Reporting on Adverse Clinical Events

Withdrawal-Emergent Dyskinesia

A 9-year-old male patient with autism spectrum disorder and attention-deficit hyperactivity disorder, a combined type, developed hyperprolactinemia (40 ng/mL) and galactorrhea during chronic therapy with risperidone (4 mg daily). Concurrent medications included dexmethylphenidate (extended release 20 mg daily), dexmethylphenidate (7.5 mg daily), and clonidine (0.2 mg daily). Risperidone was tapered and discontinued over a period of 4 days. Within the next 5 days, the patient developed abnormal involuntary movements (eg, lip smacking, eye blinking, body rocking and shakes, and writhing movements of the neck). Treatment with oral benztropine, lorazepam, and diphenhydramine were ineffective. The patient was hospitalized for a series of metabolic and infectious screenings, all of which were negative. On hospital day 1, risperidone (1 mg twice daily) was restarted, resulting in significant improvement in abnormal movements within 24 hours. The patient was discharged on hospital day 5 taking risperidone 1 mg twice daily. Risperidone was gradually tapered and discontinued over an 8-month period without event.

The authors concluded that this patient experienced withdrawal emergent dyskinesia associated with the discontinuation of chronic risperidone therapy. They suggested that the neurodevelopmental disorders may have been risk factors for the development of this event.

Risperidone [“Risperdal”]

Kumar M et al (R Baweja, Department of Psychiatry, Penn State University College of Medicine, Hershey, PA; e-mail: rbaweja@pennstatehealth.psu.edu) Withdrawal-emergent dyskinesia after acute discontinuation of risperidone in a child with autism spectrum disorder. J Clin Psychopharmacol 36:640–642 (Dec) 2018

Angioedema

A 29-year-old female patient developed severe facial edema and marked periorbital edema within 24 hours after using henna hair dye containing paraphenylenediamine. The patient had no previous history of problems with hair dye or tattoos using black henna. Initial treatment with oral amoxicillin (no dosage provided) for the management of cellulitis was ineffective and the patient was hospitalized 48 hours after the onset of the reaction. Treatment with intravenous hydrocortisone (200 mg) and intramuscular promethazine (25 mg) did not result in improvement and the patient was transferred to a tertiary hospital where the doses were repeated (100 mg and 25 mg, respectively). Inpatient treatment included oral prednisone (40 mg daily), vitamin D (weekly), oral calcium, and chlorpheniramine maleate (4 mg daily). Topical cetomacrogol cream was also applied to de-crust her scalp, which was followed by clobetasol cream. The clobetasol was tapered to methylprednisolone on day 5 followed by 1% hydrocortisone ointment by day 7. Complete resolution was observed by day 5. The patient was discharged on cetomacrogol and fluocinolone gel for the scalp and 1% hydrocortisone ointment for the face. A positive patch test indicated sensitivity to paraphenylenediamine.

The authors concluded that this patient experienced angioedema related to hair dye containing paraphenylenediamine based on the temporal relationship between the administration of the product and the appearance and resolution of the symptoms.

Paraphenylenediamine [Hair Dye]

Ngwanya RM et al (RM Ngwanya, Division of Dermatology, Groote Schuur Hospital, University of Cape Town, Observatory Cape Town, South Africa) Angioedema, an unusual reaction to hair dye. Pan Afr Med J 30:103 (Jun) 2018

Intracranial Hypertension

A 16-year-old female patient was hospitalized with binocular diplopia and intracranial hypertension approximately 4 months after starting risperidone (1 mg daily). Concurrent medications included beclomethasone/formoterol (100/6 µg twice a day) and salbutamol (as needed use). The patient had a 4.3% weight gain during risperidone therapy (body mass index = 28.1 kg/m²). On admission, an ophthalmological examination revealed bilateral papilledema. A cerebral scan and magnetic resonance imaging revealed the tortuous appearance of the optic nerves, a concave pituitary gland, and stenosis of the left transverse sinus. Though the cerebrospinal fluid was normal, the pressure was high (55 cm H₂O). Two lumbar punctures improved symptoms, but visual blurring remained. Treatment included the initiation of acetazolamide (500 mg twice daily) and the substitution of aripiprazole (5 mg daily) for risperidone. Follow-up was uneventful.

The authors concluded that this patient experienced intracranial hypertension associated with the administration of risperidone. They noted that this event is rare but that obesity may increase the risk of its occurrence.

