Chronic Diseases Epidemiology And Audit

Diabetes Audit and Research in Tayside, Scotland (DARTS) The MEMO DARTS collaboration is a joint initiative of the Department of Medicine and MEMO at the University of Dundee, together with the Diabetes Units at three Tayside Health Care Trusts (Ninewells Hospital and Medical School, Dundee Perth Royal Infirmary and Stracathro Hospital, Brechin) and all Tayside GPs with an interest in diabetes care. They have combined their expertise to create the Diabetes Audit and Research in Tayside,...

References

Easterbrook M (1999) Detection and prevention of maculopathy associated with antimalarial agents. Intl Ophthalmol Clin 39 49-57. Edwards IR, Biriell C (1995) Harmonisation in pharma-covigilance. Drug Safety 10 93-102. Fraunfelder FT (1985) National Registry of Drug-Induced Ocular Side Effects. In Inman WH, ed., Monitoring for Drug Safety. London MTP Press, pp. 363-9. Fraunfelder FT, Fraunfelder FW (2001) Drug-Induced Ocular Side Effects, 5th edn. Woburn, MA Butterworth Heinemann. Fraunfelder...

Adr Highlights From 2000

The 2000 drug safety arena was notable for the large number of labelling changes and regulatory actions that resulted from safety concerns. Investigations into the association between antiretroviral drugs and metabolic disorders continued. After receiving a lot of bad press in previous years, the news on vaccines in 2000 was more positive. In 2000, two drugs that have been on the market for many years, cisapride and phenylpropanola-mine, were withdrawn in some markets due to concern over...

Pharmaceutical Legislation 2001 Review

A major review of European pharmaceutical legislation was carried out on behalf of the Commission by independent consultants and published in October 2000. Following this, the Commission announced proposals for legislative reform in July 2001. The Commission identified seven main goals, including guaranteeing tighter surveillance of the market, in particular by strengthening pharmacovigilance procedures. The proposed changes to existing regulatory requirements include an obligation to prepare...

Adr Headlines From 1999

In 1999, confidence in vaccinations received another blow following the withdrawal of rotavirus vaccine (RotaShield) because of reports of intussusception, and there was misleading press coverage regarding the safety of the measles, mumps and rubella (MMR) vaccine. Investigations continued into the link between anorectic agents and valvular heart disease, the safety of sildenafil, and metabolic disorders associated with protease inhibitors. Fluoroquino-lones came into the spotlight when...

Spontaneous Signalling Methods Used At The Identification Step

Identification procedures apply explicit or implicit statistical models to one or more spontaneous reports in order to screen for product-AE pairs of interest. Much of the published statistical research concerning AE signalling methodology has been directed toward developing methods that are used at this step. Like sorting, the identification step is carried out using reports, not cases, so that the output of such activity is intended to undergo further refinement using case-based methods. It...

Proportional Reporting Ratios

Proportional reporting ratios (PRRs) compare the proportion of reports for a specific ADR reported for a drug with the proportion for that ADR in all other drugs (Evans et al, 1998, 2001). The principles are not new, but were set out in a similar way by Patwary (1969) and Finney (1974) for ADR reporting with WHO data. The methods were not fully used subsequently, either in WHO or in the United Kingdom, and were effectively reinvented in 1995 at the UK MCA, where they have been used routinely...

Info

Was stopped the patients made a full and uneventful recovery. The first documented report of haemolytic anaemia, published in the Lancet, came from France. This was a case of immune haemolytic anaemia and acute renal failure in a 50-year-old woman, who was diagnosed in May 1978 (Bournerias and Habibi, 1979). She had had seven episodes of malaise, chills, pain and fever of 2-4 h duration that were accompanied by dark urine and transient jaundice. During one of the episodes in July 1978, she had...

Exanthematous Drug Eruption

Exanthematous or maculo-papular eruptions, often reported as drug rashes'' or drug eruptions'' are the most common ADRs affecting the skin. The main mechanism is probably immunologic, and may correspond to type IV delayed cellmediated hypersensitivity reaction. The eruption usually occurs between 4 and 14 days after beginning a new therapy, and even a few days after it has ceased (''eruption of the ninth day''). However, it can develop sooner, especially in the case of rechallenge. The eruption...

