Postmarketing Surveillance Data Research Articles

Postmarketing Surveillance

The postmarketing monitoring and evaluation of the safety and effectiveness of all medicines is essential. The patterns of use, effectiveness and safety of a drug in general use may be substantially different to that in clinical trials due to differences in prescribing and patient groups; differences include the limited number of patients in studies, restrictions in patient populations (e.g. pregnancy and nursing mothers, children, the elderly and those predisposed to develop adverse events are frequently excluded), and the limited duration of drug use or period of evaluation in clinical trials. In addition, knowledge about effectiveness and safety in off-label use and interactions with concomitantly used drugs remains unknown. It is important to recognise that clinical trials and postmarketing surveillance address different issues. Postmarketing surveillance data provide new information that was unavailable in premarketing studies. Much larger observational studies can be done, at a lesser cost, to evaluate a drug in a customary use situation. Highest priority in a postmarketing surveillance system should be given to new chemical entities, populations in which drug effects are not well documented, certain important medical events (e.g. birth and death) and their relationship to drug use and pattern of prescription. Surveillance per se, or its results, will not and cannot be used to change the biological properties or effects of a drug, but can be used to minimise the harmful consequences and maximise the optimal use of a drug. LEADING ARTICLE

Eszopiclone

Eszopiclone [Lunesta, Estorra] is a short-acting hypnotic agent that is a stereoselective isomer of the agent zopiclone, which has been available in Europe since 1992. Eszopiclone is structurally unrelated to the benzodiazepines, and Sepracor (the originator of eszopiclone) has stated that the drug acts rapidly, with the duration of effect lasting up to 6 hours. This may result in improved sleep maintenance, with less nocturnal awakening.Originally, racemic zopiclone was developed and marketed by Rhone-Poulenc Rorer, which merged with Hoechst Marion Roussel to form Aventis. Sepracor anticipates that eszopiclone will have equivalent efficacy to the racemic version with potential for an improved side effect profile. In October 1999, Sepracor exclusively licensed Aventis Pharma's preclinical, clinical and postmarketing surveillance data package for zopiclone, its isomers and metabolites. The company intends to use this information in addition to data from Sepracor's own studies as part of the regulatory package to gain approval of eszopiclone in the US. In July 2004, Sepracor announced terms of an additional agreement with Aventis under which it would have the right to read and reference Aventis' regulatory filings related to zopiclone outside the US for the purpose of development and regulatory registration of eszopiclone outside the US. Additionally, Aventis would assign Sepracor the foreign counterparts to the US patent covering eszopiclone and its therapeutic use. In August 2004, Paul Royalty Fund II, an affiliate of Paul Capital Partners, purchased from Sanofi-Aventis the royalty rights on US sales of eszopiclone. In exchange for the rights, Sanofi-Aventis will receive fixed and milestone payments totalling up to US$115 million. In December 2004 the US FDA approved eszopiclone (Lunesta) for the treatment of insomnia. It is indicated for patients who experience difficulty falling asleep as well as for patients who have sleep maintenance difficulty, and is approved for long-term treatment. The recommended dosing to improve sleep onset and/or maintenance is 2mg or 3mg for adult patients (aged 18-64 years) and 2mg for older adult patients (aged > or =65 years). The 1mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. The launch of eszopiclone in the US is expected to take place in the first quarter of 2005. The approval follows an NDA submission in January 2003, an approvable letter in February 2004, and a resubmission of the NDA in June 2004. The NDA contained data from 24 clinical trials that included >2700 adult and elderly subjects, as well as data from >60 preclinical studies. Six phase III trials in adult and elderly patients with chronic or transient insomnias were also included in the data submission. Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause. Sepracor has been granted a US patent for eszopiclone [S-zopiclone, (+)-zopiclone, Lunesta, Estorra], a single isomer of zopiclone.US patents (Nos. 6,319,926 and 6,444,673) have been issued covering the use of eszopiclone for the treatment of insomnia, eszopiclone and pharmaceutical compositions comprising eszopiclone.

Are novel drugs more risky for patients than less novel drugs?

