topiramate and Drug-Related-Side-Effects-and-Adverse-Reactions

Although the association between CGRP and migraine disease is well-known and studied, therapies can target other pathways to minimize migraine symptoms. It is important to understand the role of these medications as options for migraine treatment and the varied mechanisms by which symptoms can be addressed. In the present investigation, the role of non-CGRP antagonist/non-triptan options for migraine disease therapy is reviewed, including NSAIDs, ß-blockers, calcium channel blockers, antidepressants, and antiepileptics. Pharmacologic therapies for both acute symptoms and prophylaxis are evaluated, and their adverse effects are compared.. At present, the Food and Drug Association has approved the beta-blockers propranolol and timolol and the anti-epileptic drugs topiramate and divalproex sodium for migraine prevention. Clinicians have other options for evidence-based treatment of episodic migraine attacks. Treatment decisions should consider contraindications, the effectiveness of alternatives, and potential side effects. NSAIDs are effective for the acute treatment of migraine exacerbations with caution for adverse effects such as gastrointestinal upset and renal symptoms. Beta-blockers are effective for migraine attack prophylaxis but are associated with dizziness and fatigue and are contraindicated in patients with certain co-morbidities, including asthma, congestive heart failure, and abnormal cardiac rhythms. Calcium channel blockers do not show enough evidence to be recommended as migraine attack prophylactic therapy. The anti-epileptic drugs topiramate and divalproex sodium and antidepressants venlafaxine and amitriptyline are effective for migraine exacerbation prophylaxis but have associated side effects. The decision for pharmacologic management should ultimately be made following consideration of risk vs. benefit and discussion between patient and physician.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Calcium Channel Blockers; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Propranolol; Serotonin 5-HT1 Receptor Agonists; Topiramate; Tryptamines; Valproic Acid

To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy.. We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded.. A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin.. The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.

Topics: Adult; Anticonvulsants; Child; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Male; Sex Characteristics; Topiramate; Vigabatrin

Relative to migraine generally, chronic migraine (CM) imposes greater disability, healthcare utilization and socioeconomic burden. Six therapies currently possess a credible evidence base for prevention/suppression of CM. This review is intended to provide an assessment of their relative utility, defined as a blend of safety, tolerability and efficacy, focusing in particular on their safety and tolerability.Areas Covered: We discuss all six medications currently FDA-approved for migraine prevention which also specifically possess credible evidence of efficacy in treating CM. While we do address the efficacy of each, our primary emphasis involves assessment of safety and tolerability data derived from clinical trials and post-marketing experience.Expert Opinion: Recent research involving CM has led to the identification of highly targeted and typically well-tolerated therapies. For patients who experience obstacles to accessing these newer therapies, topiramate is available as an evidence-based alternative, but contraindications, drug-drug interactions and poor tolerability may limit or prevent its use. Although data to support such intervention presently is limited, clinically challenging CM cases may benefit from combination therapy. 'Real world' studies are needed to evaluate such polytherapy, along with studies intended to assess the long-term safety of the individual therapies and their use during pregnancy and breast-feeding.

Topics: Chronic Disease; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Topiramate

A generalized tonic-clonic seizure (GTCS) is the most severe form of common epileptic seizure and carries the greatest risk of harm. The aim of this review is to provide an evidence-based guide for the selection of antiepileptic drugs (AEDs) for patients with GTCSs. Eight AEDs are approved in Europe and the USA for the treatment of both primarily GTCSs (PGTCSs) and secondarily GTCSs (SGTCSs) and are considered in this paper.. Each AED is evaluated using five criteria: (1) efficacy, by seizure type (a: PGTCSs and b: SGTCSs); (2) adverse effects; (3) interactions; (4) adherence and dosing; and (5) mechanism of action (MOA). To ensure the inclusions of robust data, only efficacy data accepted by regulatory authorities were considered, and data related to adverse effects, interactions, adherence, and MOA were all extracted from UK Summaries of Product Characteristics (SPCs).. (1a) There is class 1 evidence of the efficacy of only four AEDs in controlling PGTCSs (lamotrigine, levetiracetam, perampanel, and topiramate). (1b) There is no class 1 evidence of the efficacy of any AED in SGTCSs although some evidence from pooled/subgroup analyses or meta-analyses supports the use of the four AEDs (levetiracetam, perampanel, topiramate, and with less robust data for lamotrigine). (2) AEDs are associated with different, but to some extent overlapping, common adverse effect profiles but have differing idiosyncratic adverse effects. (3) Pharmacokinetic interactions are seen with most, but not all, AEDs and are most common with carbamazepine and phenytoin. (4) Good adherence is important for seizure control and is influenced by frequency of dosing, among other factors. (5) Mechanism of action is also a consideration in rationalising AED selection when switching or combining AEDs.. Ultimately, the choice of AED depends on all these factors but particularly on efficacy and adverse effects. Different patients will weigh the various factors differently, and the role of the treating physician is to provide accurate information to allow patients to make informed choices.

