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Lamotrigine and toxic epidermal necrolysis
THE LANCET
the Joint European Task Force Guidelines are “far better” as regards accuracy. The Sheffield table, despite its much simpler format, includes two major risk factors missing from the European Task Force table—diabetes and left ventricular hypertrophy. HDL cholesterol is the only risk factor in the Framingham function to be omitted from the Sheffield table, and has been assigned population average values of 1·15 mmol/L for men, and 1·4 mmol/L for women. Jackson correctly suggests that the total cholesterol to HDLcholesterol ratio can be incorporated readily, and this does improve accuracy (in preparation). However, we are uncertain whether the resulting table would be as acceptable to ordinary doctors—an overriding concern for us. Chamberlain and Fraser highlight the issue of monogenic dyslipidaemias, and the absence of family history from the Sheffield table (and the Framingham risk function). In fact, family history is a fairly weak independent predictor of CHD risk when compared with the risk factors included,5 and remains so even when age of parental death or the death of one or both parents is included.5 Nevertheless, it is not our intention that those with a very strong family history should not be screened, or that those with familial dyslipidaemias should be denied drug treatment. For this reason family history is quite properly a footnote to the table. *L E Ramsay, I U Haq, P R Jackson, W W Yeo University Department of Medicine and Pharmacology, Section of Clinical Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
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3 4
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Shepherd J, Cobbe SM, Ford I, et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR, Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Jönsson B. Measurement of health outcome and associated costs in cardiovascular disease. Eur Heart J 1996; 17(suppl A): 2–7. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993; 306: 983–87. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: strategy for use in general practice. BMJ 1986; 293: 474–79.
On May 30, lamotrigine 25 mg every other day was added. 12 days later she reacted with a flare, at first suspected to be caused by exposure to sun. On June 12 the flare had increased, and lamotrigine was stopped. 2 days later the reaction had progressed and her skin was starting to peel. A skin biopsy confirmed early TEN. She was transferred to the burns unit, where she was treated with plasmapheresis and put on positive-pressure ventilation. After a week, 40% of her skin was involved. She improved and was transferred to her local hospital on July 9. Genotyping did not reveal mutations in the genes of the drug-metabolising enzymes N-acetyltransferase 2, cytochromes P450 2D6 and 2C19, nor in the promoter of the UDP-glucuronosyltransferase 1*1 gene. A 22-year-old man given valproic acid 2400 mg daily and for the past 3 months lamotrigine 75 mg daily, is being treated in the burns unit for TEN involving all his skin. Rash develops in about 5% of patients starting lamotrigine.1 It appears to be related to the rate at which the drug is introduced, which is why gradual dose escalation has been recommended.1 The pathogenesis of TEN is still unknown, but may be an immunological hypersensitivity.2 All the patients in this report reacted within 14 days, which is compatible with the development of immune sensitisation.2 Another possible mechanism is altered drug metabolism resulting in reactions mediated by toxic intermediate metabolites.2 Lamotrigine is predominantly metabolised by glucuronidation, and it has been shown that patients with Gilbert’s syndrome, who have defective glucuronidation, have a lower clearance of lamotrigine,3 but the most common mutation causing this syndrome4 was not found in patient 2. However, all patients had co-medication with valproic acid, which interacts with the metabolism of lamotrigine by inhibiting its glucuronidation.5 The incidence of rash of lamotrigine is especially high when combined with valproic acid,1 but it is not known if the risk of developing TEN is higher. *Mia Wadelius, Torbjörn Karlsson, Claes Wadelius, Anders Rane Departments of *Clinical Pharmacology, Anaesthesiology, and Clinical Genetics, University Hospital, S-751 85 Uppsala, Sweden
1
Lamotrigine and toxic epidermal necrolysis SIR—Eight cases of severe skin reactions associated with lamotrigine have been reported in Sweden since 1994. Four of the reports concern Stevens-Johnson’s syndrome (SJS), and four of them toxic epidermal necrolysis (TEN). We describe here three lamotrigine-induced cases of TEN reported to the Regional Pharmacovigilance Centre in Uppsala. A 22-year-old woman with generalised epilepsy was treated with valproic acid 1500 mg daily. Because of inadequate seizure control, lamotrigine was added on April 14, when valproic acid was decreased to 1300 mg daily. On the twelfth day of medication she sunbathed in a solarium. She reacted with an intense flare, which rapidly progressed to blisters and fever, at first suspected to be a phototoxic reaction. Lamotrigine was discontinued, but the reaction progressed. She was transferred to the burns unit on May 2. TEN was verified by skin biopsy, and treatment with plasmapheresis was started. On May 5, when the toxic epidermal necrolysis involved her trachea and 70% of her skin, she was put on mechanical ventilation because of pain. After 3 weeks in the burns unit she was transferred to her local hospital. A 21-year-old mentally retarded woman with intractable temporal lobe epilepsy was treated with valproic acid 720 mg daily, levothyroxine, and medroxyprogesterone.
