Final results from 18 years of the International Lamotrigine Pregnancy Registry.

OBJECTIVE: To monitor for a signal for major teratogenicity following in utero lamotrigine exposure. METHODS: Health care providers reported lamotrigine exposure during pregnancy, and subsequent outcomes, on a voluntary basis. Prospective reporting early in pregnancy was encouraged. Major congenital malformations (MCMs) were classified according to the Centers for Disease Control and Prevention (CDC) criteria and were reviewed by a pediatrician on the Registry's Scientific Advisory Committee. The proportion of infants with MCMs was calculated by trimester and therapy type and descriptively compared to population-based reference estimates. RESULTS: Over an 18-year period, 35 infants with MCMs were observed among 1,558 first-trimester monotherapy exposures: 2.2%(95% confidence interval [CI] 1.6%-3.1%). This was similar to estimates from general population-based cohorts. The observed proportion of infants with MCMs among 150 lamotrigine/valproate polytherapy exposures was 10.7% (95% CI 6.4%-17.0%) and was 2.8% (95% CI 1.5%-5.0%) among 430 infants exposed to lamotrigine polytherapy without valproate. No consistent pattern of malformation type, or malformation frequency by dose, was observed. DISCUSSION: The Registry did not detect an appreciable increase in MCM frequency following first-trimester lamotrigine monotherapy exposure. With over 1,500 first-trimester monotherapy exposures, the Registry was powered to detect major teratogenicity. The proportion of infants with MCMs following lamotrigine/valproate polytherapy exposure was high, but similar to that previously reported with valproate monotherapy. The Registry failed to observe an increased MCM frequency with increasing lamotrigine dose. Monitoring of specific malformations among lamotrigine-exposed pregnancies will continue through case-control surveillance in the European Congenital Anomalies and Twins Registers network.

Evaluation of cancer risk related to atopic dermatitis and use of topical calcineurin inhibitors.

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with Type 2 diabetes: a population-based analysis in the UK.

AIMS: The aim of this retrospective cohort study was to estimate the time to insulin initiation in patients with Type 2 diabetes inadequately controlled on oral glucose-lowering agents (OGLAs). METHODS: Insulin-naïve patients failing on OGLAs were identified from The Health Improvement Network database, which collects records from general practices throughout the UK. Patients were included if they were aged > or = 40 years, had concomitant prescriptions for > or = 2 OGLAs, and > or = 1 year of available records prior to the first occurrence of HbA(1c) > or = 8.0% after > or = 90 days of OGLA polytherapy at > or = 50% of maximum recommended dosages. RESULTS: A total of 2501 eligible patients with Type 2 diabetes who had an HbA(1c) above the OGLA failure threshold of > or = 8.0% were identified (54.0% male; 30.9% aged 60-69 years). It was estimated that if all the eligible patients were followed for 5 years, 25% would initiate insulin within 1.8 years of OGLA failure (95% CI 1.6-2.0), and 50% within 4.9 years (95% CI 4.6-5.8). The presence of diabetes-related complications had no substantial impact on the time to insulin initiation. CONCLUSIONS: This study found that 25% of patients with Type 2 diabetes had insulin initiation delayed for at least 1.8 years, and 50% of patients delayed starting insulin for almost 5 years after failure of glycaemic control with OGLA polytherapy, even in the presence of diabetes-related complications. Interventions that reduce this delay to insulin initiation are required to help achieve and maintain recommended glycaemic targets in patients with Type 2 diabetes.

The relationship between dosing of alosetron and discontinuation patterns reported by patients participating in a follow-up programme.

BACKGROUND: Alosetron was reintroduced for treatment of irritable bowel syndrome with a risk management programme in November 2002. Recommended starting dosage was 1 mg/day for 4 weeks. If symptoms remained uncontrolled, dosage could be changed to 2 mg/day. AIM: To describe alosetron dosages and associated patient characteristics from the Lotronex follow-up survey programme. METHODS: Patients reported dosages of alosetron at start and regular follow-up intervals. Analyses were limited to patients with the potential to have at least 1 year of follow-up (enrolled between 9 December 2002 and 31 December 2003). RESULTS: At baseline, 75% of 2817 respondents reported starting on 1 mg/day, 17% on 2 mg/day and 8% on other doses. Adherence to recommended starting dosage did not vary by status at end of follow-up, previous alosetron experience or age. At last reported dose, 50% of respondents were using 1 mg/day; 29% were using 2 mg/day. Discontinuation was not related to baseline doses. Longer times to discontinuation were associated with previous use, symptoms for more than 6 months and dose change throughout follow-up. CONCLUSIONS: High adherence to recommended dosing at baseline and follow-up suggests that the risk management programme is encouraging safe use of alosetron, including adherence to dosing recommendations.

