Abstract
Keywords
Metronidazole No. 29
Encephalopathy, Neurotoxicity
A 43-year-old female patient developed sudden bilateral hearing loss, ataxia, and vertigo approximately 20 days after starting metronidazole (total dose = 28 g) as part of a regimen for the treatment of Helicobacter pylori. A physical examination revealed lethargy, encephalopathy, slurred speech, and apathy. Despite normal muscle tone, the muscle force was decreased on the right side of the body. Screenings for infectious etiologies were negative. A brain magnetic resonance imaging demonstrated bilateral symmetric T2-weighted hypersignal lesions in dentate nucleus, the splenium of corpus callosum, and cerebral white matter. Metronidazole was discontinued and treatment with L-carnitine and coenzyme Q10 was initiated with significant improvements observed in hearing and walking within 3 days.
The authors concluded that this patient experienced metronidazole-induced encephalopathy and neurotoxicity based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. Suggested mechanism of action included mitochondrial dysfunction, inhibition of protein synthesis by binding to neural RNA, and modifying cerebellar and vestibular γ-aminobutyric acid receptors.
Metronidazole [“Flagyl”]
Agah E et al (A Tafakhori, NeuroImmunology Research Association, Universal Scientific Education and Research Network, Tehran, Iran; e-mail:
Everolimus No. 30
Acute Kidney Injury
A 57-year-old women developed oliguric kidney damage over 2 weeks after receiving 3 weeks of everolimus therapy during a clinical trial for metastatic breast cancer. Concurrent trial medications included zoledronic acid. Significant laboratory findings included increased serum creatinine (baseline 74 µmol/L to 1200 µmol/L) and urea (baseline 8.6 mmol/L to 46 mmol/L). Renal biopsy revealed extensive tubular epithelial injury, cytoplasmic vacuolation, luminal shedding of cells, tubular dilatation, and epithelial simplification. Treatment included 3 weeks of hemodialysis, discontinuation of everolimus and zoledronic acid, and administration of sodium bicarbonate. After renal function returned to baseline, zoledronic acid was restarted. No adverse effects on renal function occurred. Six months later, everolimus was reinitiated and resulted in impaired renal function (serum creatinine 800 µmol/L). Additional treatment included 1 week of hemodialysis and discontinuation of everolimus. Chronic kidney dysfunction not requiring dialysis (serum creatinine 160 µmol/L) remained, and hormone-based chemotherapy was initiated.
The authors concluded that this case described non-oliguric kidney damage related to everolimus therapy. The proposed mechanism was everolimus-induced tubular injury via autophagy of tubular epithelial cells.
Everolimus [“Afinitor,” “Afinitor Disperz”]
Chan S et al (S Chan, Cancer Care Services, Redcliffe Hospital, Queensland, Australia) Everolimus-induced tubular toxicity in non-renal cancer. Intern Med J 46:1454–1455 (Dec) 2016
Fluorouracil (Topical) No. 31
FDA Center for Veterinary Medicine Update: Pet Deaths
On January 18, 2017, the US Food and Drug Administration (FDA) alerted pet owners, veterinarians, health care providers, and pharmacists regarding an increased risk of illness and death in pets associated with the human use of topical Fluorouracil Cream USP 5%. This alert was based on the receipt of fatal reports of 5 dogs that became ill and died after accidentally ingesting the topical cream. In one case, a dog punctured the tube during play with another dog. The dog that punctured the tube began vomiting, seizing within 2 hours, and died 12 hours later. In another case, complete ingestion of a tube by a dog resulted in eventual euthanization despite attempts to save the dog’s life. Although no reports have been received to date involving fluorouracil cream and cats, it is suspected that cats would be similarly susceptible to serious side effects with ingestion. In addition, owners are cautioned that using the cream without washing their hands before petting their cats would potentially expose the cats to ingestion when grooming themselves. The FDA recommends that people who use fluorouracil take care to prevent their pets from accidentally ingesting the medication.