Risperidone [“Risperdal”]

Riquin E et al (E Riquin, University Hospital of Angers, Angers Cedex, France) Risperidone and intracranial hypertension: a case report and literature review. Ann Pharmacother 52:1261–1262 (Dec) 2018

Vanishing Bile Duct Syndrome

A 40-year-old female patient was hospitalized for acute onset of jaundice, which progressively worsened over the course of 30 days during chronic intermittent ibuprofen (300 mg twice daily for 2 to 3 days each month) for menalgia. Concurrent medications included oral acarbose (50 mg 3 times daily) and metformin 500 mg (3 times daily). Additional symptoms included profound fatigue and dark urine. Abnormal laboratory values included hemoglobin (82 g/L), alkaline phosphatase (1598 U/L), alanine transaminase (207 U/L), aspartate transaminase (247 U/L), total bilirubin (103 µmol/L), and direct bilirubin (75 µmol/L). Serological screenings for infectious etiologies were negative. Ibuprofen was discontinued on admission. A magnetic resonance cholangiopancreatography revealed gallbladder stones without intrahepatic or extrahepatic bile duct dilatation. A computed tomography scan revealed a few small enhanced patchy lesions on the left hepatic lobe likely due to the abnormal perfusion, mild splenomegaly, but no vascular abnormalities or intraperitoneal free fluid. On the day of first evaluation, the Roussel Uclaf Causality Assessment Method score was 6 (grade III liver injury). A liver biopsy revealed biliary injury and absence of small terminal bile ducts around hepatic arteries. Treatment included supportive care with intravenous polyene phosphatidylcholine (930 mg daily), silibinin capsule (200 mg daily), glutathione (2.4 g daily), and ursodeoxycholic acid (250 mg 3 times daily). Symptoms gradually improved with some abatement in laboratory values. The patient was discharged on day 47. At outpatient follow-up on day 315, the hyperbilirubinemia persisted with normal prothrombin time. In addition, the patient had persistent hyperlipidemia during the entire observational period. Due to the prolonged elevation of bilirubin and alanine transaminase, a second liver biopsy was performed on day 213, revealing the absence of small terminal bile ducts, interstitial fibrous tissue hyperplasia, bile salt deposition in the peripheral liver cells, Ishak necroinflammatory activity score of 4, and fibrosis score of 2.

The authors concluded that this patient developed vanishing bile duct syndrome with hyperlipidemia associated with ibuprofen therapy. They noted that this is a rare but serious occurrence that has been reported with the use of ibuprofen.

Ibuprofen [“Motrin”]

Xie W et al (CQ Pan, Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University School of Medicine, 132-21 41 Ave, Flushing, NY 11355; e-mail: Panc01@NYU.edu) Vanishing bile duct syndrome with hyperlipidemia after ibuprofen therapy in an adult patient: a case report. BMC Gastroenterol 18:142 (Sep) 2018

Vestibulotoxicity

A 72-year-old male patient developed loss of balance shortly after receiving a single intravenous dose of gentamicin (240 mg) prior to knee replacement surgery with continued symptoms for 2 years, including occasional episodes of falls. Additional complaints included vision changes but no hearing changes. Other medications were not reported. Video head impulse testing revealed severe bilateral loss of semicircular function, but an audiogram demonstrated age-related hearing loss unchanged from 3 years ago.

The authors suggested that this patient developed vestibulotoxicity related to a single dose of gentamicin.

Gentamicin [Gentamicin]

Halmagyi GM & Curthoys IS (GM Halmagyi, Royal Prince Alfred Hospital, Camperdown, Sydney, New South Wales 2050, Australia; e-mail: gmh@icn.usyd.edu.au) Adverse effects of a single dose of gentamicin. Br J Clin Pharmacol 84:2936 (Dec) 2018

Severe Gastrointestinal Bleeding in Patients With Acute Renal Failure

Two cases of severe upper gastrointestinal bleeding related to dabigatran therapy are described.

Patient 1. An 89-year-old female patient developed severe upper gastrointestinal bleeding resulting in a hemorrhagic shock during dabigatran (110 mg twice daily) therapy for atrial fibrillation. An upper gastrointestinal endoscopy revealed a bleeding gastric ulcer with diffuse bleeding from gastric mucosal erosions. Treatment included the transfusion of red blood cells (13 units), plasma (9 units), and fibrinogen (9 g), and the administration of tranexamic acid (2 g) and 4-factor prothrombin complex (5000 units). On intensive care admission, the dabigatran concentration was elevated (330 ng/mL). Abnormal laboratory values included activated partial thromboplastin time (68.8 seconds), fibrinogen (4.4 g/L), and Factor XIII activity (55%). An additional dose of tranexamic acid (2 g) was administered for suspicion of hyperfibrinolysis. A repeat upper gastrointestinal endoscopy revealed no active bleeding. Oozing at vascular insertion sites prompted the intravenous administration of idarucizumab (5 g), which resulted in the normalization of activated partial thromboplastin time and international normalized ratio. Renal laboratory values indicated acute renal failure requiring continuous venovenous hemodialysis for 7 days. The patient was discharged on day 37 to a nursing home.

Patient 2. A 78-year-old female patient was hospitalized with severe acute upper gastrointestinal bleeding and hemorrhagic shock and stage 3 acute renal failure while on dabigatran therapy (110 mg twice daily) for atrial fibrillation. Elevated laboratory values included plasma dabigatran concentrations (582 ng/mL), activated partial thromboplastin time (85.5 seconds), and international normalized ratio (6.0). An upper gastrointestinal endoscopy revealed diffuse bleedings from several gastric and duodenal erosions. Treatment included the transfusion of red blood cells (6 units) and the administration of idarucizumab (5 g). The plasma dabigatran level, measured 8 hours after the antidote injection, remained elevated. Acute renal failure was observed on admission and treatment with continuous venovenous hemodialysis was initiated for 3 days followed by a sustained low-efficiency daily dialysis for 2 days. Plasma dabigatran levels decreased after sustained low-efficiency daily dialysis but remained elevated. Recurrent bleeding was not observed despite elevated dabigatran levels. The patient was discharged on day 10.

The authors concluded that these patients experienced severe gastrointestinal bleeding related to dabigatran administration and that urgent endoscopic management is essential in the effective management.

Dabigatran [“Pradaxa”]

Pfrepper C et al (S Petros, University Hospital Leipzig, Liebigstr 20, 04103 Leipzig, Germany; e-mail: Sirak.petros@medizin.uni-leipzig.de) Management of dabigatran-associated bleeding in two elderly patients with acute renal failure. Ann Hematol 57:2519–2521 (Dec) 2018

Rhabdomyolysis

A review of the Food and Drug Administration Adverse Event Reporting System data from the first quarter of 2011 to the fourth quarter of 2017 revealed 44 cases of rhabdomyolysis related to abiraterone therapy. All patients were male (mean age = 76 years), most frequently receiving the drug for prostate cancer. Of the 44 cases reported, rhabdomyolysis resulted in hospitalization in the majority of cases (82%). Approximately one third of the patients (34%) had concomitant hepatotoxicity, and nephrotoxicity developed in approximately half of the patients (55%). A total of 14 patients (32%) were also taking a statin.

The authors concluded that a review of the Food and Drug Administration Adverse Event Reporting System database revealed several cases of rhabdomyolysis related to abiraterone therapy.

Abiraterone [“Zytiga”]

Moore DC & Ringley JT (DC Moore, Atrium Health, Rock Hill, SC) Rhabdomyolysis with abiraterone exposure: a brief review of the Food and Drug Administration Adverse Event Reporting System (FAERS). Ann Pharmacother 52:1160–1161 (Nov) 2018

Worsening Psoriatic Arthritis

Three cases of disabling severe psoriatic arthritis during ustekinumab treatment are described.

Patient 1. A 48-year-old male patient developed severe joint pain in the hands, knees, and ankles after receiving 2 doses of ustekinumab (90 mg) for the management of psoriatic arthritis. Previous therapy with etanercept was not effective. No other concurrent medications were noted. The patient was unable to walk without aid. A rheumatology consultation revealed flare-up of psoriatic arthritis, and adjunctive methotrexate (15 mg/week) was added without benefit; the arthritis became progressively disabling. Ustekinumab was discontinued and adalimumab was started. Approximately 1 month later, the cutaneous lesions and arthritis had significantly improved.

Patient 2. An 18-year-old female patient developed severe joint inflammation of the knees, ankles, and fingers after receiving 2 doses of ustekinumab for the management of psoriatic arthritis. Previous therapies included topical corticosteroids, acitretin, methotrexate, etanercept, and infliximab. No other concurrent medications were reported. The patient was unable to walk without the aid of a cane, and flexion deformity developed on the fourth finger of the left hand. Ustekinumab was discontinued; therapy with adalimumab and methotrexate was initiated. Approximately 1 month later, modest improvement in symptoms was observed.

Patient 3. A 30-year-old female developed a severe relapse of psoriatic arthritis after receiving 3 doses of ustekinumab (45 mg). Previous therapies included methotrexate, leflunomide, infliximab, etanercept, and adalimumab. No other concurrent medications were reported. Ustekinumab was stopped and a certolizumab regimen was initiated with subsequent improvement.

The authors concluded that these patients developed worsening symptoms of psoriatic arthritis after receiving a limited number of ustekinumab doses.

Ustekinumab [“Stelara”]

Onsun N et al (N Onsun, Departments of Dermatology and Venerology, Bezmialem Vakif University Medical School, Fatih, Istanbul, Turkey) Worsening of psoriatic arthritis after ustekinumab treatment. Am J Ther 25:e381–e382 (May) 2018

Muscle Tear

A 75-year-old male patient developed right knee pain and swelling approximately 2 weeks after starting a 10-day course of oral levofloxacin (750 mg daily) for the management of uncomplicated diverticulitis. Concurrent medication included metronidazole (2 g daily). On physical examination, nonpitting edema of the right leg extending from the popliteal fossa down to ankle was observed. A Doppler ultrasound revealed a 12-cm hematoma medial to the gastrocnemius. Because of the temporal relationship, the muscle tear was strongly suspected to be secondary to levofloxacin therapy. The patient was hospitalized and managed with bed rest and pain control. Improvement occurred without surgical intervention.

The authors concluded that this patient developed a muscle tear with hematoma related to levofloxacin therapy based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms.

Levofloxacin [“Levaquin”]

Murtaza G & Boonpheng B (G Murtaza, East Tennessee State University, Johnson City, TN) Fluoroquinolone-associated muscle tear and hematoma: a case report. Am J Ther 53:e386–e388 (May) 2018

Takotsubo-Like Cardiomyopathy

A 37-year-old female patient was hospitalized after an intentional overdose with loperamide (200 tablets of 2 mg). A urine toxicology test on admission was positive for phencyclidine, which was determined to be a false positive result related to venlafaxine therapy. The plasma level of desmethyl-loperamide, an inactive loperamide metabolite, was 32 mg/mL. An electrocardiogram demonstrated a prolonged QTc (606 ms with diffuse T-wave inversions). There was a mildly elevated creatine kinase-MB (5.48 ng/mL) and troponin T level (0.17 ng/mL). An initial transthoracic echocardiography demonstrated regional wall motion abnormalities in the anterior, lateral, septal, apical, and inferior apexes, which when repeated 4 days later showed mild improvement. At this time QTc prolongation was also resolved. The wall motion abnormalities were thought to be Takotsubo cardiomyopathy possibly related to loperamide ingestion. Treatment included magnesium replacement and an intravenous dopamine infusion. The patient eventually recovered and was discharged.

The authors concluded that this patient developed Takotsubo-like cardiomyopathy related to the loperamide overdose. A suggested mechanism was that large doses of loperamide, an m-receptor agonist, may alter the myocardial function. According to the Naranjo causality algorithm, this event was rated as probable.

Loperamide [“Imodium”]

Patel K et al (KM Patel, Department of Medicine, SUNY Upstate Medical University, Syracuse, NY) Takotsubo-like cardiomyopathy after loperamide overdose. Am J Ther 23:e548–e550 (Sep) 2018

Overdose Resulting in Metabolic Acidosis

A 55-year-old female patient was hospitalized approximately 5 hours after a multidrug overdose, which included extended-release metformin (132 g). Treatment with continuous venovenous hemodiafiltration for 3 hours and noradrenaline for metabolic acidosis (pH 7.0, lactate = 17 mmol/L) was not effective, but intermittent hemodialysis initially improved acidosis (pH 7.13, lactate = 26 mmol/L) but then worsened again with continuous venovenous hemodiafiltration recommencement. The combination of intermittent hemodialysis (12 hours), continuous venovenous hemodiafiltration (26 hours), and vasopressor therapy for 7 days resulted in survival. Peak metformin concentration (8 hours post ingestion) was 292 µg/mL. Intermittent hemodialysis was most effective in increasing clearance of the drug, though there was a time lag in the clearance.

The authors noted that intermittent hemodialysis was most effective in increasing drug clearance in a patient with a massive metformin (extended release) overdose.

Metformin [“Glucophage XR”]

Chiew AL et al (AL Chiew, New South Wales Poisons Information Centre, Children’s Hospital at Westmead, Westmead, New South Wales, Australia; e-mail: angela.chiew@health.nsw.gov.au) Massive metformin overdose. Br J Clin Pharmacol 84:2923–2927 (Dec) 2018

Methemoglobinemia

A 75-year-old female inpatient developed shortness of breath and was cyanotic. Medications at the time of admission included methotrexate, dapsone, and hydroxychloroquine. Pulse oximetry revealed SpO₂ of 84% on 2 liters of oxygen. A chest X-ray showed posterior segmental pulmonary embolism in the right upper lobe. Because of increased saturation gap, the methemoglobin level was checked, which was 11% (hemoglobin 10.1 g/dL). Treatment included the administration of methylene blue, which resulted in symptomatic improvement approximately 1 hour later with additional improvement in oxygen saturation. When repeated the methemoglobin level was 3%. The pulmonary embolism was treated with heparin, which was switched to rivaroxaban on discharge.

The authors concluded that this patient developed methemoglobinemia related to dapsone therapy with coexisting pulmonary embolism.

Dapsone [Dapsone]

Amjad W et al (W Amjad, Department of Internal Medicine, Long Island Jewish Forest Hills Hospital, Northwell Health, Forest Hills, NY) A case of cyanosis: dapsone induced methemoglobinemia and coexisting pulmonary embolism. Am J Ther 25:e493–e495 (Jul) 2018

Autoimmune Hepatitis

A 70-year-old female patient was hospitalized with abnormal liver function tests approximately 3 weeks after receiving a blood transfusion without any documented transfusion reaction. The only medication listed in the report was hydralazine. Other medications were not noted. Abnormal values included aspartate aminotransferase (1203 U/L), alanine aminotransferase (2559 U/L), and alkaline phosphatase (164 U/L). A urine toxicology screen was insignificant. Ultrasound of the liver demonstrated gall stones, echogenic liver, but no evidence of common bile duct dilation. Screenings for infectious etiologies were negative. Treatment with N-acetylcysteine for 3 days did not result in improvement. An elevated antinuclear antibody titer (1:320) was suggestive of autoimmune hepatitis. The anti-histone antibody was 1.5, but the remainder of the autoimmune panel was negative. The hydralazine was discontinued, and a tapering regimen of prednisone over a 6-week period was initiated. The liver function tests started to decline almost immediately and the patient was discharged. Postdischarge follow-up at 6 weeks and 6 months revealed liver function tests within normal limits and without event.

The authors concluded that this patient experienced autoimmune hepatitis related to hydralazine therapy.

Hydralazine [Hydralazine]

Amjad W et al (W Amjad, Department of Medicine, Northwell-Long Island Jewish Forest Hills Hospital, Forest Hills, New York, NY) Hydralazine-induced autoimmune hepatitis precipitated by the blood transfusion. Am J Ther 25:e514–e516 (Jul) 2018

Mood Elevation

A 26-year-old female patient developed accelerated flow of speech shortly after taking the first dose of tramadol (50 mg) for the management of lower back pain. Concurrent medications included chlorzoxazone, ranitidine (150 mg daily), and desloratadine (10 mg daily). She became overactive and experienced increased energy, insomnia, and increased irritability. She took tramadol twice more on days 4 and 7, with the recurrence of similar symptoms, which lasted exactly 4 hours each time. No other neurological symptoms occurred. Tramadol was discontinued.

The authors concluded that this patient experienced mood elevation related to tramadol therapy, based on the temporal relationship between the administration of the drug and the appearance and resolution of symptoms. In addition, rechallenge twice with the medication resulted in similar symptoms.

Tramadol [“Ultram”]

Osman M & Mustafa M (M Osman, Armed Forces Centre for Psychiatric Care, Armed Forces Hospital in Taif Region, Taif, Saudi Arabia; e-mail: mugtaba.osman@ucdconnect.ie). Tramadol-induced mood elevation in a patient with no previous psychiatric history. Case Rep Psychiatry 9574395 (Oct) 2018. doi:10.1155/2018/9574395

Hand-Foot Skin Reaction

A 55-year-old female patient developed erythematous, painful, mildly itchy lesions on both hands, arms, and feet approximately 1 month after starting sorafenib (400 mg twice daily) in the management of metastatic renal carcinoma. Symptoms included painful palmoplantar erythema with numbness and tingling sensation, bullae and erosions on distal fingers, palms, and soles, then palmoplantar hyperkeratosis. Results from a skin biopsy revealed mild spongiosis, acanthosis, and basal cell vacuolization. Treatment included the discontinuation of sorafenib and the initiation of oral corticosteroids, antihistamines, and emollients, which resulted in complete resolution in 15 days. Rechallenge occurred with a lower dose of sorafenib without further event during a 2-month follow-up.

The authors concluded that this patient experienced sorafenib-induced hand-foot skin reaction and erythema multiforme-like lesions based on the temporal relationship between initiation of drug and appearance of lesions.

Sorafenib [“Nexavar”]

Guilani A et al (MS Kumaran, Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab 160012, India; e-mail: drsen_2000@yahoo.com) Severe hand-foot skin reaction and erythema multiforme-like lesions due to sorafenib. Postgrad Med J 94:535–536 (Sep) 2018