The Food and Drug Administration has accelerated the approval of therapeutically novel drugs so that patients have faster access to innovative drug therapies. Little research, however, has examined the variation in risks among therapeutically novel and less novel drugs. Do drugs that represent greater novelty also entail greater risks for patients? This paper uses post-marketing drug safety surveillance data from the FDA to examine the adverse drug reactions (ADRs) associated with novel and less novel drugs. Negative binomial regressions are used to examine the impact of a drug's FDA novelty rating on its ADR count controlling for differences in drug utilization, the conditions being treated, disease characteristics, patient characteristics, drug review times, and year-specific effects. Results show that drugs deemed novel by the FDA are associated with a greater number of serious drug reactions, including those that result in hospitalization and death, than less novel drugs. These results suggest that novel drugs pose greater risk of serious ADRs for patients relative to less novel drugs.

Association of asthma therapy and churg-strauss syndrome: An analysis of postmarketing surveillance data

Background: Churg-Strauss syndrome (CSS), also known as allergic granulomatous angiitis (AGA), is a rare vasculitis that occurs in patients with bronchial asthma. The nature of the association of CSS with various asthma therapies is unclear.Objective: This study investigated the associations of different multidrug asthma therapy regimens and the reporting of AGA (the preferred code for CSS in the coding dictionary for the Adverse Event Reporting System [AERS]) by applying an iterative method of disproportionally analysis to th AERS database maintained by the US Food and Drug Administration.Methods: The public-release version of the AERS database was used to identify reports of AGA in patients receiving asthma therapy. Reporting of AGA was examined using iterative disproportionality methods in patients receiving ≥1 of the following drug classes: inhaled corticosteroid (ICS), leukotriene receptor antagonist (LTRA), short-acting β2-agonist (SABA), or long-acting β2-agonist (LABA). The Bayesian data-mining algorithm known as the multi-item gamma poisson shrinker was used to determine the relative reporting rates by calculation of the empirical Bayes geometric mean (EBGM) and its 90% CI (EB05 = lower limit and EB95 = upper limit) for each drug. Subset analyses were performed for each drug with different medication combinations to differentiate the relative reporting of AGA for each.Results: A strong association was found between LTRA use and AGA (EBGM = 104.0, EB05 = 95.0, EB95 = 113.8) that persisted with all combinations of therapy studied. AGA was also associated with the ICS, SABA and LABA classes (EBGM values of 27.8, 14.6 and 40.4, respectively). However, the latter associations were mostly dependent on the presence of concurrent LTRA and, to a lesser extemt, oral corticosteroid therapy and became negligible (ie, EB05 < 2) for patients who were not receiving these concurrent treatments.Conclusions: Differences based on relative reporting were observed in the patterns of association of AGA with LTRA, ICS, and β2-agonist therapies. A strong association between LTRA use and AGA was present regardless of the use of other asthma drugs.

Benefit-risk assessment of tolterodine in the treatment of overactive bladder in adults.

