Current Drug Safety - Volume 10, Issue 2, 2015

Restless leg syndrome (RLS) is a common disorder, frequently of unclear origin, which is often associated with significant distress. There are a few case reports of atypical antipsychotic agents (AAP) causing RLS. The pathophysiological mechanisms resulting in emergence of these movements suggest central dopaminergic dysfunction. Dopamine agonists and L-dopa reduce the symptoms of RLS, and some agents that block the dopaminergic system aggravate RLS. Genetic influences are implicated in RLS and an association between gene polymorphisms and antipyschotic-associated onset of RLS has been postulated. Greater awareness of potential causes of RLS, and its differentiation from akathisia and illness related agitation might help in reducing the distress associated with it and improving patient compliance in patients using atypical antipsychotic agents.

Patent ductus arteriosus (PDA) is the most common cardiac condition in preterm infants. The most commonly used drugs for this purpose are cyclooxygenase inhibitors, mainly indomethacin and ibuprofen, which block the conversion of arachidonic acid to prostaglandins. On the other hand, several adverse effects have been reported with such medications, including peripheral vasoconstriction, gastrointestinal bleeding and perforation, weakened platelet aggregation, hyperbilirubinemia and renal failure. The role of oral paracetamol as an alternative treatment for the closure of PDA has gained importance in recent years. In this review, we aimed to determine safety of therapeutic drugs used in management of PDA in preterm infants rather than their efficacy in ductal closure. Two worldwide commonly used therapeutics (indomethacin and ibuprofen) and a new alternative medication as paracetamol are discussed. Ibuprofen seems to be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects than indomethacin. Recent studies suggest that paracetamol may be a medical alternative in the management of PDA with low adverse events and side effects.

Background: In 2005, the FDA approved the Roche AmpliChip™ for clinical application. The AmpliChip is a microarray chip that has the capability to play an important role in clinical pharmacogenetics. Objective: Because of the possible influence the AmpliChip may have on patient medication management, the purpose of the review is to address the available evidence for the AmpliChip’s overall performance at three key levels: analytic validity (genotyping accuracy, and prediction of the phenotype from the genotype) and clinical utility. Data Sources: We searched Medline, Embase and PubMed for studies of the AmpliChip. Limits were English language and 2005 (the year of FDA approval) and onwards, and we corresponded with authors for further papers of interest. Results: 17 articles provided data for analysis in this review: 4 involving genotype accuracy, 7 involving genotype to phenotype prediction and 9 involving clinical utility. Conclusion: There is limited literature comparing AmpliChip results to gold standard tests and test-retest reliability when assessing genotype accuracy. Also, there is limited literature on the accuracy of AmpliChip predictions of phenotypes from genotypes and minimal evidence with appropriately powered studies whether the AmpliChip genotype to phenotype predictions result in clinical benefit. At all three levels there is significant evidence that the AmpliChip has the potential to be a robust clinical tool. However, more and adequately powered studies are required to determine fully whether the AmpliChip is a clinically effective tool.

Background: The efficacy of clozapine for the treatment of schizophrenia has been demonstrated. However, a range of adverse events have been associated with its use. To date, there remains a paucity of data regarding the prevalence of clozapine-induced cardiovascular (CV) and parameters associated with the development of metabolic syndrome, alongside associated risk factors for their development. Methods: An observational, clinical cohort study design of 355 clozapine patients who were enrolled in the Barwon Health Clozapine Program at Geelong Hospital, Victoria, Australia, between 2008-12. Medical records were accessed retrospectively. Multivariate logistic regression was used to determine associations with adverse event(s). Results: Older age of commencement with clozapine was consistently associated with increased risk of CV abnormalities, with the exception of tachycardia where older age was protective (Odds Ratio [OR]: 0.97; 95% Confidence Intervals [CI]: 0.95, 0.99). Males had significantly greater odds of most metabolic disturbances with the exception of being obese (BMI: ≥30 OR: 0.45; 95% CIs: 0.24, 0.85). Older age of commencement was a significantly associated variable with High- Density Lipoprotein-cholesterol (OR: 1.03; 95% CIs: 1.01, 1.07) and fasting glucose (OR:1.04; 95% CIs: 1.02, 1.07). An increase in BMI was consistently and significantly associated with all metabolic events. Conclusion: Male patients who are obese at any point during treatment and older at treatment commencement may be the most vulnerable to adverse CV and metabolic events. While future studies using a matched case-control design may be required to verify these findings, we recommend that treating clinicians consider these risks when assessing patient suitability to clozapine therapy.

