The safety of medicines is critically important to health care. A DTC may have a significant impact on preventing and managing drug safety problems through:
• assessing the literature on safety issues of new medicines proposed for the formulary (see chapter 4)
• preventing the occurrence of ADRs by ensuring that patients are carefully evaluated before medicines are prescribed and ensuring staff are trained accordingly (see section 7.2)
• implementing systems to monitor the occurrence of ADRs, which includes the regular review of ADR reports
• evaluating suspected ADRs
• reporting ADRs to regulatory authorities and manufacturers
• monitoring and investigating medication errors (see section 5.1)
• monitoring and investigating problems of medicine quality (see section 5.2).
The following definitions were adopted by national centres participating in the WHO International Drug Monitoring Programme in September 1991. Further information can be obtained from the WHO Collaborating Centre at Uppsala (http://www.who-umc.org).
Any unintended effect of a pharmaceutical product occurring at doses normally used in humans which is related to the pharmacological properties of the drug. Such effects may be either positive or negative.
Adverse event or experience
Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment.
Adverse drug reaction (ADR)
A response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function. An unexpected adverse reaction refers to a reaction, the nature or severity of which is not consistent with domestic labelling or market authorization, or expected from characteristics of the drug. A serious adverse reaction is any medical occurrence that at any dose normally used in humans:
• results in death
• requires inpatient hospitalization or prolongation of existing hospitalization
• results in persistent or significant disability or incapacity
• is life-threatening.
Causality assessment of suspected adverse reactions
This refers to the likelihood that a medicine has caused an adverse event, and is described further in box 5.3.
• Certain causality is where a clinical event (including a laboratory test abnormality) occurs in a plausible time relationship to drug administration, and cannot be explained by concurrent disease or other drugs or chemicals. A plausible (expected) clinical response to withdrawal of the medicine must be demonstrated and, if possible, the clinical response to restarting the medicine should also be demonstrated.
• Probable or likely causality is where a clinical event occurs with a reasonable time sequence to drug administration, and is unlikely to be due to any concurrent disease or other drugs or chemicals. A plausible clinical response to withdrawal of the medicine, but not to restarting the medicine, must be demonstrated.
• Possible causality is where a clinical event occurs with a reasonable time sequence to drug administration, but which could be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
5.4.2 Adverse drug reactions (ADRs)
ADRs are a serious problem with increasing incidence, as more drugs become available and more people become exposed to them. In the USA, a review of prospective studies showed that in 1994 hospitalized patients had 2.2 million adverse drug reactions (6.7% incidence) and this resulted in 106 000 fatalities. (Lazarou et al. 1998). Box 5.3 shows the different types of ADRs.
BOX 5.3 CLASSIFICATION OF ADRS
Type A reactions
These are an exaggerated but otherwise normal pharmacological response to the effects of the medicine given in therapeutic dose. These reactions cause significant morbidity but are rarely severe. Examples include:
• pharmacodynamic, for example bronchospasm with beta-blocker administration
• toxic, for example absolute or relative overdosing of aminoglycosides causing deafness
• withdrawal syndrome or rebound effect, for example spontaneous rise in blood pressure with clonidine discontinuation.
Type B reactions
These are bizarre and unpredictable with no relation to dose and are often allergic in nature. They are often severe and cause high mortality. Examples include:
• idiosyncratic reactions, for example irreversible aplastic anaemia caused by chloramphenicol
• anaphylactic reactions, for example anaphylactic shock with penicillin
• drug-induced diseases, for example antibiotic-associated colitis.
Adverse events as a result of drug interactions
These may be of all degrees of severity and type, for example
• reduced absorption of tetracycline if administered with ferrous salts
• reduced anticonvulsant effects of phenytoin if administered with some antimalarials such as pyrimethamine
• serious and severe rise in blood pressure following concurrent administration of monoamine oxidase inhibitor antidepressants with tricyclic antidepressants or some antipsychotics.
All new medicines undergo a significant amount of testing and evaluation before marketing to ensure the product is not only effective, but also safe. There are no drugs that are free of side-effects or adverse reactions. Though many products have an extremely low incidence, some have a relatively high incidence of adverse reactions that may result in death. Even the most effective medicines, prescribed by the most careful practitioners, have a certain amount of risk attached. For example, oral polio vaccine has nearly eliminated the disease worldwide but can, very rarely, cause cases of polio. Thus, every drug has risks and benefits, which must be balanced, and which may depend on many factors such as the condition(s) being treated, other problems, age, gender, etc.
