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Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients
Adult
Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients Cynthia L. Harden, Syed Hosain, Blagovest Nikolov, and Douglas R. Labar
A retrospective analysis of charts of patients who received gabapentin (GBP) as adjunctive anticonvulsant therapy in its first year of marketing, between March 1994 and April 1995 was conducted to evaluate patterns of use, side effects, and efficacy in the general epilepsy population. Ninety patients (45 men, 45 women) with an average age of 33.5 years (range: 7 months–78 years) were included. Average GBP dosage was 1700 mg/day; 46 patients took ,1800 mg, and 44 patients took Ä1800 mg/day. Duration of GBP treatment ranged from 1 month–14 months. Patients took an average of 1.7 concurrent antiepileptic drugs while on GBP. A total of 13 patients were on GBP monotherapy, four at the outset joined by nine others during the study. Gabapentin was associated with improvement as assessed by reduction of seizure frequency in 69 patients (77%). Sixty patients (67%) who reported no side effects had a mean GBP dosage of 1900 mg/day (median: 2000 mg/day). The 30 patients who experienced side effects had a mean GBP dosage of 1600 mg/day (median: 1500 mg/day). Gabapentin was discontinued in 21 patients, six because of side effects, nine because of lack of efficacy, and six because of a combination of both. Gabapentin was used in more difficult patients with intractable epilepsy and was generally well tolerated. Higher doses were not associated with more side effects, suggesting that GBP-related side effects may not be dose-related. Key Words: Epilepsy—Seizures—Gabapentin—Adjunctive therapy. © 1998 by Elsevier Science Inc. All rights reserved.
Approximately 25%– 41% of patients with epilepsy are not satisfactorily controlled with currently available antiepileptic drugs AEDs (1). Several facReceived September 24, 1996; accepted October 28, 1996. From the Comprehensive Epilepsy Center, New York Hospital-Cornell University Medical Center, New York, NY, U.S.A. Address correspondence and reprint requests to Dr. Cynthia Harden, Comprehensive Epilepsy Center, Room K-615, New York Hospital-Cornell University Medical Center, 525 East 68th Street, New York, NY 10021, U.S.A. J. Epilepsy 1998;11:130 –135 © 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
tors have an impact on the effectiveness of AEDs, including type of epilepsy, correct identification of seizure type, selection of appropriate drug therapy, optimization of AED therapy, balancing efficacy with adverse effects, choice of monotherapy or polytherapy, compliance, and needs of individual patients (2). It is current practice to add one or more AEDs to the treatment regimen when one AED is not adequate for seizure control. Although no major new drugs for the treatment of epilepsy were available in the United States from 1978 –93 (3), since 1993,
0896-6974/98/$19.00 PII S0896-6974(97)00140-0
GABAPENTIN IN EPILEPSY PATIENTS
gabapentin (GBP), lamotrigine, topiramate, and tiagabine were approved for by the FDA for very similar uses, which are as adjunctive therapy in treating partial seizures in adults. Gabapentin is a novel AED that has efficacy in treating partial seizures. It was approved in 1994 for adjunctive treatment of partial seizures with or without secondary generalitzation in adults and children 12 years of age and older. In three large, double-blind, placebo-controlled, add-on studies, GBP has been shown to be effective in treating partial onset seizures, with and without secondary generalization (4 – 6). Patients enrolled in these studies were intractable to treatment with standard AEDs and were required to have had a minimum of four partial seizures per month prior to receiving add-on therapy with GBP. The protocols of these standard clinical trials mandated inclusion of a patient population that was difficult-to-treat and greatly impaired. The effectiveness of GBP has not been studied in the larger pool of less intractable seizure patients reflective of those treated in an office setting. Moreover, the side effects reported by patients treated in general practice may be different from those observed in the group with more intractable seizures, because patients in research settings are instructed to report all side effects, while those in clinical settings may only report the most debilitating, drug-related side effects. The less intractable, presumably higher functioning group may have different sensitivities to side effects and find specific side effects more or less limiting than the intractable population. The aim of this study was to evaluate the use of GBP in a sample of patients from the presumably less intractable, general epilepsy population, including patterns of use, side effects, and efficacy. This review also offers the opportunity to assess the severity of epilepsy in the postmarketing population in whom GBP is being used.
