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EXTRAPYRAMIDAL REACTIONS DUE TO DOMPERIDONE
802 EXTRAPYRAMIDAL REACTIONS DUE TO DOMPERIDONE
SIR,-Domperidone (’ Motilin’; Janssen Pharmaceutica) is an antivomiting drug that is available as drops, suppositories, tablets, and ampoules. The drug is thought to act by increasing the muscle tone of the lower oesophageal sphincter (cardia) and simultaneously decreasing the tone of the pylorus, leading to an easier evacuation of the stomach contents into the gut. Domperidone is said to have antidopamine properties. The only side-effects mentioned by the manufacturer are "rare cases of headache and slight somnolence". We would like to report one case in which the administration of domperidone was associated with severe neurological problems. A 4-month-old infant, who had been on breast milk and later on various formulm, developed well and gained weight normally. Because of repeated episodes of vomiting since 2 months of age, domperidone was prescribed at a dose of 6 drops three times daily. This corresponds exactly to the dosage of 1 drop/kg three or four times daily (0’33 mg/kg every 6-8 h) recommended by the manufacturer. 2 h after the second dose the child presented with irritability and crankiness. According to his mother, he had become stiff and kept his neck stretched backwards; his eyeballs rolled to one side. The child remained alert and the mother states that she never lost contact with him. At this point, the infant was referred to our hospital. He was a well nourished boy weighing 6 kg. Temperature 36.6°C, blood pressure 105/50 mm Hg. Right after admission, he became irritable again and had a crying spell with dystonic movements of both arms in extension and deviation of both eyes and head to the right side. Throughout the attack, which lasted for about 10 min, the child remained alert. He was easily consolable immediately afterwards, and physical neurological examination was normal. No postictal sleepiness was observed. 1 h after admission, he had a third attack, similar to the previous one, which lasted for about 15 min. It was difficult to console this obviously distressed but alert child during the dystonic crisis. Laboratory data did not help in the differential diagnosis. Electrolytes and blood gases were normal. The spinal fluid was clear without cells, normal sugar (1-33 mmol/l, 23 mg/dl) and protein (27 mg/dl). An EEG done the next day was normal for age. No anticonvulsive drug was given and the child recovered uneventfully. He was discharged on the following day. No recurrence of the symptoms has been noted in the 6 months of follow-up. Dystonic spells with no loss of consciousness or post-ictal manifestations are well known extrapyramidal reactions observed in a small percentage of patients after ingestion of metoclopraniide.1i These neurological manifestations can be idiosyncratic and therefore not related to the amount of drug absorbed. Domperidone is not chemically related to metoclopramide. It is, however, derived from the butyrophenone neuroleptics, which induce disturbances of the extrapyramidal motor system. The occurrence of extrapyramidal manifestations after absorption ofdomperidone, although not mentioned by the manufacturer, is thus not totally unexpected. Like metoclopramide, domperidone is a useful drug for the pxdiatrician. But, also like metoclopramide, it does probably have significant neurological adverse effects. Pædiatric Service, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
PETER SOL BERNARD PELET JEAN-PIERRE GUIGNARD
SIR,-The antiemetic antidopaminergic drug domperidone is stated to have the advantage of not provoking extrapyramidal effects. The following case is therefore of interest. In 1978, a 27-year-old woman with cutaneous allergy to penicillin
prescribed metoclopramide; severe extrapyramidal effects ensued which disappeared completely 2 min after an intravenous injection of ethybenztropine hydrobromide (’Ponalide’). One year later, she was given domperidone syrup for severe vomiting due to pyelocystitis, and again severe extrapyramidal effects ensued, with recovery 1-2 min after ponalide. was
A, ed. Martindale: The extra pharmacopœia, Press, 1977: 934-36.
