- Email: [email protected]
First-choice drug for newly diagnosed epilepsy
Comment
First-choice drug for newly diagnosed epilepsy See Articles pages 1000 and 1016
The two articles by Anthony Marson and colleagues in today’s Lancet1,2 outline the results of the SANAD study, a large multicentre trial in which patients with newly diagnosed epilepsy were randomised to several different therapies. These investigators had the expectation that the results would help physicians select the drug of first choice for patients with newly diagnosed epilepsy. The study is particularly timely, because of the large number of new antiepileptic drugs that have become available over the past few decades (table). Yet several appraisals that substantially influence availability of these drugs for prescribers (eg, guidelines by the UK National Institute for Health and Clinical Excellence3) have concluded that standard drugs must be the drugs of first choice. Such guidelines have not been received with overwhelming acceptance. Many physicians feel (rightly or wrongly) that the new drugs provide some advantages over the old. The “new is better than old” philosophy has been fuelled by studies that have compared an established antiepileptic drug, such as carbamazepine or phenytoin, in head-tohead comparisons against one of the newer drugs, such as lamotrigine, topiramate, or levetiracetam. These studies are almost always sponsored by the pharmaceutical company that manufactures the newer drug, and
Drug
Year of launch
Primary indication
Felbamate*
USA: 1993
Monotherapy or adjunctive therapy in refractory partial seizures or Lennox-Gastaut syndrome
Gabapentin
UK: 1993 USA: 1994
Adjunctive therapy and/or monotherapy in adults and children with partial seizures
Lamotrigine
Ireland: 1991 (UK shortly thereafter) USA: 1994
Adjunctive therapy and/or monotherapy in adults and children with partial seizures, generalised tonic-clonic seizures, Lennox-Gastaut syndrome
Levetiracetam
USA: 1999
Adjunctive therapy and/or monotherapy in adults and children with partial seizures±juvenile myoclonic epilepsy and generalised tonic-clonic seizures
Oxcarbazepine
A few European countries: 1990 Adjunctive therapy and/or monotherapy in adults and UK: 2002 children with partial seizures
Pregabalin
Europe: 2004 USA: 2005
Adjunctive therapy in adults with partial seizures
Tiagabine
USA: 1997
Adjunctive therapy in adults with partial seizures
Topiramate
UK: 1995 USA: 1996
Adjunctive therapy and/or monotherapy in adults and children for partial seizures±generalised tonic-clonic seizures and Lennox-Gastaut syndrome
Vigabatrin*
Europe: 1989
Adjunctive therapy in partial seizures, infantile spasms
Zonisamide
USA: 2000 (earlier in Japan) UK: 2005
In adults with partial seizures (other indications including myoclonus in Japan)
*Felbamate and vigabatrin have special safety issues, and should only be prescribed when risk-benefit ratio of use has been assessed.
Table: Newer antiepileptic drugs
970
almost always conclude that the newer drug is equally as effective but better tolerated than the established drug. Unfortunately, methodological problems, including small sample size, questionable selection of patients, titration schedules, dose and dose form, and short duration of study, have limited the acceptance of the results.4–6 Many of these methodological problems have been overcome in SANAD, which was large and followed patients up for several years. The conclusion is that lamotrigine is the drug of first choice for patients with partial epilepsy, and valproate for generalised and unclassifiable epilepsy. This answer is satisfying for the many physicians, in general practice and specialists, who are overwhelmed by the number of available antiepileptic drugs, both old and new, and would welcome a clear-cut strategy for therapy. The result may also be welcomed by payers, because lamotrigine will soon go off patent and become inexpensive, and valproate is less expensive than many of the newer drugs. Yet the question still remains: is it possible to select a drug of first choice for patients with epilepsy? To select an antiepileptic drug of first choice, one must know about the properties of the drugs that might make them more or less advantageous. These include, of course, their ability to control seizures, overall tolerability, cost, likelihood that they will produce serious health risks, and pharmacokinetic properties. SANAD’s conclusions are highly driven by the first three, because they are the easiest to measure in a randomised trial. Patients can report whether they have had seizures, and how they are feeling. Their willingness to remain on the drug can also be measured, as an overall determination of effectiveness. But what of the other properties? It is difficult if not impossible to measure the consequences of pharmacokinetic differences between drugs, particularly a potential for drug interactions. SANAD was too small to address even the most common serious adverse event related to the drugs that were tested. Yet the fact that such events might occur is still considered by most physicians to be an important characteristic of a drug, and one that affects prescribing. For example, the incidence of potentially life-threatening pancreatitis with valproate is one per 3000 exposures, and there is also am increased risk of hepatic failure.7,8 How are these facts to be weighted, when selecting valproate as drug of first choice? Even efficacy and www.thelancet.com Vol 369 March 24, 2007
