Adverse Drug Reaction Probability Scale Research Articles

Intraoperative anaphylaxis associated with bacitracin irrigation

Three cases of severe anaphylactic reactions associated with prophylactic bacitracin irrigation during cardiac procedures are describe. In all three cases, bacitracin irrigation was concentrated at 50,000 units per 10 mL and applied directly to the pacemaker pocket. The first case described involved an 88-year-old woman undergoing pacemaker insertion to correct bradycardia. Within 10 minutes of bacitracin irrigation, she lost consciousness and developed apnea, diffuse erythema, and hypotension. In the second case, a 69-year-old man receiving a cardiac resynchronization defibrillator implant developed apnea, hypotension, decreased pulse, erythema of the extremities, and a maculopapular rash within 15 minutes of bacitracin administration. The third case involved an 83-year-old woman undergoing a dual pacemaker battery change; she became agitated and was noted to have hypotension, anxiety, and other symptoms 8 minutes after bacitracin irrigation. Two of the three cases involved apnea and loss of consciousness, and all three patients developed erythema or rash. Application of the adverse drug reaction probability scale developed by Naranjo et al. yielded a score of 3 (indicating a possible adverse reaction to bacitracin) in all three cases. As in other published reports of anaphylactic reactions associated with bacitracin irrigation, development of hypotension within 15 minutes of bacitracin administration was the first sign of an adverse reaction in these cases. Three patients developed severe adverse reactions after prophylactic bacitracin irrigation, two during pacemaker insertions and one during a cardiac resynchronization defibrillator implantation.

5‐Fluorouracil—Induced Tako‐Tsubo—Like Syndrome

Tako-Tsubo cardiomyopathy (also known as apical ballooning syndrome) is a relatively new clinical entity characterized by reversible left ventricular dysfunction. Its clinical presentation and electrocardiographic findings are similar to acute myocardial infarction but without significant coronary artery disease. Cardiotoxicity is a major complication of various anticancer drugs; however, only a few cases of Tako-Tsubo cardiomyopathy associated with anticancer drugs, including 5-fluorouracil, have been reported. We describe a 48-year-old man who developed acute coronary syndrome, thought to be similar to Tako-Tsubo syndrome, after receiving a chemotherapy regimen consisting of 5-fluorouracil, oxaliplatin, and calcium folinate (FOLFOX protocol) for colic adenocarcinoma. Approximately 24 hours after receiving his first cycle of chemotherapy, the patient, who did not have a history of cardiovascular disease, developed chest pain, with abnormal electrocardiographic results and a mildly increased troponin T level. Coronary angiography did not show any significant coronary lesions. Echocardiography revealed marked left ventricular dysfunction (left ventricular ejection fraction [LVEF] 15%) with severe hypokinesia in all apical and median segments. The patient was stabilized with the introduction of an intraaortic balloon pump and pressor therapy. One month later, myocardial magnetic resonance imaging confirmed total recovery of left ventricular systolic function. Thus, the second chemotherapy cycle was administered at half the dose-intensity, along with ramipril and diltiazem. The chemotherapy regimen was well tolerated. Two weeks later, at the end of the third chemotherapy cycle, administered using the full-dose regimen, the patient experienced cardiac arrest, necessitating cardiopulmonary resuscitation. After transfer to the cardiology intensive care unit, acute heart failure recurred (LVEF 35%). Normal recovery of left ventricular function occurred a few days later. Chemotherapy was discontinued, and treatment with bisoprolol was started. Four months later, the patient remained completely asymptomatic of any cardiac manifestations. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 8) between the patient's development of acute coronary Tako-Tsubo-like syndrome and 5-fluorouracil. Clinicians should be aware of this potential adverse effect when monitoring patients receiving chemotherapy with 5-fluorouracil.