Overactive bladder is associated with symptoms of urgency, with or without urge incontinence, usually with daytime frequency and nocturia in the absence of local pathological factors. Muscarinic receptor antagonists (antimuscarinics) are the first-line pharmacotherapy. Tolterodine, a competitive, nonselective antimuscarinic specifically developed for the treatment of overactive bladder, demonstrated tissue selectivity for the bladder over the parotid gland in an animal model. As of March 5, 2003, the immediate-release (IR) formulation had been approved in 72 countries and the extended-release (ER) formulation had been approved in 28 countries, and tolterodine had been administered to 5 million patients. This review evaluates the benefit-risk profile of tolterodine in the treatment of adults with overactive bladder, summarising clinical trial and postmarketing surveillance data. Tolterodine has been found to significantly reduce micturition frequency, urgency perception and the number of episodes of urge incontinence and increase the volume voided per micturition. Dry mouth, an antimuscarinic class effect, is the most commonly reported adverse effect but is mostly mild to moderate in severity. Serious adverse effects are reported infrequently. Based on summary and review of postmarketing surveillance and clinical trial safety data received by the market authorization holder and contained in the Periodic Safety Update Reports for tolterodine, several monitored serious events of the gastrointestinal tract (e.g. ileus or haemorrhage), nervous system (e.g. syncope, convulsions and memory disorders) and cardiovascular system (e.g. ventricular arrhythmia, atrial fibrillation, palpitations, bradycardia, transient ischaemic attacks and hypertension) were not considered related to tolterodine. QT or corrected QT (QTc) prolongation was not observed in any of the five cases of verified ventricular arrhythmia in patients administered tolterodine; there is insufficient evidence to indicate that tolterodine causes ventricular arrhythmia or extrasystoles or any specific type of cardiac rhythm abnormality. The safety profile of tolterodine is similar in patients aged > or =65 years and in younger adults. Clinically relevant drug interactions are limited to cytochrome P450 3A4 inhibitors, such as ketoconazole, and co-administration with such agents warrants a tolterodine dosage decrease. In addition, tolterodine IR 2mg twice daily is similar in efficacy to oxybutynin IR 5mg three times daily, and tolterodine ER 4 mg once daily is similar in efficacy to oxybutynin ER 10mg once daily. Dry mouth occurred less frequently with tolterodine than oxybutynin, and moderate to severe dry mouth occurred more than three times less frequently. Based on the low frequency of adverse events, the absence of unexpected adverse events and the very low frequency of serious adverse events, we conclude that tolterodine is a well tolerated treatment for overactive bladder in adults, in whom it should be considered as first-line therapy.

Haematological effects of interferon-beta-1a (Rebif) therapy in multiple sclerosis.

Interferon-beta-1a (Rebif) is an established treatment for relapsing-remitting multiple sclerosis (MS) and haematological changes are commonly reported in clinical trials of this agent. The combined clinical trial and postmarketing safety database for subcutaneous interferon-beta-1a (Rebif) allows a comprehensive, retrospective assessment of both common and infrequent haematological effects associated with interferon-beta therapy. Haematological laboratory abnormalities were analysed from six randomised, controlled clinical trials of subcutaneous interferon-beta-1a in MS, five of which were placebo-controlled. Treatment data were collected from 2482 patients for up to 6 months, 1178 patients for up to 2 years and 786 patients for up to 6 years. Total interferon-beta-1a doses ranged from 22 microg once weekly to 44 microg three times weekly. Postmarketing surveillance data were also analysed. Treatment with interferon-beta-1a led to asymptomatic dose-related reductions in all cell lineages under investigation, predominantly white blood cells. The greatest differences between interferon-beta-1a therapy and placebo were seen for total leucocyte and neutrophil counts. At least two-thirds of patients affected by cytopenia experienced the onset of cytopenia within the first 6 months of therapy. The majority of events were mild and generally resolved within 3--4 months, while continuing therapy. Dose reductions were uncommon and only a small proportion (6 of 727; 0.8%) of patients stopped treatment over 2 years because of haematological abnormalities when receiving the highest dose of interferon-beta-1a, 44 microg three times weekly. Postmarketing safety reports were similarly related to asymptomatic cytopenias, although one case of potentially related autoimmune haemolytic anaemia was reported. Although haematological abnormalities are common and dose-related in patients with MS receiving interferon-beta-1a, the events are mainly mild and transient, with little impact on adherence to therapy. Haematological events are rarely of clinical significance and do not adversely affect the benefit-to-risk ratio that favours high-dose interferon-beta-1a therapy.

Indomethacin responsiveness of patent ductus arteriosus and renal abnormalities in preterm infants treated with indomethacin

Objectives We evaluated the factors related to indomethacin responsiveness of the patent ductus arteriosus (PDA) and subsequent renal and electrolyte abnormalities in a large number of low birth weight infants. Methods The ductus was evaluated by Doppler echocardiogram or clinical signs after the last administration of indomethacin for 2538 low birth weight infants, through the use of postmarketing surveillance data. Results Multivariate logistic regression analyses demonstrated that clinical closure of PDA was significantly associated with pregnancy-induced hypertension and respiratory distress syndrome. In contrast, a 1-point increase of cardiovascular dysfunction score or a 1-day increase in postnatal age at the first indomethacin treatment decreased the responsiveness of the ductus to indomethacin. Clinical ductal reopening was significantly less likely to occur for each week of increased gestational age. Ductal reopening was more likely for each day of postnatal life at the first administration of indomethacin. Infants with preexisting renal and electrolyte abnormalities and infants whose mothers had received indomethacin tocolysis or who had chorioamnionitis were at increased risk of development of renal impairment. Conclusions Both antenatal and postnatal factors predict good or poor response to indomethacin therapy for PDA.