1. Wade
27th ed. London: Pharmaceutical
This observation refutes the message of some pharmacological studies where differences in fixation of various antidopaminergic agents to certain cerebral sites in some animals suggested that extrapyramidal effects would not be a problem with the clinical use of domperidone. The manufacturers do not mention extrapyramidal effects as a possible adverse reaction-indeed they affirm the contrary. Experience with extrapyramidal effects with antidopaminergic agents used regularly as anti emetics suggests that these reactions are idiosyncratic; their frequency is certainly low. Haachstraat 19, 3008 Veltem, Belgium
O. DEBONTRIDDER
SULINDAC-INDUCED BONE MARROW TOXICITY
SIR,—Dr Stambaugh and his colleagues (Sept. 13, p. 594) report a of leukopenia and thrombocytopenia secondary to sulindac (’Clinoril’). Their definition of leukopenia seems controversial since the white cell count was 3800/µl with normal differential and the label "return to normal" was applied to white cell counts of 4100 and 3900/µl. Theirs is not the first reported case of hæmatological toxicity due to sulindac: two cases of aplastic anaemia were published earlier this year. 1,2 We have observed haxmatological adverse effects after sulindac ingestion in two women-a fatal case
aplastic anaemia and a transitory erythroblastopenia. Case 1 A 54-year-old woman was referred to hospital with a severe anaemic syndrome 15 days after taking sulindac for 7 days because of joint pain. She had a severe pancytopenia (Hb 8 g/dl, reticulocytes and platelets less than 20 x 109/1, polymorphs less than 0 - 5 109/l) indicative of aplastic anasmia, later confirmed by bone marrow 111 aspiration and biopsy, In-transferrin bone marrow scanning, and ferrokinetic study. Bone marrow transplantation was not attempted because an identical donor was not available. We immediately started therapy with oxymetholone, fluprednisolone, and packed red cell transfusions. After clinical improvement the patient was discharged. Few infectious and hasmorragic complications appeared during the next months though severe pancytopenia was unchanged. However, two units of packed red cells were required every 2-3 weeks to keep the Hb at 8-10 g/d1. 4 months after diagnosis the patient was admitted to hospital again seriously ill with a clinical and radiological picture of pneumonia that developed into fatal septic shock despite antibiotic therapy and intensive care. Case 2 A 56-year-old woman was referred to our outpatient clinic because she had occasional ecchymoses. The peripheral blood picture showed mild pancytopenia (Hb 11-55 g/dl, reticulocytes 80 x 109/l, platelets 54 x 109/1, white cell count 2 - 6 x 109/1 with 57% polymorphs). We suspected a peripheral mechanism for the pancytopenia, possibly autoimmune, because of the following results: normal bone marrow examination, short survival of 51 Cr-labelled platelets, positive platelet antibodies, haptoglobin always below 10/-lg/ml, and return to normal Hb and white cell count while on prednisone 1 mg/kg daily. Systemic lupus erythematosus was ruled out. Recently, the mild pancytopenia that had been stable for 16 months was roughly interrupted. The patient was pale and complained of weakness 20-30 days after starting treatment with sulindac (400 mg/day) prescribed by a rheumatologist for her interphalangeal osteoarthritis. After 40 days of continuous sulindac ingestion, the blood picture was: Hb 7 -8g/dl, reticulocytes zero, white cell count 2.5x109/l with 22% of polymorphs and 35x109/l platelets. The bone marrow aspiration smear showed a complete erythro1. Miller JL. Marrow aplasia and sulindac. Ann Intern Med 1980; 92: 129. 2. Bennett L., Schlossman R, Rosenthal J, Balzora JD, Bennet AJ, Rosner F. anemia and sulindac. Ann Intern Med 1980; 92: 874.
Aplastic
SIR,-Domperidone (’ Motilin’; Janssen Pharmaceutica) is an antivomiting drug that is available as drops, suppositories, tablets, and ampoules. The drug is thought to act by increasing the muscle tone of the lower oesophageal sphincter (cardia) and simultaneously decreasing the tone of the pylorus, leading to an easier evacuation of the stomach contents into the gut. Domperidone is said to have antidopamine properties. The only side-effects mentioned by the manufacturer are "rare cases of headache and slight somnolence". We would like to report one case in which the administration of domperidone was associated with severe neurological problems. A 4-month-old infant, who had been on breast milk and later on various formulm, developed well and gained weight normally. Because of repeated episodes of vomiting since 2 months of age, domperidone was prescribed at a dose of 6 drops three times daily. This corresponds exactly to the dosage of 1 drop/kg three or four times daily (0’33 mg/kg every 6-8 h) recommended by the manufacturer. 2 h after the second dose the child presented with irritability and crankiness. According to his mother, he had become stiff and kept his neck stretched backwards; his eyeballs rolled to one side. The child remained alert and the mother states that she never lost contact with him. At this point, the infant was referred to our hospital. He was a well nourished boy weighing 6 kg. Temperature 36.6°C, blood pressure 105/50 mm Hg. Right after admission, he became irritable again and had a crying spell with dystonic movements of both arms in extension and deviation of both eyes and head to the right side. Throughout the attack, which lasted for about 10 min, the child remained alert. He was easily consolable immediately afterwards, and physical neurological examination was normal. No postictal sleepiness was observed. 1 h after admission, he had a third attack, similar to the previous one, which lasted for about 15 min. It was difficult to console this obviously distressed but alert child during the dystonic crisis. Laboratory data did not help in the differential diagnosis. Electrolytes and blood gases were normal. The spinal fluid was clear without cells, normal sugar (1-33 mmol/l, 23 mg/dl) and protein (27 mg/dl). An EEG done the next day was normal for age. No anticonvulsive drug was given and the child recovered uneventfully. He was discharged on the following day. No recurrence of the symptoms has been noted in the 6 months of follow-up. Dystonic spells with no loss of consciousness or post-ictal manifestations are well known extrapyramidal reactions observed in a small percentage of patients after ingestion of metoclopraniide.1i These neurological manifestations can be idiosyncratic and therefore not related to the amount of drug absorbed. Domperidone is not chemically related to metoclopramide. It is, however, derived from the butyrophenone neuroleptics, which induce disturbances of the extrapyramidal motor system. The occurrence of extrapyramidal manifestations after absorption ofdomperidone, although not mentioned by the manufacturer, is thus not totally unexpected. Like metoclopramide, domperidone is a useful drug for the pxdiatrician. But, also like metoclopramide, it does probably have significant neurological adverse effects. Pædiatric Service, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
PETER SOL BERNARD PELET JEAN-PIERRE GUIGNARD
SIR,-The antiemetic antidopaminergic drug domperidone is stated to have the advantage of not provoking extrapyramidal effects. The following case is therefore of interest. In 1978, a 27-year-old woman with cutaneous allergy to penicillin
prescribed metoclopramide; severe extrapyramidal effects ensued which disappeared completely 2 min after an intravenous injection of ethybenztropine hydrobromide (’Ponalide’). One year later, she was given domperidone syrup for severe vomiting due to pyelocystitis, and again severe extrapyramidal effects ensued, with recovery 1-2 min after ponalide. was
A, ed. Martindale: The extra pharmacopœia, Press, 1977: 934-36.