Other Agents Of The Same Pharmacological Class

This particular scenario requires that the safety database be expanded to exclude any class-related risks. A number of antianginal drugs have been shown to prolong the QT interval and induce proarrhythmias. These include prenylamine, be-pridil, lidoflazine, tedisamil, perhexiline, fendiline and aprindine. Therefore, terodiline as well as other antianginal drugs should be evaluated routinely during their preclinical and clinical development for their potential to prolong the QT interval just as...

Kaiser Permanente Northwest

Kaiser Permanente Northwest (KPNW) serves over 430 000 members, approximately 25 of the population of the area (Friedman et al., 2000), mostly in the outpatient setting, with one hospital in Portland and beds contracted in other community hospitals. The distribution of the membership by age, race, and gender proportionately reflects that of the population of the Portland-Vancouver area. Services provided by KPNW include hospital and surgical care, maternity care, X-rays, mam-mography,...

Case Series Imputation Methods

With subjective case series an evaluator diagnos-tically interprets case causal information without formally specifying rules. As a result, the development of subjectively imputed case series is strongly influenced by an evaluator's individual medical and epidemiologic judgment. As with individual report imputation, subjective assessments of case series are probably the most common way in which associative evidence for product-AE relationships is summarized. Rule-based case series are created...

Pancreatic Enzyme Supplements

Some 90 of patients with cystic fibrosis receive pancreatic enzyme supplements for management of the symptoms of exocrine pancreatic insuffi ciency (FitzSimmons, 1993). By reducing steator-rhea and faecal fat excretion, the supplements improve the nutritional status of the patient. Pancreatic extracts have been used for many years, but in 1994 five cases of stricture of the ascending colon in children with cystic fibrosis who were receiving extracts were published (Smyth et al., 1994)....

Photosensitivity

Cutaneous photosensitivity diseases may be idio-pathic, produced by endogenous photosensitizers (e.g. porphyrins) or associated with exogenous photosensitizers like drugs. The association of light and a drug can be responsible for acute inflammation of the skin. The photosensitivity reactions are divided into two types phototoxicity and photoallergy (Gould et al., 1995). Phototoxic disorders are not rare and always predictable. It can occur in any person who receives sufficient quantities of a...

Cyp2a6

Isoniazid Sulfamethazine Procainamide Amonifide Dapson Sufasalazine Paraminosalicylic acid Heterocyclic amines (food mutagens) Slow Y clearance and 9 risk of toxicity, including toxic neuritis, lupus erythematosus, bladder cancer Rapid Y efficacy, 9 risk of toxicity in some cases (amonifide) colorectal cancer Slow facial flushing Rapid protection from liver cirrhosis aCompiIed from Ingleman-Sundberg et al. (1999), Meyer (2000), Evans and Relling (1999), Sadee (2000) and Manicelli et al. (2000)...

Rebirth Of Terodiline

Terodiline (Figure 11.1) was first marketed in 1965 as an antianginal agent (Bicor) in Scandinavia (Wibell, 1968), a relatively small market. This period of original marketing of terodiline is worthy of note for three reasons (a) it antedates any serious regulatory or clinical interest in drug-induced prolongation of the QT interval, (b) it antedates the first description of torsade de pointes, a unique proarrhythmia associated with prolonged QT interval (Dessertenne, 1966) and (c) the drug...

Pharmacokinetic Interactions

Drug interactions may result in impaired drug absorption from the gastrointestinal tract. The rate at which a drug is absorbed may be decreased by drugs such as anticholinergics, which inhibit gastric motility conversely, drugs such as meto-clopramide (which increase gastric motility) may enhance the absorption rate. Certain drugs form chelates and complexes with other drugs, altering their solubility and absorption. For example, agents that bind to digoxin in the gut (such as antacids and...

Postmarketing Sources Of Data Regarding Reproductive Safety

Once a medication is marketed, there are a number of resources that can provide observational data regarding drug safety in pregnancy. 1. Clinician case reports published in the medical literature can delineate a phenotype in an affected infant born to a mother with a specific prenatal medication exposure. However, these reports must be initiated spontaneously, and therefore may involve investigator as well as publication bias. Furthermore, without a known denominator of exposed pregnancies...

Development Of The Full Feature Gprd

Researchers have provided critical input to help the MCA develop the Full Feature GPRD. Some indicated that, in the past, they had been precluded from using the GPRD or using it as extensively as they might. The cost of access, requirement for extensive software and hardware to store the data, and the need for sophisticated programs to extract and analyse the data were cited as rate limiting factors in its use, and this has informed the development approach adopted for the new database and...