Fluorouracil, Topical [“Carac,” “Effudex,” “Fluoroplex”]
FDA Center for Veterinary Medicine Update: FDA warns of illnesses and deaths in pets exposed to prescription topical (human) cancer treatment: fluorouracil. http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm537434.htm (Jan 18) 2017
Calcineurin Inhibitors No. 32
Hyperkalemic Renal Tubular Acidosis in Solid Organ Transplant Recipients
Four cases of hyperkalemia and renal tubular acidosis associated with the use of calcineurin inhibitors are summarized.
Patient 1. A 59-year-old male patient with end-stage renal disease and subsequent renal transplantation developed hyperkalemia (6.0 mmol/L) on postoperative day 13.
Posttransplant therapy included cyclosporine A (350 mg/day), mycophenolate sodium, prednisone, and sulfamethoxazole-trimethoprim. The early postoperative recovery phase was uneventful with appropriate graft function. Initial treatment with sodium bicarbonate and loop diuretics resulted in potassium normalization, and the patient was eventually discharged. However, on postoperative day 19, the patient was readmitted with a urinary tract infection and an increased creatinine level (418 µmol/L). Though treatment with an antibiotic resulted in decreased serum creatinine by day 31 (152 µmol/L), the potassium levels were elevated and remained elevated despite treatment. An arterial blood gas on postoperative day 43 revealed a non-gap metabolic acidosis, suggesting hyperkalemic renal tubular acidosis. Treatment was initiated with fludrocortisone (0.2 mg daily), which resulted in a decreased potassium level by discharge on day 49 (4.26 mmol/L). Follow-up during the next 2 years revealed that though the graft function remained stable attempts to wean the fludrocortisone dosage were unsuccessful, resulting in recurrence of hyperkalemia.
Patient 2. A 52-year-old male with end-stage renal disease and subsequent renal transplantation was readmitted on postoperative day 32 with weakness, palpitations, hyperkalemia (6.4 mmol/L), increased serum creatinine (202 µmol/L), and an increased anion gap (9.7 mmol/L) and urinary anion gap (28 mmol/L), suggestive of hyperkalemic renal tubular acidosis. The initial immunosuppression regimen consisted of tacrolimus, mycophenolate mofetil, and prednisone without evidence of hyperkalemia, though delayed graft function was noted. Treatment with sodium bicarbonate and loop diuretics was initiated with correction of hyperkalemia. During an 18-month follow-up, the serum creatinine remained stabilized with recurrence of hyperkalemia.
Patient 3. A 59-year-old male patient with hepatitis B virus–related hepatic cirrhosis and hepatocellular carcinoma and subsequent liver transplantation developed hyperkalemia on postoperative day 20 (6.18 mmol/L), noted on a routine follow-up visit. Renal function was normal prior to the transplant but at the time of increased potassium levels, it was also elevated (124 µmol/L). Immunosuppressive therapy posttransplant consisted of tacrolimus, mycophenolate mofetil, and prednisone. Antiviral drug, which was initially lamivudine and adefovir, was switched to entecavir. Arterial blood gases revealed a non-gap metabolic acidosis, suggestive of hyperkalemic renal tubular acidosis. Treatment with sodium bicarbonate and loop diuretics resulted in normalization of renal function and rapid reduction of potassium levels. Sirolimus was substituted for tacrolimus. Follow-up was uneventful.
Patient 4. A 48-year-old male patient with biventricular heart failure and subsequent heart transplantation developed sudden hyperkalemia and non-gap metabolic acidosis with hyperchloremia on postoperative day 35. Immunosuppressive therapy posttransplant consisted of tacrolimus, mycophenolate mofetil, and prednisone. Treatment with sodium bicarbonate and loop diuretics resulted in the normalization of potassium levels. However, during follow-up, hyperkalemia recurred frequently, requiring the substitution of sirolimus for tacrolimus.
The authors concluded that these patients experienced hyperkalemic renal tubular acidosis related to calcineurin inhibitor therapy, possibly caused by a defect in potassium secretion.