Possible Association of New‐Onset Seizure with the H1N1 Influenza Vaccine

Since the introduction of the H1N1 influenza vaccine in the wake of the 2009 H1N1 influenza pandemic, many serious and nonserious adverse events related to the vaccine have been reported. We describe a 59‐year‐old African‐American man with severe chronic heart failure and chronic obstructive pulmonary disease who experienced a new‐onset, generalized tonic‐clonic seizure less than 1 hour after receiving the H1N1 vaccine. He had never experienced any reactions to previous seasonal influenza vaccines. His medical history, physical examination, and targeted investigations revealed no evidence of other potential etiologies for his seizure. After this event, the patient, who was discharged without anticonvulsant therapy, remained seizure free for the next 10 months. Use of the Naranjo adverse drug reaction probability scale indicated a possible relationship (score of 4) between the patient's seizure and the receipt of the H1N1 vaccine. This is the first case report, to our knowledge, to suggest a possible association between the H1N1 influenza vaccine and seizure. The mechanism of the association is unclear. Further case series may clarify the nature of the association.

Monitoring of incidence, severity, and causality of adverse drug reactions in hospitalized patients with cardiovascular disease

Background:Patients admitted to cardiology department are mostly on polypharmacy. So drug-drug interactions and adverse effects of drugs are quite common. Yet, there is a paucity of data regarding adverse drug reaction (ADR) monitoring in cardiology department in India. The present study is an effort to fill up these lacunae.Materials and Methods:A prospective, observational study registering 966 indoor cardiology patients according to predetermined inclusion and exclusion criteria was conducted for one year. ADR profile was noted by spontaneous reporting and intensive monitoring. Naranjo ADR probability scale was used to establish the causality.Results:A total of 208 ADRs were reported from 188 patients (19.5%). Of these 188 patients, 62 patients (33%) were hospitalized primarily due to the development of ADRs, while 126 (67%) patients developed ADRs during hospital stay. Nitrates were the most common offender drug group (17.8%).Conclusion:Development of ADR in one of every five cardiac patient points toward a grave situation, but a higher incidence of Type A reactions in cardiology department means that these can be avoided.

Myoclonus After Dextromethorphan Administration in Peritoneal Dialysis

To report a case of myoclonus that developed after administration of dextromethorphan. A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

Temporomandibular dislocation due to aripiprazole induced dystonia

We wish to report the case of a patient who developed temporomandibular joint dislocation due to dystonia following a single dose of aripiprazole. Our patient was a 23-year-old woman presenting with persistent low mood, fatiguability, insomnia and suicidal ideation. There was no past history of psychiatric morbidity. There was family history of depressive episode and deliberate self harm in her husband who was her paternal cousin. She was given 10 mg escitalopram and 0.5 mg clonazepam for insomnia on a diagnosis of a moderate depressive episode and improved over the next 3 weeks. However she developed irritability and agitation while on the above medications for which she was given a single dose of aripiprazole 10 mg at night by another psychiatrist not attached to our institution, which was not appropriate for her condition. The patient had taken 10 mg escitalopram in the morning. There was no history of intake of any over the counter drugs or herbal preparations. Twelve hours after the first dose she developed sedation and salivation and her care givers withheld subsequent doses of aripiprazole, escitalopram and clonazepam. Twenty hours after the first dose, she developed painful spasms of the muscles of her neck on the right side. She also had forced opening and deviation of jaw, both to the left and right. This was followed by persistent deviation of the jaw to the left and pain in the left temporomandibular joint. She was unable to close her mouth, swallow or talk for which she was brought to the emergency department of our hospital. A left-sided temporomandibular dislocation was diagnosed and a manual reduction was performed, after which the pain subsided. The next morning she was examined by us and seen to have forced mouth opening, excessive salivation and bilateral hand tremors. There were no other dystonic reactions. The dystonia and temporomandibular joint dislocation could not be part of the somatic symptoms of depression. We gave her 50 mg promethazine intramuscularly on suspicion of an aripiprazole induced dystonia. Two hours later, the dystonic movements subsided and the patient was sent home on oral promethazine. She did not have dystonic movements on follow-up the next morning. A rechallenge with aripiprazole could not be done for ethical reasons. The dystonia was rated as possibly due to aripiprozole according to the Naranjo adverse drug reaction probability scale [1]. She was restarted on escitalopram and clonazepam. A 1 month follow-up did not reveal any dystonic reactions. The adverse drug reaction was reported to the regional pharmacovigilance reporting centre. Aripiprazole is a second generation anti-psychotic which has a low propensity to cause extra-pyramidal side effects [2]. There are reports of acute dystonia induced by aripiprazole in drug-naive [3], and cocaine dependent patients [4] and in a patient on sertraline [5]. It has been proposed that aripiprazole caused dystonia because it lacked a protective anti-cholinergic action unlike other second generation anti-psychotics like clozapine [3]. Temporomandibular joint dislocations have been reported with conventional neuroleptics [6, 7] but no case has been reported with aripiprazole. Aripiprazole has been found to have no meaningful effect on the pharmacokinetics of escitalopram [8].We propose that our patient developed temporomandibular dislocation due to a dystonic reaction to aripiprazole possibly mediated through a pharmacodynamic synergism with escitalopram as selective serotonin re-uptake inhibitors can cause extrapyramidal side effects including dystonias through serotonergically mediated inhibition of the dopaminergic system [9]. From our case report we recommend a lower starting dose of aripiprazole especially in drug naive non psychotic patients and close monitoring of such patients.