Materials and Methods The study was performed by a retrospective analysis of all charts for patients who received GBP after it became available in pharmacies in March 1994. Study enrollment ended April 1995. The patient population for this study was drawn from the Comprehensive Epilepsy Center, an outpatient epilepsy clinic at New York Hospital-Cornell University Medical Center in New York City, and from all
associated private neurology practices. Patients were excluded if follow-up efficacy or tolerability data were lacking or if they were lost to follow-up after starting GBP treatment. Information about patient demographics, seizure history, prior or concomitant treatment with AEDs, GBP dose titration, duration of GBP treatment, reported side effects, seizure reduction, and use of healthcare resources such as office visits and emergency room visits were entered into an IBM-compatible computer database for analysis. Tolerability ratings were based on patient reports of side effects and were coded as ‘‘excellent’’ if the patient reported no side effects, ‘‘good’’ if insignificant, mild side effects were reported, ‘‘fair’’ if dose-limiting or activity-limiting side effects occurred, and ‘‘poor’’ if the side effect was a reason for stopping GBP. All reported side effects were included in the analysis. Insignificant side effects were those judged mild in severity, not requiring dose reduction of GBP. Seizure calendars with careful seizure counts were not used in this study, so the assessment of GBP’s overall effectiveness was based on patients’ subjective reports compared with the period prior to starting GBP. An effectiveness rating of ‘‘much better’’ was used for patients with a dramatic seizure reduction and a reported improvement in activities of daily life, ‘‘better’’ was used for any lesser improvement in seizures. Ratings of either ‘‘worse’’ or ‘‘much worse’’ resulted in discontinuing GBP due to seizure exacerbation.
Results Ninety patients (45 men, 45 women) with a mean age of 33.5 years (range: 7 months–78 years) were included in this retrospective analysis. Eighty-five patients had partial epilepsy, and five had generalized epilepsy. Seizure etiology is shown in Table 1. Patients reported taking an average of 2.4 AEDs prior to starting GBP. However, this estimate probably is low, since the data collection methods allowed for a maximum of three previous AEDs to be entered into the database. In order of decreasing frequency of use, patients had taken phenytoin, carbamazepine, valproate, felbamate, phenobarbital, and mysoline before GBP was used. Prior to starting GBP, 46 patients had discontinued one or more AEDs due to lack of efficacy, and 47 had one or more previous AEDs discontinued due to side effects. Additionally, 18 patients had felbamate disJ EPILEPSY, VOL. 11, NO. 3, 1998 131
C. L. HARDEN ET AL.
Table 1. Etiology of seizures (n 5 90) Etiology
Table 2. Tolerability of GBP (n 5 90)
Number of patients (%)
Physician rating
Number of patients (%)
Mean (median) (mg/d)
Range (mg/d)
40 (44%) 10 (11%) 10 (11%) 9 (10%) 8 (%) 4 (4%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 3 (3%)
Excellent Good Fair Poor
36 (40%) 24 (27%) 18 (20%) 12 (13%)
2000 (2000) 1700 (1800) 1700 (1500) 1500 (1500)
500–3600 600–2800 600–2400 600–3000
Cryptogenic etiology Traumatic brain injury Congenital malformation Vascular etiology Perinatal injury Neoplastic etiology Febrile etiology Brain infection Alcohol abuse Tuberous sclerosis Idiopathic
continued following reports of aplastic anemia associated with felbamate. After GBP was started, 33 patients stopped taking a total of 37 additional AEDs: for 18 of the 37 AEDs, the discontinued drug was felbamate. This suggests that when felbamate was discontinued due to the possible negative sequelae associated with its use, GBP was added. Prior to initiation of GBP, the mean seizure frequency including simple partial seizures was approximately 16 per month. Forty-four patients had experienced fewer than four seizures per month. The maximum seizure frequency was an estimated 320 simple partial seizures per month in one patient.