Vol 348 • October 12, 1996
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3
4
5
Brodie MJ. Lamotrigine versus other antiepileptic drugs: a star rating system is born. Epilepsia 1994; 35 (suppl 5): S41–S46. Friedmann PS, Strickland I, Pirmohamed M, Park BK. Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994; 130: 598–604. Park BK, Kitteringham NR, Pirmohamed M, Tucker GT. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41: 477–91. Bosma P, Chowdhury RJ, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13.
Regression of MALT lymphoma and treatment for Helicobacter pylori SIR—Alkan and colleagues (July 27, p 268)1 report the disappearance of a salivary gland MALT lymphoma coincident with treatment for helicobacter-associated gastritis. Their conclusions are unacceptable on the evidence presented. A large proportion of 62-year-old Asians in the USA would be expected to harbour Helicobacter pylori in the stomach. Thus the association of the salivary tumour with H pylori-associated gastritis could be purely coincidental—it cannot be cited as evidence that helicobacter produced the lymphoma. Additionally, treatment was given to eliminate helicobacter, but no evidence is presented to show that this
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the Joint European Task Force Guidelines are “far better” as regards accuracy. The Sheffield table, despite its much simpler format, includes two major risk factors missing from the European Task Force table—diabetes and left ventricular hypertrophy. HDL cholesterol is the only risk factor in the Framingham function to be omitted from the Sheffield table, and has been assigned population average values of 1·15 mmol/L for men, and 1·4 mmol/L for women. Jackson correctly suggests that the total cholesterol to HDLcholesterol ratio can be incorporated readily, and this does improve accuracy (in preparation). However, we are uncertain whether the resulting table would be as acceptable to ordinary doctors—an overriding concern for us. Chamberlain and Fraser highlight the issue of monogenic dyslipidaemias, and the absence of family history from the Sheffield table (and the Framingham risk function). In fact, family history is a fairly weak independent predictor of CHD risk when compared with the risk factors included,5 and remains so even when age of parental death or the death of one or both parents is included.5 Nevertheless, it is not our intention that those with a very strong family history should not be screened, or that those with familial dyslipidaemias should be denied drug treatment. For this reason family history is quite properly a footnote to the table. *L E Ramsay, I U Haq, P R Jackson, W W Yeo University Department of Medicine and Pharmacology, Section of Clinical Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
1
2
3 4
5
Shepherd J, Cobbe SM, Ford I, et al for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–07. Haq IU, Ramsay LE, Pickin DM, Yeo WW, Jackson PR, Payne JN. Lipid-lowering for prevention of coronary heart disease: what policy now? Clin Sci (in press). Jönsson B. Measurement of health outcome and associated costs in cardiovascular disease. Eur Heart J 1996; 17(suppl A): 2–7. Sever P, Beevers G, Bulpitt C, et al. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ 1993; 306: 983–87. Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: strategy for use in general practice. BMJ 1986; 293: 474–79.
