Drugs

, Volume 46, Issue 1, pp 152–176 | Cite as

Lamotrigine

A Review of its Pharmacological Properties and Clinical Efficacy in Epilepsy
  • Karen L. Goa
  • Susan R. Ross
  • Paul Chrisp
Drug Evaluation

Abstract

Synopsis

Lamotrigine is an antiepileptic drug which is believed to suppress seizures by inhibiting the release of excitatory neurotransmitters. Efficacy has been demonstrated for lamotrigine as add-on therapy to existing regimens in patients with resistant partial seizures. Total seizure frequency was reduced by 17 to 59% compared with placebo, and 13 to 67% of patients experienced reductions of ⩾50% in seizure frequency. Secondarily generalised tonic-clonic seizures respond well to lamotrigine, and there is preliminary evidence of improvement in patients with primary generalised seizures, Lennox-Gastaut syndrome and in children with multiple seizure types. Seizure control has been maintained in patients who have continued to receive lamotrigine as monotherapy after discontinuation of other medications. Results of one trial suggest similar efficacy for lamotrigine monotherapy as for carbamazepine, but confirmation of its use in this setting awaits more extensive controlled comparisons with established agents.

Adverse events associated with lamotrigine as add-on therapy are typical of antiepileptic drugs, namely dizziness, ataxia and other CNS-related symptoms. Rash, which has occurred in 10% of patients in placebo-controlled trials, may be severe and its appearance has led to discontinuation of therapy in 1% of patients. Lamotrigine appears well tolerated in the longer term, but this facet of its profile requires further monitoring. Influences of valproic acid and enzyme-inducing antiepileptics on lamotrigine elimination necessitate dosage modification of lamotrigine. Conversely, lamotrigine has little apparent influence on the pharmacokinetics of other agents, although it may increase plasma concentrations of the active metabolite of carbamazepine during concomitant administration.

Thus, lamotrigine permits improved seizure control in some patients with refractory partial seizures, and may prove to be especially effective in secondarily generalised tonic-clonic seizures. As is usual at this stage in a drug’s development, several aspects of the profile of lamotrigine are incompletely defined, notably its efficacy in other seizure types, in children, as monotherapy, and its longer term tolerability. Nonetheless, lamotrigine presently offers a worthwhile alternative for the physician confronted with the challenge of treating patients with intractable partial seizures with or without secondarily generalised seizures, and shows potential for broader applications in other areas of epilepsy management.

Pharmacodynamic Properties

Lamotrigine probably exerts its anticonvulsant effects by blocking voltage-dependent sodium channels, thus stabilising the presynaptic membrane and preventing the release of excitatory neurotransmitters, predominantly glutamate. Its lack of activity at the N-methyl-d-aspartate (NMDA) receptor negates the possibility of phencyclidine-like central nervous system (CNS) effects occurring with its use.

The profile of anticonvulsant activity of lamotrigine in animal studies resembles that of phenytoin and carbamazepine. Lamotrigine suppressed seizures induced in rodents by maximal electroshock and pentetrazol (pentylenetetrazol), suggesting activity against partial and generalised tonic-clonic seizures. The drug also decreased electrically evoked after-discharge duration in various animals, a further indication of activity in simple and complex partial seizures. Activity was demonstrated in the photically evoked after-discharge test, which is considered a model of the absence seizure, and some patients with this seizure type have responded to lamotrigine (see Clinical Efficacy).

Single oral doses of lamotrigine 240mg have suppressed interictal epileptiform discharges recorded by electroencephalographic tracings in epileptic patients, but to a lesser extent than diazepam 20mg, and doses of lamotrigine 120 to 240mg reduced the photosensitivity range in patients with a photoconvulsive response. Effects on psychomotor function have been minimal in healthy volunteers administered single doses of lamotrigine 120 to 300mg, and were fewer than occurred with diazepam 10mg, phenytoin 1000mg or carbamazepine 400 and 600mg.

Pharmacokinetic Properties

Linear pharmacokinetics are demonstrable for lamotrigine over the dose range 50 to 400mg, with some recent reports indicating linearity up to 700mg in epileptic patients receiving concomitant enzyme-inducing antiepileptic drugs. Maximum plasma lamotrigine concentrations determined in kinetic studies in healthy subjects and patients with epilepsy were generally achieved within 1 to 3 hours of oral administration of doses in this range. Bioavailability of lamotrigine is calculated as approximately 98%, and apparent volume of distribution as 0.9 to 1.3 L/kg. Plasma protein binding is about 55%.