Objective: Preventive therapy in migraine must be started with frequent or disabling headaches in children, while, no drugs have been approved for migraine preventive therapy of them up to now. The aim of the present research was to investigate safety and efficacy of melatonin in pediatric migraine prophylaxis. Methods: In a quasi- experimental study, monthly frequency, severity and duration of headache, migraine disability and clinical side effects in sixty migraineur referred children to Pediatric Neurology Clinic of Shahid Sadoughi Medical Sciences University, Yazd, Iran from January to June 2013 whom were treated with single dose of 0.3 mg/kg melatonin for three months, were evaluated. Results: Thirty two (53.3%) girls and 28(46.7%) boys with mean age of 10.31 ± 2.39 years were evaluated, 38 of whom (63.3%) had migraine without aura. Clinical adverse events were seen in 23.3% (N=14) of children including sleepiness in seven, vomiting in four, mild hypotension in two and constipation in one child. Excessive daytime sleepiness as a serious side effect was seen in three children which caused the drug use to be stopped. Monthly frequency, severity and duration of headache reduced from 15.63±7.64 to 7.07±4.42 attacks, from 6.20±1.67 to 3.55± 2.11 scores, and from 2.26±1.34 to 1.11±0.55 hours, respectively. Pediatric Migraine Disability Assessment score decreased from 31.72 ±8.82 to 17.78 ±10.64. (All p < 0.05). Conclusion: Melatonin might be considered as an effective and without life-threatening side effects drug in prophylaxis of migraine in children.

Background: Adverse drug reaction (ADR) is a global drug therapy problem. It has been rated as one of the top leading causes of morbidity and mortality. In Nigeria, not much is known about ADRs especially with the existing weak post marketing surveillance for monitoring drug use, and its effect on the population. Objectives: The study is aimed at determining the incidence of ADRs, presentations of ADRs, classes of drugs that frequently cause ADRs and predictors of ADRs in adult medical in-patients in LASUTH. Method: A retrospective study of six hundred and twenty four (624) case notes of all patients admitted to the medical wards in LASUTH between January 1, 2009 and December 31, 2009 was carried out. Information obtained included age, gender, and adverse drug reaction and drug details. The results obtained were analyzed using SPSS version 16 statistical software. Level of significance was set at p ≤ 0.05. Results: A total of 624 case notes consisting of 358 males and 266 females were assessed. The number of patients who experienced adverse drug reactions was 67 (n = 624, 10.7%). The incidence rate of ADRs in LASUTH from the study was 10.7 per 100 patients’ population. Most of the ADRs observed were type A reactions (97.8%). Mostly implicated classes of drugs were antidiabetics (26.7%) and NSAIDs (29.3%). Conclusion: The incidence rate of ADRs was 10.7%. ADRs which are predictable and preventable occur in hospitalized patients, such may be prevented or minimized by implementing measures to target specific drugs that are commonly suspected.

Purpose: To report our results concerning the safety and efficacy of repeated sustainedrelease dexamethasone 0.7 mg implants (Ozurdex, Allergan, Inc., Irvine, CA) in patients with persistent Macular Edema (ME) due to Retinal Vein Occlusion (RVO) previously treated with anti- VEGF injections. Patients and Methods: Ten patients (5 males and 5 females/ 5 with CRVO and 5 with BRVO), all previously treated with at least 3 consecutive anti- VEGF injections and presented lack of anatomic improvement (CRT >250μm in OCT) accompanied by lack of visual improvement (no change or deterioration of VA), received one or more Ozurdex injections (up to five). Ozurdex was administrated on an ‘as needed’ regimen and patients underwent a complete ophthalmological examination, including Best Corrected Visual Acuity (BCVA) measurements, biomicroscopy, tonometry, and Fourier Domain Optical Coherence Tomography (FD-OCT) on a monthly basis. Furthermore, mean time intervals for OZURDEX re-injection were estimated. Results: In 9 out of 10 cases, the patients experienced improvement in BCVA after the Ozurdex implantation with reduction in CRT. The most frequently observed adverse events included IOP elevation (20% of cases), cataract progression (10%) and cataract formation (10%). No serious systemic or topical adverse events were observed in eyes undergoing repeated Ozurdex implantations. In one of the patients, it was observed that the implant was fractured into two pieces without affecting the efficacy of the implant or causing any side effects. Conclusion: Provided the complexity of molecular mechanisms involved in ΜΕ development and the effect of corticosteroids on many of these mechanisms, in our case series, Ozurdex appeared to be a safe and beneficial treatment option for persistent ME due to RVO, in patients with poor or complete lack of response after at least 3 consecutive monthly intravitreal anti-VEGF injections. The complication rate of cataract reported in our study is relatively high compared to previous reports. This might be attributed to the multiple injections, as the incidence of cataract increases with time. Regarding IOP elevation, there is no consensus among published clinical trials on the percentage of patients requiring IOP-lowering medications. Further studies with a greater patient population as well as a control group are required in order to confirm our findings.