Calcineurin Inhibitors [Tacrolimus, Cyclosporine]
Lin W et al (L Mou, Department of Nephrology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, No. 88, Jiefang Road, Hangzhou, Zhejiang 310009, China; e-mail:
Dopamine Agonists No. 33
Heart Failure
A pharmacoepidemiological study was performed via a case/noncase analysis using data from the World Health Organization Global Individual Case Safety Reports database to evaluate a potential signal strengthening of heart failure in patients over the age of 45 years treated with dopamine agonists for Parkinson’s disease. A total of 16 897 World Health Organization Global Individual Case Safety Reports involved dopamine agonists. Of these, 154 were registered as heart failure in patients with Parkinson’s disease that received a dopamine agonist. Mean age was 69.9 ± 9.7 (range = 48-89) years. The majority (51.3%) were women. Dopamine agonists included bromocriptine, pergolide, cabergoline, rotigotine, piribedil, pramipexole, ropinirole, and apomorphine. A signal between dopamine agonist exposure and the occurrence of heart failure was observed with pergolide (reporting odds ratios = 4.66, 95% confidence interval = 3.72-5.58; P < .001) and cabergoline (reporting odds ratio = 3.72, 95% confidence interval = 2.76-5.02; P < .001). A signal was not observed between the following dopamine agonists and the occurrence of heart failure: bromocriptine (reporting odds ratio = 0.47, 95% confidence interval = 0.24-0.9), rotigotine (reporting odds ratio = 0.37, 95% confidence interval = 0.19-0.72), piribedil (reporting odds ratio = 0.37, 95% confidence interval = 0.12-1.16), pramipexole (reporting odds ratio = 0.97, 95% confidence interval = 0.75-1.26), ropinirole (reporting odds ratio = 0.54, 95% confidence interval = 0.39-0.76), or apomorphine (reporting odds ratio = 0.67, 95% confidence interval = 0.37-1.22). A signal was also observed with ergot derivatives in general (reporting odds ratio = 2.78, 95% confidence interval = 2.33-3.30; P < .0001); however, a signal was not observed with non-ergot dopamine agonists (reporting odds ratio = 0.68, 95% confidence interval = 0.56-0.81) or dopamine agonists in general including both ergot and non-ergot dopamine agonists (reporting odds ratio = 1.15, 95% confidence interval = 1.02-1.31).
The authors concluded that results of this study demonstrated a significant signal between the occurrence of heart failure and exposure to ergot dopamine agonists, but not non-ergot dopamine agonists, in patients with Parkinson’s disease. The proposed mechanism was ergot dopamine agonist-induced stimulation of cardiac 5HT2B receptors resulting in activation of fibroblasts, pulmonary hypertension, and ultimately heart failure.
Dopamine Agonists [“Apokyn,” “Dostinex,” “Mirapex,” “Neupro,” “Parlodel,” “Permax,” “Piribedil,” “Requip”]
Montastruc F et al (JL Montastruc, Laboratoire de Pharmacologie Médicale et Clinique de la Faculté de Médecine et du Centre Hospitalier Universitaire de Toulouse, Toulouse, France; e-mail:
PNC-27 No. 34
FDA Safety Alert: Bacterial Contamination
On January 10, 2017, the US Food and Drug Administration (FDA) alerted patients not to purchase or use PNC-27 products as laboratory analysis had revealed contamination with Variovorax paradoxus in a PNC-27 solution sample for inhalation. This product is sold via the Internet for the treatment of cancer. Immunosuppressed patients, many who have cancer, are at increased risk of developing potentially life-threatening infections with the use of such a product. To date, the FDA has not received reports of illnesses or serious adverse events related to PNC-27 use.