Hypersensitivity pneumonitis due to high-dose colistin aerosol therapy

We report a case of hypersensitivity pneumonitis, possibly due to aerosolized colistin therapy for severe multi-resistant Gram-negative pneumonia. Microbiological eradication was achieved with colistin therapy, which was stopped after 12 days in view of rising eosinophilia and possible lung fibrosis. The eosinophil count started to normalize 3 days after stopping colistin therapy and the patient was eventually weaned to minimal ventilatory support.

Reversal of refractory sulfasalazine-related renal failure after treatment with corticosteroids

Background: Sulfasalazine is a combination of sulfapyridine and 5-aminosalicylic acid and is used as a first-line treatment in inflammatory bowel disease. Objective: We describe a case of acute interstitial nephritis that presented after 7 months of sulfasalazine therapy. Despite the discontinuation of the drug, the patient's renal function continued to deteriorate and recovered only when systemic corticosteroid treatment was initiated. Case summary: A 19-year-old white male (weight, 65 kg) presented in November 2006 with upper abdominal pain, fever ≥38°C, bloody diarrhea, anorexia, and weight loss. Ulcerative colitis involving the left colon was diagnosed based on results of a colonoscopy and intestinal biopsy, and treatment was initiated with cefprozil 1 g/d, mesalamine 3 g/d, methylprednisolone 32 mg/d, and ranitidine 300 mg/d. All drugs were administered orally. Cefprozil and ranitidine were discontinued after 10 days. Mesalamine was discontinued 1 month later because of gastrointestinal adverse effects (vomiting and diarrhea), and methylprednisolone was tapered over the next 3 months to zero. The patient then had a relapse, and sulfasalazine 2 g/d orally was administered. Seven months after the initiation of sulfasalazine, the patient developed fatigue, nausea, fever more prominent in the afternoon (increased from 38°C to 40°C), and nocturia, and he was admitted to the hospital. He had no history of renal impairment. Laboratory test results showed elevated serum urea and creatinine levels (170 and 7 mg/dL, respectively), while kidney ultrasound showed normal kidneys without obstruction. The patient had a Naranjo Adverse Drug Reaction Probability scale score of 6, indicating a probable adverse drug reaction with sulfasalazine. Based on these findings, sulfasalazine-related nephrotoxicity was suspected, and the drug was discontinued. During the next 4 days, serum urea and creatinine values increased to 212 and 8.3 mg/dL, respectively, and then remained stable for 3 days. A renal biopsy was performed, which revealed changes compatible with granulomatous interstitial nephritis. The patient received methylprednisolone 500 mg IV for 3 days, followed by oral administration of methylprednisolone 16 mg/d for 1 month. Renal function recovered completely a few days after initiation of corticosteroids, and the patient's condition continued to be stable 1 year later (eg, serum urea, 34 mg/dL; creatinine level, 0.9 mg/dL). Conclusions: Although this isolated case of sulfasalazine- related interstitial nephritis cannot lead to definite conclusions, treatment with corticosteroids was effective in this patient and should be considered irrespective of the time of exposure to sulfasalazine. However, randomized controlled trials are needed to provide evidence regarding the efficacy and tolerability profile of corticosteroids.