Lamotrigine undergoes biotransformation by glucuronidation to a 2-N-glucuronide derivative, which accounts for approximately 75 to 90% of the amount recoverable in the urine after a single oral dose, and to a 5-N-glucuronide. Under steady-state conditions, 43 to 87% of an oral dose of lamotrigine was retrievable within 24 hours, 95% as the glucuronide metabolite and the remainder as parent drug. Total clearance is about 0.03 L/h/kg in healthy persons.

The steady-state elimination half-life (t½) of lamotrigine in healthy young adults is approximately 25 to 30 hours. This value is halved in epileptic patients also receiving enzyme-inducing drugs such as carbamazepine and phenytoin, and doubled in the presence of valproic acid. Despite findings that the t½ of lamotrigine was lengthened in patients with Gilbert’s syndrome (asymptomatic unconjugated hyperbilirubinaemia), and in the elderly, t½ values nonetheless remained within the normal range. The pharmacokinetic profile of lamotrigine in children has not been well described, but elimination of the drug appears faster in these patients than in adults.

Any relationship between plasma lamotrigine concentrations and therapeutic effect appears tenuous; therefore, dosage should be modified according to clinical response rather than to a defined therapeutic range.

Clinical Efficacy

Lamotrigine as add-on therapy suppresses seizures in patients with intractable partial epilepsy, with some improvement observed in at least 55 to 65% of trial participants. Data amassed from crossover placebo-controlled studies indicate that lamotrigine (75 to 400mg daily for 8 to 18 weeks) produced reductions in total seizure frequency of 17 to 59%, and decreases in seizure frequency of ⩾50%, in 13 to 67% of patients, relative to placebo. Efficacy persisted during treatment for 24 weeks with lamotrigine 500 mg/day, which was superior to 300 mg/day and placebo. Patients with secondarily generalised tonic-clonic seizures have responded at least as well as those with partial seizures. Preliminary evidence suggests potential for the combination of lamotrigine and vigabatrin.

Although detailed longer term data are scarce, response to lamotrigine has been maintained for periods of up to 33 months in a few patients in noncomparative trials. In some patients, the addition of lamotrigine to the therapeutic regimen has facilitated withdrawal of all other antiepileptic medications, with several patients continuing on lamotrigine monotherapy for up to 4 years. An interim report found lamotrigine 100 and 200 mg/day monotherapy to be of comparable efficacy to carbamazepine 600 mg/day. Some evidence of improved quality of life and seizure severity during lamotrigine therapy is of interest, and further such investigations are awaited.

Encouraging preliminary results have been obtained with lamotrigine as add-on therapy in children with multiple seizure types participating in small noncomparative trials, and in some patients with Lennox-Gastaut syndrome. Anecdotal evidence of efficacy exists for lamotrigine in patients with primary generalised seizures.

Tolerability

Most adverse events recorded during lamotrigine administration as add-on therapy are CNS-related, notably dizziness, diplopia, somnolence and ataxia. Rash, which may be severe and has led to discontinuation of lamotrigine in 1% of patients, has occurred in 2.3% of patients in non-comparative trials, and in 10% of lamotrigine recipients versus 5% of placebo groups in controlled comparisons. Rash leading to treatment withdrawal was less frequent with lamotrigine (1%) than carbamazepine (6%) in a comparative trial. Lamotrigine has been well tolerated in the longer term, although present evidence is limited, as are data regarding its tolerability profile in children.

Drug Interactions

Concomitant administration of lamotrigine does not appear to affect the pharmacokinetics of other antiepileptic drugs, although there is conflicting evidence regarding a possible influence on plasma concentrations of the active 10, 11-epoxide metabolite of carbamazepine. Hepatic enzyme-inducing drugs such as carbamazepine and phenytoin reduce the elimination t½ of lamotrigine by 50%; conversely, valproic acid doubles this parameter. These clinically important interactions require dosage adjustment of lamotrigine. The efficacy of oral contraceptives is not compromised by the concomitant use of lamotrigine.

Dosage and Administration

Dosage regimens of lamotrigine differ depending on whether patients are also receiving concomitant valproic acid, or enzyme-inducing drugs (e.g carbamazepine, phenytoin, phenobarbital, primidone). Dosage guidelines, obtained from clinical trials investigating the use of lamotrigine as add-on therapy in adults and children aged ⩾12 years with refractory partial epilepsy, can be found on page 172, as can guidelines for younger children.

