Postmarketing Drug Surveillance Research Articles

Postmarket drug surveillance network to be overseen by Canadian Institutes of Health Research

The Drug Safety and Effectiveness Network, promised by Prime Minister Stephen Harper in December 2007 and charged with the early identification of postmarket problems associated with prescription drugs, will be overseen by the Canadian Institutes of Health Research (CIHR). The network, which is

Overtreating Chronic Back Pain: Time to Back Off?

Chronic back pain is among the most common patient complaints. Its prevalence and impact have spawned a rapidly expanding range of tests and treatments. Some of these have become widely used for indications that are not well validated, leading to uncertainty about efficacy and safety, increasing complication rates, and marketing abuses. Recent studies document a 629% increase in Medicare expenditures for epidural steroid injections; a 423% increase in expenditures for opioids for back pain; a 307% increase in the number of lumbar magnetic resonance images among Medicare beneficiaries; and a 220% increase in spinal fusion surgery rates. The limited studies available suggest that these increases have not been accompanied by population-level improvements in patient outcomes or disability rates. We suggest a need for a better understanding of the basic science of pain mechanisms, more rigorous and independent trials of many treatments, a stronger regulatory stance toward approval and post-marketing surveillance of new drugs and devices for chronic pain, and a chronic disease model for managing chronic back pain.

The Evaluation of a Prothrombotic Risk in a Human Fibrinogen Concentrate

Fibrinogen is a circulating coagulant protein which is converted to polymerizable fibrin by thrombin. The human fibrinogen concentrate (FC) (CSL Behring) has been used for the treatment of bleeding in fibrinogen deficiency. In this investigation we investigated the prothrombotic potential of FC using the in-vivo, Wessler venous stasis assay in rabbits Thrombogenicity in clinical use was assessed in a postmarketing drug surveillance review. Forty-five rabbits were randomized to receive either placebo or 40 mg/kg of one of four different lots of FC, injected into a marginal ear vein. Thirty seconds thereafter, a segment of the right jugular vein (1.5 – 2.0 cm) was ligated. After 15 minutes the segment was removed and evaluated for thrombus formation according to a score system from 0 –3. Thrombogenic materials, such as activated prothrombin complexes, have consistently shown high scores of thrombus formation in this assay. The mean score in the FC treated rabbits (0.85 ± 1.04) was not different from that in the placebo-treated rabbits (0.8 ± 0.84). Postmarketing data was comprised of spontaneous reports to a postmarketing surveillance system for Adverse Drug Reports (ADR). The number of ADR reports was expressed relative to the number of estimated single standard doses. The estimated dose per patient was adjusted to the degree of bleeding (between one to eight gram). Between January 01, 1986 and April 30, 2008 in total 983,195 g of Haemocomplettan® P had been distributed. Very few reports (n=9) of thromboembolic events have been reported throughout postmarketing surveillance, corresponding to one case report for every 13,655 treatments of 8 grams FC. The reported thromboembolic events occurred in patients with congenital afibrinogenemia or acquired hypofibrinogenemia. In most cases, patients had additional risk factors (e.g. concomitant administration of blood products prothrombin complex concentrate, platelet concentrates, activated factor VII, etc.). Although a causal relationship to administration of FC could not be definitely excluded, the occurrence of thromboembolic events is very rare. From congruent results of both a classical preclinical model of thrombogenicity and analysis of postmarketing data, FC appears to have a very low risk of thrombogenicity.

National addictions vigilance intervention and prevention program (NAVIPPRO™): a real‐time, product‐specific, public health surveillance system for monitoring prescription drug abuse

