Year withdrawn
Drug (generic name)
Reason withdrawn
1982
Clomacron
Hepatotoxicity (UK)
1983
Zimeldine
Hypersensitivity, Guillain-Barre syndrome (worldwide)
1986
Nomifensine
Hemolytic anemia (worldwide)
1991
Triazolam
Depression, amnesia (UK, France, and other countries)
1994
Remoxipride
Aplastic anemia (worldwide)
1995
Alpidem
Hepatotoxicity (worldwide)
1999
Amineptine
Hepatotoxicity, abuse (France and other countries)
2005
Thioridazine
Cardiotoxicity (UK and other countries)
2005
Pemoline
Hepatotoxicity (USA)
2011
Aceprometazine/acepromazine/clorazepate
Cumulative adverse effects, misuse, fatal side effects (EU)
2013
Tetrazepam
Serious cutaneous reactions (EU)
Rimonabant is a selective CB1 endocannabinoid receptor antagonist indicated for the treatment of obesity. Although available in Europe since 2006 for use as an adjunct to diet and exercise for obese or overweight patients with associated risk factors, rimonabant failed to secure FDA approval in the USA. Concerns had been growing that patients taking rimonabant were at increased risk of psychiatric adverse events, including suicidality. In October 2008, following a review of post-marketing data, the EMEA recommended suspension of the drug’s marketing authorization on safety grounds. Data had shown a doubling of the risk of psychiatric disorders in patients taking rimonabant in comparison with placebo.
Another drug that has been banned in the USA is pergolide, an ergot-derived dopamine receptor agonist used for the treatment of Parkinson’s disease. In 2007, it was discontinued due to increased rates of cardiac valve regurgitation, along with pleuropulmonary or retroperitoneal fibrosis related to its use.
The suspension of the marketing authorizations of tetrazepam-containing medicines across the European Union in 2013 is derived from the evidence of a low but increased risk of serious skin reactions of tetrazepam compared with other benzodiazepines (European Medicines Agency 2013).
In addition, psychotropic medications represent a group of drugs for which several boxed warnings or other product labeling changes were performed by all the regulatory agencies (Table 2.2). For instance, the US FDA issued a series of advisories culminating in a black box warning for all antidepressants for patients under age 18 (Food and Drug Administration 2004), following a consistent finding of an increased risk of suicidality in children and adolescents. Moreover, epidemiologic findings led to an update to the 2004 boxed warnings to include information about an increased risk of suicidality in young adults ages 18–24 during initial treatment with all antidepressants in 2007 (Food and Drug Administration 2007). The EMA issued analogous warnings for SSRIs and, additionally, contraindicated prescriptions of SSRIs in youths (European Medicines Agency 2005).
Medicine | Adverse events | Actions taken |
|---|---|---|
ADHD drugs | Cardiovascular adverse events, neuropsychiatric symptoms | Black box warning, medication guides, contraindications in at-risk patients |
Agomelatine | Hepatotoxicity | Monitoring of liver function, warning in patients aged 75 years or over, medication guide for patients |
Antidepressants | Increased risk of suicidality in children, adolescents, and young adults | Boxed warnings or other product labeling changes |
Antiepileptics | Adverse effects on the bone | Vitamin D supplementation for at-risk patients |
Antipsychotics | Venous tromboembolic events | SpC updated |
Atomoxetine | Increased risk of suicidal thinking in children and adolescents | Boxed warning, SpC updated |
Buproprion | Seizures | Improved warnings and revised dosing instructions |
Citalopram/escitalopram | QT interval prolongation | Daily dose restrictions, contraindications |
Codeine | Risk of severe ADRs for infants with ultra-rapid metabolizer breastfeeding mothers | SpC updated, warnings |
Respiratory depression | Restrictions on the use in children contraindicated in at-risk patients, boxed warning | |
Lamotrigine | Increased risk of potentially fatal rash, particularly in children | Warnings, SpC updated |
Topiramate | Oligohydrosis, hyperthermia | SpC updated |
Varenicline | Depression, increased risk of suicidal thinking and behavior | Boxed warnings, SpC updated |
Ziprasidone | Drug reaction with eosinophilia and systemic symptoms (DRESS) | SpC updated |
Zoplicone | Risk of next-day impairment | Dosage recommendations, SpC updated |
Zonisamide | Oligohydrosis and hyperthermia in pediatric patients | SpC updated, monitoring for evidence of decreased sweating and increased body temperature |
Similarly, in 2005 FDA and Health Canada warned of increased suicidality in children and adolescents being treated with atomoxetine for ADHD. Furthermore, all ADHD medications were involved in warnings about their cardiac risks (Clavenna and Bonati 2009).
Post-marketing safety regulatory actions frequently concern liver injury related to drug treatment. Hepatotoxic reactions, even severe forms with fatal outcomes, have been reported for many antidepressants, like nefazodone, which was suspended from the US market in 2003 (Choi 2003), or amineptine, which was withdrawn from the market in France in 1999 due to its potential of abuse (Prescrire Editorial Staff 1999).
More recently, liver problems have been reported in patients taking agomelatine, a novel antidepressant, first approved in 2009 by the EMA for major depression in adults. The attention to its hepatic side effect profile has gradually increased, leading the EMA to recommend in 2014 further measures aimed to minimize the risk of liver toxicity, such as monitoring of liver function during treatment and contraindication in patients aged 75 years or above, since they might be at an increased risk of severe hepatic effects (European Medicines Agency 2014).
