Positive Rechallenge Research Articles

Drug-Induced Acute Pancreatitis: Underdiagnosis and Overdiagnosis

As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important [1, 2]. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis [3]. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence of a history of alcoholism, absence of imaging demonstrating gallstones (ultrasound and/or MRI), and a normal triglyceride level, it is reasonable to consider a drug as the cause of acute pancreatitis. When considering a particular medication as causing acute pancreatitis, often the first step is a literature search. Data from pharmaceutical companies and/or the Food and Drug Administration (FDA) is not helpful. Typically, these sources cite many medications as causing acute pancreatitis despite the fact that the evidence provided does not have sufficient detail as to demonstrate causation. Published case reports, if detailed properly, can give more definitive information as to the diagnosis of acute pancreatitis and whether other causes besides drugs have been properly ruled out. A recent thorough review of the literature found over 100 drugs implicated in causing acute pancreatitis [4]. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. The case reports are plagued by a combination of failing to provide the definitive diagnosis of acute pancreatitis and clarity in ruling out more common causes of acute pancreatitis such as alcoholism, gallstones, and hypertriglyceridemia. Due to problems in the literature, many patients with important causes of acute pancreatitis that need to be recognized such as gallstones, hypertriglyceridemia, and tumors, are falsely labeled as having drug-induced acute pancreatitis. This has resulted in the overdiagnosis of drug-induced pancreatitis. Conversely, some patients with idiopathic recurrent pancreatitis are not recognized as being on a medication that is causing their pancreatitis. This has resulted in the under-diagnosis of drug-induced pancreatitis. There have been multiple attempts to critically review the literature and determine which drugs have the best evidence as causing acute pancreatitis [4–7]. The more recent critical reviews [4, 7] utilize a classification system of the published case reports based on the level of evidence for each drug implicated as causing acute pancreatitis. Both of these reviews describe the best evidence of a particular drug causing acute pancreatitis if there is a either a positive rechallenge, a larger number of case reports for a particular drug and/or a consistent latency among the reports for a particular drug. A positive rechallenge is where the drug is stopped after a patient is found to have acute pancreatitis. After resolution of the pancreatitis, when the drug is restarted, acute pancreatitis develops again. This finding typically is reported as the clinicians caring for the patient made an error and did not blame the drug for causing acute pancreatitis. Despite a lack of a rechallenge, a drug may also be strongly suspected if there is a consistent latency among the case reports between initiating the drug and the onset of acute pancreatitis. A consistent latency may be a sign that the drug has a common mechanism of action. The Class I drugs, those with the most evidence causing acute pancreatitis, include mesalamine, amiodarone, S. Tenner (&) Medical Education and Research, Division of Gastroenterology, Maimonides Medical Center, Department of Medicine, State University of New York-Health Sciences Center, 2211 Emmons Ave, Brooklyn, NY 11235, USA e-mail: DrTenner@BrooklynGI.com

Interferon Alfa-associated Anterior Ischemic Optic Neuropathy

To report a possible association between interferon alfa therapy and anterior ischemic optic neuropathy (AION). Database study and review of the literature. Thirty-six case reports from spontaneous reporting systems and the literature. Case reports from a review of the literature were combined with spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the Food and Drug Administration looking for reports on interferon therapy associated with optic neuropathy. Data from the spontaneous reports include the type of interferon, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, systemic disease, and dechallenge and rechallenge data. Thirty-six case reports of AION are described in association with interferon alfa therapy. The average age of subjects was 54.5 years; 26 were male and 10 were female. The median duration of therapy to onset of AION was 4.5 months, with 50% of subjects having some form of permanent vision loss. Anterior ischemic optic neuropathy was bilateral in 67% of subjects. There are 3 positive rechallenge case reports. Interferon alfa's association with AION can be classified as "possible" using the World Health Organization classification system. If optic neuropathy is suspected, rapid cessation of interferon therapy may portend a better prognosis because multiple case reports indicate visual defects may be permanent if this possible ADR remains unrecognized.