Preliminary evidence suggests that lamotrigine should be slowly initiated using dosage escalation to avoid the development of rash, and should be withdrawn slowly to prevent rebound seizures.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson GD, Gidal BE, Levy RH, Yau MK, Wolf KB, et al. Effect of lamotrigine on the pharmacokinetics and biotransformation of valproic acid. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  2. Avrutsky GJ, Rudik VP, Peck AW. An open add-on trial of lamotrigine (Lamictal®) in patients with treatment resistant epilepsy. Abstract. Journal of Neurology 237 (Suppl.): S32, 1990Google Scholar
  3. Banks GK, Beran RG. Neuropsychological assessment in lamotrigine treated epileptic patients. Clinical and Experimental Neurology 28: 231–237, 1991Google Scholar
  4. Bass J, Matsuo F, Leroy RF, Willmore LJ, Laxer K, et al. Lamotrigine monotherapy in patients with partial epilepsies. Abstract. Epilepsia 31: 643–644, 1990Google Scholar
  5. Baxter MG, Critchley MAE, Dopson ML. Lamotrigine (Lamictal®) is not PCP-like in rats: evidence from drug discrimination and working memory tests. Abstract. Acta Neurologica Scandinavica 82 (Suppl.): 39, 1990Google Scholar
  6. Besag FM. Use of the ‘Monolog’ spike and wave monitor to evaluate lamotrigine for absence seizures. Abstract. Epilepsia 32 (Suppl. 1): 89–90, 1991Google Scholar
  7. Betts T. Communication of pooled results of 27 open studies of lamotrigine (Lamictal®) as add-on therapy for up to 12 months in adults with treatment resistant epilepsy. Abstract. Journal of Neurology 237 (Suppl. 1): S52, 1990Google Scholar
  8. Betts T, Goodwin G, Withers RM, Yuen AWC. Human safety of lamotrigine. Epilepsia 32 (Suppl. 2): S17–S21, 1991aPubMedGoogle Scholar
  9. Betts T, Davies G, Yuen AWC. Preliminary data from an open multicenter trial of lamotrigine in patients with treatment-resistant epilepsy on one antiepileptic drug. Abstract. Epilepsia 32 (Suppl. 1): 95, 1991bGoogle Scholar
  10. Betts T. Clinical use of lamotrigine. Seizure 1: 3–6, 1992PubMedGoogle Scholar
  11. Binnie CD, van Emde Boas W, Kasteleijn-Nolste-Trenite DGA, de Korte RA, Meijer JWA, et al. Acute effects of lamotrigine (BW430C) in persons with epilepsy. Epilepsia 27(3): 248–254, 1986PubMedGoogle Scholar
  12. Binnie CD. Preliminary evaluation of potential anti-epileptic drugs by single dose electrophysiological and pharmacological studies in patients. Journal of Neural Transmission. 72: 259–266, 1988PubMedGoogle Scholar
  13. Binnie CD, Debets RMC, Engelsman M, Meijer JWA, Meinardi H, et al. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Research 4: 222–229, 1989PubMedGoogle Scholar
  14. Blanken horn V, Hoffman H.-G., Polatschek B. Acute intoxication with the new antiepileptic drug lamotrigine in a suicide attempt. (Translated into English from German.) Epilepsia 91: 473–475, 1992Google Scholar
  15. Brodie MJ. Lamotrigine. Lancet 339: 1397–1400, 1992PubMedGoogle Scholar
  16. Callaghan N. Lamictal as adjunctive treatment in patients with intractable epilepsy. Abstract. Epilepsia 32 (Suppl. 1): 100, 1991Google Scholar
  17. Cheung H, Kamp D, Harris E. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Research 13: 107–112, 1992PubMedGoogle Scholar
  18. Cohen AF, Ashby L, Crowley D, Land G, Peck AW, et al. Lamotrigine (BW430C), a potential anticonvulsant. Effects on the central nervous system in comparison with phenytoin and di-azepam. British Journal of Clinical Pharmacology 20: 619–629, 1985PubMedGoogle Scholar
  19. Cohen AF, Land GS, Breimer DD, Yuen WC, Winton C, et al. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clinical Pharmacology and Therapeutics 42: 535–541, 1987PubMedGoogle Scholar