Topics: Anticonvulsants; Benzodiazepines; Carbamazepine; Drug and Narcotic Control; Drug-Related Side Effects and Adverse Reactions; Humans; Lamotrigine; Levetiracetam; Nitriles; Phenytoin; Pyridones; Seizures; Topiramate; Treatment Outcome

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents.. The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel.. The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.

Topics: Acetazolamide; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Antibodies, Monoclonal; Anticonvulsants; Antineoplastic Agents; Benzodiazepines; Carbonic Anhydrase Inhibitors; Celecoxib; Clinical Trials as Topic; Contraindications; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Isoxazoles; Methazolamide; Phenobarbital; Sulfanilamide; Sulfanilamides; Sulfonamides; Sulfonic Acids; Thiazines; Thiophenes; Topiramate; Zonisamide

In 2014 we have 4 new weight loss medications and one older medication with very different mechanisms of action – all approved for chronic weight management. Each medication has its own unique risk profile that makes patient selection important. Knowledge of the contraindications and safety issues can guide physicians to the most appropriate choice for a particular patient. Obesity medicine is entering a new era where our available options for prescribing have been very well studied. There should be no surprises, because bupropion, naltrexone, phentermine, topiramate and liraglutide have been prescribed for many years in millions of patients and lorcaserin has high specificity for a single receptor subtype. The FDA demanded very detailed risk-oriented studies to have these medications approved. In addition, the FDA has established REMS programs or risk management strategies to help ensure that the patients do not receive inappropriate medications. These medications were approved by the US FDA after very thorough testing. The decision to approve these medications was based on the benefits out-weighing the risks. Thus, if following the appropriate guidelines according to package labels, the practitioner can feel safe in prescribing these medications.

Topics: Anti-Obesity Agents; Benzazepines; Bupropion; Delayed-Action Preparations; Drug-Related Side Effects and Adverse Reactions; Drugs, Investigational; Fructose; Glucagon-Like Peptide 1; Humans; Liraglutide; Naltrexone; Obesity; Phentermine; Topiramate; United States; United States Food and Drug Administration; Weight Loss

Worldwide obesity prevalence has nearly doubled since 1980. Due to numerous co-morbidities, obesity represents a serious health and socioeconomic problem worldwide. Pharmacotherapy should be an integral part of comprehensive obesity management. Drug therapy can assist in weight loss and its maintenance in those individuals who do not achieve appropriate weight loss through lifestyle interventions alone. After the withdrawal of sibutramine from the market in 2010, orlistat, a lipase inhibitor, was the only remaining prescription drug approved for the long-term treatment of obesity. In 2012, phentermine/topiramate extended-release (PHEN/TPM ER) combination and lorcaserin were approved by the US FDA as novel medications for long-term weight management. Three major phase III trials conducted with each drug confirmed their efficacy in terms of weight loss/maintenance and improvement of cardiometabolic risks. No head-to-head studies between the two new anti-obesity drugs have been carried out. However, in the existing studies PHEN/TPM ER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin. Both drugs were well-tolerated, and adverse events were modest in intensity, dose dependent, rather rare, and tended to decrease with the duration of treatment. Major safety concerns regarding PHEN/TPM ER include elevations in resting pulse rate, teratogenicity, mild metabolic acidosis, and psychiatric and cognitive adverse events. Valvulopathy, cognitive impairment, psychiatric disorders, and hypoglycemia represent major safety concerns for lorcaserin. Although existing trials have not demonstrated any significant issues with PHEN/TPM ER-induced heart rate elevation and lorcaserin-induced valvulopathy, all safety concerns should be seriously taken into account in patients treated with either of these novel anti-obesity medications.

