thompson classification, the DoTS classification is based on dose relatedness, timing and patient susceptibility.

DoTS classification of ADR



Factors that Affect Susceptibility



Causality Assessment

The TRIP acronym can be used to help determine whether an ADR has occurred.

  • Timing
    • Depending on the type of adverse reaction, its time to onset can vary from minutes after receiving a drug to months.
  • Recovery
    • Do symptoms improve or resolve completely when the suspected drug is stopped?
    • Does the reaction improve when a specific treatment is given? (e.g. procyclidine to treat dystonia caused by metoclopramide.)
  • Independent evidence
    • Is there another plausible non-drug cause for the problem?
    • A rechallenge will cause symptoms to recur if the suspect drug is restarted.
  • Predictability
    • Are the characteristics of the adverse event consistent or inconsistent with the known pharmacology of the drug?
    • Check whether similar events have been reported previously with the drug or a related drug.

Also, several methods of assessing causality have been developed using standardised decision algorithms to increase objectivity and reduce assessor bias.

  • One of the most commonly used is the Naranjo algorithm.

Naranjo Algorithm



Managing ADRs

When confronted with an ADR, ask yourself:

  • The severity of the reaction.
  • Is this a dose-related reaction of not?
  • Whether you are certain that you know which drug is responsible.
  • The consequences if you stop the offending medicine. Is it safe? What other medicines can be used instead?
  • Whether a dose reduction is feasible or practical.
  • The ability to successfully treat the side effect.

Managing ADRs

Also, it is important to

  • Document the ADR in the patient's medical record.
  • Report the ADR to the appropriate authorities to help track the incidence of ADRs and identify any potential safety concerns.
  • Educate the patient about the ADR.
  • Monitor the patient for any further changes in their condition.



Reporting to the Appropriate Authorities

When drugs are newly introduced to the market, their safety profile is inevitably provisional (i.e. limited data available).

  • Pre-marketing trials do not have the power to detect important reactions that occur at rates of 1 in 10,000 or fewer, drug exposures.
  • Additionally, patients within trials are often relatively healthy, without the multiple disease states, multiple risk factors or complex drug histories of patients in whom the drug will be used.

Therefore, the vigilance of health professionals is an essential factor in discovering these new risks, together with regulatory authorities that continuously monitor reports of adverse effects throughout the lifetime of a marketed medicinal product.

  • For Malaysia, information on reporting adverse drug reactions can be found here.
  • In UK, it is reported through yellow card scheme.

NOTE: A major reason for drug products to get a "Black box" warning that may lead to market withdrawal is that studies conducted before the drug enters the market (premarket) fail to detect uncommon drug effects.



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