Ulcérations des membres inférieurs sous sunitinib

Sunitinib is an antiangiogenic tyrosine kinase inhibitor indicated in the treatment of metastatic renal cancer and gastrointestinal stromal tumours (GIST). We report a case of leg ulcer apparently triggered by this drug and we discuss the potential implication of the antiangiogenic effect of sunitinib in ulcer genesis. A 73-year-old woman with a history of deep venous thrombosis of the lower limbs was treated with sunitinib for renal cancer with hepatic and pulmonary secondaries. While on this treatment, she developed painful ulcers of the right lower limb, despite having never previously presented leg ulceration. On discontinuation of sunitinib, the lesions improved, and resumption of this drug, even at a lower dosage, resulted in relapse of her ulcers. Although questions may legitimately be asked about the contribution of the patient's venous condition, withdrawal of sunitinib followed by a positive rechallenge tend to suggest the role of this drug in recurrence of ulcers. Their recurrence despite the decreased dosage of the drug points to a nondose-dependent pathogenic mechanism.

Carbamazepine-induced Pancreatitis With Positive Rechallenge

Carbamazepine-induced Pancreatitis With Positive Rechallenge

A Phase I Dose Escalation Study of Steroid Sulfatase Inhibitor BN83495/STX64 in Postmenopausal Women with ER Positive Breast Cancer.

Abstract Background: BN83495/STX64 is an irreversible steroid sulfatase (STS) inhibitor blocking the hydrolysis of sulfated estrone E1S and dehydroepiandrosterone DHEAS to their unsulfated active forms and thereby preventing conversion to Estradiol (E2) and Androstenediol (adiol), respectively. A phase I dose escalation study was conducted in post-menopausal women (PW) with ER+ metastatic breast cancer (MBC). The aim of the study was to determine the optimal biological dose (OBD) defined as the dose at which STS inhibition in peripheral blood mononuclear cells (PBMCs) ≥ 95% after 7 (D7) and 28 (D28) days of repeated oral daily administration and which also showed a maximal reduction in plasma E2 and adiol levels at D28 with no drug-related Grade 3 (Gr 3) or higher toxicity. Pharmacokinetics (PK), safety, tolerability and anti-tumour activity of BN83495 were also assessed.Methods: Patients (pts) had received at least one line of hormone therapy (HT) and at most 2 lines of chemotherapy (CT) in the adjuvant and/or advanced disease setting. Three to six pts were recruited into each of 5 sequential dose cohorts (1, 5, 20, 40 and 80 mg). The steady-state PK of BN83495 were assessed in all pts. Serum concentrations of E2 and Adiol were determined pre-dose, on D7 and D28 by HPLC-MS/MS analysis. Objective antitumor response was assessed according to RECIST criteria (version 1.0).Results: 29 pts were evaluable for safety. All had received one prior HT for MBC (Aromatase Inhibitors (AI): 86.2% Tamoxifen: 13.8%) and 12 (41.4%) received 2 lines of HT for MBC. BN83495 was well tolerated at doses up to 40 mg. Gr 3 fatigue with positive rechallenge was observed after 3 months of treatment in one pt at 80 mg. The main toxicity was dry skin Gr≤2 (N=12) that was observed in some pts in all cohorts from 20 mg up and was treated with emollient creams. Other toxicities included Gr 1/2 fatigue (N=6), hot flushes (N=3) and nausea (N=2).27 pts were evaluable for efficacy and hormone and STS evaluation. 14 pts received ≥ 3 months treatment. There were 3 SD ≥ 6 months, one each at 13 months (#020, 40 mg), 8 months (#015, 20 mg) and 7 months (#027, 80 mg, hormone resistant pt). Biopsy-proven erythematous skin infiltration in one patient (#027) was no longer visible after 1 month of treatment. Nearly complete STS enzyme inhibition was observed at all doses. The OBD was determined to be 40 mg. At this dose, mean Adiol reduction was -54.0% (-74.0—34.0) and E2 was –27.4% (-47.6- -7.2).An additional cohort (6 pts) was enrolled at 40 mg and FDG PET-scan was performed. Decrease >25% in hypermetabolic volume was noted in 2/5 lesions in 2 patients for whom data are available.Conclusion: BN83495 was well tolerated. Disease stabilizations ≥ 6 months were observed in this heavily pre-treated population including in one hormone resistant pt. The OBD was determined to be 40 mg. Complete FDG-PET scan data will be presented. Based on data obtained so far, BN83495 has shown activity. The study is ongoing. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4097.