Meropenem‐Induced Vanishing Bile Duct Syndrome

Vanishing bile duct syndrome (VBDS) is a rare and potentially life-threatening disorder in which progressive destruction and disappearance of small intrahepatic bile ducts occur, with resultant cholestasis. The mechanism by which biliary epithelial cells are damaged and intrahepatic bile ducts are lost has not been fully elucidated. However, many etiologies have been reported,and several drugs have been implicated. Meropenem is a widely used, well tolerated broad-spectrum carbapenem antibiotic indicated for the treatment of intraabdominal infections, complicated skin and skin structure infections, and pediatric bacterial meningitis. We describe what we believe is the first reported case of meropenem-induced VBDS. A 60-year-old woman was diagnosed with VBDS after being treated with meropenem for a left temporal lobe brain abscess. Three weeks after starting the drug, the patient developed mixed hepatocellular and cholestatic liver injury with jaundice and pruritus.Meropenem-induced liver injury was suspected, and the drug was discontinued. Diagnostic tests ruled out other causes of cholestasis, including infectious and immunologic conditions. A liver biopsy, performed due to persistent liver injury, demonstrated an absence of bile ducts, which, in conjunction with the patient's clinical course, was consistent with the diagnosis of VBDS. Several months after the cessation of meropenem, the patient's liver function test results improved. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6)between the patient's development of VBDS and meropenem therapy. A high index of suspicion is necessary to diagnose VBDS and other types of drug induced liver injury. Clinicians should consider VBDS as a potential diagnosis in patients receiving meropenem who have prolonged cholestasis, especially after other more probable causes have been excluded.

Allergic shock and death associated with protamine administration in a diabetic patient

Background: Insulin is used to treat patients with both type 1 and type 2 diabetes mellitus. Allergic reac- tions to insulin might be triggered by insulin itself or inactive ingredients in the insulin formulation, includ- ing proteins such as protamine in neutral protamine Hagedorn (NPH) insulin. The use of highly purified animal insulin and human recombinant insulin has reduced the incidence of anaphylactic reactions to insulin from ~30% to <1%. Objective: We report a case of fatal allergic shock after the administration of protamine in a patient with a history of allergy to fish and a protamine-containing insulin. Case summary: A 72-year-old Chinese male patient (height, 175 cm; weight, 80 kg) with a history of diabetes and progressive limb weakness was diagnosed with spinal vascular malformations after admission to the Xuan Wu Hospital of Capital Medical University, Beijing, People's Republic of China. He underwent epidural spinal cord arteriovenous fistula embolization with a liquid embolic agent (ethylene vinyl alcohol copolymer) after spinal cord angiography. During the operation, heparin was infused every hour with 6250, 2500, 2500, and 1250 IU, respectively. The last dose of heparin was administered ~10 minutes before the opera- tion was completed. This was followed by the admin-istration of protamine to neutralize the remaining heparin in the patient's body. Blurry vision and dizziness 5 minutes after protamine administration were followed by pruritus and hives over his neck and face. Oxygen was administered and 10 mg of dexamethasone with 2 mg of epinephrine was injected. The patient's heart rate dropped, his blood pressure decreased, and his arterial oxygen saturation (SaO 2) declined progressively. About 10 minutes after the administration of protamine sulfate, the patient developed bradycardic arrest. Cardiopulmonary resuscitation efforts were undertaken and the patient was administered epinephrine 2 mg IV, atropine 0.5 mg IV, and subsequently, intravenous dopamine (50 mg/h). Ten minutes later, the patient's heart rate gradually increased, but blood pressure fluctuated, and SaO 2 ranged from 90% to 100%. Despite the initial response, the patient lost consciousness and heart rate declined progressively within 5 hours. Vasoactive agents including dopamine, norepinephrine, and adrenaline were administered. After all these measures proved inef- fectual, the patient died. It was later determined that the patient had a history of allergic reactions to fish as well as to a premixed insulin that contained soluble human insulin 30% and low-protein intensive insulin zinc 70% (NPH). The Naranjo adverse drug reaction probability scale score for the association of protamine with the allergic reaction was 4, suggesting a possible relationship. Conclusion: This case report highlights a preventable fatal allergic reaction possibly associated with protamine administration in a patient with a history of allergy to a protamine-containing insulin.