Gabapentin Use The duration of treatment with GBP ranged from 1 month–14 months. Patients who did not take GBP for at least 1 month were not included. The median length of treatment during the study period was 8 months, and one patient stopped GBP after 1 month. Fifty-five patients were followed for 8 months or more. The mean dose of GBP reached at stabilization or prior to discontinuation was 1700 mg/day; the median dose was 1800 mg/day. Fortysix patients took ,1800 mg/day and 44 patients took Ä1800 mg/day. Doses ranged from 500 –3600 mg/day. In those who discontinued GBP treatment, the mean dose was 1600 mg/day, the median dose was 1200 mg/day, and doses ranged from 500 –3600 mg/day. Four patients initially took GBP as monotherapy. The remaining 86 patients were taking an average of 1.7 concomitant AEDs; 15 patients took three concomitant AEDs, 33 took two concomitant AEDs, and 38 took one concomitant AED. Concommittent 132 J EPILEPSY, VOL. 11, NO. 3, 1998
AEDs were carbamazepine in 39 patients, phenytoin in 26, valproate in 26, felbamate in 21, phenobarbital in 15, primidone in 10, lamotrigine in five, acetozolamide in two, clonazepam, lorazepam, vigabatrin, nitrazepam and methsuximide in one each. Four of the 86 patients eventually achieved GBP monotherapy, for a total of eight patients taking GBP monotherapy. The mean dose of these eight patients was 2100 mg/day.
Side Effects Overall tolerability was rated by physicians as excellent in 36 patients, good in 24, fair in 18, and poor in 12 patients (Table 2). As shown in Table 2, patients who had fair or poor tolerability had lower mean GBP dosages than those with excellent or good tolerability. Sixty patients (67%) reported no significant side effects. The mean GBP dose for these 60 patients was 1900 mg/day (median 2000 mg/day). Twentyeight patients took ,1800 mg/day, and 32 took Ä1800 mg/day. Forty-three adverse events (AEs) were reported in the remaining 30 patients who were taking a mean GBP dose of 1600 mg/day (median 1500 mg/day). Twenty of the 30 patients had one complaint (Table 3). In the eight patients who achieved monotherapy, tolerability was rated as excellent in five patients and good in three patients. The most commonly reported side effect was sedation, which occurred in 15 patients; carbamazepine was a comedication in five of these patients, phenytoin was a comedication in six, and five were also taking phenobarbital. Ten of the 15 patients who reported sedative side effects were taking more than one additional AED; seven were on two additional AEDs, and three taking three additional AEDs. The remaining five were taking one additional AED. Three patients complained of dizziness; all three were taking carbamazepine. Two out of the three patients who reported headache were taking phenytoin. None of the three patients with reported weight gain were taking valproate: one was on GBP
GABAPENTIN IN EPILEPSY PATIENTS
Table 3. Significant side effects of GBP (n 5 30 patients) Side effect Sedation Dizziness Headache Weight gain Mental clouding Diarrhea Blurred vision Body/joint aches Nausea Fever Depression Rash Ankle edema Decreased libido Tremulousness Antispasticity Urinary frequency Increased bruising
Number reported (% of patients reporting) 15 (17%) 3 (3%) 3 (3%) 3 (3%) 3 (3%) 2 (2%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
monotherapy, one was taking felbamate and phenytoin, and one was taking carbamazepine. In addition to sedation, dizziness, headache, and weight gain, other significant side effects were mental clouding in three patients, body or joint aches in two, diarrhea in two, blurred vision in two, and nausea, fever, depression, rash, ankle edema, increased bruising, tremulousness, antispasticity, urinary frequency, and decreased libido in one patient each. Of the eight patients with more than one AE, four patients had two complaints, three had three complaints, and one had four complaints. Gabapentin was discontinued due to side effects alone in 12 patients (mean GBP dose: 1500 mg/day; median: 1500 mg/day) and due to side effects combined with lack of efficacy in six patients (mean GBP dose: 1300 mg/day; median: 1800 mg/day). Of the patients with side effects as the sole reason for discontinuing GBP, five patients discontinued because of central nervous system side effects such as sedation and mental clouding (mean GBP dose: 900 mg/day; range: 600 –1600 mg/day). The remaining seven patients discontinued due to more idiosyncratic reactions including rash, fever, ankle edema, joint pain, and weight gain. No specific AED combination was associated with any of the most frequently reported side effects. One patient who was taking valproate and warfarin had elevation of liver function tests after GBP was initiated, which resolved after GBP was stopped. Gabapentin does not undergo hepatic metabolism, suggesting that this side effect was unre-
lated to GBP; therefore, this patient was not included in Table 3. One patient with partial complex seizures was hospitalized because of side effects while taking GBP; this patient complained of nausea, mild fever (documented at 37.9°C), and diarrhea. She was hospitalized due to the severity of her complaints, and while in the hospital gradually improved as GPB was discontinued. All laboratory tests were normal and she was discharged in good condition. She was gradually changed to methsuximide for seizure treatment. This patient had a history of developing a lupus-like reaction to carbamazepine associated with a positive ANA test, was allergic to phenytoin, and was in general poorly tolerant of AEDs.