Formation Of A Chemically Reactive Intermediate

For a number of drugs that undergo metabolism, CRM will be formed irrespective of the dose of the drug (Pirmohamed et al., 1996). When a drug is taken in therapeutic dosage, any toxic metabolite formed will be detoxified by normal enzymatic or non-enzymatic cellular defence mechanisms. An imbalance between bioactivation and bioinactiva-tion leading to toxicity may however be created by taking a drug overdose. This will lead to the formation of large amounts of chemically reactive metabolites,...

Micturin And Torsades De Pointes

Micturin (Mictrol , terodiline hydrochloride) was withdrawn from sale in 1991 after the discovery of an association with serious cardiac arrhythmias, most notably a rare form of ventricular tachycardia known as torsades de pointes (TP) (Wild, 1992). In most patients, TP occurs in short, self-limiting bursts that lead to temporary interruption of the circulation, causing symptoms of cerebral impairment such as dizziness, acute confusion, syncope or epileptiform fits. Occasionally, it may convert...

Day Alert Reports

Applicants and licensed manufacturers must submit a ''15-day Alert report'' for each domestic or foreign adverse product experience that is both ''serious'' and ''unexpected'' to the FDA within 15 calendar days of the receipt of information about the experience. 21 C.F.R. 310.305(d), 314.80(c)(1)(i), 600.80(c)(1)(i). The definition of ''serious'' for post-marketing adverse product experiences is identical to that for IND adverse product experiences discussed above. 21 C.FR. 310.305(b),...

Visual Field Defects Common With Vigabatrin

The reporting in 1997 of visual field defects, almost always asymptomatic, in several patients receiving long-term vigabatrin has led to extensive re-evaluation of its use. Preliminary data suggest that this defect occurs in approximately one-third of vigaba-trin recipients, although two studies presented at the 23rd International Epilepsy Congress in the Czech Republic in September 1999 reported a slightly higher rate (52 and 45 ).773 3 Also in September, researchers from Finland reported a 40...

Relative Frequencies Of Drugs Implicated

Advances in drug development have allowed the replacement of many potentially toxic drugs with ''safer'' alternatives. For example, oxyphenisatin has been withdrawn as a laxative in most countries, alpha-methyldopa is now rarely used as an antihypertensive agent, and perhexilene has been replaced by alternative, safer agents. As might be expected, this has led to a change in the pattern of implicated drugs causing hepatotoxicity over the last few decades. In the 1960s chlorpro-mazine was most...

Numerous Regulatory Actions

The year 2000 was notable for the number of Dear Healthcare Professional letters, public health advisories, labelling changes and other regulatory actions that occurred in the United States and other major markets. Rho(D) immunoglobulin In January, the prescribing information for Rho(D) immunoglobulin (WinRho SDF) was revised in the United States following reports of intravascular haemolysis in Rho(D)-positive patients with immune thrombo-cytopenic purpura receiving the product.785 2 The...

The Value Of Clinical Appraisal

Personal examination of all events resulted in the identification of a new adverse reaction to sumatriptan. Aggravation or activation of pain was noted at sites of trauma or inflammation in 22 reports. The varied descriptions did not link them with any particular body system or organ and there was no reaction or event term in use which could be used to identify these events. Recall of the various events by the reviewer resulted in linking Table 27.5. Titles of articles in Prescriber Update...

Description Of Data Mining Methodology Used By The

The UMC's main purpose is to find novel drug safety signals new information. From experience a principal argument has evolved in drug safety, that, if important signals are not to be missed, the first analysis of information should be free from prejudice and a priori thinking (Hand, 1999). Quantitative filtering of the data focuses clinical review on the most potentially important ADR combinations (Bate et al., 1998 Hand, 1999 Lindquist et al., 1999, 2000 Orre et al., 2000). Human intelligence...

Medicaid Databases

The US Medicaid Program is a health insurance system created in 1965 to provide access to medical care for economically disadvantaged and disabled persons. It consists of a series of 54 programs, supported jointly by federal and state funds, and managed independently by states or jurisdictions. The Welfare Reform Act of 1996 defined eligible individuals to include children younger than six pregnant women whose family income is 133 of the federal poverty level or lower children younger than 19...

Initial Regulatory Deliberations

Questions arise, inevitably in retrospect, as to whether terodiline should have been approved at all and whether its proarrhythmic potential could have been anticipated. While it may be easy to answer these in retrospect, the commentary that follows is not based entirely on the benefit of hindsight because the nature of the problem had become apparent at the regulatory authority immediately on receipt of the first two to three reports of cardiotoxicity. There is little doubt that urinary...