Rechallenge in drug-induced liver injury: the attractive hazard

Progress in the understanding of drug-induced liver injury (DILI) is clearly hampered by the lack of specific markers of the disease. In this scenario, recrudescence of the liver injury upon re-exposure to the suspicious drug is considered the more reliable evidence of DILI. On-purpose re-exposure, however, entails both practical and ethical issues because the bulk of situations in clinical practice are non-immunoallergic DILI in which a provocation test frequently would give negative results. Besides, deliberate re-exposure with a drug that is not considered vital or essential is potentially harmful and, hence, hardly justified in DILI, and rechallenge is more commonly described in an unintentional basis. The causes, characteristics and consequences of rechallenge have been specifically addressed recently. For causality assessment, a positive rechallenge test carries the strong value, and is accordingly scored by clinical algorithms. Such clinical scales, however, reward drugs that are associated with a positive rechallenge response, but might be considered biased against those where re-administration fails to elicit a response or, more commonly, for which no rechallenge is attempted.

Neonatal Parenteral Nutrition Hypersensitivity: A Case Report Implicating Bisulfite Sensitivity in a Newborn Infant

This report describes a case of parenteral nutrition hypersensitivity in a 37 weeks' gestation infant with congenital diaphragmatic hernia complicated by bowel necrosis and functional short bowel syndrome. The patient developed a rash with subsequent urticaria beginning on the 50th day of life. The reactions were confirmed with a positive rechallenge. After the amino acid solution was replaced with a non-bisulfite-containing product, the infant was able to continue to receive nutrition support through parenteral nutrition without recurrence of symptoms. It is speculated that the bisulfite additive in the amino acid solution may have interacted with the lipid emulsion to sensitize the patient.

Recent Developments in Acute Pancreatitis

The incidence of acute pancreatitis (AP) has been increasing worldwide, but the major etiologies remain gallstones and alcohol. Several studies have reported that smoking is an independent risk factor for developing AP. Classification of AP has traditionally used the categories of mild and severe disease. However, a new intermediate category of moderately severe AP has been described with intermediate characteristics including a high incidence of local complications but a low mortality. Assessment criteria that can serve as early predictors of AP severity are often complex and not sufficiently accurate. However, several recently described criteria that rely on criteria such as the body mass index, physical findings, and simple laboratory measurements could prove useful if validated in large prospective studies. Many issues related to the therapy of AP are still unresolved. Although preliminary studies support the importance of early volume expansion for the treatment of acute pancreatitis, optimization of the amount and type of fluids will require further studies. Similarly, preliminary studies suggest that enteral nutrition might benefit patients with AP and could even be useful early in the course of disease. However, the timing and type of fluids as well as the intestinal infusion site require further study. Finally, issues related to the prophylactic use of antibiotics in patients with severe AP have not been resolved. While the process of clinical investigation moves slowly, progress has been made in clinical studies of AP.

Recurrent dysosmia induced by pyrazinamide

Pyrazinamide can have adverse effects such as hepatic toxicity, hyperuricemia or digestive disorders. In rare cases, alterations in taste and smell function have been reported for pyrazinamide when combined with other drugs. We report a case of reversible olfactory disorder related to pyrazinamide in a woman, with a positive rechallenge. The patient presented every day a sensation of smelling something burning 15 min after drug intake. Dysosmia disappeared completely after pyrazinamide withdrawal and recurred after its rechallenge. The case was reported to the Tunisian Centre of Pharmacovigilance.