Although all medicines undergo mandatory clinical trials before marketing in order to establish efficacy, safety, and quality, such trials will only uncover the commonest ADRs (>1% incidence). Less common ADRs (<1% incidence) will only be discovered through post-market surveillance of much larger numbers of patients taking the drug. Such post-market surveillance relies mostly on spontaneous reporting by physicians, pharmacists and patients. Often the national regulatory body is responsible for monitoring ADRs at the national level. If this authority identifies a serious drug safety issue, it may organize recall of the drug, or revision of the package insert, or distribution of letters to doctors explaining the safety issues. What is done will depend on the nature and seriousness of the problem. However, many ADRs are due not to inherently unsafe drugs but to problems of use or quality, which can be corrected locally.
The DTC should implement a system to monitor, track, investigate and report adverse reactions to drugs and vaccines within their hospital and/or health facility. Any serious findings should be reported to the national monitoring centre, which is often the drug regulatory body. ADRs are monitored not just for the sake of reporting and statistics, but more importantly, to encourage safer use of medicines by minimizing unsafe use of all drugs and avoiding the use of unsafe medicines. The DTC should therefore investigate all serious ADRs in depth and collate and report on all ADRs in order to see how they can be avoided and risk factors for their occurrence reduced. Any ADR monitoring system should include, as a minimum:
• reporting of an ADR to the DTC on standard forms (see annex 5.2)
• investigation and analysis of reports by a selected DTC member
• discussion and evaluation of reports by the DTC on a regular schedule (quarterly) and report to medical staff
• reporting to manufacturers and national regulatory authorities of all events thought to be ADRs (and not known side-effects).
5.4.3 Assessing and managing spontaneous ADR reports
An important part of monitoring ADRs is to process and analyse spontaneous ADR case reports arising from patients and medical providers. These spontaneous reports may be difficult to interpret and to assign causality.
Common problems include the following:
• A generic drug is alleged to cause an ADR whereas the brand named product does not.
• A brand named product is alleged to cause more side-effects than another branded product.
• An antibiotic suspension causes a reaction and it is unclear whether the antibiotic is responsible or one of the components of the suspension, i.e. a dye or other excipient in the suspension.
• An injectable product causes a reaction and it is unclear if the causative agent is the active ingredient, or the preservative or some other agent in the solvent, or the injection technique.
• A patient is on several medicines when a new adverse event is reported and assigning causality is difficult because any of the medicines could be the cause.
• The patient has co-morbidity that may have a bearing on the medicine and suspected ADR.
ADRs should be assessed and managed in three steps, as described below; an example is shown in box 5.4.
STEP 1 Evaluate the nature of the ADR
• Obtain a detailed history of the patient including current health status, current drug therapy, past medical history. Use an ADR reporting form to organize reporting (annex 5.2).
• Establish and document the clinical syndrome described by checking the description with health workers and looking up the clinical description and suspected medicine(s) in the literature.
• Classify severity of the reaction:
- severe: fatal or life threatening
- moderate: requires antidote, medical procedure, or hospitalization
- mild: symptoms requiring only the discontinuation of drug therapy
- incidental: very mild symptoms where the patient can choose whether to continue drug therapy or not
• Assess the likelihood of the suspected medicine being the cause of the ADR. This may be done using the definitions of causality (section 5.4.1). An alternative method is to use the Naranjo algorithm (see annex 5.3). This algorithm asks specific questions (based on the same definitions of causality) and scores the answers. Individual scores are then added up and the total score used to give some indication of the likelihood that an ADR was caused by the suspected medicine.
BOX 5.4 INVESTIGATION OF AN OUTBREAK OF ADRS IN PANAMA
A DTC in Panama served 11 clinics and a hospital. Recently a different brand of procaine penicillin injection had been purchased and distributed. Shortly after introduction of the new brand of procaine penicillin, one clinic reported to the DTC that within a short period of time there had been an unusually high number of ADRs following intramuscular injection of penicillin. The nurses were alarmed, refused to use the new product and demanded to change back to the old brand of penicillin. The adverse event was described as an adult patient suddenly (within seconds of the injection) experiencing feelings of doom, anxiety and faintness, necessitating lying down. Patients were reported to be pale, but with normal or slightly high blood pressure. The nurses immediately gave diphenhydramine (intravenous or intramuscular) for a suspected anaphylactic reaction to penicillin. After 10-15 minutes the patients would completely recover and leave the clinic unassisted.
A DTC member was assigned to investigate the ADR outbreak and the issue was dealt with as follows:
• The clinical syndrome described was looked up in the literature and found to be consistent with Hoigné syndrome or pseudo-allergy to penicillin caused by the procaine component of the injection when accidentally injected intravenously. Diphenhydramine was thought to be inappropriate treatment for either this reaction to procaine or any potential anaphylactic allergic reaction (where adrenaline was the recommended treatment).
• Using the number of penicillin-related ADR events reported in the clinic injection rooms and the number of procaine penicillin doses used, an event rate was calculated for each health facility for a fixed time period. This revealed that the rate of procaine penicillin-related ADRs in two clinics was double the rate occurring in the other clinics, and that the two affected clinics had a relatively high workload. Although one clinic had noticed and complained about the increased rate of ADRs, the other clinic had not noticed the problem before the investigation.