Role Of Pharmacogenetics As A Risk Factor

It appears probable that the metabolism of both terodiline and prenylamine may be controlled by the P450 cytochrome CYP2D6, the isoform responsible for debrisoquine hydroxylation. This major drug metabolising isozyme is expressed polymorphically in a population, resulting in two major phenotypes extensive (EM) and poor (PM) metabolisers. The latter are unable to effect the metabolic elimination of many CYP2D6 substrates which include antiarrhythmics, -blockers, antihypertensives, neurolep-tics...

Terodilineinduced Proarrhythmias

One of the fist indications of proarrhythmic activity of terodiline was a sudden unexpected death following an overdose in 1987 reported by Cattini et al. (1989). Forensic toxicological analysis on this 20-year-old previously healthy man with fatal overdose of terodiline revealed the presence of a potentially fatal blood level of terodiline. His blood and urine levels were greater than 10 mg mL, whereas therapeutic concentrations in serum are usually not more than 1 mg mL. No other drugs were...

Postmarketing Experience 19831986

The increasing incidence of haemolytic anaemia from 1983 might appear to have been related to the launch of the 100 mg single daily dose formulation on 31 January 1983 (see Figure 12.1). However, no evidence emerged to support this. It appears that new additional sales were generated by this launch and that the associated promotion may have made doctors more aware of nomifen-sine. Prescriptions, sales and market share increased in 1983 by 21 , 32 and 18 , respectively. This, together with the...

Spontaneous Reporting Schemes

There is widespread agreement that spontaneous reporting schemes are here to stay. They are economical and embrace the entire population of patients and reporters. However, it is important to treat all such reports as hypotheses. Some will almost certainly be causally linked with the suspect drug, whereas others will turn out not to be so. With the increase in acceptance of reports from pharmacists and nurses in addition to doctors, the balance may vary somewhat from region to region and from...

Spontaneous Signalling Methods Used At The Case Series Formation Step

Case series formation methods are procedures used to create case series evidence in favor of a potential relationship between a product and an AE. The concept of case-based signalling (i.e. signal evaluation), coming after and based on report-based signalling (i.e. signal detection), is inherent in much of the spontaneous methods literature, and dates at least to the early writings of Finney (Finney, 1966). In recent years, this distinction has also been emphasized by Meyboom, who has stressed...

Metabolic Idiosyncrasy

The suggestion of dose dependence in some cases of drug-induced liver injury indicates that a host-dependent idiosyncrasy in the metabolism or excretion of these drugs may be responsible for hepatotoxicity. Although several xenobiotics are transformed by the cytochrome P450 system (CYPs) into stable metabolites, many others are oxidised into unstable, chemically reactive intermediates. These reactive intermediates attack hepatic constituents such as unsaturated lipids, proteins or DNA and can...

The Impact Of Pharmacogenetics On Clinical Drug Development

Historically, fewer than 10 of new chemical entities (NCEs) entering preclinical development are approved for clinical use, often because of unacceptable toxicity in animal studies or Phase I human trials or insufficient efficacy (Kleyn and Table 43.4. Comparison of different types of ''genetic testing''. Pharmacogenetics medicine response tests *Rare Mendelian (monogenic) diseases, ''causal'' genes *Complex common diseases (multifactorial), susceptibility genes Prediction of occurrence,...

Type B Or Idiosyncratic Adverse Drug Reactions

Idiosyncratic adverse reactions are less common than the pharmacological adverse reactions, but are as important, if not more so, because they are often more serious, and account for many drug-induced deaths. The possible mechanisms of idiosyncratic adverse effects (Park et al., 1992) are listed in Table 6.5. The toxic reactions may affect many organ systems either in isolation or in combination (Table 6.6). Type B adverse drug reations have been characterized as being dose-independent (Table...

Causality Assessment Methods

The lack of specific tests for diagnosing drug hepatotoxicity poses particular problems for definitively attributing a liver reaction to an implicated drug. The approach to the diagnosis of a drug-induced liver disease involves physician awareness, exclusion of other causes of the reaction and an objective weighing of the circumstantial evidence. These considerations have been termed ''causality assessment and form the cornerstone to the diagnosis of drug-induced hepatotoxicity. An...