Droperidol, QT prolongation, and sudden death: What is the evidence?

Study objective: Droperidol is a butyrophenone commonly used as an antiemetic and antipsychotic in the United States since US Food and Drug Administration (FDA) approval in 1970. Its labeling has recently been revised, with a black box warning for cases of QT prolongation leading to torsades de pointes and death. A black box warning is applied when serious adverse drug reactions are uncovered for medications. We sought to examine the evidence of a causal association suggested by the black box warning to aid clinicians in their risk-benefit analyses regarding further use of droperidol. Methods: A literature search was undertaken to determine the evidence regarding the association between droperidol and QT prolongation or torsades de pointes. The evidence was then evaluated by using evidence-based medicine principles. In addition, a review of the FDA regulatory process is presented. Results: Three clinical studies, 1 published abstract, and 7 case reports were reviewed. Available postmarketing surveillance data (MedWatch reports) were also reviewed. Applying the criteria of evidence-based medicine and Hill's criteria, the evidence is not convincing for a causal relationship between therapeutic droperidol administration and life-threatening cardiac events. Conclusion: The recent black box warning appears to have originated from postmarketing surveillance data rather than data reported in the peer-reviewed medical literature. Ongoing monitoring of drug safety and more definitive study appear appropriate. [Ann Emerg Med. 2003;41:546-558.]

Hepatic Reactions During Treatment of Multiple Sclerosis with Interferon-??-1a

Hepatic dysfunction, manifested as liver enzyme elevations, occurs frequently in patients who are treated with interferon, however, data for patients with multiple sclerosis are limited. To retrospectively assess the safety profile of interferon-beta-1a therapy with respect to liver function during clinical trials and postmarketing surveillance in the treatment of multiple sclerosis. Adverse effects and laboratory abnormalities were analysed from six randomised, controlled clinical trials (five of which were placebo-controlled) that assessed the use of interferon-beta-1a in patients with multiple sclerosis. Treatment data were collected for 2819 patients for up to 12 months, of whom 1995 received interferon-beta-1a (337 [12%] received Avonex intramuscular therapy, and 1658 [59%] received Rebif subcutaneous therapy), and 824 (29%) received placebo. Data for 2 years were collated for 1178 patients (from two studies). Total weekly interferon doses were 22-132 microg. Postmarketing surveillance data were also analysed. In patients receiving interferon-beta-1a, there were significant elevations of alanine aminotransferase (ALT) levels, of all grades of severity, in up to 59% of patients at 6 months, up to 64% of patients at 12 months and up to 67% of patients at 24 months; ALT elevations were asymptomatic and dose related. More than 50% of elevations in liver enzymes occurred during the first 3 months of treatment, and more than 75% occurred during the first 6 months. Elevated enzyme levels resolved spontaneously or with dosage adjustment. Although the overall incidence of liver enzyme elevation was high during the early months of therapy, after 2 years, the proportion of patients with abnormal liver enzyme levels was 11% of those receiving Rebif 44 microg three times weekly compared with 6% of placebo-treated patients. Only 0.4% of patients discontinued interferon-beta-1a treatment because of hepatic adverse effects. Serious symptomatic interferon-related hepatic toxicity occurs, but is uncommon. Concomitant medication use was not associated with increased risk. Asymptomatic hepatic dysfunction is common in patients with multiple sclerosis who are treated with interferon-beta-1a, and is dose related. Adverse effects are mainly mild and transient, with little impact on adherence to therapy, although rare serious events can occur. Regular liver function monitoring during the first 6 months is recommended.