Acute hepatitis associated with the use of levofloxacin

Background: Levofloxacin is a fluoroquinolone used globally to treat respiratory, skin, and genitourinary tract infections. It is generally well tolerated and there is a very low risk for liver injury in patients taking this antibiotic. Objective: We report an acute case of hepatitis following treatment with levofloxacin for pneumonia. Case summary: A 77-year-old white male (height, 162 cm; weight, 58 kg) with chronic bronchitis presented to the emergency department of the Hospital Curry Cabral, Lisbon, Portugal, with respiratory difficulty and productive cough. The patient had a history of chronic bronchitis, arterial hypertension, hypercholesterolemia, and benign prostatic hyperplasia, and was being treated with salmeterol 50 μg plus fluticasone 250 μg BID, and amlodipine 5 mg, simvastatin 20 mg, alfuzosin 10 mg, and finasteride 5 mg once daily. Initially, the patient refused admission and was sent home, medicated with levofloxacin 500 mg once daily (single dose) for pneumonia and acetaminophen 1 g (as needed, maximum TID) if axillary temperature exceeded 38.0°C (100.4°F). Three days later, the patient returned for a follow-up visit, and despite clinical and radiologic improvement, blood tests revealed a slight aggravation of anemia. On the seventh day of treatment with levofloxacin, the patient showed an elevation of transaminases. The temporal relation between the use of levofloxacin and the liver injury, the exclusion of other causes of hepatitis, and a compatible liver biopsy (conducted 14 days after identification of hepatitis) was consistent with the diagnosis of levofloxacin-associated hepatotoxicity. Levofloxacin treatment was stopped and the patient made a full recovery. The Naranjo Adverse Drug Reaction Probability Scale score for this association was “probable” (score 7) and the Roussel Uclaf Causality Assessment Method Scale score was “highly probable” (score 9). Unlike the 5 reported cases in the literature, this is the only case in which both a liver biopsy was performed in the course of the disease and the patient survived. Conclusion: The acute hepatitis observed in this elderly patient was probably associated with the administration of levofloxacin.

Lisinopril‐Induced Nightmares

Drug‐induced nightmares have been reported in the literature and are a known adverse effect of certain antihypertensive agents such as α‐agonists and β‐blockers. Data are limited, however, on the association of this adverse effect with angiotensin‐converting enzyme (ACE) inhibitors. We describe a 63–year‐old, obese woman, with no history of illicit drug abuse, alcohol abuse, or psychiatric illness, who developed nightmares after starting lisinopril 10 mg/day for blood pressure control. The drug was discontinued, triamterene‐hydrochlorothiazide was started, and her nightmares ceased. One year later, the patient continued to have no complaints of nightmares. At that time, however, her blood pressure was slightly elevated. Triamterene was discontinued, and lisinopril was restarted at a lower dose of 5 mg/day in addition to hydrochlorothiazide 25 mg/day. Her nightmares returned; however, the patient decided to continue taking the lisinopril and tolerate the nightmares. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient's development of nightmares and lisinopril therapy. The exact mechanism by which ACE inhibitors cause this drug reaction is not known. Clinicians should be aware of this potential adverse effect when monitoring patients receiving ACE inhibitors.

Hepatotoxicity Associated with Chinese Skullcap Contained in Move Free Advanced Dietary Supplement: Two Case Reports and Review of the Literature

Move Free Advanced is a widely available dietary supplement in the United States, marketed to comfort sore joints and improve flexibility and mobility. This product contains glucosamine, chondroitin, hyaluronic acid, and Uniflex proprietary extract, which is a combination of Chinese skullcap and black catechu. We describe two patients who developed hepatotoxicity after ingesting a Move Free Advanced product. In both patients, the hepatotoxicity resolved after discontinuation of the supplement. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6 for both patients) between the patients' development of hepatotoxicity and the Move Free Advanced supplement. Based on a review of the literature, the herbal extract Chinese skullcap is the most likely cause of the hepatotoxicity. To our knowledge, these two cases are the first to be published regarding possible hepatotoxicity associated with Move Free Advanced. Patients seeking dietary supplements for osteoarthritis may want to avoid glucosaminechondroitin products such as Move Free Advanced that also contain Chinese skullcap.