PNC-27 [“PNC-27”]
FDA Safety Alert: FDA warns cancer patients not to use PNC-27 products for treatment. http://www.fda.gov/Drugs/DrugSafety/ucm536094.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery (Jan 10) 2017
Nonsteroidal Anti-Inflammatory Drugs No. 35
Cardiovascular Risk
A meta-analysis reviewed 26 studies (randomized, controlled trials, and prospective cohort studies) in an evaluation of cardiovascular risk associated with the use of 8 selected nonsteroidal anti-inflammatory drugs (celecoxib, diclofenac, etoricoxib, ibuprofen, lumiracoxib, naproxen, meloxicam, and rofecoxib). Primary endpoints for cardiovascular risk included any myocardial infarction, any stroke, and cardiovascular death, and a composite cardiovascular outcome. Meloxicam was dropped from the analysis when the only study did not meet inclusion criteria. Incidence of myocardial infarction was increased by rofecoxib when compared to all nonsteroidal anti-inflammatory drugs (odds ratio = 1.811, 95% confidence interval = 1.379-2.378), placebo (odds ratio = 1.655, 95% confidence interval = 1.029-2.661), nonselective nonsteroidal anti-inflammatory drugs (odds ratio = 2.155, 95% confidence interval = 1.146-4.053), and COX inhibitors (odds ratio = 1.800, 95% confidence interval = 1.217-2.662). Incidence of stroke was increased by rofecoxib in comparisons with all nonsteroidal anti-inflammatory drugs and other COX inhibitors ([odds ratio = 1.488, 95% confidence interval = 1.027-2.155] and [odds ratio = 1.933, 95% confidence interval = 1.052-3.549], respectively). Celecoxib exhibited a decrease in stroke when compared with all nonsteroidal anti-inflammatory drugs (odds ratio = 0.603, 95% confidence interval = 0.410-0.887, P = .010) and other COX inhibitors (odds ratio = 0.509, 95% confidence interval = 0.280-0.925, P = .027). None of the studied nonsteroidal anti-inflammatory drugs exhibited significant difference in cardiovascular death. Celecoxib demonstrated an overall lower incidence of the composite cardiovascular outcome when compared with all nonsteroidal anti-inflammatory drugs and the other COX inhibitors, but this benefit did not persist when rofecoxib was excluded from the COX inhibitors analysis.
Based on the findings of this analysis, the authors suggested that COX-2 selectivity may not play a role in the cardiovascular risk of nonsteroidal anti-inflammatory drugs. They noted that rofecoxib was the only drug to demonstrate harm and possibly skewed the data of the COX-2 selective group in the analysis.
Celecoxib [“Celebrex”]
Diclofenac [“Diclofenac”]
Etoricoxib [“Eflam,” “Etocox,” “Etorix”]
Ibuprofen [“Advil,” “Motrin”]
Lumiracoxib [“Prexige”]
Naproxen [“Aleve”]
Rofecoxib [“Vioxx”]
Gunter BR et al (S Harirforoosh, Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Box 70594, Johnson City, TN 37614-1708; e-mail:
Rivaroxaban No. 36
Severe Esophagitis Dissecans (First Report*)
An 82-year-old female developed chest pain radiating into the back, odynophagia, and vomiting approximately 8 weeks after initiating rivaroxaban for the treatment of acute pulmonary embolus. No concurrent medications were reported. A computed tomography revealed marked posterior mediastinitis and a distended esophagus with solid debris. Gastroscopy revealed longitudinal tears, desquamation of the esophagus, and food impaction on the sloughed esophageal tissue. Treatment included clearing of the bolus and discontinuation of rivaroxaban. Anticoagulation was changed to enoxaparin while conversion to warfarin was completed.
The authors concluded that this was the first report of esophagitis dissecans during rivaroxaban therapy. The authors stated that the mechanism was unknown.
Rivaroxaban [“Xarelto”]
Cox R et al (R Cox, Department of Gastroenterology, The Townsville Hospital, Townsville, Queensland, Australia) Novel oral anticoagulant drugs and severe oesophagitis dissecans. Intern Med J 46:1456–1457 (Dec) 2016
Sofosbuvir, Daclatasvir No. 37
Erythema Multiforme Drug Eruption in Patient With a History of Psoriasis
A 55-year old male patient was hospitalized with general erythema with pruritus, which had developed approximately 3 weeks after starting sofosbuvir (400 mg daily) and daclatasvir (60 mg daily) for the treatment of hepatitis C (genotype 1). Prior to hospitalization, the patient also used ultraviolet irradiation therapy, which worsened the condition; erythroderma covered the entire body. As the reaction was suspected to be related to drug therapy, the hepatitis regimen was discontinued. In addition to the general erythema on the entire body, thick desquamation was also present on the trunk, arms, and legs, with pustular rashes on the neck.