The National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) is a scientific, comprehensive risk management program for scheduled therapeutics. NAVIPPRO provides post-marketing surveillance, signal detection, signal verification and prevention and intervention programs. Here we focus on one component of NAVIPPRO surveillance, the Addiction Severity Index-Multimedia Version (ASI-MV) Connect, a continuous, real-time, national data stream that assesses pharmaceutical abuse by patients entering substance abuse treatment by collecting product-specific, geographically-detailed information. We evaluate population characteristics for data collected through the ASI-MV Connect in 2007 and 2008 and assess the representativeness, geographic coverage, and timeliness of report of the data. Analyses based on 41,923 admissions to 265 treatment centers in 29 states were conducted on product-specific opioid abuse rates, source of drug, and route of administration. ASI-MV Connect data revealed that 11.5% of patients reported abuse of at least one opioid analgesic product in the 30 days prior to entering substance abuse treatment; differences were observed among sub-populations of prescription opioid abusers, among products, and also within various geographic locations. The ASI-MV Connect component of NAVIPPRO represents a potentially valuable data stream for post-marketing surveillance of prescription drugs. Analyses conducted with data obtained from the ASI-MV Connect allow for the characterization of product-specific and geospatial differences for drug abuse and can serve as a tool to monitor responses of the abuse population to newly developed "abuse deterrent" drug formulations. Additional data, evaluation, and comparison to other systems are important next steps in establishing NAVIPPRO as a comprehensive, post-marketing surveillance system for prescription drugs.

Efficacy of an Adverse Drug Reaction Electronic Reporting System Integrated into a Hospital Information System

Adverse drug reaction (ADR) spontaneous reporting is the primary method of postmarketing drug surveillance; although it is an important part of postmarketing drug surveillance, it is underused. Before 2004, almost no ADRs were reported in our 400-bed hospital. As an electronic hospital information system was available in our hospital, we developed a tool (ADR-RS-IHIS) for ADR reporting integrated into the hospital information system to facilitate reporting through easy use, automatic input of certain information, increased accessibility, real-time review, and intervention. To analyze the efficacy of the ADR-RS-IHIS in increasing ADR reporting to the national drug surveillance system, propose and implement improvements to increase ADR reporting, and evaluate the impact of these improvements. Every ADR reported through the ADR-RS-IHIS was evaluated retrospectively. Two study phases for evaluating ADR-RS-IHIS efficacy were identified. Phase I took place April 2004-August 2006; in April 2006, an interim analysis was performed to propose improvements. Phase II took place September 2006-April 2007 for evaluation of the impact made by the proposed improvements. Efficacy in the phase I and improvement impact on phase II were measured as the number of ADRs reported to the national drug surveillance system. The rate of ADRs reported per month to the national system increased from 0 before 2004 to 0.91 in phase I and 1.62 in phase II (2.25 if delayed reporting was considered). Improvement measures included: allowing nurses to report ADRs in the same way as physicians and pharmacists, automatic form filling of certain information from the electronic hospital information system, easier ADR report analysis, and automatic notification to the allergy department regarding suspected allergies. An ADR reporting system integrated into the electronic hospital information system is effective for increasing the number of ADRs reported to the national drug surveillance system. Allowing nurses to report ADRs in a manner similar to that of physicians and pharmacists, as well as automatic entry of certain data into the form, contributes to the improvement of the system.

Health Canada's investment in new post-market drug surveillance network a "pittance"

In the wake of mounting public concern about prescription drug safety and high-profile drug withdrawals, Health Canada has announced a $1 million investment in an independent research network to study the safety of prescription drugs taken by Canadians. But observers say that the investment,

Real-Life Evaluations of Compliance with Mandatory Drug Safety Monitoring Exemplified with Tolcapone in Parkinson’s Disease

Background/Aims: In 1998, the European Medicines Agency suspended the approval for tolcapone in Parkinson’s disease (PD) with motor complications due to the drug’s implication in fulminant liver failure and the consequent death of 3 patients. Clinical data obtained by ongoing use of tolcapone in other countries proved that adequate safety can be achieved if liver enzymes are strictly monitored. In 2005, tolcapone was relaunched in the European Union under the prerequisite of biweekly liver enzyme monitoring. The objective of this study was to evaluate the compliance with mandatory drug safety monitoring under real-life conditions. Methods: Twenty-one Parkinson’s disease patients receiving tolcapone were analyzed with regard to their compliance in performing and reporting the required laboratory tests. Results: Tolcapone was effective and well tolerated. Yet, less than 25% of the patients regularly performed and reported the required laboratory tests and the compliance declined when comparing the first and second half-years of therapy. Conclusions: Our data shed light on the incongruity between requirements of postmarketing drug surveillance and every-day reality. The depicted noncompliance is most likely a general problem in postmarketing drug surveillance with an impact for physicians, manufacturers and legal authorities. Practical, legal and ethical aspects will be discussed.