Topics: Anti-Obesity Agents; Benzazepines; Benzoxazines; Bupropion; Chemistry, Pharmaceutical; Drug-Related Side Effects and Adverse Reactions; Fructose; Glucagon-Like Peptide 1; Humans; Liraglutide; Naltrexone; Obesity; Phentermine; Topiramate

Migraine is a widespread disorder. Migraine patients experience worse health-related quality of life than the general population. The availability of effective and tolerable treatments for this disorder is an important medical need. This narrative review focuses on the clinical pharmacology of topiramate, an antiepileptic drug that was approved for the prophylaxis of migraine where it should act as a neuromodulator.. A PubMed database search (from 2000 to 24 January 2011) and a review of the human studies published on topiramate and migraine was conducted.. Topiramate is an important option for the prophylaxis of migraine and is of proven efficacy and tolerability. It has also been studied in chronic migraine with encouraging results, even in patients with medication overuse. However, in migraine prevention its efficacy is comparable to the other first-line drugs and there are no published trials with a superiority design which can establish topiramate's role in the available therapeutic armamentarium.

Topics: Anticonvulsants; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Migraine Disorders; Time Factors; Topiramate

To compare adverse drug reactions (ADRs) to topiramate in patients with migraine and patients with epilepsy, we systematically reviewed all published randomized controlled trials (RCTs) that compare topiramate monotherapy in epilepsy and migraine. We included four epilepsy RCTs (N = 1,179 patients; vs. active comparators) and six migraine RCTs (N = 1,723 patients; vs. placebo). Behavioral ADRs and headache were found only in the case of epilepsy, whereas cognitive complaints and alteration of taste were found only in the case of migraine. The risk ratios (RRs) for paresthesia in migraine vs. epilepsy trials were 2.5 (99% confidence interval (CI): 1.66-3.77) for 50 mg, 2.7 (99% CI: 1.80-3.97) for 100 mg, and 3.0 (99% CI: 1.95-4.56) for 200 mg. For ADR-related dropouts, the RR was 2.5 (95% CI: 2.03-2.98) for 50 mg but no different for the other doses. We conclude that when treated with the same doses of topiramate, migraineurs show different ADRs than patients with epilepsy and are more likely to drop out because of ADRs.

Topics: Drug-Related Side Effects and Adverse Reactions; Epilepsy; Fructose; Humans; Migraine Disorders; Randomized Controlled Trials as Topic; Risk Factors; Topiramate

Initially synthesized as an oral hypoglycemic agent, topiramate was approved for use as an anticonvulsant in 1996. Its broad spectrum efficacy in epilepsy, including as monotherapy and in children, is well established. Topiramate has also been used in the management of nonepileptic neurologic and psychiatric conditions, including migraine prophylaxis (with firmly established efficacy), obesity (with some evidence of long-term maintenance of weight loss), substance dependence, bipolar disorder and neuropathic pain, and it has been investigated as a possible neuroprotective agent. Paresthesias and cognitive side effects are the most common troublesome adverse effects. Recent trends towards lower doses may help achieve the best combination of efficacy and tolerability.