Abnormal laboratory values included albumin (26 g/L), serum prealbumin (4.6 mg/dL), immunoglobulin E (>2500 IU/mL), and cholinesterase (3097 U/L). Additional values demonstrated hyponatremia, hypochloremia, hypocalcemia, hypophosphatemia, and hypomagnesemia. Screenings for other infectious etiologies were negative. Treatment included human immunoglobulin, compound glycyrrhizin (160 mg/day), loratadine (10 mg/day), ebastine (10 mg/day), zinc oxide boric acid cream, calcium supplements, and albumin infusion. In addition, cyclosporine was also initiated to help control pustular psoriasis. With this therapy, the patient’s condition improved, resulting in discharge. The patient did not start new therapy for the hepatitis C.
The authors concluded that this patient (with a history of psoriasis) developed an erythema multiforme drug eruption related to hepatitis C treatment with sofosbuvir and daclatasvir based on the temporal relationship between the drug administration and the appearance and resolution of symptoms. The drug causality relationship was classified as probable when evaluated according to the Naranjo algorithm.
Sofosbuvir [“Harvoni”]
Daclatasvir [“Daklinza”]
Wang Y & Liu P (P Liu, Department of Infectious Diseases, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, China; e-mail:
Tanning Bed No. 38
Hypervitaminosis D
A 48-year-old postmenopausal female patient was noted to have increased levels of total alkaline phosphatase and 25-(OH)D during evaluation of a spontaneous pubic and bilateral sacrum fracture. Calcium levels were normal. Treatment with a single zoledronic acid infusion normalized alkaline phosphatase levels. Retesting approximately 1.5 years later confirmed elevated 25-(OH)D levels and increased 1,25-dihydroxyvitamin D3. There was no history of calcium or vitamin D ingestion but that patient did report using a tanning bed 4 to 5 times weekly and sitting in natural sunlight as much as possible to alleviate chronic musculoskeletal pain. On advice, the patient reduced tanning bed activity to once weekly, which resulted in normalization of 25(OH)-D and 1,25-dihydroxyvitamin D concentrations during the next several months.
The authors concluded that this patient experienced hypervitaminosis D related to tanning bed use, most likely due to ultraviolet B exposure.
Tanning Bed [Tanning Bed]
Laurent MR et al (MR Laurent, University Hospitals Leuven, Leuven, Belgium) Hypervitaminosis D associated with tanning bed use: a case report. Ann Intern Med 166:155–156 (Jan) 2017
Posaconazole No. 39
Acute Pancreatitis
A female patient (age not provided) developed severe epigastric pain and mild nausea approximately 5 days after starting posaconazole (300 mg 3 times daily) therapy for severe refractory mucositis. A physical examination revealed epigastric and right upper quadrant tenderness but abdominal wall rigidity was absent. Abnormal laboratory values included serum lipase (289 IU/L). Liver function tests and lipid panel were within normal limits. The temporal relationship between the drug and appearance of symptoms focused posaconazole as a potential suspect and the drug was discontinued on day 20 of therapy. Once the drug was discontinued, improvements in pain occurred with complete resolution by 6 weeks. Follow-up at 3 months revealed no further events and complete recovery. Lipase levels were within normal limits, and a follow-up abdominal magnetic resonance imaging demonstrated no abnormalities.
The authors concluded that posaconazole-induced acute pancreatitis occurred in this patient based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. Potential proposed mechanisms of action included pancreatic duct constriction, cytotoxic and metabolic effects, accumulation of a toxic metabolite or intermediary, and hypersensitivity reactions. Though this is suspected to be a rare adverse event associated with this drug, the authors suggested that clinicians be aware of its possibility.