Drug Interaction Between Itraconazole and Bortezomib: Exacerbation of Peripheral Neuropathy and Thrombocytopenia Induced by Bortezomib

To investigate whether a drug interaction exists between bortezomib and the cytochrome P450 (CYP) 3A4 inhibitor itraconazole and/or the CYP2C19 inhibitor lansoprazole that results in increased severity of bortezomib-induced peripheral neuropathy and thrombocytopenia. Retrospective medical record review. Hematology-oncology ward of a university-affiliated hospital in Japan. Six adults with relapsed multiple myeloma who received intravenous bortezomib plus oral dexamethasone as the first course of a 21-day cycle between July 2007 and December 2008. Four of the six patients were treated concomitantly with itraconazole or lansoprazole: two with itraconazole, one with lansoprazole, and one with both itraconazole and lansoprazole. Using the National Cancer Institute's Common Terminology Criteria for Adverse Events, we identified the presence and graded the severity of peripheral neuropathy and thrombocytopenia before and during each patient's first 21-day course of bortezomib plus dexamethasone therapy. All three patients who received itraconazole experienced new or worsening peripheral neuropathy; they also experienced grade 4 thrombocytopenia. The patient who received lansoprazole alone, as well as the two patients who did not receive itraconazole or lansoprazole, had no changes in either adverse effect. We also evaluated the relationship between peripheral neuropathy and bortezomib plus dexamethasone therapy by using the Naranjo adverse drug reaction probability scale, and a probable relationship was found. We further assessed whether a drug interaction between bortezomib and itraconazole and/or lansoprazole had occurred involving the CYP3A4 and/or the CYP2C19 pathways, respectively-resulting in increased severity of the bortezomib-induced peripheral neuropathy and thrombocytopenia-by using the Horn drug interaction probability scale. We found that the occurrence of this drug interaction was strongly supported. Itraconazole appears to exacerbate peripheral neuropathy and thrombocytopenia induced by bortezomib; however, the mechanism of this drug interaction is unknown. Clinicians should closely monitor for bortezomib-induced adverse effects when itraconazole, or any other potent CYP3A4 inhibitor, is administered concomitantly with bortezomib.

Probable valproate sodium-associated hypotension

Background: Valproate sodium, a commonly used antiepileptic drug (AED), is effective for the treatment of status epilepticus and is often used as a second-line agent when other AEDs are contraindicated. Some studies have reported that infusion of valproate sodium is generally well tolerated, whereas other studies have reported various degrees of hypotension during infusion. The objective of this case report was to call attention to the potential risk of hypotension after intravenous infusion of valproate sodium. Case summary: This was the case of a 75-year-old Hispanic man (height, 145 cm; weight, 68 kg) who developed hypotension after receiving an intravenous loading dose of valproate sodium. The patient received the loading dose 12 hours after administration of his last dose of phenytoin (300 mg daily), which had been discontinued secondary to a cutaneous drug reaction. The patient's medical history was significant for seizure disorder, a cerebrovascular accident, and controlled type 2 diabetes mellitus. He was taking glyburide 5 mg daily and aspirin 81 mg daily. At baseline, the patient's blood pressure (measured while seated, at rest, using an upper-extremity cuff) was 135/70 mm Hg. The intravenous loading dose of valproate sodium (20 mg/kg) was administered at a rate of 14 mg/min (total dose, 1280 mg over 90 min). Approximately 2.5 hours after completion of the loading dose, the patient's blood pressure decreased to 107/48 mm Hg. Because our standard operating procedure is to measure blood pressure every 4 hours after the baseline measurement, the patient's hypotension was not detected during the infusion. The next morning (22 hours after completion of the valproate sodium infusion), divalproex sodium 1000 mg orally once daily was initiated as maintenance therapy. The patient's blood pressure reached a nadir of 82/44 mm Hg. The hypotension was treated initially with intravenous fluid hydration with normal saline, but the blood pressure correction was transient using this approach. The patient remained hypotensive for 3 days. The hypotension was ultimately found to be self-limited, and the patient was asymptomatic throughout his hospital stay. The patient's Naranjo adverse drug reaction probability scale score was 6, indicating that the relationship between valproate sodium infusion and hypotension was probable. Conclusion: In this case report, infusion of valproate sodium at a rate of 14 mg/min was a probable cause of hypotension in a 75-year-old man.