Topics: Clinical Trials as Topic; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Expert Testimony; Fructose; Humans; Nervous System Diseases; Neuroprotective Agents; Topiramate

To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy.. Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure.. At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047).. This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anticonvulsants; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Emergency Medical Services; Epilepsy; Female; Fructose; Humans; Male; Middle Aged; Phenytoin; Recurrence; Risk Factors; Topiramate; Treatment Outcome

Topics: Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Humans; Levetiracetam; Topiramate

Data on drug-induced liver injury (DILI) caused by newer antiseizure medications (ASMs) in the elderly are scarce and mainly come from literature case reports. We analyzed Individual Case Safety Reports (ICSRs) of DILI in elderly patients treated with newer ASMs reported to VigiBase.. Empirica™ Signal software was used to retrieve ICSRs reported to VigiBase up to 31 December 2021 and to calculate Empirical Bayesian Geometric Mean and corresponding 90% confidence intervals (EB05, EB95) for each drug-event pair. EB05 > 2,. There were 1399 ICSRs reporting 1947 events of hepatotoxicity. 56.97% of the reports were reported in females, 67.05% were serious, and 3.36% resulted in death. For one or more events of hepatotoxicity, signals were detected for lamotrigine, levetiracetam, oxcarbazepine, topiramate, and zonisamide. Age- and gender-biased reporting frequency was identified for topiramate-induced hyperammonemia, with disproportionally higher reporting frequency in ≥75-year-old male patients.. The results of our study indicate differences among newer ASMs in their potential to cause DILI in the elderly. Further studies are needed to confirm the associations identified in this study.

Topics: Aged; Anticonvulsants; Bayes Theorem; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Levetiracetam; Male; Topiramate

Time- and resource-demanding activities related to processing individual case safety reports (ICSRs) include manual procedures to evaluate individual causality with the final goal of dismissing false-positive safety signals. Eminent experts and a representative from pharmaceutical industries and regulatory agencies have highlighted the need to automatize time- and resource-demanding procedures in signal detection and validation. However, to date there is a sparse availability of automatized tools for such purposes.. ICSRs recorded in spontaneous reporting databases have been and continue to be the cornerstone and the most important data source in signal detection. Despite the richness of this data source, the incessantly increased amount of ICSRs recorded in spontaneous reporting databases has generated problems in signal detection and validation due to the increase in resources and time needed to process cases. This study aimed to develop a new artificial intelligence (AI)-based framework to automate resource- and time-consuming steps of signal detection and signal validation, such as (1) the selection of control groups in disproportionality analyses and (2) the identification of co-reported drugs serving as alternative causes, to look to dismiss false-positive disproportionality signals and therefore reduce the burden of case-by-case validation.. The Summary of Product Characteristics (SmPC) and the Anatomical Therapeutic Chemical (ATC) classification system were used to automatically identify control groups within and outside the chemical subgroup of the proof-of-concept drug under investigation, galcanezumab. Machine learning, specifically conditional inference trees, has been used to identify alternative causes in disproportionality signals.. By using conditional inference trees, the framework was able to dismiss 20.00% of erenumab, 14.29% of topiramate, and 13.33% of amitriptyline disproportionality signals on the basis of purely alternative causes identified in cases. Furthermore, of the disproportionality signals that could not be dismissed purely on the basis of the alternative causes identified, we estimated a 15.32%, 25.39%, and 26.41% reduction in the number of galcanezumab cases to undergo manual validation in comparison with erenumab, topiramate, and amitriptyline, respectively.. AI could significantly ease some of the most time-consuming and labor-intensive steps of signal detection and validation. The AI-based approach showed promising results, however, future work is needed to validate the framework.

Topics: Adverse Drug Reaction Reporting Systems; Amitriptyline; Artificial Intelligence; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Topiramate; United States; United States Food and Drug Administration