Mixed‐effects Poisson regression analysis of adverse event reports: The relationship between antidepressants and suicide

A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system.

Pharmacoepidemiology and “in silico” drug evaluation: is there common ground?

Pharmacoepidemiology and “in silico” drug evaluation: is there common ground?

Rapid Identification of Hematology-Associated Serious Adverse Drug Reactions (sADRS) with Small Datasets: Findings from the Research on Adverse Drug Events and Reports (RADAR) Project.

Current FDA and pharmaceutical industry drug safety efforts rely on statistical review of large databases populated with voluntary reports of sADRs. These data are limited by low rates of complete reporting and high rates of underreporting. Improved post-marketing drug surveillance efforts are needed to improve patient safety. The RADAR project is an academic pharmacovigilance program that focuses on small numbers of thoroughly researched cases of sADRs. In the last decade, RADAR has utilized the resources of a comprehensive cancer center and a global network of collaborators to evaluate and disseminate information on sADRs, many of which are related to hematology. Between 1998 and 2007, RADAR investigated and reported 16 hematology-associated sADRs. RADAR disseminated information on over half of the sADRs within 2 years of FDA approval, compared to half of all new sADRs documented in the Physician's Desk Reference within 7 years of FDA approval. RADAR's novel pharmacovigilance methods identified previously undetected sADRs based on small numbers of completely described reports. The RADAR project's experience shows that private sector programs that utilize small yet comprehensive datasets can significantly contribute to pharmacovigilance networks in hematology. As the FDA develops public-private networks to evaluate safety concerns associated with new drugs, focused independent efforts can assume increasing importance to address unmet needs.Summary of 16 hematology-associated sADRs reported by RADAR since 1998.Drug (FDA approval)sADR (# of reports)Clinical Setting (yr)Data SourceTime to detection (yrs)FDA/Company alertPEG-rHuMGDF(unapproved)ITP (13)Healthy volunteers (2001)Phase I trialsPreclinical detectionNAPEG-rHuMGDF(unapproved)Lymphomas (3)Healthy volunteers (2003)Case reportsPreclinical detectionNATiclopidine (1991)TTP (13)CVA pts (1998)Case reports<1DHP letter; boxed warningGemtuzumab (2000)VOD (50)Leukemia or AML (2000)Phase II trials<1Boxed warningLenalidomide (2005)VTE (75)Multiple myeloma (2005)Phase III trial<1Boxed warningEnoxaparin (1993)Hemorrhage (5)PTCA (2003)Case reports1NAClopidogrel (1997)TTP (39)CAD pts (1998)Case reports1Company warningThalidomide (1998)VTE (91)Multiple myeloma (2002)Phase II trials1Black box warningNevirapine (1996)Stevens-Johnson syndrome (3)Healthcare workers (2002)Case series2Boxed warningNevirapine (1996)Hepatotoxicity (5)Healthcare workers (2002)Case series2Boxed warning; DHP letterEPO (1993)PRCA (9)ESRD (2000)Referral hematologist5Boxed warning; DHP letterEPO (1993)Loss of efficacy (2)Counterfeit drug (2000)Case reports7NAEPO(1993)/ Darb (2001)VTE (52)Cancer (2004)Phase III trial10(EPO)/3 (Darb)FDA alert; DHP letter; boxed warningEPO (1993)/ Darb(2001)Death (NA)Cancer (2006)Clinical trials10(EPO)/3 (Darb)FDA alert; DHP letter; boxed warningG-CSF (1991)AML/MDS (16)Breast Ca (2007)SEER-Medicare12NAPiperacillin (1981)Neutropenia (1)Infection (2006)Case reports25Precaution

Population‐based drug‐related anaphylaxis in children and adolescents captured by South Carolina Emergency Room Hospital Discharge Database (SCERHDD) (2000–2002)