Efficacy Addition of GBP to the regimen allowed discontinuation of another AED in one-third of the study population. Overall efficacy was rated as much better in eight patients (9%), better in 61 (68%), worse in 20 (22%), and much worse in one patient (1%). All patients who had worsened seizure control were discontinued from GBP. Of the 15 patients in whom GBP was stopped due to lack of efficacy alone, the mean dose was 1700 mg/day (median: 1500 mg/day; range: 500 –3600 mg/day). Lack of efficacy was a supplemental reason, along with side effects, for discontinunation in an additional six patients (mean GBP dose: 1200 mg/day; median: 1800 mg/day). Eight patients had emergency room visits due to seizure; nine patients were hospitalized due to seizures. Gabapentin was used in two patients with symptomatic generalized epilepsy with seizure improvement reported for both; these patients had static encephalopathy and suffered multiple seizure types. Additionally, GPB was used in three patients with idiopathic primary generalized epilepsy, because AEDs indicated for treatment of this condition were poorly tolerated or ineffective in these patients. Electroencephalograms were consistent with this diagnosis in all three patients; two of three had seizure histories consistent with Juvenile Myoclonic Epilepsy (JME). The JME patients both had improvement in myoclonus with GBP, and neither patient achieved monotherapy. However, one patient was able to reduce the valproate dose and the other remained on phenytoin without change. J EPILEPSY, VOL. 11, NO. 3, 1998 133
C. L. HARDEN ET AL.
Discussion This review suggests that in its first year of release, GBP was used in a highly intractable patient population, similar to the premarketing study population. In these 90 difficult-to-treat patients, most (77%) reported some reduction in seizure frequency. This high rate of perceived improvement is consistent with a seizure-reducing effect of GBP, but also may have been produced by, perhaps in part, improved AED compliance with the addition of a new medication, or placebo effect. Elevations in concomitant AED levels would not explain improvement, as GPB does not interact with other AEDs. Gabapentin was very well tolerated, with tolerability rated as excellent or good in 73% of patients. The majority of AEs, particularly the most common one of sedation or sleepiness, occurred at low GBP doses. This suggests that if side effects do not occur at low doses when the drug is started, a dose escalation to higher doses (.1800 mg/day) may be accomplished with little worry about the onset of dose-related side effects. The side effects reported by the study population were similar to those reported in the premarketing studies, with no surprising deviation from the adverse event profile previously described (4 – 8). Titration of GBP doses above 1800 mg/day appears to be associated with a low risk of side effects. Our study indicates that side effects, especially sedation, are more likely to occur at lower doses, and suggest that if sedation does not occur at a low dose, it will not appear with higher doses. Although some of the patients in our retrospective study achieved doses of nearly 3600 mg/day, further evaluation is necessary to determine the usefulness of GBP at doses in the highest range. The doses of GBP used in this study reflect the lower doses used immediately after its availability. It is possible that greater efficacy could have been achieved in the patients who discontinued due to lack of efficacy if higher doses had been used. However, recent data does suggest that doses of GBP , 1800 mg/day are adequate for patients with milder epilepsy and that patients with more difficult to control seizures require titration to doses . 1800 mg/day (9). Two open-label studies suggest that GBP is safe, well-tolerated, and effective in patients with drugresistant partial and secondarily generalized epileptic seizures over the long-term, for a period of at least 4 years (7,8). In the first study, 25 patients were followed for 4 years in an open-label study, using 134 J EPILEPSY, VOL. 11, NO. 3, 1998