Comment
tolerability outcomes are not completely cut and dried, for several reasons. First, some of these outcomes may be influenced by the way the physician elected to use the drug. For example, two of the drugs in SANAD, carbamazepine and lamotrigine, are associated with treatment-emergent rash. The occurrence of rash can be highly correlated with the titration schedule. For both drugs, a faster titration schedule will lead to a higher frequency of rash.9,10 Because lamotrigine is the newer of the two drugs, a great deal of attention has been paid to selecting an ideal titration schedule. By contrast, carbamazepine tends to be titrated more rapidly. Because the titration schedule was not mandated in SANAD (although there was a recommended regimen), it is unclear whether the rash rates might have been lower if the titration had been slower. This point is important because 21% of treatment failures for carbamazepine were related to rash (vs 14% for lamotrigine). In a recent study11 that compared carbamazepine and levetiracetam and in which the titration rate for carbamazepine was slower, the dose was lower, and a controlled-release formulation was used in all cases, the rate of rash for carbamazepine was 5·5% compared with a per-protocol rate of 32% in SANAD. Of course, the two studies had different durations, but discontinuation due to rash tends to occur during the first 6 months of use. Is it possible that the mode of use of carbamazepine was the sole explanation of a difference in tolerability between carbamazepine and lamotrigine? It could be argued that the next randomised study should be a comparison between carbamazepine (as used in practice) and carbamazepine (as used in a specific regimen). Only then could the true risks of carbamazepine be known. The second and perhaps more compelling concern in designating one drug as first choice is that it may reduce the likelihood that a physician will make an effort to match the drug to the patient. This point relates to the many characteristics of a drug that are not necessarily addressed in pragmatic trials such as SANAD. For example, lamotrigine can cause insomnia, and might not be ideal for patients who have known sleep disorders.12 Lamotrigine’s clearance can increase several fold during pregnancy.13 This aspect of the drug complicates use in women of childbearing years. Valproate, as mentioned by the SANAD investigators, is not currently recommended as a drug of first choice in women of childbearing potential because, in several studies, offspring of mothers who had used valproate during pregnancy have had a higher frequency www.thelancet.com Vol 369 March 24, 2007
of fetal malformations and cognitive delay.14 Valproate has also been associated with a higher likelihood of weight gain. For some individuals, weight gain is an important outcome, whereas it is inconsequential to others. Also, valproate has been associated with alterations in liver function tests and platelet counts. This drug would not be a wise choice for patients who have bleeding risks, and for patients who might need hepatic monitoring for other reasons. Therefore it might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice. Simple is good, but overly simplistic may not provide the optimum benefit to our patients. Jacqueline A French Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA [email protected] I have received compensation for consulting and lectures from Johnson & Johnson, Medpointe, UCB, Abbott, Pfizer, UCB Pharma, Cephalon, GlaxoSmithKline, and Eisai. 1
2
3 4 5 6
7 8
9
10 11
12 13
14
Marson AG, Al-Kharusi AM, Alwaidh M, on behalf of the SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M. et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26. National Institute for Clinical Excellence. Newer drugs for epilepsy in adults. March, 2004: http://www.nice.org.uk/TA076guidance (accessed May 4, 2004). French JA, Chadwick DW. Drugs for the elderly: using the old to focus on the new. Neurology 2005; 64: 1834–35. Arroyo S, Sander JW. Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten. Neurology 1999; 53: 1170–74 Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47: 1094–120. Chapman SA, Wacksman GP, Patterson BD. Pancreatitis associated with valproic acid: a review of the literature. Pharmacotherapy 2001; 21: 1549–60. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994; 35: 1005–15. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology 1997; 49: 542–46. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother 1999; 33: 1037–42. Ben-Menachem E, Brodie MJ, Perucca E, on behalf of the N01061 Study Group. Efficacy of levetiracetam monotherapy; randomized double-blind head-tohead comparison with carbamazepine-CR in newly diagnosed epilepsy patients with partial onset or generalised tonic-clonic seizures. American Academy of Neurology, San Diego, California, April 4, 2006. Sadler M. Lamotrigine associated with insomnia. Epilepsia 1999; 40: 322–25. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004; 62: 292–95 Meador KJ, Baker GA, Finnell RH, for the NEAD Study Group. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006; 67: 407–12.