Safety issues have also appeared recently for psychotropic drugs that have been on the market for more than 50 years (e.g., thiopental, codeine). An example is the signal concerning codeine and life-threatening toxicity (in particular, respiratory depression) in specific subgroups of patients at special risk of such side effects, such as cytochrome P450 2D6 ultra-rapid metabolizers or children below 12 years (European Medicines Agency 2013). This safety issue, due to a more striking conversion of codeine into morphine in the body of at-risk patients, resulted in several restrictions or contraindications being introduced in order to minimize the risk of serious side effects.
Among recent safety communications related to nervous system drugs, an example is the advisory issued in 2014 by Health Canada to healthcare professionals to inform about the risks of next-day impairment after exposure to the hypnotic zopiclone and ways to minimize it, including new dosing recommendations (Health Canada 2014). A recent warning issued by FDA in 2014 concerns the association between the use of ziprasidone and the onset of drug rash with eosinophilia and systemic symptom (DRESS) syndrome (Food and Drug Administration 2014).
Finally, several alerts released by regulatory agencies in 2011 on the potential cardiac toxicity (dose-dependent QTc prolongation) of citalopram and escitalopram resulted in daily dose restrictions (including in elderly patients) and contraindications of use of these drugs (Food and Drug Administration 2011; Italian Medicines Agency 2011).
2.4 Classification of ADRs
Adverse drug reactions can be difficult and sometimes impossible to distinguish from the patient’s disease as they act through the same physiological and pathological pathways. Moreover, some distinctive and specific physical signs can be considered with a high probability drug-related (e.g., extrapyramidal disorders or Stevens-Johnson syndrome). Because adverse drug reactions can mimic or precipitate different pathological conditions, if the physician does not consider medications as a potential cause of the patient’s symptoms, additional drug therapy may be prescribed to treat the adverse effect of the original drug, causing what is called a “prescribing cascade.” The use of metoclopramide may induce parkinsonism, which will be treated with levodopa. Drug-induced cognitive impairment is among the most common causes of reversible dementia (e.g., narcotics, antihistamines). Falls can be precipitated by a wide variety of drugs (e.g., psychotropics, antihypertensives), and the anticholinergic effect of many drugs (e.g., amitriptyline, oxybutynin) can result in dry mouth, constipation, urinary retention, blurred vision, and confusion.
Knowledge and use of ADR classification systems can give the health professional greater clarity about an ADR and suggest ways of managing or avoiding a future event.
Adverse drug reactions can be classified in various ways: immunologic or non-immunologic, predictable or unpredictable, and common or rare.
The most common classification, proposed by Rawlings and Thompson (1977), divides ADRs into type A and type B reactions on the basis of the mechanism of action.
2.4.1 Type A Adverse Event
Type A reactions are due to an exaggerated, but otherwise normal, pharmacological action of a drug (A indicates augmented) given in the usual therapeutic doses. They are therefore largely predictable on the basis of the drug’s known pharmacologic action (Riedl and Casillas 2003) and usually reversible on either adjusting the dose or withdrawing the drug. Examples of a type A reaction include antipsychotic-induced parkinsonism (a known and predictable side effect caused by the block of dopamine receptors), or daytime somnolence after a sedative-hypnotic taken for sleep. Furthermore, these reactions are expected to possibly occur in a certain percentage of individuals based on current scientific evidence. More than 80 % of all occurring ADRs are type A reactions, which include toxic effects (such as digoxin toxicity and serotonin syndrome caused by selective serotonin reuptake inhibitors), side effects, secondary effects (e.g., antibiotic-associated diarrhea), and drug interactions (e.g., lithium toxicity due to NSAID-induced inhibition of its excretion).
The effect of type A ADRs is generally less severe than type B events and is dose related; for example, some degree of anticholinergic symptoms can be observed in nearly everyone taking tricyclic antidepressants, provided the dose is large enough. However, they are not necessarily caused by overdosage but can be also seen after a normal dose is administered in a susceptible subject (e.g., constipation due to morphine or gastrointestinal irritation with nonsteroidal anti-inflammatory drugs).
Generally, type A reactions can be reproduced and studied experimentally and are often already identified during the clinical trials done before marketing.
2.4.2 Type B Adverse Event
Unlike type A reactions, type B ADRs cannot be explained based on the pharmacologic actions of the offending agent, are not dose related in most patients, and may develop quite unpredictably in susceptible individuals (the B indicates bizarre) (Riedl and Casillas 2003; Pillans 2008). They are generally serious and notoriously difficult to study. The majority of type B reactions can occur in predisposed patients as a result of an immune-mediated mechanism (allergic or hypersensitivity reactions, pseudoallergy or anaphylactoid reaction), where the drug acts as an antigen or allergen. Less frequently, type B ADRs may occur with a mechanism not yet understood (idiosyncratic reactions), generally due to a genetic or acquired enzyme abnormality with the formation of toxic metabolites. Neuroleptic malignant syndrome, hyperthermia of anesthesia, and tardive dyskinesia caused by neuroleptic drugs fall into this category.
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