Inactivated hepatitis A vaccine: immunogenicity, efficacy, safety and review of official recommendations for use

There is 10 years of marketing experience with the hepatitis A vaccine Havrix™. It is highly immunogenic, provides lasting protection in healthy individuals and generates protective levels of antibodies in patients with chronic liver disease or impaired immunity. Postmarketing surveillance data have confirmed the outstanding safety profile of the vaccine. The timing of the booster dose is not critical to effectiveness, which has advantages for the protection of travelers to regions of high endemicity. The vaccine is effective in curbing outbreaks of hepatitis A and also when administered postexposure, due to rapid seroconversion and the long incubation period of the disease. In intermediate endemic regions, an epidemiological shift in hepatitis A infection has driven the development of universal preventive strategies to be added to the targeting of at-risk groups. Existing official recommendations and future directions for vaccine use are reviewed.

Varicella: a vaccine preventable disease?

To present a review of varicella disease, vaccine development and implementation of universal vaccination, discuss common questions about the vaccine and the epidemiology of the disease since licensure of the varicella vaccine. Review the incidence of complications from varicella disease prior to vaccine licensure, safety of the varicella vaccine from clinical trials and post-marketing surveillance data, the impact of the vaccine on disease incidence where high vaccine coverage has been achieved, and address some barriers to vaccination. Raise issues that developed since 1995. The safety data gathered during the 20-year-gestation period of this vaccine prior to licensure has been confirmed. The vaccine works-in areas where vaccine coverage is over 70%, there has been a decline in disease, most marked in the age group with the best vaccine coverage (the 1-4-year olds), leading to a concern that unexposed susceptible children may reach adulthood and remain susceptible unless better practice of universal vaccination of ALL susceptible is practiced. Varicella disease has declined in areas with moderate vaccine coverage. Continued implementation of existing vaccine policies will lead to further reductions of varicella morbidity and mortality throughout the USA.

Fluvoxamine: safety profile in extensive post-marketing surveillance.

The safety profile of the selective serotonin reuptake inhibitor, fluvoxamine, has been assessed in clinical and post-marketing studies. Post-marketing surveillance provides the opportunity to assess a drug's safety in every day clinical conditions in a much greater patient population than in clinical trials and therefore serves as a useful tool to detect signals for adverse effects with an incidence of less than 1 : 10,000. The safety profile of fluvoxamine was evaluated based on data from 17 years of global post-marketing surveillance in an estimated 28 million patients exposed to fluvoxamine. A total of 6,658 adverse drug reaction reports received from world-wide sources were reviewed and analysed. Post-marketing surveillance data confirmed the favourable safety profile already observed in clinical and post-marketing studies. A remarkably low level of suicidality, switch to mania, and sexual dysfunction was found. Serotonin syndrome appeared to be a very rare complication of fluvoxamine treatment. No signals for drug interactions unknown so far were identified. Withdrawal symptoms were observed in everyday clinical conditions, which were generally mild and resolved spontaneously. However, no cases suggestive for drug dependence have been reported. In conclusion, the data presented underlined that fluvoxamine offers a safe and well-tolerated option in the treatment of depression and obsessive-compulsive disorder.

A review of epidemiological studies on cancer in relation to the use of anti-ulcer drugs.

H2-receptor antagonists have been widely used since the late 1970s for the treatment of gastrointestinal ulcers and other benign conditions of the stomach, oesophagus and duodenum. Several case reports suggested that long-term therapy with H2-receptor antagonists, mainly cimetidine and ranitidine, might increase the risk of gastric cancer. After early case reports, at least six analytical epidemiological studies (two cohort and four case-control) were published, including a total of about 1000 cases of gastric cancer. The relative risks (RR) were systematically and substantially elevated in the first year since starting H2-receptor antagonist use, and levelled off in the following years. Some excess risk was still apparent during the first 5 years of drug use, probably due to incorrect diagnosis and treatment of pre-existing neoplastic gastric lesions, but the estimated RR was not above unity for > or = 10 years since starting drug treatment in the two studies including information on long-term use. The findings of analytical epidemiological studies are thus consistent with the absence of a causal association between H2-receptor antagonist use and gastric cancer risk. Data on oesophageal and colorectal cancer do not support a relevant relation between cimetidine use and the risk of these neoplasms. With reference to total cancer mortality, in a Danish cohort study, for males the RR was 1.9 in the first year, and 1.4 in the first 5 years; corresponding values for females were 1.7 and 1.5. In a British cohort study, the RR was 3.4 in the first year, and 1.3 in the years 2-10. The excess risk in the first year was essentially due to gastric cancer. Post-marketing surveillance data for omeprazole and other proton pump inhibitors are much scantier than for H2-receptor antagonists, particularly on long-term use.