  20. Cohen AF, Hamilton MJ, Yuen WC, Peck AW. Human pharmacology of lamotrigine (Lamictal®): comparison with diazepam, phenytoin and carbamazepine in healthy volunteers. Abstract. Journal of Neurology 237 (Suppl.): S32, 1990Google Scholar
  21. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 22: 489–501, 1981Google Scholar
  22. Davies G, Kench SV, Clifford JS, Yuen AWC and Study 105 Investigators. Preliminary data from an an open, multicentre trial of lamotrigine (Lamictal®) in patients with treatment-resistant epilepsy on one antiepileptic drug withdrawing to monotherapy. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  23. Davies G, Yuen AWC. Preliminary data from an open multicentre trial of lamotrigine (Lamictal) in patients with treatment- resistant epilepsy on one antiepileptic drug withdrawing monotherapy. Abstract. Epilepsia 33 (Suppl. 3): 81, 1992Google Scholar
  24. Depot M, Powell JR, Messenheimer Jr JA, Cloutier G, Dalton MJ. Kinetic effects of multiple oral doses of acetaminophen on a single oral dose of lamotrigine. Clinical Pharmacology and Therapeutics 48: 346–355, 1990PubMedGoogle Scholar
  25. Dichter MA. The epilepsies and convulsive disorders. In Wilson et al. (Eds) Harrison’s Principles of Internal Medicine, 12th ed., pp. 1968–1977, McGraw-Hill Inc., New York, 1991Google Scholar
  26. Dichter MA. Cellular mechanisms of epilepsy and potential new treatment strategies. Epilepsia 30 (Suppl. 1): S3–S12, 1989PubMedGoogle Scholar
  27. Doig MV, Clare RA. Use of thermospray liquid chromatographymass spectrometry to aid in the identification of urinary metabolites of a novel antiepileptic drug, Lamotrigine. Journal of Chromatography 554: 181–189, 1991PubMedGoogle Scholar
  28. Dren AT, Moore EL, and the U.S. Lamictal Protocol 05 Clinical Trial Group. Placebo-controlled, dose-response evaluation of the efficacy and safety of lamotrigine (Lamictal) as add-on therapy in epileptic outpatients with partial seizures. Abstract. Epilepsia 32 (Suppl. 3): 20, 1991Google Scholar
  29. Dren AT, Womble GP, Yau MK, Risner ME, Rudd GD, et al. Placebo-controlled clinical studies demonstrating the efficacy and safety of lamotrigine (Lamictal®) as add-on therapy in patients with refractory partial seizures. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  30. Dulac O, Withers RM, Yuen AWC. Add-on lamotrigine in pediatric patients with treatment-resistant epilepsy. Abstract. Epilepsia 32 (Suppl. 1): 95, 1991Google Scholar
  31. Faught ER, Leroy RF, Messenheimer JA, Matsuo F, Bergen D, et al. Clinical experience with lamotrigine (Lamictal) monotherapy for partial seizures in adult outpatients. Abstract. Epilepsia 33 (Suppl. 3): 82, 1992Google Scholar
  32. Faught ER, Leroy RF, Messenheimer J, Matsuo F, Bergen D, et al. Clinical experience with lamotrigine (Lamictal®) monotherapy for partial seizures in adult outpatients. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992aGoogle Scholar
  33. Fazio A, Artesi C, Russo M, Trio R, Oteri G, et al. A liquid Chromatographic assay using a high-speed column for the determination of lamotrigine, a new antiepileptic drug, in human plasma. Therapeutic Drug Monitoring 14: 509–512, 1992PubMedGoogle Scholar
  34. Foletti G, Schmidt M, Delisle MC, Molleyres D, Volanschi D. An open study on effectiveness of lamotrigine in the treatment of secondary bilateral synchrony, unsatisfactorily controlled by conventional drugs. Abstract. Journal of Neurology 239 (Suppl. 2): S71, 1992Google Scholar
  35. Garnett WR. Epilepsy. In DiPiro et al. (Eds) Pharmacotherapy. A pathophysiologic approach, pp. 611–631, Elsevier, New York, 1989Google Scholar