Purpose: This study evaluated the effects of concomitant pravastatin and paroxetine use on the incidence of Type 2 Diabetes Mellitus (T2DM). Methods: A new-user retrospective cohort design was employed using data selected from US health insurance claims databases (OptumInsight and MarketScan) between July 1, 2002, and December 31, 2009. Patients included were of age ≥18; newly prescribed pravastatin or paroxetine; and enrolled in the database for ≥180 days prior to the index date (i.e., first prescription of incident drug). Patients were assigned to either incident pravastatin or incident paroxetine user groups. Patients were followed until the study endpoint (T2DM), discontinuation of incident drug, second drug, or end of study/patient data. Cox proportional hazards models compared T2DM in users of pravastatin who were also taking paroxetine at index the date (combination users) versus pravastatinonly users. A similar analysis among users of paroxetine evaluated the use or non-use of pravastatin at index date. Results: OptumInsight yielded 288,678 incident users of pravastatin or paroxetine; 443,137 were identified in MarketScan. The risk of T2DM among combination users compared to incident pravastatin only users was 1.05 (95% CI: 0.76, 1.44) and 0.94 (95% CI: 0.90, 0.97) in OptumInsight and MarketScan, respectively. The risk of T2DM among combination users compared to incident paroxetine only users was 1.03 (95% CI: 0.69, 1.54) in OptumInsight and 1.02 (95% CI: 0.97, 1.07) in MarketScan. Conclusion: The results indicate no increase in the risk of T2DM due to combined use of pravastatin and paroxetine compared to individual use of the two drugs; however, this study is limited by short mean follow-up.

In June, 2012 the United States Food and Drug Administration (FDA) developed a “blueprint” for prescriber education as a means of directing Certified Medical Education (CME) activities that included content which would meet the regulatory requirements of the class-wide, longacting/ extended-release (LA-ER) opioid Risk Evaluation Mitigation Strategies (REMS). Within the blueprint is the suggested adoption of Patient-Provider Agreements (PPAs) to be used in association with opioid prescribing, but, to our knowledge, there have been no reported evaluations of the role played by opioid-agent PPAs in clinical practice, or of the perceptions of this regulatory mandate by clinicians. Therefore, we conducted a survey regarding PPA perceptions by opioid prescribers that was posted for five weeks on a well-trafficked online CME service provider (Medscape). Of the 1,232 respondents (reflecting a 99.5% completion rate), 52.4% treat acute or chronic pain with opioids. The survey identified an improvement of opioid safe-use education (21% of respondents) as the most frequently selected beneficial element of PPAs. Conversely, the challenges to adoption included time constraints (21% of physicians) as well as lack of evidence that PPAs will reduce drug misuse, and the lack of a uniform, patient-friendly PPA. Based on our survey, clinicians consider the PPA of potential value, but data regarding the utility of such an instrument are lacking.

In clinical practice, adherence to drugs and their safety may differ from randomised controlled trial settings. This study was undertaken to investigate the adherence to dabigatran, a direct thrombin inhibitor, and its safety in a real-world setting. We studied a prospective cohort of 114 elderly consecutive patients with non valvular atrial fibrillation (AF) who were treated with dabigatran 150 mg twice-daily (N=39) or 110 mg twice-daily (N=76). These patients were studied at baseline and after an average of 6 months. Mean age was 80 years and 53% were women. At entry, the average CHA2DS2VASc score was 4 and the HAS-BLED score was 2. AF was permanent in 49% of patients, persistent in 30%, paroxysmal in 12% and new-onset in 24%. In the follow-up clinical visit we ascertained vital status, adherence to treatment according to refill prescription orders, and side effects. Adherence was ≥80% in 76.5% of patients. Heartburn, the most frequent adverse effect, was reported by 25 patients (22%). Major and minor bleedings were experienced by 2 (1.8%) and 9 (7.9%) patients, respectively. Permanent discontinuation occurred in 18 patients (16%). The most frequent cause of permanent discontinuation was heartburn (10 patients). This real-life study suggests that safety of dabigatran and adherence to this drug in an elderly cohort of AF patients at high or very high risk of thromboembolism are generally good. Heartburn is the main cause of treatment discontinuation.