Clozaril Labels to Add New Heart-Related Warning

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessClozaril Labels to Add New Heart-Related WarningJim RosackJim RosackSearch for more papers by this authorPublished Online:15 Mar 2002https://doi.org/10.1176/pn.37.6.0025The Food and Drug Administration (FDA) announced in late February that Novartis Pharmaceuticals Corp. had agreed to add a new section to the boxed warnings in the labeling of its atypical antipsychotic, Clozaril (clozapine). In addition, the entire boxed-warnings section has been moved to the front of the labeling insert in an effort to emphasize the relative dangers of prescribing the drug.The new section warns prescribers of the increased risk of patients on clozapine developing a potentially fatal myocarditis, most commonly in the initial three to six weeks of drug therapy. FDA officials said that the added warning further strengthens the recommendation that clozapine therapy be reserved for those patients whose schizophrenia has proven refractory to other approved treatments.Overall, according to postmarketing surveillance data from four countries, 82 cases of myocarditis have been reported in patients receiving clozapine. They have resulted in 31 deaths—a 38 percent mortality rate.The established incidence of myocarditis, according to the data, is 0.3 cases per 100,000 patient years of exposure to clozapine, with a fatality rate of 0.2 cases for 100,000 patient years. Although the incidence of myocarditis varies greatly between subgroups of the general population—for example, between children and the elderly—these rates represent an incidence among those taking clozapine of at least 17 times greater than the average of the overall general population and a mortality rate of at least 14 times greater than the general population.According to cardiologists consulted by Psychiatric News, the development of myocarditis may be difficult to diagnose in patients with schizophrenia who are being treated with clozapine.First of all, myocarditis in general presents with variable and usually vague symptoms. Most commonly patients have tachycardia, which has also been associated with patients on the drug who have no signs of myocarditis. Patients may experience palpitations. In patients whose heart muscle is inflamed, corresponding fatigue that is otherwise unexplained and shortness of breath are also common. Some patients may experience an atypical, hard-to-describe chest pain that could be referred to as dull, constant, or heavy. Fever, usually low grade, is often present, but may be entirely absent.In addition, cardiologists told Psychiatric News that patients with myocarditis may have an elevated white blood count and/or elevated erythrocyte sedimentation rate (ESR) and often show an enlarged cardiac silhouette on a chest X-ray. Some patients’ electrocardiograms may show nonspecific ST-T wave abnormalities.According to the new labeling, because tachycardia is the most common presenting symptom of myocarditis, patients who develop increased heart rates during the first month of clozapine therapy should be monitored closely for any other signs of developing myocarditis. If suspicion of myocarditis arises, clozapine should be discontinued immediately and a complete cardiac evaluation sought.Patients who develop clozapine-related myocarditis should not be restarted on the drug once the myocarditis resolves as postmarketing data also revealed the majority of cases recur upon reinitiation of the drug.Novartis and the FDA are urging psychiatrists to report any and all adverse events in patients taking clozapine to either the company’s surveillance program or the FDA’s MedWatch program, regardless of whether a direct connection to the medication is suspected.Adverse events in patients taking clozapine should be reported to Novartis (for those taking the Clozaril brand) at (800) 448-5938 or online at www.novartis.com. Reports involving both the Novartis brand and the available generic may be reported to the FDA’s MedWatch program by phone at (800) FDA-1080, by fax at (800) FDA-0178, or on the Web at www.accessdata.fda.gov/scripts/medwatch. ▪ ISSUES NewArchived

A critical review of the fluoroquinolones: focus on respiratory infections.