Anaphylaxis is a life-threatening condition; drug-related anaphylaxis represents approximately 10% of all cases. We assessed the utility of a statewide emergency department (ED) database for identifying drug-related anaphylaxis in children by developing and validating an algorithm composed of ICD-9-CM codes. There were 1 314,760 visits to South Carolina (SC) emergency departments (EDs) for patients <19 years in 2000-2002. We used ICD-9-CM disease or external cause of injury codes (E-codes) that suggested drug-related anaphylaxis or a severe drug-related allergic reaction. We found 50 cases classifiable as probable or possible drug-related anaphylaxis and 13 as drug-related allergic reactions. We used clinical evaluation by two pediatricians as the 'alloyed gold standard'1 for estimating sensitivity, specificity, and positive predictive value (PPV) of our algorithm. ED-treated drug-related anaphylaxis in the SC pediatric population was 1.56/100,000 person-years based on the algorithm and 0.50/100,000 person-years based on clinical evaluation. Assuming the disease codes we used identified all potential anaphylaxis cases in the database, the sensitivity was 1.00 (95%CI: 0.79, 1.00), specificity was 0.28 (95%CI: 0.16, 0.43), and the PPV was 0.32 (0.20, 0.47) for the algorithm. Sensitivity analyses improved the measurement properties of the algorithm. E-codes were invaluable for developing an anaphylaxis algorithm although the frequently used code of E947.9 was often incorrectly applied. We believe that our algorithm may have over-ascertained drug-related anaphylaxis patients seen in an ED, but the clinical evaluation may have under-represented this diagnosis due to limited information on the offending agent in the abstracted ED records. Post-marketing drug surveillance using ED records may be viable if clinicians were to document drug-related anaphylaxis in the charts so that billing codes could be assigned properly.

Association between tetracycline or doxycycline and hepatotoxicity: a population based case-control study1

An FDA Working Group, along with representatives of PhRMA and the American Association for the Study of Liver Diseases, as well as the Institute of Medicine Report 'To Err is Human: Building a Safer Health Care System' have suggested that post-marketing drug surveillance is a important method to decrease adverse drug events. While tetracyclines are known to cause hepatotoxicity, no post-marketing drug surveillance studies have examined the risk of developing hepatotoxicity with tetracyclines. Therefore, the objective of this study is to determine the difference in risk of hepatotoxicity in patients receiving doxycycline or tetracycline using California Medicaid claims. This study used a retrospective, matched case-control study using California Medicaid claims data. The cases were defined as recipients who had at least one diagnosis of hepatotoxicity any time from 1 July 1999 to 31 December 2001. One control was identified for each case, matched on age, gender and race. Logistic regression was used to determine the adjusted odds ratio (OR) and 95% confidence intervals for current users and past users of tetracycline and doxycycline. Covariates controlled for in the analysis were age, use of other hepatotoxic drugs, renal dysfunction, pregnancy, and alcohol or illicit drug use. A total of 3377 cases of hepatotoxicity were identified. Current users and past users of tetracycline had a statistically significant increased risk of developing hepatotoxicity (current use OR 3.70, 95% CI 1.19-11.45; past use OR 2.72, 95% CI 1.26-5.85). Current users or past users of doxycycline did not have an increased risk of developing hepatotoxicity (current use OR 1.49, 95% CI 0.61-3.62; past use OR 1.74, 95% CI 0.99-3.06). Tetracycline was commonly used for acne, acute bronchitis and upper respiratory infections. Doxycycline was commonly used for acute bronchitis, vaginitis and acne. Doxycycline was potentially less hepatotoxic than tetracycline. Doxycycline could potentially be a safe substitute for tetracycline, when appropriate.

Adverse Drug Reaction Surveillance System in Korea

Despite extensive researches and pre-market clinical trials, only limited information on the adverse drug reactions (ADRs) of a drug can be collected at the time of market approval from regulatory agency. ADRs constitute a major public health problem. Post-marketing surveillance of drugs is important to detect signals for ADR. In Korea, one of the main methods for monitoring the safety of marketed drugs is spontaneous reporting system of suspected ADRs. Re-examination and re-evaluation system are in force for monitoring safety of new market approval drugs and currently under marketing drugs, respectively. Recently, regional pharmacovigilance centers were designated from Korean Food and Drug Administration for facilitating ADR surveillance. Over recent years, with the development of information technology, there has been an increased interest in establishing data mining system for detecting signals from Health Insurance Review Agency database. The purpose of this paper is to review the current status of Korean ADR surveillance system and suggest the possible solutions for developing active pharmacovigilance system in Korea.