  36. Gibbs J, Appleton RE, Rosenbloom L, Yuen WC. Lamotrigine for intractable childhood epilepsy: a preliminary communication. Correspondence. Developmental Medicine and Child Neurology 34: 368–371, 1992Google Scholar
  37. Grant SM, Heel RC. Vigabatrin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 41: 889–926, 1991PubMedGoogle Scholar
  38. Graves NM, Leppik IE. Antiepileptic medications in development. DICP: Annals of Pharmacotherapy 25: 978–986, 1991PubMedGoogle Scholar
  39. Graves NM, Ritter FJ, Wagner ML, Floren KL, Alexander BJ, et al. Effect of lamotrigine on carbamazepine epoxide concentrations. Abstract. Epilepsia 32 (Suppl. 3): 13, 1991Google Scholar
  40. Greenblatt DJ, Sellers EM, Shader RI. Drug disposition in old age. New England Journal of Medicine. 306: 1081–1088, 1982PubMedGoogle Scholar
  41. Hamilton MJ, Cohen AF, Yuen AWC, Harkin N, Land G, et al. Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage. Epilepsia 34: 166–173, 1993PubMedGoogle Scholar
  42. Holdich T, Whiteman P, Orme M, Back D, Ward S. Effect of lamotrigine on the pharmacology of the combined oral contraceptive pill. Abstract. Epilepsia 32 (Suppl. 1): 96, 1991Google Scholar
  43. Jawad S, Oxley J, Yuen WC, Richens A. The effect of lamotrigine, a novel anticonvulsant, on interictal spikes in patients with epilepsy. British Journal of Clinical Pharmacology. 22: 191–193, 1986PubMedGoogle Scholar
  44. Jawad S, Yuen WC, Peck AW, Hamilton MJ, Oxley JR. Lamotrigine: single dose pharmacokinetics and initial 1 week experience in refractory epilepsy. Epilepsy Research 1(3): 194–201, 1987PubMedGoogle Scholar
  45. Jawad S, Richens A, Goodwin G, Yuen WC. Controlled trial of lamotrigine (Lamictala) for refractory partial seizures. Epilepsia 30: 356–363, 1989PubMedGoogle Scholar
  46. Kirker S, Reynolds EH. Vigabatrin and lamotrigine in a patient with intractable epilepsy. Abstract. Acta Neurologica Scandinavica 82 (Suppl.): 38, 1990Google Scholar
  47. Krejcova H, Salcmanova Z, Trnavska Z, Clark SJ. Open 12 months trial of lamotrigine (Lamictal®) add-on therapy in treatmentresistant epilepsy. Abstract. Journal of Neurology 237: S32, 1990Google Scholar
  48. Lamb RJ, Miller AA. Effect of lamotrigine and some known anticonvulsant drugs on visually-evoked after-discharge in the conscious rat. Abstract. British Journal of Pharmacology 86: 765P, 1985Google Scholar
  49. Leach MJ, Marden CM, Miller AA. Pharmacological studies on — lamotrigine, a novel potential antiepileptic drug. II. Neurochemical studies on the mechanism of action. Epilepsia 27: 490–497, 1986PubMedGoogle Scholar
  50. Lindeman RD. Changes in renal function with aging. Implications for treatment. Drugs & Aging 2: 423–431, 1992Google Scholar
  51. Loiseau P, Yuen AWC, Duché B, Ménager T, Arné-Bès MC. A randomised double-blind placebo-controlled crossover add-on trial of lamotrigine in patients with treatment-resistant partial seizures. Epilepsy Research 7: 136–145, 1990PubMedGoogle Scholar
  52. Matsuo F, Bergen D, Faught E, Messenheimer JA, Dren AT, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. Neurology, in press, 1993Google Scholar
  53. McGeer E, Zhu SG. Lamotrigine protects against kainate but not ibotenate lesions in rat striatum. Neuroscience Letters 112: 348–351, 1990PubMedGoogle Scholar
  54. Meldrum BS. Excitatory amino acid transmitters in epilepsy. Epilepsia 32 (Suppl. 2): Sl–3, 1991Google Scholar
  55. Messenheimer JA, Ramsay RE, Leroy RF, Zielinski JJ, Willmore LJ, et al. Multicenter, long-term study of lamotrigine (Lamictal) in outpatients with partial seizures. Abstract. Epilepsia 33 (Suppl. 3): 82, 1992Google Scholar
