Clinical Pharmacology

"Adverse Drug Event of the month"

Loss of consciousness after consumption of Ondansetron and Metoclopramide: irrational use of anti-emetics.

Case report:
A six year old girl was admitted in an unconscious state to the pediatric ward of our Institute. The child was prescribed syrup Ondem (each 5ml containing 2mg of ondansetron) and half a tablet (10 mg) of metoclopramide (Day 1). The child received 5ml of ondansetron and 5mg of metoclopramide. Within an hour of consuming the drug doses, the child fell unconscious and was rushed to the hospital (Day 2). The comparison of dosage received by the child with standard therapeutic doses is provided in Table 1. On examination the patient was lethargic and was responding only to painful stimuli. The pupils were bilaterally equal and reacting to light. Other vital parameters were stable. Investigations done subsequently are shown in Table 2.Patient was treated with intravenous Mannitol (3.5cc/ktg/dose) 70 cc thrice a day, intravenous Ranitidine (1mg/kg/dose) 20 mg twice a day, intravenous Ampicillin (100mg/kg/day) 500mg four times a day and intravenous fluids. The patient gained consciousness after 14 hours (Day 3) and was discharged on fifth day of hospitalization (Day 6) after an uneventful course.

Discussion:
Ondansetron Hydrochloride is a selective 5-HT3 (5-hydroxytryptamine) receptor antagonist. Its therapeutic action of inhibiting nausea and vomiting is believed to be mediated via antagonism of 5-HT3 receptors located in the chemoreceptor trigger zone in area postrema of the brain. Ondansetron is used particularly for the control of nausea and vomiting associated with chemotherapy and radiotherapy and for the prevention and treatment of postoperative nausea and vomiting. (1,2) In a multi-center post-marketing surveillance carried out at Denver, USA, it was noted that 88% of patients who received Ondansetron were being treated for chemotherapy induced emesis and all other accounted for 12% prescription for ondansetron. It was also found that dosing of ondansetron was off label (non - approved indication) in 15% and 73% of patients prior to and after an ematogenic exposure (3)

Adverse reactions associated with Ondansetron include headache, constipation, sensation of flushing and warmth in the epigastrium and rarely a hypersensitivity reaction. Extrapyramidal reactions seem to be extremely rare; with only one case of dystonic reaction to ondansetron having been reported so far (4). There has been only one report of a subject having tonic- clonic movements and frothing at the mouth in after infusion of Ondansetron. The adverse event has occurred 90 minutes after receiving the infusion and convulsions were controlled with intravenous diazepam. (2) Although ondansetron is indicated for the prevention of nausea and vomiting associated with chemotherapy, radiotherapy and post surgery in adults, sufficient information about its use and safety in children is not available.

Metoclopramide is a dopamine receptor antagonist. It acts as an antiemetic agent by blocking central D2 receptors. (1) Metoclopromide is mainly used for the treatment of motility disorders of upper gastrointestinal tract, particularly delayed gastric emptying and nausea and vomiting from causes other than motion sickness. Being a dopamine antagonist metoclopramide is known to cause extra-pyramidal symptoms like dystonia, dyskinesia and rarely Parkinsonism and tardive dyskinesia. Other adverse reactions with Metoclopramide include restlessness, drowsiness, dizziness, headache and bowel upset. There are isolated reports of dose related delirium, depression, and uncontrolled crying in patients treated with Metoclopramide. Neuroleptic malignant syndrome has also been reported after the use of the drug. (2)

Children especially young female patients are particularly at increased risk of developing adverse reactions to Metoclopramide. About 70% of adverse reactions with Metoclopromide occur in females and substantial proportion are prescribed dose above the limit indicated by the manufacturer. Hence it should be prescribed with caution in pediatric age group and daily dose should be below 500 mg per Kg of body weight.

Ondansetron is shown to be superior to Metoclopramide for the treatment of chemotherapy-induced nausea and vomiting however, data about their concomitant use is not available. (5) Irrational drug combinations can lead to serious consequences; hence care should be taken while prescribing two or more drugs together. Drugs, which have higher incidence of adverse reaction in vulnerable group, should be prescribed with care. Judicious and rational use of medication can help preventing such serious adverse events.

References
1. Dollery C, Boobis A, Rawlins M, Thomas S, Wilkins M, editors. In: Therapeutic Drugs. 2nd ed. UK: Churchill Livingston Company, 1986. p. M 132- 36, O 21 - 24

2. Gastro-Intestinal Agents In: Reynolds JE, editor. Martindale The extra pharmacopoeia. 31st edition. London: Royal Pharmaceutical Society of Great Britain. 1996. p.1191-1249.

3. McQueen K D, Milton JD.Multicenter postmarketing surveillance of ondansetron therapy in pediatric patients. Ann Phrmacother.1994; 28:85 - 92

4. Spring J, Chaudhary FM, Hall BA.Extrapyramidal reactions to ondansetron: cross reactivity between ondancetron and prochlorperazine. Anaesth. Analg.2003; 96:1374 - 6

5. Sledge GW Jr, Einhorn L, Nagy C, House K. Phase III double blind comparison of intravenous ondansetron and Metoclopramide as antiemetic therapy for patient receiving multiple day cisplatin based chemotherapy. Cancer 1992; 70:2524 - 8

Table 1: Comparison of dose received by the patient with standard doses

Table 2:

Department of Clinical Pharmacology*
and Department of Pediatrics**
Seth G S medical College and KEM Hospital,
Parel,
Mumbai 400 012.