Migraine is the primary cause of headache in children. Most patients can be treated with lifestyle changes and acute attack prophylaxis. Prophylaxis should be considered when symptoms cause frequent school absenteeism, poor quality of life, recurring emergency room visits, and frequent analgesic use. We aimed to compare the efficacy and side effects of drugs used in migraine prophylaxis, chosen according to the clinical and/or demographic characteristics of the patients.. One hundred eighty-six patients aged 6-18 years were evaluated and who were diagnosed with migraine according to The International Classification of Headache Disorders, 3rd edition beta version (ICH-3β). Propranolol, topiramate, flunarizine, and cyproheptadine were given as prophylactic treatment. The Pediatric Migraine Disability Assessment Score (PedMIDAS) score, severity, duration, and frequency of the headache attacks were evaluated from the medical records and pre- and post-treatment values were compared.. The median age of the patients was 14 years (range, 6-18 years) and the mean duration of headache was 29.6 ± 21.02 months. The mean PedMIDAS score was 29.9 ± 21.2 before and 14.9 ± 12.5 after treatment. Most reduction in the frequency of attacks was observed in the topiramate group. All four drugs significantly reduced the PedMIDAS score. The most common side effect was palpitations.. Significant improvement was found in PedMIDAS scores in all drug groups. Topiramate was found to be the most effective drug in reducing the frequency of attacks. All four drugs in this study may be utilized for migraine prophylaxis in terms of effectiveness and safety.

Topics: Child; Drug-Related Side Effects and Adverse Reactions; Fructose; Headache; Humans; Infant; Migraine Disorders; Quality of Life; Topiramate

Sulfonamides have been related to drug-induced acute angle closure of the eye, but scarce reports exist concerning furosemide. We describe the second case of acute chamber narrowing (ACN) during furosemide exposure. A 65-year-old man with a renal transplant presented with ACN, after 3 months of furosemide intake. Finally, the patient required a bilateral iridotomy and right lens replacement. ACN has been associated with drugs containing sulfonamide derivatives, but an evaluation with pharmacovigilance scales for adverse drug reaction (ADR)-standardised causality assessment has not been provided. We use this case to illustrate how medicines and an ADR should be evaluated and reported. The spreading of pharmacovigilance information on what should be a rare and unexpected condition related to a drug could mean that other reports emerge about ADR with this drug and regulatory agencies perform consequently, as happened with topiramate.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Drug-Related Side Effects and Adverse Reactions; Furosemide; Humans; Male; Pharmacovigilance; Topiramate

The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased the therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes.. Better seizure control was found in children both in the whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were not related to PL.. Change of TR is not recommended.

Topics: Adult; Anticonvulsants; Child; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Fructose; Humans; Seizures; Topiramate

Antiseizure drugs (ASDs) are known to cause a wide range of adverse drug reactions (ADRs). Recently, electronic health care data using the common data model (CDM) have been introduced and commonly adopted in pharmacovigilance research. We aimed to analyze ASD-related ADRs using CDM and to assess the feasibility of CDM analysis in monitoring ADR in a single tertiary hospital.. We selected five ASDs: oxcarbazepine (OXC), lamotrigine (LTG), levetiracetam (LEV), valproic acid (VPA), and topiramate (TPM). Patients diagnosed with epilepsy and exposed to monotherapy with one of the ASDs before age 18 years were included. We measured four ADR outcomes: (1) hematologic abnormality, (2) hyponatremia, (3) elevation of liver enzymes, and (4) subclinical hypothyroidism. We performed a subgroup analysis to exclude the effects of concomitant medications.. From the database, 1344 patients were included for the study. Of the 1344 patients, 436 were receiving OXC, 293 were receiving LTG, 275 were receiving LEV, 180 were receiving VPA, and 160 were receiving TPM. Thrombocytopenia developed in 14.1% of patients taking VPA. Hyponatremia occurred in 10.5% of patients taking OXC. Variable ranges of liver enzyme elevation were detected in 19.3% of patients taking VPA. Subclinical hypothyroidism occurred in approximately 21.5% to 28% of patients with ASD monotherapy, which did not significantly differ according to the type of ASD. In a subgroup analysis, we observed similar ADR tendencies, but with less thrombocytopenia in the TPM group.. The incidence and trends of ADRs that were evaluated by CDM were similar to the previous literature. CDM can be a useful tool for analyzing ASD-related ADRs in a multicenter study. The strengths and limitations of CDM should be carefully addressed.