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin. Ciprofloxacin still maintains the best in vitro activity against Pseudomonas aeruginosa. Clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin display improved activity against anaerobes (e.g. Bacteroides fragilis) versus ciprofloxacin. All of the new fluoroquinolones display excellent bioavailability and have longer serum half-lives than ciprofloxacin allowing for once daily dose administration. Clinical trials comparing the new fluoroquinolones to each other or to standard therapy have demonstrated good efficacy in a variety of community-acquired respiratory infections (e.g. pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis). Limited data suggest that the new fluoroquinolones as a class may lead to better outcomes in community-acquired pneumonia and acute exacerbations of chronic bronchitis versus comparators. Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids). The new fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin) offer several advantages over ciprofloxacin and are emerging as important therapeutic agents in the treatment of community-acquired respiratory infections. Their broad spectrum of activity which includes respiratory pathogens such as penicillin and macrolide resistant S. pneumoniae, favourable pharmacokinetic parameters, good bacteriological and clinical efficacy will lead to growing use of these agents in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis. These agents may result in cost savings especially in situations where, because of their potent broad-spectrum activity and excellent bioavailability, they may be used orally in place of intravenous antibacterials. Prudent use of the new fluoroquinolones will be required to minimise the development of resistance to these agents.

Dental device–associated problems: An analysis of FDA postmarket surveillance data

The authors provide an analysis of dental device adverse event reports collected through the U.S. Food and Drug Administration's, or FDA's, mandatory and voluntary reporting programs between Aug. 1, 1996, and June 30, 1999. This study includes an analysis of the total number of dental device adverse events reported during the study period and uses descriptive statistics to depict reporters' occupations, types of adverse events (deaths, injuries, malfunctions), device categories, device problems and patient problems. A total of 272,241 device reports were received during the 35-month study period, 28,555 (10.5 percent) of which involved dental devices. Within these reports, two deaths (0.007 percent), 18,406 injuries (64.4 percent) and 9,942 device malfunctions (34.8 percent) were reported. The most commonly reported dental devices were endosseous implants, which represented more than 90 percent of all dental device reports. Most reports (84.1 percent) provided the reporter's occupation, and the most frequently cited occupation was dentist (76.3 percent), followed by dental assistant (4.2 percent). Dentists and dental staff members are a vital link in the FDA's adverse event reporting system and are encouraged to report device problems to the FDA MedWatch program.

Latest Industry Information on the Safety Profile of Levofloxacin in Japan

This paper focuses on the development of four major adverse drug reactions (ADRs) associated with some fluoroquinolones: convulsions, phototoxicity, cardiac effects, and hepatotoxicity. CNS adverse events have been linked to fluoroquinolone administration, including seizures, which are more likely with co-administration of NSAIDs. Only 61 cases of convulsions have been reported with levofloxacin, with 33 of those affected having received NSAIDs. The assumed rate of serious convulsions was as low as 1/65,000 with NSAIDs and 1/260,000 without NSAIDs. Levofloxacin has a very low phototoxicity-inducing potential confirmed by pre-clinical animal studies and the results of post-marketing surveillance (PMS). Pre-clinical results demonstrated that levofloxacin was 20 times less phototoxic than sparfloxacin and PMS data show that serious phototoxicity develops in only 1 in 1.8 million cases treated with levofloxacin. While many fluoroquinolones are associated with cardiac effects, pre-clinical data has shown that compared with sparfloxacin and grepafloxacin, levofloxacin has no effect on myocardial conduction. PMS data further support the safety of levofloxacin in this regard. While trovafloxacin is associated with serious hepatic problems, PMS data demonstrates that levofloxacin has a very low incidence of 1/100,000 hepatic effects. These results were confirmed in a prospective study that confirmed a low 1.3% incidence rate for all ADRs associated with levofloxacin.