The potential of the European network of congenital anomaly registers (EUROCAT) for drug safety surveillance: a descriptive study

European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe surveying more than 1 million births per year, or 25% of the births in the European Union. This paper describes the potential of the EUROCAT collaboration for pharmacoepidemiology and drug safety surveillance. The 34 full members and 6 associate members of the EUROCAT network were sent a questionnaire about their data sources on drug exposure and on drug coding. Available data on drug exposure during the first trimester available in the central EUROCAT database for the years 1996-2000 was summarised for 15 out of 25 responding full members. Of the 40 registries, 29 returned questionnaires (25 full and 4 associate members). Four of these registries do not collect data on maternal drug use. Of the full members, 15 registries use the EUROCAT drug code, 4 use the international ATC drug code, 3 registries use another coding system and 7 use a combination of these coding systems. Obstetric records are the most frequently used sources of drug information for the registries, followed by interviews with the mother. Only one registry uses pharmacy data. Percentages of cases with drug exposure (excluding vitamins/minerals) varied from 4.4% to 26.0% among different registries. The categories of drugs recorded varied widely between registries. Practices vary widely between registries regarding recording drug exposure information. EUROCAT has the potential to be an effective collaborative framework to contribute to post-marketing drug surveillance in relation to teratogenic effects, but work is needed to implement ATC drug coding more widely, and to diversify the sources of information used to determine drug exposure in each registry.

Estimating post-marketing exposure to pharmaceutical products using ex-factory distribution data

The pharmaceutical industry has an obligation to identify adverse reactions to drug products during all phases of drug development, including the post-marketing period. Estimates of population exposure to pharmaceutical products are important to the post-marketing surveillance of drugs, and provide a context for assessing the various risks and benefits, including drug safety, associated with drug treatment. This paper describes a systematic approach to estimating post-marketing drug exposure using ex-factory shipment data to estimate the quantity of medication available, and dosage information (stratified by indication or other factors as appropriate) to convert the quantity of medication to person time of exposure. Unlike the non-standardized methods often used to estimate exposure, this approach provides estimates whose calculations are explicit, documented, and consistent across products and over time. The methods can readily be carried out by an individual or small group specializing in this function, and lend themselves to automation. The present estimation approach is practical and relatively uncomplicated to implement. We believe it is a useful innovation.

Risk Management Strategies in the Postmarketing Period

In view of the shortcomings of the current system for postmarketing drug surveillance that is based on voluntary spontaneous adverse drug reaction (ADR) reporting, new approaches are needed. We describe an approach involving a combination of limited distribution, patient and physician education, as well as a novel pharmaco-vigilance system that is capable of promoting the safe and adequate use of a new drug. Importantly, it provides the possibility of calculating true ADR occurrence rates, as the exposed population (denominator) and the number of patients with events (numerator) are known. These measures were taken for the oral dual endothelin ET(A)/ET(B) antagonist bosentan (Tracleer). In recent guidelines issued by the European Society of Cardiology, American College of Chest Physicians and the WHO, this drug is considered as first-line oral treatment for the treatment of pulmonary arterial hypertension, a devastating orphan disease associated with a poor prognosis. Bosentan was approved in 2001/2 on the basis of two pivotal studies that showed improved exercise capacity and haemodynamic parameters while delaying time to clinical worsening. Elevations in serum liver aminotransferase levels of >3 times the upper limit of normal were noted in 10.2% of patients (placebo-subtracted incidence). Therefore, liver function tests have to be performed on a regular basis. In addition, bosentan has potential as a teratogen. In the US, a controlled distribution network for bosentan (Tracleer) Access Program [T.A.P.]) and the development of a patient database to follow patients was set up. Accompanied by comprehensive physician and patient education programmes, T.A.P. was developed to provide a mechanism to assist with the primary risk management goals for bosentan therapy, namely pregnancy prevention and liver enzyme monitoring and prevention of hepatic injury. In Europe, the Tracleer) Excellence (TRAX PMS) database is a novel European non-interventional, prospective, internet-based surveillance system initiated by the manufacturer in cooperation with the European Medicines Agency. It collected potential safety signals associated with bosentan use including adverse events, elevations of liver aminotransferase levels, other abnormal laboratory values, death and hospitalisation. TRAX PMS has accrued 79% of all known patients in the EU and the data provide supportive 'real-life' evidence on the long-term safety of bosentan. The two different systems had similar goals and outcomes. The data received concerning thousands of patient-years of use have confirmed the clinical trial results regarding product safety and the favourable benefit/risk ratio of bosentan, especially with regard to known type A adverse events. The clinical monitoring algorithm has also been confirmed. In addition, no rare type B events were uncovered despite the increased reporting rate. These systems might serve as templates for future pharmaco-vigilance efforts regarding drugs that require particular safety attention.