  56. Mikati MA, Schachter SC, Schomer DL, Keally M, Osborne-Shafer P, et al. Long-term tolerability, pharmacokinetic and preliminary efficacy study of lamotrigine in patients with resistant partial seizures. Clinical Neuropharmacology 12: 312–321, 1989PubMedGoogle Scholar
  57. Miller AA, Sawyer DA, Roth B, et al. Lamotrigine. In Meldrum BS et al. (Eds) New anticonvulsant drugs. London, John Libbey, 1986aGoogle Scholar
  58. Miller AA, Wheatley P, Sawyer DA, Baxter MG, Roth B. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug. I. Anticonvulsant profile in mice and rats. Epilepsia 27: 483–489, 1986bPubMedGoogle Scholar
  59. Mims J, Ritter FJ. Compassionate plea use of lamotrigine in children with incapacitating and/or life-threatening epilepsy. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  60. Mims J, Ritter FJ, Dren AT, Valakas AM. Compassionate plea use of lamotrigine in children with incapacitating and/or life-threatening epilepsy. Epilepsia 33 (Suppl. 3): 83, 1992Google Scholar
  61. O’Donnell RA, Miller AA. The effect of lamotrigine upon development of cortical kindled seizures in the rat. Neuropharmacology 30: 253–258, 1991PubMedGoogle Scholar
  62. Oiler LFV, Russi A, Oiler Daurella L. Lamotrigine in the Lennox-Gastaut syndrome. Epilepsia 32 (Suppl. 1): 58, 1991Google Scholar
  63. Panayiotopoulos CP, Ferrie CD, Knott C, Robinson RO. Interaction of lamotrigine with sodium valproate. Correspondence. Lancet 341: 445, 1993PubMedGoogle Scholar
  64. Peck AW. Clinical pharmacology of lamotrigine. Epilepsia 32 (Suppl. 2): S9–S12, 1991PubMedGoogle Scholar
  65. Pisani F, Russo M, Trio R, Artesi C, Fazio A, et al. Lamotrigine in refractory epilepsy. A long-term open study. New Antiepileptic Drugs (Suppl. 3): 187–191, 1991aGoogle Scholar
  66. Pisani F, Russo M, Trio R, Fazio A, Artesi C, et al. Lamotrigine in patients with refractory epilepsy. A follow-up of 33 months. Abstract. Epilepsia 32 (Suppl. 1): 58, 1991bGoogle Scholar
  67. Pisani F, Gallitto G, di Perri R. Could lamotrigine be useful in status epilepticus? A case report. Correspondence. Journal of Neurology, Neurosurgery and Psychiatry 54: 845–846, 1991cGoogle Scholar
  68. Pisani F, Di Perri R, Perucca E, Richens A. Interaction of lamotrigine with sodium valproate. Letter. Lancet 341: 1224, 1993PubMedGoogle Scholar
  69. Posner J, Cohen AF, Land G, Winton C, Peck AW. The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia (Gilbert’s syndrome). British Journal of Clinical Pharmacology 28: 117–120, 1989PubMedGoogle Scholar
  70. Posner J, Webster H, Yuen WC. Investigation of the ability of lamotrigine, a novel antiepileptic drug, to induce mixed function oxygenase enzymes. Abstract. British Journal of Clinical Pharmacology 32: 658P, 1991aGoogle Scholar
  71. Posner J, Holdich T, Crome P. Comparison of lamotrigine pharmacokinetics in young and elderly healthy volunteers. Journal of Pharmaceutical Medicine 1: 121–128, 1991Google Scholar
  72. Pugh CB, Garnett WR. Current issues in the treatment of epilepsy. Clinical Pharmacy 10: 335–358, 1991PubMedGoogle Scholar
  73. Ramsay RE, Pellock JM, Garnett WR, Sanchez RM, Valakas AM, et al. Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy. Epilepsy Research 10: 191–200, 1991PubMedGoogle Scholar
  74. Rey E, Vauzelle F, Pons G, Schlumberger E, Dulac O, et al. Pharmacokinetics of lamotrigine in young epileptic children. Abstract. Presented at the Vth World Conference on Clinical Pharmacology and Therapeutics, Yokohama, Japan, July 26–31, 1992Google Scholar
  75. Richens A. Pharmacokinetics of lamotrigine. In Richens A (Ed.) Clinical update on lamotrigine: a novel antiepileptic agent, pp. 21–27, Wells Medical Limited, Royal Tunbridge Wells, 1992aGoogle Scholar