Topics: Anticonvulsants; Common Data Elements; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records; Epilepsy; Humans; Lamotrigine; Levetiracetam; Oxcarbazepine; Topiramate; Valproic Acid

Topiramate, an anticonvulsant used for prophylaxis of migraines and epilepsy, is commonly associated with adverse effects of cognitive dulling and fatigue. Chest pain is a potential adverse effect that to our knowledge has not been reported with the use of topiramate.. We present the case of a 38-year-old female with a seizure disorder who experienced chest pain after the first dose of topiramate. On day 1, she presented to the emergency department, was admitted, and over the course of 3 days had a chest X-ray, electrocardiogram (ECG), and echocardiogram, and her vitals, basic metabolic panel, complete blood counts, troponin, and d-dimer levels were monitored. The chest pain improved when the topiramate was held. No identifiable causes of chest pain were apparent, other than the topiramate.. The Naranjo probability scale was utilized to determine the causality of topiramate. The resulting score of 3 indicates that it is possible that the chest pain was due to the topiramate.. This report demonstrates an example of a patient who experienced chest pain possibly caused by the initiation of topiramate. The objective of this case report is to increase the awareness of chest pain as an adverse effect of topiramate.

Topics: Adult; Anticonvulsants; Chest Pain; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Epilepsy; Female; Hospitalization; Humans; Topiramate

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001-2015, 1308 pre-dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%-7% of cases in bi- or triple therapy. About 61% of plasma levels were found within the TR during 2001-2005, compared to 75% and 74% during 2006-2010 and 2011-2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3-fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001-2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.

Topics: Adolescent; Anticonvulsants; Carbamazepine; Child; Child, Preschool; Czech Republic; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Humans; Incidence; Lamotrigine; Levetiracetam; Male; Metabolic Clearance Rate; Severity of Illness Index; Topiramate; Valproic Acid

Topics: Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Topiramate; Vision, Ocular

Psychiatric comorbidities are common in people with epilepsy. A retrospective study of characteristics associated with withdrawal due to psychiatric side effects was undertaken in patients with treated epilepsy participating in prospective audits with new antiepileptic drugs (AEDs). A total of 1058 treated patients with uncontrolled seizures (942 focal-onset seizures, 116 generalized genetic epilepsies [GGEs]) participated in eight prospective, observational audits from 1996 to 2014. These patients were prescribed adjunctive topiramate (n=170), levetiracetam (n=220), pregabalin (n=135), zonisamide (n=203), lacosamide (n=160), eslicarbazepine acetate (n=52), retigabine (n=64), or perampanel (n=54). Doses were titrated according to efficacy and tolerability to optimize zeizure outcomes and reduce side effects. Psychiatric comorbidities were recorded prior to and after the addition of each AED. At baseline, patients with focal-onset seizures (189 of 942; 20.1%) were statistically more likely to have psychiatric diagnoses compared to patients with GGEs (14 of 116, 12.1%; p=0.039). Following adjunctive AED treatment, neuropsychiatric adverse effects led to AED withdrawal in 1.9-16.7% of patients. Patients with a pre-treatment psychiatric history (22 of 209; 10.5%) were statistically more likely to discontinue their new AED due to psychiatric issues compared to patients with no previous psychiatric diagnosis (50 of 849; 5.9%; p=0.017). Patients receiving sodium channel blocking AEDs (4 of 212, 1.9%) were statistically less likely to develop intolerable psychiatric problems, compared to those on AEDs possessing other mechanisms of action (68 of 846, 8.0%; p=0.012). Depression was the commonest problem, leading to discontinuation of AEDs in 2.8% (n=30) patients. Aggression was statistically more common in men (11 of 527, 2.1%) compared to women (1 of 531, 0.2%; p=0.004). Patients with learning disability (12 of 122, 9.8%; p=0.0015) were statistically less likely to have psychiatric issues prior to adjunctive AED treatment compared to other patients (208 of 936, 22.2%), but there were no statistically significant differences once the new AEDs were added (8 of 122 patients with learning disability, 6.6%; 64 of 936 other patients, 6.8%). Awareness of these issues may assist clinicians in avoiding, identifying and treating psychiatric comorbidities in people with epilepsy.