A patient follow-up survey programme for alosetron: assessing compliance to and effectiveness of the risk management programme.

BACKGROUND: In November 2002, alosetron HCl (Lotronex, GlaxoSmithKline Research Triangle Park, NC, USA) was re-introduced to the US marketplace for women with severe diarrhoea-predominant irritable bowel syndrome. In support of the re-introduction, a risk management programme was implemented, which included a patient follow-up study in which all users of alosetron could participate. AIM: We report on the methods used and the effectiveness of key elements of the risk management programme. METHODS: Patients voluntarily enroled in the study and completed questionnaires at baseline, after 5 and 10 weeks, and quarterly thereafter. Questions focussed on patient eligibility, knowledge of risks and benefits, and adherence to the recommended programme elements for education, prescribing and dispensing. RESULTS: Between December 2002 and 2004, 4,803 patients enrolled in the study, and <3% were lost to follow-up. The average follow-up time was approximately 6 months, and the response rate for each assessment was >95%. A total of 90% of patients at baseline met the full clinical criteria recommended for the treatment. Patient adherence to the risk management programme was >87%. CONCLUSIONS: Using the Lotronex risk management programme, patients met clinical criteria, were knowledgeable about treatment risks and benefits, and were adherent to the process elements of the programme. These patients seemed to engage in active dialogue with their physicians about symptoms and use of alosetron.

Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder, and its prevalence and demographics have been evaluated by different methodologies with varying results. AIM: To evaluate irritable bowel syndrome demographic and prevalence characteristics utilizing a web-enabled panel. METHODS: From an existing 150 000-member panel, 31 829 individuals were randomly selected and sent screening questionnaires to evaluate irritable bowel syndrome symptoms. Individuals who agreed to participate and completed the screening questionnaire received a second questionnaire related to a diagnosis of irritable bowel syndrome, a more detailed symptom description, and additional burden of illness data. RESULTS: Irritable bowel syndrome prevalence was 7%. Prevalence was higher in women vs. men, unmarried individuals vs. married individuals and unemployed individuals vs. employed individuals. Of those completing the second questionnaire, 51% had seen their physicians for irritable bowel syndrome symptoms in the past year and most had an episode within the past 3 months. During the past year, approximately half of the participants had used a prescription medication, and over 90% had used an over-the-counter medication for irritable bowel syndrome. Participants with irritable bowel syndrome demonstrated quality-of-life reductions relative to norms of the United States population. CONCLUSIONS: Web-enabled data collection represents a novel tool for rapidly surveying a large population of individuals with irritable bowel syndrome symptoms.

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study.

Clinical and epidemiologic evidence suggest serious cutaneous reactions to antiepileptic drugs are more likely to occur during the first few months of use. However, studies have quantified risk for these reactions by including all users and their entire duration of use in denominator estimates possibly underestimating the risk. The objective of this study was to measure risk of serious cutaneous reactions in new users of phenytoin, carbamazepine, or valproic acid. We identified serious cutaneous reactions that included hospitalization and occurred within 60 days of the first or second prescription for new users of each study drug in the Saskatchewan Health data files. To classify outcome diagnoses, a dermatologist reviewed hospital discharge summaries. In 8,888 new phenytoin users there were eight serious cutaneous reactions. These included two probable and two possible cases of hypersensitivity syndrome, yielding a risk of 2.3 to 4.5 per 10,000 for this syndrome. There were six serious cutaneous reactions in 9,738 new carbamazepine users. These included one probable case and four possible cases of hypersensitivity syndrome, yielding a risk of 1 to 4.1 per 10,000 for this syndrome. There were no confirmed serious cutaneous diagnoses in 1,504 new valproate users. During the first few weeks of initiating therapy with phenytoin or carbamazepine, the clinician should be aware of the uncommon but not rare possibility that a cutaneous eruption could evolve into a significantly more serious reaction.

Sudden unexplained death in epilepsy: observations from a large clinical development program.

PURPOSE: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database. METHODS: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator. RESULTS: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/ highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG. CONCLUSIONS: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.

Sudden unexplained death among subjects with refractory epilepsy.