1. Wade
27th ed. London: Pharmaceutical
This observation refutes the message of some pharmacological studies where differences in fixation of various antidopaminergic agents to certain cerebral sites in some animals suggested that extrapyramidal effects would not be a problem with the clinical use of domperidone. The manufacturers do not mention extrapyramidal effects as a possible adverse reaction-indeed they affirm the contrary. Experience with extrapyramidal effects with antidopaminergic agents used regularly as anti emetics suggests that these reactions are idiosyncratic; their frequency is certainly low. Haachstraat 19, 3008 Veltem, Belgium
O. DEBONTRIDDER
SULINDAC-INDUCED BONE MARROW TOXICITY
SIR,—Dr Stambaugh and his colleagues (Sept. 13, p. 594) report a of leukopenia and thrombocytopenia secondary to sulindac (’Clinoril’). Their definition of leukopenia seems controversial since the white cell count was 3800/µl with normal differential and the label "return to normal" was applied to white cell counts of 4100 and 3900/µl. Theirs is not the first reported case of hæmatological toxicity due to sulindac: two cases of aplastic anaemia were published earlier this year. 1,2 We have observed haxmatological adverse effects after sulindac ingestion in two women-a fatal case
aplastic anaemia and a transitory erythroblastopenia. Case 1 A 54-year-old woman was referred to hospital with a severe anaemic syndrome 15 days after taking sulindac for 7 days because of joint pain. She had a severe pancytopenia (Hb 8 g/dl, reticulocytes and platelets less than 20 x 109/1, polymorphs less than 0 - 5 109/l) indicative of aplastic anasmia, later confirmed by bone marrow 111 aspiration and biopsy, In-transferrin bone marrow scanning, and ferrokinetic study. Bone marrow transplantation was not attempted because an identical donor was not available. We immediately started therapy with oxymetholone, fluprednisolone, and packed red cell transfusions. After clinical improvement the patient was discharged. Few infectious and hasmorragic complications appeared during the next months though severe pancytopenia was unchanged. However, two units of packed red cells were required every 2-3 weeks to keep the Hb at 8-10 g/d1. 4 months after diagnosis the patient was admitted to hospital again seriously ill with a clinical and radiological picture of pneumonia that developed into fatal septic shock despite antibiotic therapy and intensive care. Case 2 A 56-year-old woman was referred to our outpatient clinic because she had occasional ecchymoses. The peripheral blood picture showed mild pancytopenia (Hb 11-55 g/dl, reticulocytes 80 x 109/l, platelets 54 x 109/1, white cell count 2 - 6 x 109/1 with 57% polymorphs). We suspected a peripheral mechanism for the pancytopenia, possibly autoimmune, because of the following results: normal bone marrow examination, short survival of 51 Cr-labelled platelets, positive platelet antibodies, haptoglobin always below 10/-lg/ml, and return to normal Hb and white cell count while on prednisone 1 mg/kg daily. Systemic lupus erythematosus was ruled out. Recently, the mild pancytopenia that had been stable for 16 months was roughly interrupted. The patient was pale and complained of weakness 20-30 days after starting treatment with sulindac (400 mg/day) prescribed by a rheumatologist for her interphalangeal osteoarthritis. After 40 days of continuous sulindac ingestion, the blood picture was: Hb 7 -8g/dl, reticulocytes zero, white cell count 2.5x109/l with 22% of polymorphs and 35x109/l platelets. The bone marrow aspiration smear showed a complete erythro1. Miller JL. Marrow aplasia and sulindac. Ann Intern Med 1980; 92: 129. 2. Bennett L., Schlossman R, Rosenthal J, Balzora JD, Bennet AJ, Rosner F. anemia and sulindac. Ann Intern Med 1980; 92: 874.
Aplastic