Posaconazole [“Noxafil,” “Posanol”]
Pilmis B et al (B Pilmis, Paris Descartes University, Sorbonne Paris Cité, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Necker-Enfants Malades University Hospital, AP-HP, Imagine Institute, Paris, France; e-mail:
Intravenous Immunoglobulin No. 40
False Positive Hepatitis B Surface Antibodies
A 60-year-old male patient tested positive for HB core antibody after receiving intravenous immunoglobulin and high-dose oral prednisone (1 mg/kg/day) for the treatment of chronic inflammatory demyelinating polyneuropathy. Testing was performed after partial response to this therapy prompted the initiation of cyclophosphamide. Because guidelines note that there is a moderate risk of hepatitis B virus reactivation with the use of cyclophosphamide, the patient was tested as a baseline precaution. Testing occurred at 13 days following the most recent intravenous immunoglobulin infusion. As a result of the positive test, lamivudine antiviral prophylaxis was started. It was determined that the patient was HB core antibody negative prior to receiving intravenous immunoglobulin infusions. Subsequent testing revealed a decrease in HB core antibody levels, suggesting that the first batch of intravenous immunoglobulin was primarily responsible for the positive HB core antibody results.
The authors concluded that this patient became HB core antibody positive as a result of HB surface antibody transfused from intravenous immunoglobulin as the patient tested HB core antibody negative prior to intravenous immunoglobulin therapy, had no history of hepatitis B virus vaccination, and the titer reduced after the first batch of intravenous immunoglobulin administration.
Immunoglobulin [Intravenous Immunoglobulin]
Benwell N et al (N Benwell, Department of Immunology, Fiona Stanley Hospital and Pathwest Laboratory Medicine, Perth, Western Australia, Australia) False positive hepatitis B virus core and surface antibodies due to intravenous immunoglobulin. Internal Med J 47:119–120 (Jan) 2017
Alteplase No. 41
Angioedema
A 70-year-old male patient experienced tongue swelling, difficulty speaking, and swallowing shortly after (30 minutes) receiving a dose of intravenous alteplase. The patient was initially admitted with left facial droop, left-sided hemiparesis, hemisensory loss, and right gaze deviation for less than 1 hour prior to admission. Medications on admission included lisinopril (10 mg daily), metformin (500 mg twice daily), and aspirin (325 mg daily). The patient had no known allergies or history of angioedema events. The symptoms initially improved but then rapidly reversed with tongue swelling developing rapidly. Treatment included intubation and the administration of methylprednisolone and diphenhydramine. The angioedema resolved over the next 24 hours.
The authors concluded that this patient experienced angioedema related to alteplase use based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. They noted that the risk of angioedema was increased due to concurrent angiotensin-converting enzyme inhibitor therapy (lisinopril), which together with alteplase contributed to an overall increased levels of bradykinin. Although a rare event, the authors cautioned clinicians to be aware of this possible event when combined with angiotensin-converting enzyme inhibitor therapy.
Alteplase [“tPA”]
Krishnaiah B et al (B Krishnaiah, Department of Neurology, Penn State Hershey Medical Center, 30 Hope Drive, Hershey, PA 17033; e-mail:
Hydrogen Peroxide Mouthwash No. 42
Gastritis and Colitis
A 54-year-old female patient was hospitalized with acute postprandial epigastric and abdominal pain and nonbloody diarrhea, which began approximately 4 weeks after starting an endodontic procedure that required the washing/rinsing of a root canal with 3% hydrogen peroxide solution (50 mL). The disinfecting procedure was performed once a week. Additional symptoms, including mild pharyngalgia and a sore mouth, progressively worsened over the 2-month treatment period during repeated disinfection sessions. No other medications were noted in the report. An upper and lower gastrointestinal endoscopy did not reveal any abnormalities. However, gastric biopsies revealed mild gastritis with focal superficial erosions. Colorectal biopsies under microscopic examination also revealed mucosal edema, vascular congestion, and mild gland atrophy. The use of hydrogen peroxide mouthwash resulted in complete resolution of symptoms.
The authors concluded that this patient’s gastrointestinal symptoms were related to the inadvertent ingestion of hydrogen peroxide based on the temporal relationship between the administration of the agent and the appearance and resolution of symptoms. They noted that the gastrointestinal toxicity is well known with the use of hydrogen peroxide and that in this patient, the amount and chronic use most likely contributed to the adverse event.
Hydrogen Peroxide [Hydrogen Peroxide]
Zanelli M et al (M Ragazzi, Anatomic Pathology Unit, Arcispedale Santa Maria Nuova—IRCCS, Viale Risorgimento, 80, 42123 Reggio Emilia, Italy; e-mail: