Tipepidine hibenzate intoxication

Abstract

Tipepidine hibenzate is a centrally acting cough suppressant in the opioid family. It was developed in Japan in 1959 and is used in citrate and hibenzate salts. The drug comes in tablet, fine granule, and syrup forms. It is commonly believed that tipepidine hibenzate is very safe and easy to use. As such, it is frequently used by Japanese pediatricians in outpatient clinics. It is not well known that the side-effects of tipepidine hibenzate include drowsiness, vertigo, delirium, disorientation, disturbance of consciousness, and confusion. In severe cases, barbiturate administration is required. 1 Herein, we describe a pediatric case of intoxication due to tipepidine hibenzate overdose. We also present a review of the literature. Case reportA 3-year-old boy with a history of good health developed a cough and nasal discharge and was diagnosed as having an upper respiratory tract infection. He was prescribed a syrup consisting of carbocysteine in a daily dose of 400 mg, mequitazine in a daily dose of 1.5 mg, and tipepidine hibenzate in a daily dose of 40 mg in three divided portions. The patient weighed 14 kg and was well developed; the prescription dosage was thus appropriate for his bodyweight. The prescription was filled at a local pharmacy. He was given a 6-day course of medicine in one bottle. This mixed syrup was administered for 6 days. One hour after his last dose of medication, he suddenly grew agitated. Because of his persistent excitement, his family brought him to the emergency room at Nihon University Itabashi Hospital 3 h after the onset of symptoms.At this point the boy was delirious, crying loudly, and unable to answer simple questions regarding his name or age. On physi-cal examination his pulse rate was a regular 90 beats/min. The systolic blood pressure was 108 mmHg and the diastolic was 66 mmHg, and his temperature was 36.9°C. The pupils were equal but dilated to 5 mm and were sluggish to light. Other cranial nerves were normal, and there was no sign of meningeal irritation. He could stand but his gait was unsteady. There was no muscle weakness or limitation of movement in any joint. Deep tendon reflexes could be elicited. Heart and lungs auscultation was normal, and the abdomen was flat and soft without any signs of hepatosplenomegaly. Results of laboratory tests, including complete blood count, liver and renal function tests, blood sugar, serum electrolytes, and blood gas analysis, were within normal limits. Computed tomography of the brain was normal. Electroencephalogram results 12 h after the onset of symptoms showed nearly normal slow alpha waves merging with theta waves without any paroxysmal discharge.After admission, additional history was provided by his mother. At this point it was found that the patient's last dose had included a thick precipitate at the bottom of the bottle. We suspected medication overdose on the basis of the symptoms and the history; we then measured the serum concentration of tipepidine hibenzate and mequitazine 5 h after the last dose of medication, using high-pe...

Efficacy and safety of tipepidine as adjunctive therapy in children with attention‐deficit/hyperactivity disorder: Randomized, double‐blind, placebo‐controlled clinical trial

“…Furthermore, given that methylphenidate is metabolized by hepatic and peripheral esterases, it probably does not interact with the cytochrome P450 enzyme‐based metabolism of tipepidine . Several studies, however, reported a toxic effect for tipepidine, causing agitation, toxic epidermal necrosis, and fixed drug eruption in pediatric populations . In terms of safety, we identified that tipepidine add‐on to methylphenidate resulted in no major adverse events.…”

Tipepidine in adolescent patients with depression: a 4 week, open-label, preliminary study

“…Additional trials are needed to evaluate the efficacy and safety for tipepidine use in adolescent depression. Although tipepidine is widely used, however, there are reports25–27 indicating a possible toxic effect like agitation, fixed drug eruption and toxic epidermal necrolysis also in pediatric populations. So we must pay attention to the mood symptoms, especially irritability and cutis symptoms, because there were patients for whom a feeling of irritation and a cutis symptom appeared in this tipepidine study.…”

Acute Confusional State Caused by Tipepidine Hibenzate Intoxication in an Elderly: Caution About Suspended Solution

“…As tipepidine syrup is suspended in solution, sediment could have formed at the bottom of the bottle. Tipepidine syrup has been reported to form sediment easily when mixed with other drugs [1], but this may also occur with tipepidine syrup alone. Ingestion of excessive amounts of thickened syrup with sediment might explain why this patient became acutely intoxicated.…”

“…Imai et al summarized six pediatric cases of acute tipepidine hibenzate intoxication, all of which presented with delirium [1]. In adults, Cuomo reported a 21-year-old woman who developed convulsions after a therapeutic dose of tipepidine ingestion [3].…”

“…It has been prescribed mainly in Japan and other Asian countries since 1959. As it acts on the central nervous system, overdose can cause altered mental status and other neurological symptoms; however, there have been few reports of tipepidine intoxication, including six cases [1] in children and no cases in adults. We report a case of an elderly woman who presented with acute confusional state and choreiform movements of the lower extremities due to tipepidine hibenzate intoxication.…”