Diplopia and Fluoroquinolones

To report a possible association between fluoroquinolones and diplopia. Database study. A total of 171 subjects were studied. Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, World Health Organization, and Food and Drug Administration were collected on fluoroquinolones and diplopia. Data garnered from the spontaneous reports include the type of fluoroquinolone, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data. A total of 171 case reports of diplopia associated with fluoroquinolones were reported, including 76 men, 91 women, and 4 case reports in which the gender was not specified. The median age was 51.6 years. Dosage varied between the different fluoroquinolone drugs, with the median dosage within the range recommended in the package insert for each different fluoroquinolone. Median time from beginning of therapy to appearance of the ADR was 9.6 days (range 1 day to 5 months). Seventeen subjects also had concomitant tendinitis, 49 patients were 60 years or older, 1 patient had renal cysts, and 4 patients were taking systemic anti-inflammatory steroids. There were 53 positive dechallenge and 5 positive rechallenge case reports. According to World Health Organization criteria, the relationship between fluoroquinolone therapy and diplopia is "possible." This causality assessment is based on the time relationship of drug administration and ADR development, the multiple positive dechallenge and rechallenge reports, and the plausible mechanism by which diplopia could occur: possible tendinitis of the extraocular muscles. Proprietary or commercial disclosure may be found after the references.

Sandostatin causing reversible thrombocytopenia

Esophageal variceal bleeding can be serious or life threatening. Drug-induced thrombocytopenia can further complicate such bleeding episodes. Thrombocytopenia because of sandostatin has been reported in the literature only once previously. We describe a case of sandostatin-induced reversible thrombocytopenia with a positive rechallenge. Platelet count decreased during administration of sandostatin and recovered only when the infusion was halted. The proposed mechanism of thrombocytopenia during both episodes is immunologic. Physician awareness of sandostatin-induced thrombocytopenia can prevent unnecessary complication during episodes of esophageal variceal bleeding and is rapidly reversed with discontinuation of the drug.

Drug-induced liver injury following positive drug rechallenge

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury. Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88 cases met inclusion criteria for analysis. Mean age was 44 years (range 0.5–83) and 56% were male. A broad spectrum of suspect drugs were identified. Many patients exhibited hepatitis symptoms or jaundice on the initial and rechallenge liver event. Twelve patients (14%) exhibited clinically worrisome severe hepatocellular injury and jaundice on either initial or rechallenge event and two died, reflecting a 2.3% fatality rate in those with positive rechallenge. The two fatalities developed severe hepatocellular injury with jaundice only upon rechallenge. Liver injury recurred in most rechallenges. Improved identification and communication of possible drug-induced liver injury is needed to avoid potentially serious and/or fatal drug rechallenges. Clinicians should generally avoid such rechallenges.

Hepatotoxicity from green tea: a review of the literature and two unpublished cases

To review the current literature on suspected green tea-related hepatic reactions and to describe two new cases reported within the framework of the Italian surveillance system of natural health products. A literature search of publication between 1999 and October 2008 retrieved 34 cases of hepatitis. Histological examination of the liver revealed inflammatory reactions, cholestasis, occasional steatosis, and necrosis. A positive dechallenge was reported in 29 cases. There was one reported death. A positive rechallenge occurred in seven cases (20%). In the two new cases, the causality assessment was judged as "possible" according to the RUCAM score. Our analysis of the published case reports suggests a causal association between green tea and liver damage. The hepatotoxicity is probably due to (-)-epigallocatechin gallate or its metabolites which, under particular conditions related to the patient's metabolism, can induce oxidative stress in the liver. In a few cases, toxicity related to concomitant medications could also be involved.