PURPOSE: To address concerns about possible increases in rates of sudden unexplained death (SUD) after use of new anticonvulsants, more information on the rate of SUD among subjects with refractory epilepsy is needed to provide a comparison. METHODS: We conducted a study to estimate the incidence of SUD among subjects younger than 50 years with refractory epilepsy, by using information from the General Practice Research Database (GPRD) in the United Kingdom. For the purposes of this study, subjects receiving two or more anticonvulsant drugs concurrently were considered to have refractory epilepsy. Potential cases of SUD were identified from the computer records, and clinical records for these subjects were reviewed by two specialists in SUD in epilepsy. RESULTS: Fifteen subjects (eight male, seven female) of the 4,150 subjects with refractory epilepsy were considered to have definite/probable or possible SUD. CONCLUSIONS: The overall incidence rate of SUD in the population was 2.2 per 1,000 person-years (95% CI, 1.3-3.6). The rate for subjects with highly probable SUD was 1.5 per 1,000 person-years (95% CI, 0.8-2.7).

Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada.

To measure the incidence of sudden unexplained death in treated persons with epilepsy (SUDEP) and to identify risk factors for SUDEP, a cohort of 6,044 persons aged 15-49 years with more than four prescriptions for antiepileptic drugs (AEDs) was identified from the Saskatchewan Health prscription drug file. To exclude subjects whose sudden deaths (SUDs) might be misattributed to another chronic underlying disease, subjects with hospitalizations for cancer or heart problems were excluded. To exclude subjects without epilepsy, subjects with > 2-year AED treatment followed by AED-free time and subjects receiving < 1 U/day were excluded. The final cohort consisted of 3,688 subjects. Follow-up was started at the first AED prescription listed in the prescription drug file and ended at the earliest of the following: age 50 years, death, or last registration in the Saskatchewan Health. For 153 of 163 deaths occurring in the cohort, copies of anonymized death certificates were obtained and copies of anonymized autopsy reports of potential SUDEP cases were examined. There were 18 definite/probable SUDs and 21 possible SUDEPs, yielding a minimum incidence of 0.54 SUDEP per 1,000 person-years and a maximum of 1.35 SUDEP per 1,000 person-years. SUDEP incidence increased with male sex, number of AEDs ever prescribed, and prescription of psychotropic drugs and was highest in males with a history of treatment with three or more AEDs and four or more psychotropic drug prescriptions. Poisson regression showed a 1.7-fold increase in risk of SUDEP for each increment in maximum number of AEDs administered, a likely surrogate for severity and persistence of seizures.

Validity of rheumatoid arthritis diagnoses listed in the Saskatchewan Hospital Separations Database.

A Saskatchewan hospital separations database was compared to abstracted hospital records to determine the reliability of the database (i.e. accuracy with which the computer data reflect the charts from which they were coded) and the validity of classifying rheumatoid arthritis status with the database (i.e. the extent to which rheumatoid arthritis mentioned in the database reflected the condition of the patient). A sample of hospitalized subjects fell into three categories: 144 who never had a database diagnosis of any arthritis, 146 who had a database diagnosis of osteoarthritis, and 142 who had a database diagnosis of rheumatoid arthritis. These 432 people experienced 1717 hospitalizations eligible to match a hospital database listing by date, and 1618 matched. Of the remaining 99, 35 were relatively recent and probably had not yet been entered into the database, 39 were possibly entered incorrectly, and 25 could not be matched in any way. Of 150 hospitalizations with a database diagnosis of rheumatoid arthritis, this diagnosis was in the hospital record for 125. Chart documentation of rheumatoid arthritis status was greatest for subjects who, according to the database, were hospitalized by a rheumatologist: of 73 subjects in this category, abstractions showed 69.9% met > or = 5 American Rheumatism Association criteria, 15.1% met < 5 criteria but had a rheumatologist's diagnosis of rheumatoid arthritis, 1.3% met < 5 criteria and had a rheumatoid arthritis diagnosis by a non-rheumatologist, and 13.7% had no mention of rheumatoid arthritis or its symptoms in any medical record abstracted. In summary, reliability of the database was excellent, but validity depended on the source of diagnosis.

Record linkage to conduct an epidemiologic study on the association of rheumatoid arthritis and lymphoma in the Province of Saskatchewan, Canada.