Evaluation of Drug-Induced QT Interval Prolongation

Assessment of proarrhythmic toxicity of newly developed drugs attracts significant attention from drug developers and regulatory agencies. Although no guidelines exist for such assessment, the present experience allows several key suggestions to be made and an appropriate technology to be proposed. Several different in vitro and in vitro preclinical models exist that, in many instances, correctly predict the clinical outcome. However, the correspondence between different preclinical models is not absolute. None of the available models has been demonstrated to be more predictive and/or superior to others. Generally, compounds that do not generate any adverse preclinical signal are less likely to lead to cardiac toxicity in humans. Nevertheless, differences in likelihood offer no guarantee compared with entities with a preclinical signal. Thus, the preclinical investigations lead to probabilistic answers with the possibility of both false positive and false negative findings. Clinical assessment of drug-induced QT interval prolongation is crucially dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. An integral part of this is a precise heart rate correction of QT interval, which has been shown to require the assessment of QT/RR relationship in each study individual. The numbers of electrocardiograms required for such an assessment are larger than usually obtained in pharmacokinetic studies. Thus, cardiac safety considerations need to be an integral part of early phase I/II studies. Once proarrhythmic safety has been established in phase I/II studies, large phase III studies and postmarketing surveillance can be limited to less strict designs. The incidence of torsade de pointes tachycardia varies from 1 to 5% with clearly proarrhythmic drugs (e.g. quinidine) to 1 in hundreds of thousands with drugs that are still considered unsafe (e.g. terfenadine, cisapride). Thus, not recording any torsade de pointes tachycardia during large phase III studies offers no guarantee, and the clinical premarketing evaluation has to rely on the assessment of QT interval changes. However, since QT interval prolongation is only an indirect surrogate of predisposition to the induction of torsade de pointes tachycardia, any conclusion that a drug is safe should be reserved until postmarketing surveillance data are reviewed. The area of drug-related cardiac proarrhythmic toxicity is fast evolving. The academic perspective includes identification of markers more focused compared with simple QT interval measurement, as well as identification of individuals with an increased risk of torsade de pointes. The regulatory perspective includes careful adaptation of new research findings.

Manufacturer's drug interaction and postmarketing adverse event data: what are appropriate uses?

Governmental agencies overseeing pharmaceutical products use a risk/benefit approach to analyse data and make regulatory decisions. Comprehensive public dissemination of the safety profile of pharmaceutical products is part of an overall strategy for reducing risk associated with the use of any medical product. In the US, reports of postmarketing surveillance of approved drugs are in the public domain. Some, but not all, of the information in drug interaction studies is available to the public through the Freedom of Information Act (FOIA). However, there are concerns over the misuse of these data for commercial or other gain. The need to protect intellectual property and foster innovation in drug development, and concerns of legal liability are often cited as reasons to limit full public access to data from drug development studies. In contrast, intellectual freedom. public safety, and a mandate for transparent decision-making processes by regulatory agencies are issues that support open access to these data. Ultimately. concern for the public safety justifies open access to postmarketing surveillance data, and to a lesser degree, data regarding drug interactions in marketed products, and should outweigh the potential loss of competitive advantage by pharmaceutical companies.

Adverse Events Associated with Hepatitis B Vaccine in U.S. Children Less Than Six Years of Age, 1993 and 1994

PURPOSE: This study evaluated infrequent adverse reactions to hepatitis B vaccine by investigating the association of this vaccine with adverse health outcomes for U.S. children less than six years of age. The evaluation of the association between hepatitis B vaccine and chronic arthritis provides needed data, relevant to the Institute of Medicine's Report that there are inadequate data available to assess the causal relationship of hepatitis B vaccine to arthritis risk. METHODS: The 1993 ( n = 5505 children) and 1994 ( n = 6515 children) National Health Interview Survey (NHIS) datasets were analyzed to provide post-marketing surveillance data from probability samples of the U.S. population. Incident cases of adverse events were determined from the temporal association between the hepatitis B vaccination and the adverse events. Logistic regression modeling was used to adjust for potential confounding. RESULTS: Controlling for age, race, and gender simultaneously in the 1994 NHIS, hepatitis B vaccine was found to be associated with prevalent arthritis [odds ratio OR = 5.91 , 95% confidence interval CI = 1.05–33.14 ], incident acute ear infections (OR = 1.60, 95% CI = 1.00–2.58), and incident pharyngitis/nasopharyngitis (OR = 1.41, 95% CI = 0.95–2.09). CONCLUSIONS: Evidence from this study suggests that hepatitis B vaccine is positively associated with adverse health outcomes in the general population of US children.