Diplopia, Blepharoptosis, and Ophthalmoplegia and 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor Use

To report the association between 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) and diplopia, blepharoptosis (ptosis), and ophthalmoplegia. Database study. Two hundred fifty-six subjects studied. Spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO), and the Food and Drug Administration were collected on statins and ptosis, diplopia, and ophthalmoplegia. Data garnered from the spontaneous reports include the type of statin, age, gender, adverse drug reaction (ADR), dosage, duration of therapy until onset of ADR, concomitant drugs, other systemic disease, and dechallenge and rechallenge data. Two hundred fifty-six case reports of ptosis, diplopia, and ophthalmoplegia associated with statins were reported, including 143 males, 91 females, and 22 case reports where the gender was not specified. The average age was 64.5+/-10 years. Dosage varied between the different statin drugs, with the average dosage within the range recommended in the package insert for each different statin. Average time from beginning of therapy to appearance of the ADR was 8.3+/-1.5 months (range, 1 day-84 months). Seven patients were taking 2 statin drugs and 5 also were taking gemfibrozil. Nine patients had diabetes mellitus. A total of 23 case reports described total ophthalmoplegia. Ptosis was reported alone 8 times and in conjunction with diplopia 18 times. There were 62 positive dechallenge and 14 positive rechallenge case reports. According to WHO criteria, the relationship between statin therapy and diplopia, ptosis, or ophthalmoplegia is possible. This causality assessment is based on the time relationship of drug administration and ADR development, the multiple positive dechallenge and rechallenge reports, and the plausible mechanism by which diplopia, ptosis, or ophthalmoplegia may occur: myositis of the extraocular muscles, the levator palpebrae superioris muscles, or both. Proprietary or commercial disclosure may be found after the references.

Isoniazide-Induced Pancreatitis

Purpose: Introduction: Isoniazid (INH) is the most commonly used agent for treatment and chemoprophylaxis of tuberculosis. Isoniazid adverse reactions include hepatitis and peripheral neuropathy. We are reporting a case of isoniazid-induced pancreatitis. Case report: We are reporting a 60 year African-American Male who presented with epigastric pain and anorexia for two weeks. Past medical history included diabetes and hypertention. He denied a history of drug or alcohol abuse. One week before his symptoms started, he had a positive PPD test during routine pre-employment physical exam. A chest x-ray was negative for active disease and the patient was started on 300 mg of INH daily. In addition, the patient was taking Lisinopril and Insulin. On Physical exam, the patient had severe epigastric tenderness on palpation. On laboratory testing: Amylase 354 u/L, lipase 386 u/L, alkaline phosphates 103 u/L, AST 58 u/L, ALT 46 u/L, calcium 9.6 mg/dl and serum triglyceride 439 mg/dl. A CT scan of the abdomen showed normal biliary system. An INH-induced pancreatitis was suspected based on diagnosis of exclusion of other causes of acute pancreatitis. The patient was admitted to the hospital and INH was held. Patient's symptoms improved within 12 hours and totally resolved at 48 hours. At the time of discharge, serum amylase and lipase were 217 and 156 respectively. Patient was discharged from the hospital within 2 days of admission and asked to avoid INH in the future. Discussion: Over the past 50 years, INH has been the 1st line of treatment and chemoprophylaxis of tuberculosis. Anti-tuberculos-therapy-induced pancreatitis has been reported in the past and attributed mostly to rifampicin. However, INH has been incriminated as a cause of pancreatitis in few case reports. Based on a review of the literature, patients with INH-induced pancreatitis usually present within a few hours to 3 weeks of introduction of Isoniziad. They respond well to withdrawal of the drug and patients may recover anytime between 2 to 14 days. INH as a cause for pancreatitis can be classified as class Ia i.e. at least 1 case reported with positive re-challenge, excluding all other causes. Re-challenge was not attempted with our patient for obvious safety reasons. Other causes of acute pancreatitis were also excluded, including medications other than INH. Thus, INH was a “probable” cause of this patient's pancreatitis. Pancreatitis should be listed as a potential adverse reaction to isoniazid treatment and treating physicians should always include this medicine in the differential diagnosis of pancreatitis patients receiving anti-tuberculosis therapy.