Statin‐Associated Muscle‐Related Adverse Effects: A Case Series of 354 Patients

To characterize the properties and natural history of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin)-associated muscle-related adverse effects (MAEs). Patient-targeted postmarketing adverse-effect surveillance approach coupling survey design with an open-ended narrative. University-affiliated health care system. Three hundred fifty-four patients (age range 34-86 yrs) who self-reported muscle-related problems associated with statin therapy. Patients with perceived statin-associated MAEs completed a survey assessing statin drugs and dosages; characteristics of the MAEs; time course of onset, resolution, or recurrence; and impact on quality of life (QOL). Cases were assessed for putative drug adverse-effect causality by using the Naranjo adverse drug reaction probability scale criteria and were evaluated for inclusion in groups for which mortality benefit with statins has been shown. Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p<0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p<0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and QOL domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy. This study complements available information on the properties and natural history of statin-associated MAEs, affirming dose dependence and strong QOL impact. The data indicating a dose-dependent relationship between MAE risk and recurrence suggest lower potency statins or discontinuation may bear consideration for ameliorating symptoms.

Off-Label and Unlicensed Medication Use and Associated Adverse Drug Events in a Pediatric Emergency Department

The study objectives were to (1) determine the types and frequency of off-label (OL) or unlicensed (UL) medications used in a pediatric emergency department (PED) and before admission, (2) describe OL/UL-associated adverse drug events (ADEs) resulting in admission to the PED and those occurring during patient care in PED, and (3) determine the outcomes of these ADEs. Medical records of patients 18 years or younger admitted to the PED over a 5-month period were reviewed. Off-label/UL use of medications was determined based on Food and Drug Administration-approved labeling. The Adverse Drug Reaction Probability Scale was used to determine ADE causality. Data were analyzed using descriptive statistics. A total of 2191 patients with 6675 medication orders were evaluated. About 26.2% (n = 1712) of medication orders were considered as OL/ UL use; 70.5% (n = 1208) of these medications were ordered as part of treatment in the PED, and the remaining 29.5% (n = 504) were home medications before their PED evaluation. Inhaled bronchodilators (30.4%), antimicrobials (14.8%), and antihistamines/antiemetics (9.1%) were the most common OL/UL medication classes. The frequency of ADEs among licensed medication use was greater compared with OL/UL use by 2-fold. Reported overall rate of ADEs was 0.6% (n = 40). Of these 40 ADEs, 5 resulted from the use of an OL/UL medication, 3 from home medication use, and 2 from PED-prescribed medications. The frequency of reported ADEs associated with OL/UL medications was less than the frequency of ADEs from licensed medication use, with overall ADE frequency of less than 1%.

Concomitant administration of simvastatin and danazol associated with fatal rhabdomyolysis

Background: Simvastatin, a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor, is indicated for the treatment of hypercholesterolemia and plays an important role in both the primary and secondary prevention of cardiovascular disease. Danazol is a steroid analogue approved for the treatment of endometriosis, fibrocystic breast disease, and hereditary angioedema. Despite not being licensed, danazol has been used for other off-label indications, such as idiopathic thrombocytopenic purpura (ITP), paroxysmal nocturnal hemoglobinuria, and aplastic anemia. Objective: We report a case of fatal rhabdomyolysis that occurred after concomitant administration of simvastatin and danazol in a patient with ITP. Case summary: An 80-year-old white male (height, 182 cm; weight, 90 kg) presented to the emergency department of the Clinical Hospital Centre Zemun, Belgrade, Serbia, with head injuries after an accidental fall caused by generalized weakness. He denied other complaints, except fatigue, mild pretibial edema, and progressive bilateral leg pain and cramping that began 7 days before. At the time of presentation, he was receiving aspirin 100 mg/d, clopidogrel 75 mg/d, ramipril 2.5 mg/d, pantoprazole 40 mg/d, danazol 600 mg/d, prednisone 60 mg/d, simvastatin 40 mg/d, and longacting insulin 24 IU/d. After the injuries were treated, he was diagnosed with collapse and nasal contusion, and discharged without any changes in his therapy. Two days after initial presentation, the patient was readmitted to the hospital due to nausea, dark urine, and oliguria. All clinical signs (oliguria, dark urine, muscle pain, and tenderness) and laboratory markers (creatine kinase levels ∼100 times the upper limit of normal, along with hyperkalemia, hyperphosphatemia, and hypoalbuminemia) were consistent with severe rhabdomyolysis. Despite intravenous hydration, forced diuresis, and hemodialysis, oliguria persisted and the patient died 6 days after admission. A score of 5 on the Naranjo adverse drug reaction probability scale was consistent with a probable association of rhabdomyolysis and concomitant treatment with simvastatin and danazol in this patient. Conclusions: Statin-induced rhabdomyolysis must be considered whenever muscle or motor symptoms occur, especially when concomitant treatment with known inhibitors of statin metabolism is administered. Patients must be strictly monitored and the statin should be promptly discontinued with the onset of first signs and symptoms of myopathy. Clinicians should be aware of the potentially fatal consequences of both approved and unapproved treatments and be alert for the early detection of toxicity.