On May 30, lamotrigine 25 mg every other day was added. 12 days later she reacted with a flare, at first suspected to be caused by exposure to sun. On June 12 the flare had increased, and lamotrigine was stopped. 2 days later the reaction had progressed and her skin was starting to peel. A skin biopsy confirmed early TEN. She was transferred to the burns unit, where she was treated with plasmapheresis and put on positive-pressure ventilation. After a week, 40% of her skin was involved. She improved and was transferred to her local hospital on July 9. Genotyping did not reveal mutations in the genes of the drug-metabolising enzymes N-acetyltransferase 2, cytochromes P450 2D6 and 2C19, nor in the promoter of the UDP-glucuronosyltransferase 1*1 gene. A 22-year-old man given valproic acid 2400 mg daily and for the past 3 months lamotrigine 75 mg daily, is being treated in the burns unit for TEN involving all his skin. Rash develops in about 5% of patients starting lamotrigine.1 It appears to be related to the rate at which the drug is introduced, which is why gradual dose escalation has been recommended.1 The pathogenesis of TEN is still unknown, but may be an immunological hypersensitivity.2 All the patients in this report reacted within 14 days, which is compatible with the development of immune sensitisation.2 Another possible mechanism is altered drug metabolism resulting in reactions mediated by toxic intermediate metabolites.2 Lamotrigine is predominantly metabolised by glucuronidation, and it has been shown that patients with Gilbert’s syndrome, who have defective glucuronidation, have a lower clearance of lamotrigine,3 but the most common mutation causing this syndrome4 was not found in patient 2. However, all patients had co-medication with valproic acid, which interacts with the metabolism of lamotrigine by inhibiting its glucuronidation.5 The incidence of rash of lamotrigine is especially high when combined with valproic acid,1 but it is not known if the risk of developing TEN is higher. *Mia Wadelius, Torbjörn Karlsson, Claes Wadelius, Anders Rane Departments of *Clinical Pharmacology, Anaesthesiology, and Clinical Genetics, University Hospital, S-751 85 Uppsala, Sweden
1
Lamotrigine and toxic epidermal necrolysis SIR—Eight cases of severe skin reactions associated with lamotrigine have been reported in Sweden since 1994. Four of the reports concern Stevens-Johnson’s syndrome (SJS), and four of them toxic epidermal necrolysis (TEN). We describe here three lamotrigine-induced cases of TEN reported to the Regional Pharmacovigilance Centre in Uppsala. A 22-year-old woman with generalised epilepsy was treated with valproic acid 1500 mg daily. Because of inadequate seizure control, lamotrigine was added on April 14, when valproic acid was decreased to 1300 mg daily. On the twelfth day of medication she sunbathed in a solarium. She reacted with an intense flare, which rapidly progressed to blisters and fever, at first suspected to be a phototoxic reaction. Lamotrigine was discontinued, but the reaction progressed. She was transferred to the burns unit on May 2. TEN was verified by skin biopsy, and treatment with plasmapheresis was started. On May 5, when the toxic epidermal necrolysis involved her trachea and 70% of her skin, she was put on mechanical ventilation because of pain. After 3 weeks in the burns unit she was transferred to her local hospital. A 21-year-old mentally retarded woman with intractable temporal lobe epilepsy was treated with valproic acid 720 mg daily, levothyroxine, and medroxyprogesterone.
Vol 348 • October 12, 1996
2
3
4
5
Brodie MJ. Lamotrigine versus other antiepileptic drugs: a star rating system is born. Epilepsia 1994; 35 (suppl 5): S41–S46. Friedmann PS, Strickland I, Pirmohamed M, Park BK. Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994; 130: 598–604. Park BK, Kitteringham NR, Pirmohamed M, Tucker GT. Relevance of induction of human drug-metabolizing enzymes: pharmacological and toxicological implications. Br J Clin Pharmacol 1996; 41: 477–91. Bosma P, Chowdhury RJ, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171–75. Yuen AWC, Land G, Weatherley BC, Peck AW. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–13.
Regression of MALT lymphoma and treatment for Helicobacter pylori SIR—Alkan and colleagues (July 27, p 268)1 report the disappearance of a salivary gland MALT lymphoma coincident with treatment for helicobacter-associated gastritis. Their conclusions are unacceptable on the evidence presented. A large proportion of 62-year-old Asians in the USA would be expected to harbour Helicobacter pylori in the stomach. Thus the association of the salivary tumour with H pylori-associated gastritis could be purely coincidental—it cannot be cited as evidence that helicobacter produced the lymphoma. Additionally, treatment was given to eliminate helicobacter, but no evidence is presented to show that this
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