Objective: To review the available evidence concerning the relationship between the exposure to metronidazole during pregnancy and the risk of preterm delivery and birth defects. Methods: Studies investigating the association between gestational use of oral metronidazole on human subjects and the risk of preterm birth or/and birth defects were systematically retrieved from MEDLINE and EMBASE databases. We selected studies published in English or French between 1964 and 2012. Where effect estimates were not reported, crude ORs along with 95% confidence intervals were calculated. Results: We selected 17 studies investigating the association between exposure to oral metronidazole and the risk of preterm birth, from which 12 were randomized clinical trials. In addition, we identified 13 studies devoted to the relationship between metronidazole and birth defects, from which 10 were cohort studies, 1 was a case-control study and 2 were meta-analysis. Conclusion: During pregnancy, treating bacterial vaginosis and trichomoniasis with metronidazole is effective and offers no teratogen risk. Benefit of metronidazole in the reduction of preterm birth was demonstrated for the combination of this medication with other antibiotics. Additional information is needed when metronidazole is used in association with other agents.

Posterior reversible encephalopathy syndrome (PRES) is an acute central nervous system disorder characterized by reversible brain vasogenic edema. We report here a new case of a nine-year-old boy with B-cell acute lymphoblastic leukemia (B-ALL) who developed PRES secondary to induction chemotherapy including dexamethasone (dexamethasone®), vincristine (oncovin®), daunorubicin (adriblastine®) and intrathecal injection. Cerebral magnetic resonance imaging (MRI) showed high signal intensity on T2 at cortical and sub cortical region of parieto-frontal and parieto-occipital lobes. The patient was put under sodium valproate (depakine®) and we decided to continue dexamethasone (dexamethasone®) and daunorubicin (adriblastine®) injection. The MRI, after four weeks, was normal. So, we resumed vincristine (oncovin®) and we started L-asparaginase injections. Then, the outcome was favorable. The treatment of PRES is based on the withdrawal of the triggering factor to avoid the risk of irreversible lesions. But, due to the severity of leukemia the discontinuation of chemotherapy is difficult because of the risk of disease progression.

Introduction: Pregabalin is a gamma-aminobutyric acid (GABA) analogue approved for the treatment of neuropathic pain, partial seizure and generalized anxiety disorder. As a GABA analogue, there is a raising concern regarding the abuse potential of this drug. Case: We present a first case of pregabalin dependence in a 26-year-old woman without a previous history of illicit drug abuse. Discussion: Physician should be aware about the addictive potential of pregabalin even in patients without a previous history of substance abuse.

Stevens-Johnson syndrome (SJS) is an uncommon life-threatening skin disease, generally induced by drugs. Extracutaneous manifestations of the syndrome can occur, and may involve the conjunctiva, buccal mucosa, gastrointestinal and genitourinary tracts. Cholestatic hepatitis has been rarely described in SJS. A 29-year-old woman was admitted with generalized cutaneous eruption. A self-medication with paracetamol had been started three days earlier. Clinical signs and skin biopsy were consistent with SJS. Five days later, the patient developed jaundice. Serial liver function tests showed rising transaminases, bilirubin, alkaline phosphatase and γ-glutamyl transferase. Liver biopsy was performed and was consistent with the diagnosis of drug-induced cholestatic hepatitis. Adequate supportive care was provided to the patient. Skin lesions disappeared within two weeks. Jaundice disappeared progressively, and liver tests returned to normal. Herein, we report the first case of SJS associated with cholestatic hepatitis after ingestion of therapeutic doses of paracetamol.

Sulindac is a long-acting nonsteroidal anti-inflammatory drug (NSAID) widely used for the management of osteoarthritis, rheumatoid arthritis, ankylosing sponydlitis, and acute gouty arthritis. Reports of sulindac toxicity in the literature are rare. We report the case of a 22-year old male with a history of bipolar disorder who was brought to the emergency department after ingesting approximately 15 g of sulindac in a suicide attempt. He was found to have acute kidney injury and hyperbilirubinemia. Despite aggressive fluid resuscitation, his renal function progressively worsened requiring the initiation of hemodialysis. Ten days following ingestion of sulindac, he began to develop ischemic skin changes with a gangrenous appearance in his hands and feet. He continued to receive supportive treatment, and his acute kidney injury, hyperbillirubinemia, and ischemic skin necrosis eventually resolved. Clinicians should be aware of this long-acting NSAID and its ability to cause prolonged multisystem organ dysfunction.