971
First-choice drug for newly diagnosed epilepsy See Articles pages 1000 and 1016
The two articles by Anthony Marson and colleagues in today’s Lancet1,2 outline the results of the SANAD study, a large multicentre trial in which patients with newly diagnosed epilepsy were randomised to several different therapies. These investigators had the expectation that the results would help physicians select the drug of first choice for patients with newly diagnosed epilepsy. The study is particularly timely, because of the large number of new antiepileptic drugs that have become available over the past few decades (table). Yet several appraisals that substantially influence availability of these drugs for prescribers (eg, guidelines by the UK National Institute for Health and Clinical Excellence3) have concluded that standard drugs must be the drugs of first choice. Such guidelines have not been received with overwhelming acceptance. Many physicians feel (rightly or wrongly) that the new drugs provide some advantages over the old. The “new is better than old” philosophy has been fuelled by studies that have compared an established antiepileptic drug, such as carbamazepine or phenytoin, in head-tohead comparisons against one of the newer drugs, such as lamotrigine, topiramate, or levetiracetam. These studies are almost always sponsored by the pharmaceutical company that manufactures the newer drug, and
Drug
Year of launch
Primary indication
Felbamate*
USA: 1993
Monotherapy or adjunctive therapy in refractory partial seizures or Lennox-Gastaut syndrome
Gabapentin
UK: 1993 USA: 1994
Adjunctive therapy and/or monotherapy in adults and children with partial seizures
Lamotrigine
Ireland: 1991 (UK shortly thereafter) USA: 1994
Adjunctive therapy and/or monotherapy in adults and children with partial seizures, generalised tonic-clonic seizures, Lennox-Gastaut syndrome
Levetiracetam
USA: 1999
Adjunctive therapy and/or monotherapy in adults and children with partial seizures±juvenile myoclonic epilepsy and generalised tonic-clonic seizures
Oxcarbazepine
A few European countries: 1990 Adjunctive therapy and/or monotherapy in adults and UK: 2002 children with partial seizures
Pregabalin
Europe: 2004 USA: 2005
Adjunctive therapy in adults with partial seizures
Tiagabine
USA: 1997
Adjunctive therapy in adults with partial seizures
Topiramate
UK: 1995 USA: 1996
Adjunctive therapy and/or monotherapy in adults and children for partial seizures±generalised tonic-clonic seizures and Lennox-Gastaut syndrome
Vigabatrin*
Europe: 1989
Adjunctive therapy in partial seizures, infantile spasms
Zonisamide
USA: 2000 (earlier in Japan) UK: 2005
In adults with partial seizures (other indications including myoclonus in Japan)
*Felbamate and vigabatrin have special safety issues, and should only be prescribed when risk-benefit ratio of use has been assessed.
Table: Newer antiepileptic drugs
970
almost always conclude that the newer drug is equally as effective but better tolerated than the established drug. Unfortunately, methodological problems, including small sample size, questionable selection of patients, titration schedules, dose and dose form, and short duration of study, have limited the acceptance of the results.4–6 Many of these methodological problems have been overcome in SANAD, which was large and followed patients up for several years. The conclusion is that lamotrigine is the drug of first choice for patients with partial epilepsy, and valproate for generalised and unclassifiable epilepsy. This answer is satisfying for the many physicians, in general practice and specialists, who are overwhelmed by the number of available antiepileptic drugs, both old and new, and would welcome a clear-cut strategy for therapy. The result may also be welcomed by payers, because lamotrigine will soon go off patent and become inexpensive, and valproate is less expensive than many of the newer drugs. Yet the question still remains: is it possible to select a drug of first choice for patients with epilepsy? To select an antiepileptic drug of first choice, one must know about the properties of the drugs that might make them more or less advantageous. These include, of course, their ability to control seizures, overall tolerability, cost, likelihood that they will produce serious health risks, and pharmacokinetic properties. SANAD’s conclusions are highly driven by the first three, because they are the easiest to measure in a randomised trial. Patients can report whether they have had seizures, and how they are feeling. Their willingness to remain on the drug can also be measured, as an overall determination of effectiveness. But what of the other properties? It is difficult if not impossible to measure the consequences of pharmacokinetic differences between drugs, particularly a potential for drug interactions. SANAD was too small to address even the most common serious adverse event related to the drugs that were tested. Yet the fact that such events might occur is still considered by most physicians to be an important characteristic of a drug, and one that affects prescribing. For example, the incidence of potentially life-threatening pancreatitis with valproate is one per 3000 exposures, and there is also am increased risk of hepatic failure.7,8 How are these facts to be weighted, when selecting valproate as drug of first choice? Even efficacy and www.thelancet.com Vol 369 March 24, 2007
Comment