US FDA addresses postmarketing drug surveillance concerns

US FDA addresses postmarketing drug surveillance concerns

US FDA addresses postmarketing drug surveillance concerns

US FDA addresses postmarketing drug surveillance concerns

Clozapine-Related Myocarditis and Cardiomyopathy in an Australian Metropolitan Psychiatric Service

Myocarditis and cardiomyopathy are rarely reported complications of clozapine treatment. The incidence of clozapine-related myocarditis has been variably reported at between 0.03% and 0.19% of initiations and cardiomyopathy has been reported even less commonly. In our Brisbane-based service, nine of 94 patients initiated on clozapine over the previous 3 years appeared to have experienced myocarditis or cardiomyopathy. The unique co-location of our service with a major cardiothoracic hospital facilitated a review of identified cases to inform decisions regarding clozapine treatment and rechallenge in this service. Cases were identified by survey of psychiatric and cardiac medical staff at The Prince Charles Hospital and subjected to re-evaluation by a multidiscipline consensus panel. The panel compared cases to international reports and identified the clinical features that supported a diagnosis of clozapine-related myocarditis or cardiomyopathy. This process resulted in the stratification of the nine cases into the following categories of diagnostic likelihood: three highly probable, three probable, and two possible cases of clozapine-related myocarditis, and one possible case of clozapine-related cardiomyopathy. Successful clozapine rechallenge/continuation was undertaken in two patients and the panel agreed that this was a viable future option for several other patients. Findings of the panel review supported the initial clinical diagnoses. This confirmed that there was an apparent high incidence of clozapine-related myocarditis within this service, for which there was no clear reason. Mechanisms underlying clozapine-related myocarditis and cardiomyopathy, as well as successful clozapine continuation and rechallenge were considered, but definitive explanations remain unknown. This review highlighted the clinician's role in post-marketing drug surveillance to guide rational management of suspected adverse drug effects.

Clozapine-related myocarditis and cardiomyopathy in an Australian metropolitan psychiatric service

Myocarditis and cardiomyopathy are rarely reported complications of clozapine treatment. The incidence of clozapine-related myocarditis has been variably reported at between 0.03% and 0.19% of initiations and cardiomyopathy has been reported even less commonly. In our Brisbane-based service, nine of 94 patients initiated on clozapine over the previous 3 years appeared to have experienced myocarditis or cardiomyopathy. The unique co-location of our service with a major cardiothoracic hospital facilitated a review of identified cases to inform decisions regarding clozapine treatment and rechallenge in this service.Cases were identified by survey of psychiatric and cardiac medical staff at The Prince Charles Hospital and subjected to re-evaluation by a multidiscipline consensus panel. The panel compared cases to international reports and identified the clinical features that supported a diagnosis of clozapine-related myocarditis or cardiomyopathy.This process resulted in the stratification of the nine cases into the following categories of diagnostic likelihood: three highly probable, three probable, and two possible cases of clozapine-related myocarditis, and one possible case of clozapine-related cardiomyopathy. Successful clozapine rechallenge/continuation was undertaken in two patients and the panel agreed that this was a viable future option for several other patients.Findings of the panel review supported the initial clinical diagnoses. This confirmed that there was an apparent high incidence of clozapine-related myocarditis within this service, for which there was no clear reason. Mechanisms underlying clozapine-related myocarditis and cardiomyopathy, as well as successful clozapine continuation and rechallenge were considered, but definitive explanations remain unknown. This review highlighted the clinician's role in post-marketing drug surveillance to guide rational management of suspected adverse drug effects.