Elizabeth B Andrews

Contergan Missbildungen

RTI Health Solutions, Research Triangle Institute, Research Triangle Park, NC, USA, and School of Public Health and School of Pharmacy, University of North Carolina at Chapel Hill, NC, USA ''Not all hazards can be known before a drug is marketed. Pharmacovigilance the study of the safety of marketed drugs under the practical conditions of clinical usage in large communities involves a paradox. The nature of the paradox is best explained by glancing back to the very early 1960s and then looking...

Immunologic Idiosyncrasy

The clinico-pathologic features of some idiosyncratic drug reactions suggest that immunological mechanisms could play an important role in the pathogenesis of drug hepatotoxicity. These include a fever, rash, lymphadenopathy, eosinophilia and involvement of other organs b hepatic inflammatory infiltrates c low frequency lt 1 1000 users d delay in appearance of the disease 2 weeks to several months and e accelerated onset after rechallenge Beaune and Lecoeur, 1997 Robin et al., 1997 . In...

Introduction

Disturbances of gastrointestinal function are common events that can be attributed to ingestion of a wide range of drug classes. Over 30 years ago it was reported that some 20 -40 of adverse drug reactions ADRs in hospital monitoring were gastrointestinal in origin Hurwitz and Wade, 1969 . More recent estimates of the incidence of ADRs in hospitalised patients Bates et al., 1993 1995a, 1995b Bowman et al., 1994 Lazarou et al., 1998 or of subjects admitted to hospital due to an ADR Col et al.,...

Drugs With Ocular Sideeffects Of Recent Clinical Importance

HYDROXYCHLOROQUINE PLAQUENIL Primary Use Hydroxychloroquine is used primarily for the treatment of rheumatoid arthritis and lupus erythematosis, dermatologie conditions, and various inflammatory disorders. Table 38.2. World Health Organization WHO definitions causality assessment of suspected adverse reactions. Certain A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or...

Pharmacovigilance And Product Liability

Consumers who claim to have been injured by medicinal products have various remedies in law against those who manufactured or supplied the products in question. Until 1988 patients in the United Kingdom who wished to bring civil claims for compensation in the absence of a contractual relationship with the supplier, were generally restricted to any claim they might have in negligence. In 1985, Directive 85 374 EEC the Directive introduced the principle of strict liability for defective products,...

The French Imputability Method

This method was first devised in 1978 Dangou-mau et al., 1978 , revised in 1985 when it was published simultaneously in French and in English Begaud et al., 1985 . It is the only imput-ability causality assessment method to have legal status. It is probably one of the most widely used, if not the most widely used, imputability method, having been applied to more than 100 000 reports, and yet it remains widely misunderstood. The method was derived when the regional network was developing, to...

Purpose And Achievements Of The Yellow Card Scheme

Amery, 1999 that it is not possible to detect all the adverse effects of a medicine during the pre-marketing clinical trials, because of a number of factors. First, trials are generally small on average 1500 patients for a new drug substance although they will detect common side effects, particularly those that are predictable from the pharmacology of the drug, they are too small to detect side effects that occur rarely incidence of 1 in 10 000 or less ....

Contributors

Medical Epidemiologist, Division of Drug Risk Evaluation, Office of Drug Safety, Center for Drug Evaluation and Research, US Food and Drug Administration, 5600 Fishers Lane, HFD-400, Rm 15B-32, Rock-ville, MD 20857, USA, AHMADS cder.fda.gov Consultant Hepatobiliary Physician, Queen's Medical Centre, University Hospital, D Floor, South Block, Nottingham NG7 2UH, UK, Senior Research Associate, Meyers Primary Care Institute, Fallon Healthcare System, and University of Massachusetts, Worcester, MA...

Italy

The European pharmacovigilance requirements have been implemented in Italy by Legislative Decree no. 178 of 29 May 1991 and Legislative Decree no. 44 of 18 February 1997. The Italian authority responsible for pharma-covigilance is the Department for the Evaluation of Medicinal Products and Pharmacovigilance of the Ministry of Health the Department of Pharmacovigilance . The Department of Pharmacovigilance liaises with regional health authorities, with the national pharmacovigilance authorities...

Diagnosing Adverse Drug Reactions Adrs

There are two types of adverse drug reactions ADRs . Type A are common, predictable, usually dose-dependent and appear as excessive manifestations of the normal pharmacology toxicology of the drug they are seldom fatal. Type B are uncommon, unpredictable, often independent of dose and usually represent abnormal manifestations of the drug's pharmacology toxicology they involve relatively high rates of serious morbidity and mortality. ADRs frequently mimic ordinary diseases and, if they are...