tolerability outcomes are not completely cut and dried, for several reasons. First, some of these outcomes may be influenced by the way the physician elected to use the drug. For example, two of the drugs in SANAD, carbamazepine and lamotrigine, are associated with treatment-emergent rash. The occurrence of rash can be highly correlated with the titration schedule. For both drugs, a faster titration schedule will lead to a higher frequency of rash.9,10 Because lamotrigine is the newer of the two drugs, a great deal of attention has been paid to selecting an ideal titration schedule. By contrast, carbamazepine tends to be titrated more rapidly. Because the titration schedule was not mandated in SANAD (although there was a recommended regimen), it is unclear whether the rash rates might have been lower if the titration had been slower. This point is important because 21% of treatment failures for carbamazepine were related to rash (vs 14% for lamotrigine). In a recent study11 that compared carbamazepine and levetiracetam and in which the titration rate for carbamazepine was slower, the dose was lower, and a controlled-release formulation was used in all cases, the rate of rash for carbamazepine was 5·5% compared with a per-protocol rate of 32% in SANAD. Of course, the two studies had different durations, but discontinuation due to rash tends to occur during the first 6 months of use. Is it possible that the mode of use of carbamazepine was the sole explanation of a difference in tolerability between carbamazepine and lamotrigine? It could be argued that the next randomised study should be a comparison between carbamazepine (as used in practice) and carbamazepine (as used in a specific regimen). Only then could the true risks of carbamazepine be known. The second and perhaps more compelling concern in designating one drug as first choice is that it may reduce the likelihood that a physician will make an effort to match the drug to the patient. This point relates to the many characteristics of a drug that are not necessarily addressed in pragmatic trials such as SANAD. For example, lamotrigine can cause insomnia, and might not be ideal for patients who have known sleep disorders.12 Lamotrigine’s clearance can increase several fold during pregnancy.13 This aspect of the drug complicates use in women of childbearing years. Valproate, as mentioned by the SANAD investigators, is not currently recommended as a drug of first choice in women of childbearing potential because, in several studies, offspring of mothers who had used valproate during pregnancy have had a higher frequency www.thelancet.com Vol 369 March 24, 2007
of fetal malformations and cognitive delay.14 Valproate has also been associated with a higher likelihood of weight gain. For some individuals, weight gain is an important outcome, whereas it is inconsequential to others. Also, valproate has been associated with alterations in liver function tests and platelet counts. This drug would not be a wise choice for patients who have bleeding risks, and for patients who might need hepatic monitoring for other reasons. Therefore it might be wiser to conclude from SANAD that lamotrigine is the drug of first choice in patients with partial seizures, and valproate for patients with generalised or unclassified seizures in the absence of factors that would lead to an alternative choice. Simple is good, but overly simplistic may not provide the optimum benefit to our patients. Jacqueline A French Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA [email protected] I have received compensation for consulting and lectures from Johnson & Johnson, Medpointe, UCB, Abbott, Pfizer, UCB Pharma, Cephalon, GlaxoSmithKline, and Eisai. 1
2
3 4 5 6
7 8
9
10 11
12 13
14
Marson AG, Al-Kharusi AM, Alwaidh M, on behalf of the SANAD Study group. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15. Marson AG, Al-Kharusi AM, Alwaidh M. et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26. National Institute for Clinical Excellence. Newer drugs for epilepsy in adults. March, 2004: http://www.nice.org.uk/TA076guidance (accessed May 4, 2004). French JA, Chadwick DW. Drugs for the elderly: using the old to focus on the new. Neurology 2005; 64: 1834–35. Arroyo S, Sander JW. Carbamazepine in comparative trials: pharmacokinetic characteristics too often forgotten. Neurology 1999; 53: 1170–74 Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; 47: 1094–120. Chapman SA, Wacksman GP, Patterson BD. Pancreatitis associated with valproic acid: a review of the literature. Pharmacotherapy 2001; 21: 1549–60. Konig SA, Siemes H, Blaker F, et al. Severe hepatotoxicity during valproate therapy: an update and report of eight new fatalities. Epilepsia 1994; 35: 1005–15. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology 1997; 49: 542–46. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother 1999; 33: 1037–42. Ben-Menachem E, Brodie MJ, Perucca E, on behalf of the N01061 Study Group. Efficacy of levetiracetam monotherapy; randomized double-blind head-tohead comparison with carbamazepine-CR in newly diagnosed epilepsy patients with partial onset or generalised tonic-clonic seizures. American Academy of Neurology, San Diego, California, April 4, 2006. Sadler M. Lamotrigine associated with insomnia. Epilepsia 1999; 40: 322–25. Pennell PB, Newport DJ, Stowe ZN, Helmers SL, Montgomery JQ, Henry TR. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004; 62: 292–95 Meador KJ, Baker GA, Finnell RH, for the NEAD Study Group. In utero antiepileptic drug exposure: fetal death and malformations. Neurology 2006; 67: 407–12.
971