An unusual systemic reaction associated with topical salicylic acid in a paediatric patient

Nongenital warts are generally harmless, self-limiting and often recover spontaneously; existing treatments usually require months to induce healing and recurrence is common [1]. Topical salicylic acid is widely use in wart removal; however, although generally well tolerated, it may elicit both local and systemic manifestations [2, 3]. Serious reactions to topical salicylate preparations so far reported are usually ascribed to percutaneous absorption of excessive amounts of salicylate ointment [3]. Here we present an unusual case of serious systemic illness arising in a child after the application of salicylic acid patches for a plantar wart. Parents sought advice for their 9-year-old son, after he had been complaining for 2 weeks of abdominal pain, nausea, constipation, increasing weakness and general illness. The abdominal pain started 2 days after beginning daily topical application of 15% salicylic acid patches (3.75 mg, 6 mm) for a plantar wart, and it was followed by the other symptoms a few days later. Familiarity with atopy, personal history of previous atopic dermatitis, food allergy, asthmatic bronchitis and cutaneous eruptions following clarithromycin administration were reported by his parents. Laboratory data (haemocrome, creatininaemia, glycaemia, transaminases, amylase, antitransglutaminase IgA, anti-Helicobacter pylori IgG) were normal except for IgE levels (53 kU l−1, normal values < 25 kU l−1). Stool samples were negative for common gastroenteritis agents (Salmonella, Shigella, Campylobacter, Rotavirus, Adenovirus, common parasites) and for occult blood. Instrumental examinations (abdominal ecosonography and X-ray) showed delayed gastric empting and coprostasis. After 3 weeks of unsuccessful therapy with domperidone and fleet enemas, the general condition significantly worsened with the appearance of mildly impaired mental performance. Symptoms considerably improved only a few days after the suspension of salicylate patch application (1 month after the beginning of treatment) and worsened again a couple of days later, when a new patch was applied for a relapsing wart. Definitive cessation of the topical treatment was followed by progressive improvement of the patient's condition and symptoms completely disappeared within 2 weeks. To the best of our knowledge, this is the first report of such a systemic clinical picture occurring after the application of salicylic acid-containing patches. Although the clinical picture described is complex and unusual, the close temporal relationship between patch application and occurrence of symptoms, together with positive dechallenge and rechallenge and with the exclusion of any other alternative explanation (e.g. gastroenteritis, coeliac disease, other drugs), strongly supports topical preparation as the causative agent of the adverse reaction. Salicylates can be absorbed percutaneously, and wounded skin can increase local and systemic concentrations [3]. In this case, however, the reaction may not necessarily have been triggered by systemic exposure, also in view of the very low amount of salicylic acid contained (3.75 mg) and the small diameter (6 mm) of the patches. Even though nausea and epigastric pain in our patient may be consistent with salicylism, only routine examinations were performed in view of the medium clinical severity of symptoms. Glycaemia was normal, whereas electrolyte balance, acid-base status, and serum salicylate levels were not evaluated. Nonetheless, other common features of salicylism, such as sweating, tinnitus, blurring of vision and tachypnoea, were not observed, therefore, systemic toxicity was deemed unlikely. Salicylic acid may also evoke pseudoallergic (‘salicylate intolerance’) reactions, which are non-immunological reactions related to overproduction of leukotriene metabolites and impaired prostaglandin (PG) synthesis due to cyclooxygenase-1 inhibition [4]. Interestingly, clinical evidence indicates that both food allergy and its non-immunological form, food intolerance, may be associated with abdominal pain, constipation and coprostasis [5, 6], the main symptoms observed in our patient. Moreover, non steroidal anti-inflammatory drug (NSAID) use may be a risk factor for chronic constipation, probably due to the inhibition of PG synthesis [7]. Thus, also in view of our patient's atopic profile, which is considered a risk factor for NSAID hypersensitivity [8], we interpreted the clinical picture as a pseudoallergic reaction to topical salycilate involving the gastroenteric tract. The parents were advised not to use any salicylic acid preparation for their son, either topical or systemic, and, in case of need, to choose paracetamol as a safe alternative, since it had been used previously in this subject and was well tolerated. In conclusion, considering the usually benign nature as well as the high rates of spontaneous remission, the risks and benefits of topical salicylate in the treatment of nongenital warts should always be carefully evaluated.