  76. Richens A. New drugs for epilepsy: a rapidly changing scene. Acta Neurologica Scandinavica 86 (Suppl.): 65–70, 1992Google Scholar
  77. Richens A, Yuen AWC. Overview of the clinical efficacy of lamotrigine. Epilepsia 32 (Suppl. 2): S13–S16, 1991PubMedGoogle Scholar
  78. Risner ME and the LAMICTAL Study Group. Multicenter, doubleblind, add-on, crossover study of lamotrigine (Lamictal) in epileptic outpatients with partial seizures. Abstract. Epilepsia 31: 619–620, 1990Google Scholar
  79. Rogawski MA. The NMDA receptor, NMDA antagonists and epilepsy therapy. A status report. Drugs 44: 279–292, 1992PubMedGoogle Scholar
  80. Sailstad JM, Findlay JWA. Immunofluorometric assay for lamotrigine (Lamictal) in human plasma. Therapeutic Drug Monitoring 13: 433–442, 1991PubMedGoogle Scholar
  81. Sander JWAS, Hart YM, Patsalos PN, Duncan JS, Shorvon SD, et al. Lamotrigine and generalised seizures. Abstract. Epilepsia 32 (Suppl. 1): 59, 1991Google Scholar
  82. Sander JWAS, Patsalos PN, Oxley JR, Hamilton MJ, Yuen WC. A randomised double-blind placebo-controlled add-on trial of lamotrigine in patients with severe epilepsy. Epilepsy Research 6: 221–226, 1990bPubMedGoogle Scholar
  83. Sander JWAS, Patsalos PN. Assessment of folate levels in patients on short-term and chronic lamotrigine therapy. Epilepsia 13: 89–92, 1992Google Scholar
  84. Sander JWAS, Trevisol-Bittencourt PC, Hart YM, Patsalos PN, Shorvon SD. The efficacy and long-term tolerability of lamotrigine in the treatment of severe epilepsy. Epilepsy Research 7: 226–229, 1990aPubMedGoogle Scholar
  85. Schachter SC. A multicenter, placebo-controlled evaluation of the safety of lamotrigine (Lamictal®) as add-on therapy in outpatients with partial seizures. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  86. Schapel GJ, Beran RG, Vajda FJE, Berkovic SF, Mashford ML, et al. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant partial seizures. Journal of Neurology, Neurosurgery, and Psychiatry 56: 448–453, 1993PubMedGoogle Scholar
  87. Schapel GJ, Dollman W, Beran RG, Dunagan FM. No effect of lamotrigine on carbamazepine and carbamazepine-epoxide concentrations. Abstract. Epilepsia 32 (Suppl. 1): 58, 1991aGoogle Scholar
  88. Schlumberger E, Chavez F, Dulac O, Moszkowski J. Open study with lamotrigine (LTG) in child epilepsy. Abstract. Seizure 1 (Suppl. A): P9/21, 1992Google Scholar
  89. Shandra AA, Godlevsky LS, Mazarati AM, Lobenko AA. Effects of lamotrigine on kainate-induced epileptic activity and parkinsonism. Abstract. Epilepsia 32 (Suppl. 1): 60, 1991Google Scholar
  90. Shorvon SD. Epidemiology, classification, natural history, and genetics of epilepsy. Lancet 336: 93–96, 1990PubMedGoogle Scholar
  91. Smith D, Baker GA, Davies G, Yuen AWC, Chadwick DW. Randomized, placebo-controlled, double-blind, cross-over trial of lamotrigine as add-on therapy in patients with refractory epilepsy. Abstract. Epilepsia 32 (Suppl. 1): 59, 1991Google Scholar
  92. Smith D, Baker G, Davies G, Dewey M, Chadwick DW. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 34: 312–322, 1993PubMedGoogle Scholar
  93. Sinz MW, Remmel RP. Isolation and characterization of a novel quaternary ammonium-linked glucuronide of lamotrigine. Drug Metabolism and Disposition 19: 149–153, 1991PubMedGoogle Scholar
  94. Stewart J, Hughes E, Reynolds EH. Lamotrigine for generalised epilepsies. Correspondence. Lancet 340: 1223, 1992aPubMedGoogle Scholar
  95. Stewart J, Hughes E, Kirker S, Reynolds EH. Combined vigabatrin and lamotrigine for very intractable epilepsy. Seizure 1 (Suppl. A): 13–39, 1992bGoogle Scholar