Trimethoprim‐Sulfamethoxazole‐Induced Hepatotoxicity in a Pediatric Patient

Due to the escalating rates of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection, trimethoprim-sulfamethoxazole (TMP-SMX) is being used increasingly in the pediatric population for skin and soft tissue infections. Although this combination agent has been associated with a hypersensitivity syndrome involving cutaneous skin eruptions, pediatric cases of TMP-SMX-induced hepatotoxicity are rare. We describe a relatively healthy, 9-year-old boy who developed a CA-MRSA skin and soft tissue infection and was treated with TMP-SMX. After 14 days of therapy, he was taken to the emergency department with a 3-day history of fever, headache, and neck pain. He was diagnosed with a viral syndrome, acetaminophen was prescribed, and he was sent home. Three days later, the patient returned to the emergency department with fever, vomiting, decreased energy and appetitie, and suprapubic abdominal pain, and he was hospitalized. Laboratory test results revealed elevated liver function test values. After other potential causes of liver toxicity were excluded, TMP-SMX was determined to be the cause of his acute liver toxicity. The drug was discontinued, his symptoms resolved, and his liver function tests returned to normal. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's development of hepatotoxicity and the TMP-SMX therapy. This rare adverse reaction to TMP-SMX has been reported in adults; however, to our knowledge, it has been reported in only five other children. Due to the increasing use of TMP-SMX in children, clinicians should be aware of this potentially life-threatening, immunemediated hypersensitivity reaction. Fortunately, however, the hepatotoxicity appears to resolve after discontinuation of the TMP-SMX therapy in most reported cases. This case report illustrates the importance of early detection of drug-induced hepatotoxicity and timely drug discontinuation to prevent the need for liver transplantation.

Solar Burn Reactivation Induced by Methotrexate

Solar burn reactivation, a rare and idiosyncratic drug reaction, has been reported with the use of a variety of drugs. This reaction is believed to be the result of exposure to ultraviolet light during the subsiding phase of an acute inflammatory reaction. It affects areas of the body that have been previously sunburned. We describe a 16-year-old girl who was receiving treatment for acute lymphoblastic leukemia and experienced a second-degree solar burn reactivation reaction to methotrexate. The patient had a mild sunburn on her face and shoulders the day she went to the oncology clinic for her interim maintenance chemotherapy with vincristine 1.5 mg/m(2)/dose and methotrexate 100 mg/m(2)/dose. Three days later, she returned to the clinic with a 2-day history of fever (<or= 100.2 degrees F), nausea, vomiting, and malaise; the sunburn on her face and shoulders also had become severe, without further sun exposure. Laboratory results revealed elevated blood urea nitrogen and serum creatinine concentrations, and her methotrexate level was elevated at 0.9 mM. The patient was diagnosed with acute renal failure, dehydration, methotrexate toxicity, and second-degree solar burn reactivation reaction. She was admitted to the children's hospital and treated with sodium bicarbonate, acetaminophen with codeine, ondansetron, and silvadene cream. On hospital day 3, the patient's methotrexate level decreased to less than 0.1 mM. The sunburn continued to heal, and after a 14-day hospital stay, complicated by a streptococcal infection, grade 3 mucositis, bacteremia, and mild gastritis and duodenitis, the patient recovered and was discharged. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 6) between the patient's solar burn reactivation and methotrexate. Although methotrexate-induced solar burn reactivation is rare, clinicians should be aware of this potential adverse reaction and consider delaying administration of methotrexate by 5-7 days if a patient reports ultraviolet-related erythema in the past 2-4 days or presents with a notable sunburn.