Hepatic Events Associated with Atomoxetine Treatment for??Attention-Deficit??Hyperactivity Disorder

This study describes and assesses potential hepatobiliary events related to atomoxetine therapy, as reported in clinical trials and as spontaneous adverse event reports post-launch in 2002. Case reports that contained potential hepatobiliary events were identified by a computerized search of the Eli Lilly and Company atomoxetine spontaneous adverse events and clinical trials databases. All cases were reviewed by at least two company physicians, one with expertise in hepatology, to determine the relevance of the information in respect of potential liver toxicity. Of 7961 paediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as having hepatobiliary events requiring additional analysis. Most of these events were mild increases in ALT and AST levels. None of these cases met Hy's rule criteria or progressed to liver failure. During the 4 years after market launch, 351 spontaneous reports of adverse events were related to the liver, of which 69 had other explanations unrelated to atomoxetine. Of the remaining 282 cases, 133 contained possible confounding factors (and were deemed to be possibly related), 146 presented too little information to assess, and three suggested atomoxetine as a probable cause of liver injuries. One of the three had a positive rechallenge. All three patients recovered after discontinuation of the drug. Since the launch of atomoxetine therapy, three spontaneously reported cases of reversible drug-induced liver injury were deemed probably related to it. Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury and should not be restarted.

Statin-Associated Psychiatric Adverse Events

The inhibitors of HMG-CoA reductase ('statins') are widely prescribed hypolipidaemic drugs, which have been evaluated in several clinical trials involving hundreds of thousands of patients. From a safety perspective, both clinical trials and post-marketing surveillance have demonstrated that statins are generally well tolerated, with rare serious adverse drug reactions (ADRs) that affect mainly muscle, liver and kidney. However, recent interest has been focused on a potential risk of psychiatric ADRs associated with statins, including memory loss, depression, suicidality, aggression and antisocial behaviour. Special attention is currently being paid to the potential for statin-induced sleep disorders. To investigate the hypothesis that statins may be associated with psychiatric adverse events using quantitative and qualitative signal analysis. The Interregional Group of Pharmacovigilance database holds reports of suspected ADRs submitted since 1988 from eight Italian regions. In the present analysis, only reports ranked at least 'possible', according to WHO causality assessment criteria, were considered. Association between statins and psychiatric events was assessed by the case/non-case methodology, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. Cases were defined as patients with at least one reported ADR combined with the system organ class (SOC) 'psychiatric disorders'. The non-cases comprised all patients who did not experience an ADR related to the SOC 'psychiatric disorders'. Index reports comprised all ADR reports involving at least one statin, while all ADR reports not involving statins as suspected drugs were used as controls. According to selection criteria, 35,314 reports were included in the analysis. A total of 71 psychiatric preferred terms combined with statins were identified in 60 reports. Among them, 14 reports (23.3%) noted a positive rechallenge. Both the unadjusted (0.8; 95% CI 0.6, 1.1) and adjusted ROR (0.7; 95% CI 0.6, 1.0) suggested a lower rate of reports of psychiatric events for statins as a whole class compared with all other drugs, although the difference was not significant. The five most frequently reported psychiatric events combined with statins were insomnia, somnolence, agitation, confusion and hallucination. Only insomnia was reported with higher frequency for statins compared with all other drugs (ROR = 3.3; 95% CI 1.9, 5.7), while confusion was reported with a lower frequency (ROR = 0.4; 95% CI 0.1, 0.9). Amongst statins available in Italy, only simvastatin (ROR = 0.5; 95% CI 0.2, 0.9) showed a significantly lower rate of reports of psychiatric events compared with all other drugs together. A relatively small number of possible statin-associated psychiatric ADRs have been found in our database. No significant risks for a higher overall reporting of psychiatric ADRs associated with statins were identified in comparison with all other drugs combined. However, statin-associated insomnia resulted in a significant ROR that requires further investigation.