  96. Study 106 Investigators. Interim report an on open multicentre lamotrigine vs carbamazepine montherapy trial in patients with epilepsy. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992Google Scholar
  97. Timmings PL, Richens A. Lamotrigine in primary generalised epilepsy. Correspondence. Lancet 339: 1300–1301, 1992PubMedGoogle Scholar
  98. Timmings PL, Richens A. Lamotrigine as an add-on drug in the management of Lennox-Gastaut syndrome. European Neuro-psychopharmacology 32: 305–307, 1992aGoogle Scholar
  99. van Wieringen A, Binnie CD, de Boer PTE, van Emde Boas W, Overweg J, et al. Electroencephalographic findings in antiepileptic drug trials. A review and report of 6 studies. Epilepsy Research 1: 3–15, 1987PubMedGoogle Scholar
  100. Wallace SJ. Add-on open trial of lamotrigine in resistant childhood seizures. Abstract. Brain and Development 12: 734, 1990Google Scholar
  101. Warner T, Patsalos PN, Prevett M, Elyas AA, Duncan JS. Lamotrigine-induced carbamazepine toxicity: an interaction with carbamazepine-10,11-epoxide. Epilepsy Research 11: 147–150, 1992PubMedGoogle Scholar
  102. Wheatley PL, Miller AA. Effects of lamotrigine on electrically induced afterdischarge duration in anaesthetised rat, dog, and marmoset. Epilepsia 30: 34–40, 1989PubMedGoogle Scholar
  103. Wolf P. Lamotrigine: preliminary clinical observations on pharmacokinetics and interactions with traditional antiepileptic drugs. Journal of Epilepsy 5: 73–79, 1992Google Scholar
  104. Woodhouse K, Wynne HA. Age-related changes in hepatic function: implications for drug therapy. Drugs & Aging 2: 243–255, 1992Google Scholar
  105. Yau MK, Adams MA, Wargin WA, Lai AA. A single-dose and steady-state pharmacokinetic study of lamotrigine in healthy male volunteers. Presented at the Third International Cleveland Clinic — Bethel Epilepsy Symposium. Cleveland, June 16–20, 1992Google Scholar
  106. Yau MK, Garnett WR, Wargin WA, Pellock JM. A single dose, dose proportionality and bioequivalence study of lamotrigine in normal volunteers. Abstract. Epilepsia 32 (Suppl. 3): 8, 1991Google Scholar
  107. Yau MK, Wargin WA, Wolf KB, Lai AA, Dren AT, et al. Effect of valproic acid on the pharmacokinetics of lamotrigine at steady state. Presented at the 1992 Annual Meeting of the American Epilepsy Society, Seattle, December 4–10, 1992aGoogle Scholar
  108. Yuen AWC, Bihari DJ. Multiorgan failure and disseminated intravascular coagulation in severe convulsive seizures. Abstract. Lancet 340: 618, 1992PubMedGoogle Scholar
  109. Yuen AWC, Chapman A. Interim report on an open multicenter lamotrigine (Lamictal) versus carbamazepine monotherapy trial in patients with epilepsy. Abstract. Epilepsia 33 (Suppl. 3): 81–82, 1992Google Scholar
  110. Yuen AWC, Und G, Weatherley BC, Peck AW. Sodium valproate acuotely inhibits lamotrigine metabolism. British Journal of Clinical Pharmacology 33: 511–513, 1992PubMedGoogle Scholar
  111. Yuen AWC, Peck AW. Lamotrigine pharmacokinetics: oral and i.v. infusion in man. Abstract. British Journal of Clinical Pharmacology 26: 242P, 1988Google Scholar
  112. Yuen AWC, Rafter JEW. Lamotrigine (Lamictal) as add-on therapy in pediatric patients with treatment-resistant epilepsy. An overview. Abstract. Epilepsia 33 (Suppl. 3): 82–83, 1992Google Scholar
  113. Zipp F, Baas H, Fischer P.-A. Lamotrigine — antiparkinsonian activity by blockade of glutamate? Journal of Neural Transmission 5: 67–75, 1993PubMedGoogle Scholar

Copyright information

© Adis International Limited 1993

Authors and Affiliations

  • Karen L. Goa
    • 1
  • Susan R. Ross
    • 1
  • Paul Chrisp
    • 1
  1. 1.Adis International LtdMairangi Bay, Auckland 10New Zealand

Personalised recommendations