• The DTC staff member visited the two clinics with higher event rates, interviewed the nurses and observed the giving of injections. The nursing assistants were observed to use less water than required to reconstitute the injections. The DTC concluded that the accidental intravenous injection of more concentrated procaine was accounting for the ADRs.
• DTC staff discussed the findings and conclusions of the investigation with the nursing staff concerned, who reviewed how to prepare and give procaine penicillin injections. The nurses agreed to continue using the new brand of procaine penicillin injection. The DTC also discouraged the use of diphenhydramine for treatment of this clinical syndrome as it was not an allergic reaction.
After this intervention, the DTC again measured the recorded event rates and found that the ADR rate had decreased in the two affected clinics and was similar across all clinics.
Source: David Lee, Management Sciences for Health. Personal communication
STEP 2 Establish the cause of the ADRs
• Confirm the clinical syndrome constituting the ADR to be investigated.
• Inspect the suspect medicine visually and check its procurement, storage and expiry date.
• Calculate the rate of ADRs occurring in different departments or clinics.
• Check whether there are any other differences between the departments or clinics showing high and low rates of ADRs to a particular medicine.
• Visit the departments or clinics with the highest rates of adverse drug reaction to observe how the suspect drug is being prescribed, dispensed and administered; this may require carrying out a drug utilization review (section 6.5) or observing the dispensing or administration processes.
• Contact other agencies, hospitals or the regulatory authorities to see if others have experienced similar ADRs, and if necessary or possible send the drug for quality testing.
STEP 3 Possible DTC action after ADR evaluation
Possible actions will depend on what the cause of the ADR is and may involve any or all of:
• reporting to the national drug authority and/or manufacturer
• implementing new prescribing procedures including restrictions
• educating prescribers if needed
• changing the formulary, if necessary, to obtain a drug of improved safety; this may mean substituting a drug that is absolutely safer or one that is easier to use by staff
• adapting the STG or formulary manual if necessary; either in terms of which medicines are recommended for the formulary, or what recommendations are made concerning how and when a formulary medicine should be used
• educating patients if necessary
• following up the rate of ADRs after action has been taken to reduce the ADRs to ascertain whether the DTC action has been successful.
5.4.4 Preventing ADRs
Prevention of ADRs is possible, and indeed necessary! Studies have shown that over 50% of adverse drug reactions may be preventable. Most ADRs are related to the prescribing of an incorrect dose or the administration of a drug to a patient with a known allergy.
Many ADRs could be avoided if the relevant health worker asked specific questions before prescribing and/or dispensing a drug, as shown in box 5.5.
The DTC can do the following things to help promote safety and limit the occurrence of ADRs:
• Encourage ADR reporting (and introduce it if it is not already in place).
• Educate staff about ADRs through in-service education, drug information bulletins and reports of collected adverse events.
• Identify drugs on the formulary that are ‘high risk’ and monitor their use closely (examples include aminoglycosides such as gentamicin, antineoplastics, digoxin, heparin, warfarin).
• Identify ‘high risk’ patient populations and monitor their treatment closely. Such patients include pregnant women, breast-feeding women, elderly people, children and patients with renal or liver dysfunction.
• Review ADR reports regularly and inform professional staff of the incidence and impact of ADRs in the region.
• Review medication error reports to take steps to control and limit these events.
• Undertake prescription audits and drug utilization evaluations (see section 6.5) in order to identify prescribing errors and take corrective action.
• Review product quality complaints and take necessary action to manage quality problems with the procurement department.
• Change the formulary or standard treatment guidelines where necessary for significant or recurring problems with adverse drug reactions.
Figure 5.1 Preventing ADRs
BOX 5.5 QUESTIONS TO ASK BEFORE PRESCRIBING AND/OR DISPENSING A MEDICINE
• Is this the correct medicine for the patient’s clinical condition?
• Is this the correct dose, route and interval?
• Has the patient had the appropriate laboratory test ordered and evaluated?
• Does the patient have any medical or physical conditions that would affect the pharmacokinetic aspects of the medicine?
• Does the patient have an allergy to this medication or a similar one?
• Is the patient on another drug (or herbal product) that would cause a significant drug interaction?
• Is the drug being prescribed a ‘high risk’ drug for producing ADRs (aminoglycosides, digoxin, warfarin, heparin, antineoplastics)? Such drugs require special precautions such as increased monitoring of the patient by the prescriber or increased laboratory monitoring (for example blood counts, drug levels, urea and electrolytes).
• Is the medicine date-expired?
• Does the drug show any visual deterioration, for example discolouration?
• Is the injection equipment sterile?