Drug-Induced Acute Pancreatitis

Drug-Induced Acute Pancreatitis

Long-Term Treatment with Deferasirox (Exjade®, ICL670), a Once-Daily Oral Iron Chelator, Is Effective in Patients with Transfusion-Dependent Anemias.

Background: The efficacy and safety of deferasirox was established during five 1-year core trials. As many patients will require lifelong chelation therapy, assessing long-term efficacy and safety is important. In the core trials, initial doses were assigned by baseline liver iron concentration (LIC). A clear dose response was observed: 5/10 mg/kg/d doses were generally insufficient to balance iron intake from ongoing transfusions, while 20 and 30 mg/kg/d maintained or reduced iron balance, respectively. This analysis evaluates serum ferritin (SF) levels and cumulative safety data during 4-year extension trials.Methods: In the extensions, dose modifications were based on safety and efficacy parameters. Safety and SF were assessed monthly. Due to methodological differences in study 105, the SF data from this trial are not included in this analysis.Results: 1034 patients with β-thalassemia (n=750), sickle cell disease (n=185), MDS (n=47) and other anemias (n=52) have received deferasirox. 703 patients received deferasirox in the core trials and have been on treatment for a median of 3.4 years; 331 crossed over to deferasirox in the extensions. 210 (20%) patients have discontinued treatment due to: AEs (74), consent withdrawal (64), unsatisfactory therapeutic effect (29) and other (43). Only 17 (1.6%) patients have discontinued in the past 12 months (9 AEs; 1 death; 4 lost to follow-up; 2 withdrew consent; 1 other). 16 patients have died, 6 in the core and 10 in the extensions. 5 patients (4 β-thalassemia, 1 sideroblastic anemia) aged 18-24 years with inadequate chelation and severe iron overload before study entry died with cardiac failure in the extensions. Other deaths were due to other complications/progression of the underlying disease. At month 42, mean (SD) dose in the 5/10, 20 and 30 mg/kg/d dose groups was 21.8 (9.3), 23.2 (8.2) and 25.4 (9.8) mg/kg/d, respectively. Median SF levels (ng/mL) are shown in the Table (n=652, deferasirox cohort only).Drug-related AEs during deferasirox treatment were generally transient, of mild/moderate severity, and showed a reduction in frequency from the core trials. No patient has developed progressive increases in serum creatinine or values >2 x ULN. 2 patients discontinued due to stable creatinine increases of 1.5 x ULN and confounding circumstances (concomitant cyclosporine and multiple infections, respectively). 1 patient discontinued due to recurrent episodes of proteinuria. 12 patients discontinued due to increases in transaminases (4 core study, 8 extension [3 crossover patients]). Drug-induced liver toxicity was likely in 2 patients with early onset and positive rechallenge. Increasing LIC due to under-chelation was the likely explanation in at least some patients.Conclusions: Over 3.5 years' treatment, deferasirox 20/30 mg/kg/d maintained/reduced SF levels in patients with various transfusion-dependent anemias. There was no increase in frequency of drug-related AEs or changes in markers of liver or renal function that differed significantly from the 1-year core trials.Initial dose, mg/kg/dMonth5/10 (n=227)20 (n=182)30 (n=243)Baseline20512375373412*265021612649242481250822713614391844207142134516672025*Dose adjustments