The objective of this effort was to assess the utility of the large automated database in Saskatchewan as a resource for pharmacoepidemiologic studies. To this end a study was undertaken to test the hypothesis that rheumatoid arthritis (RA) increases the risk of cancer, especially lymphoma. This was done by performing a retrospective cohort study based on record linkage data from Saskatchewan Health. From hospital discharge diagnoses in the hospital file an exposed group (RA) and two comparison groups matched to the RA group by age and sex were identified: (1) the RA group consisted of people with a discharge diagnosis of rheumatoid arthritis; (2) the osteoarthritis (OA) group consisted of people with OA discharge diagnoses; and (3) a comparison (CN) group consisted of hospitalized people with no discharge diagnoses of arthritis. Drug exposures were determined by linkage with the Prescription Drug File, cancer outcomes were determined by linkage with the Cancer Foundation file, and length of eligibility in the health plan and demographics information were determined by linkage with the registration file. The data were checked for quality of linkages across files and consistency with study definitions. Of 13,333 identified subjects, 2.8% were excluded because of apparent incorrect assignment to study group or age group or because of ineligibility in health plan during the study period. In order to decrease the possibility of misclassification of exposure (rheumatoid arthritis), hospital discharge diagnoses were used to exclude subjects with any inflammatory rheumatic diseases (IRD) from the CN (7.8%) and OA (8.3%) groups and subjects with IRD other than rheumatoid arthritis (4.6%) from the RA group. To decrease selection bias, those who had cancer within 1 year of enrollment (to exclude those in hospital because of symptoms of undiagnosed cancer) were excluded. Because RA subjects hospitalized by a rheumatologist were most likely to have valid rheumatoid arthritis diagnoses, each analysis was run twice: once with the entire RA group (N = 1210) and once with those in the RA group who were rheumatologist-hospitalized (N = 646). Logistic regression of incidence was used to control for age, sex, and use of individual disease-modifying anti-rheumatoid drugs (DMARDs). For the rheumatologist-hospitalized RA group compared to the CN group, a significant 4-fold greater risk for lymphoma/myeloma was detected when DMARD use was not controlled for, and a 3.4-fold increase in risk was detected even when use of individual DMARDs was controlled for.(ABSTRACT TRUNCATED AT 400 WORDS)

Drug utilization by the 30-64 year-old people in two cities in the Federal Republic of Germany in 1984.

A study has been done to describe and compare the drug utilization profiles of the 30-64 yr-old populations in two cities in the Federal Republic of Germany. Subjects from two community surveys, based on random samples in 1984, from the communities of Augsburg in the south, and Luebeck in the north, were asked to bring to interview any medications taken in the preceding seven days. Total drug use in the two communities was very similar. Women took more drugs than men. The drug categories used by at least 5% of men were analgesics/antirheumatics and antihypertensives. The prevalence of use of different drug categories by men was remarkably similar in the two cities, and the only significant difference was a greater consumption of antihypertensive drugs by Luebeck men (9.8%) compared to Augsburg men (6.3%). The drugs taken by at least 5% of women were sex hormones, analgesics/antirheumatics, antihypertensives, thyroid preparations, psychotropics, cardiac drugs and antihypotensives. Consumption by Augsburg women was significantly greater for sex hormones, cardiac drugs, thyroid drugs, and migraine drugs, whereas Luebeck women consumed significantly more antihypertensives. The high use of thyroid drugs by Augsburg women (11%) is indicative of the high frequency of endemic goitre in the southeastern quarter of the FRG. Although it has been shown from sales data that the FRG has a high consumption of cardiac glycosides, the 6% prevalence of use of preparations of them by 30-64 yr-old Augsburg women represents more precise exposure information and reflects a relatively young group of users.

Changing patterns of antihypertensive drug use in a German population between 1984 and 1987. Results of a population based cohort study in the Federal Republic of Germany.

In the MONICA Augsburg project, a cohort of 3324 men and women randomly selected from the population (aged 30 to 64 y) was surveyed in 1984/85 and in 1987/88. Their antihypertensive medication as well as their demographic characteristics, blood pressure values, and awareness of hypertension were assessed at each visit in an identical manner. In 1984/85 the prevalence of antihypertensive drug use in the cohort was 7.8% (n = 260). In 1987/88, 204 of the hypertensives were still being treated (continuously treated hypertensives) and there were 167 newly treated hypertensives, thus increasing the prevalence of antihypertensive drug use to 11.2%. Of the 204 continuously treated hypertensives, 45.6% had changed their antihypertensive medication over the three-year follow-up period. Combinations with diuretics (except those containing calcium antagonists or ACE-inhibitors) had largely been discontinued, and the prevalence of calcium antagonist mono- and combination therapy had markedly increased from 84/85 to 87/88. Men were treated more frequently with recently introduced antihypertensive agents than women. Newly treated hypertensives (n = 167) showed antihypertensive treatment patterns reflecting the changes observed in continuously treated hypertensives. Triple drug combinations, mostly in fixed ratios, were being taken by approximately 25% of all hypertensives at each visit. Prospective analysis revealed an underlying discontinuation rate of 49%. It is concluded that the epidemiology of antihypertensive therapy in individuals and in the community is subject to rapid changes and various influences. Cohort studies of treated antihypertensive individuals offer a more comprehensive understanding of its determinants.