Topics: Acetamides; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Dibenzazepines; Drug-Related Side Effects and Adverse Reactions; Epilepsy; Female; Fructose; Humans; Lacosamide; Levetiracetam; Male; Medical Audit; Mental Disorders; Middle Aged; Nitriles; Piracetam; Pregabalin; Prospective Studies; Pyridones; Retrospective Studies; Seizures; Sodium Channel Blockers; Topiramate; Young Adult

Topics: Adolescent; Adult; Canada; Child; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Migraine Disorders; Neuroprotective Agents; Randomized Controlled Trials as Topic; Topiramate; Treatment Failure; United States; United States Food and Drug Administration

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it serves as the primary route of elimination for monovalent bile acids (BAs) into the bile canaliculi. The most compelling evidence linking dysfunction in BA transport with liver injury in humans is found with carriers of mutations that render BSEP nonfunctional. Based on mounting evidence, there appears to be a strong association between drug-induced BSEP interference and liver injury in humans; however, causality has not been established. For this reason, drug-induced BSEP interference is best considered a susceptibility factor for liver injury as other host- or drug-related properties may contribute to the development of hepatotoxicity. To better understand the association between BSEP interference and liver injury in humans, over 600 marketed or withdrawn drugs were evaluated in BSEP expressing membrane vesicles. The example of a compound that failed during phase 1 human trials is also described, AMG 009. AMG 009 showed evidence of liver injury in humans that was not predicted by preclinical safety studies, and BSEP inhibition was implicated. For 109 of the drugs with some effect on in vitro BSEP function, clinical use, associations with hepatotoxicity, pharmacokinetic data, and other information were annotated. A steady state concentration (C(ss)) for each of these annotated drugs was estimated, and a ratio between this value and measured IC₅₀ potency values were calculated in an attempt to relate exposure to in vitro potencies. When factoring for exposure, 95% of the annotated compounds with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 were associated with some form of liver injury. We then investigated the relationship between clinical evidence of liver injury and effects to multidrug resistance-associated proteins (MRPs) believed to play a role in BA homeostasis. The effect of 600+ drugs on MRP2, MRP3, and MRP4 function was also evaluated in membrane vesicle assays. Drugs with a C(ss)/BSEP IC₅₀ ratio ≥ 0.1 and a C(ss)/MRP IC₅₀ ratio ≥ 0.1 had almost a 100% correlation with some evidence of liver injury in humans. These data suggest that integration of exposure data, and knowledge of an effect to not only BSEP but also one or more of the MRPs, is a useful tool for informing the potential for liver injury due to altered BA transport.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Biological Transport; Chemical and Drug Induced Liver Injury; Cluster Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Male; Multidrug Resistance-Associated Proteins; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Risk Assessment; Risk Factors; Toxicity Tests

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Topics: Amyotrophic Lateral Sclerosis; Anticonvulsants; Clinical Trials, Phase III as Topic; Costs and Cost Analysis; Drug Approval; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Lithium Compounds; Patient Advocacy; Risk; Topiramate; United States

Topics: Acidosis; Adverse Drug Reaction Reporting Systems; Anticonvulsants; Carbamazepine; Communication; Cooperative Behavior; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Fructose; Humans; Hyponatremia; Topiramate

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration

To report recent ocular adverse drug reactions identified by the National Registry of Drug-Induced Ocular Side Effects.. Case reports from the National Registry and the World Health Organization were collected and adverse drug reactions categorized as follows: certain, probable/likely, possible, unlikely, and conditional/unclassifiable.. Bisphosphonates are associated with ocular inflammation, including the first reports of drug-related scleritis. Topiramate is shown to cause angle-closure glaucoma. Cetirizine can cause an oculogyric crisis, and there is strong evidence retinoids cause intracranial hypertension.. Recent reports to the National Registry have led to identification of new ocular adverse drug reactions.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Cetirizine; Child; Child, Preschool; Diphosphonates; Drug-Related Side Effects and Adverse Reactions; Eye; Eye Diseases; Female; Fructose; Humans; Infant; Male; Middle Aged; Ophthalmic Solutions; Registries; Retinoids; Topiramate; United States; United States Food and Drug Administration; World Health Organization