GBP as add-on therapy after a 3-month, doubleblind, placebo-controlled phase (7). Twelve patients responded to GBP, while no benefit was seen in the remaining 13 patients. Seven patients took GBP for more than 4 years (median follow-up time: 54 months). Five of the seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the initial 25 patients who entered the study. The authors concluded that GBP was effective in the long-term treatment of patients with partial and secondarily generalized epileptic seizures, and that GBP was safe and well tolerated as long-term treatment. The second study included 23 patients with intractable, partial-onset seizures following a blinded, placebo-controlled, add-on, dose efficacy study (US Gabapentin Study No. 5) (8). Nine patients had no significant improvement in seizure control and stopped GBP; the remaining 14 patients were observed while treated long-term with stable-dose GBP and concomitant AEDs. Improvement was maintained over the 4-year follow-up period. The upper dose limit of 2400 mg/day allowed by the protocol was well tolerated by 16 of 23 patients, indicating that higher dose may be tolerated in a substantial fraction of patients. The authors concluded that the upper dose limit for GBP efficacy and tolerability remains to be determined. In the current study, four patients initially took GBP alone, and four others achieved GBP monotherapy during the study period. Therefore, a total of eight patients, or approximately 10%, were stabilized on GBP monotherapy. Two recent studies of GBP used as monotherapy support its efficacy in this setting, however a clear dose-response was demonstrated only when 3600 mg/day was compared to 300 mg/day in refractory partial epilepsy patients (10,11). Therefore, it would be expected that some of our study patients could achieve monotherapy with GBP safely. Consistent with data suggesting that higher doses are needed for intractable patients (9), our monotherapy patients were taking GBP at a higher mean dose than other patients in the study. Five patients in this study had generalized epilepsy, including two with JME, who reported improvement with add-on GBP. Although this good response would not be predicted from the study of GBP in another form of primary generalized epilepsy, absence epilepsy in children (12), it may be that one form of primary generalized epilepsy cannot be ‘‘lumped’’ with another in terms of response to a new AED. Gabapentin has been shown to interact with L-type voltage dependent calcium
GABAPENTIN IN EPILEPSY PATIENTS
channels, which is a property unique to GBP among AEDs (13). Therefore, because the pharmacology of GBP is still being discovered, the treatment spectrum may also be still expanding. In summary, according to a retrospective postmarketing analysis, GBP was used mainly in patients with intractable epilepsy. It was found to be effective and well tolerated as both adjunctive therapy and monotherapy. An unexpected finding was that side effects generally occur at doses less than 1800 mg/day and if GBP is well-tolerated at low doses, it can be escalated without further concern. Our review highlighted the benefits of GBP in the clinical settings of private practice and a hospital outpatient clinic, and the results of this analysis can be used to help understand the role of GBP therapy in clinical practice.
References 1. Btaiche IF, Woster PS. Gabapentin and lamotrigine: Novel antiepileptic drugs. Am J Health Syst Pharm 1995;52:61– 69. 2. Mattson RH. Drug treatment of partial epilepsy. In: Chauvel P, Delgada-Escueta AV, et al, eds. Advances in neurology (vol. 57). New York: Raven Press, 1992:643–50. 3. Fisher RS. Emerging antiepileptic drugs. Neurology 1993; 43(suppl 5):S12–S20. 4. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990;335:1114 –7. 5. The US Gabapentin Study Group No. 5. Gabapentin as add-on therapy in refractory partial epilepsy: A doubleblind, placebo-controlled, parallel-group study. Neurology 1993;432:2292– 8.
6. Anhut H, Achman P, Feurerstein TJ, Sauermann W, Saunders M, Schmidt B, and The International Gabapentin Study Group. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: A double-blind, placebo-controlled study. Epilepsia 1994;35:795– 801. 7. Sivenius J, Ylinen A, Kalviainen R, Riekkinen PJ. Long-term study with gabapentin patients with drug-resistant epileptic seizures. Arch Neurol 1994;51:1047–50. 8. Handforth A, Treiman DM. Efficacy and tolerance of longterm, high-dose gabapentin: Additional observations. Epilepsia 1994;35:1032–7. 9. Morell M, McLean M, Willmore J, Lagnus-Miller Leslie, Podolnik PB, Rose-Legatt A. Efficacy of gabapentin (Neurontin) as add-on therapy for patients with partial epilepsy (abstract). Neurology 1997;48(suppl 2):A335. 10. Bergey GK, Morris HH, Rosendeld W, Blume WT, Penovich PE, Morell MJ, Leiderman DB, Crockatt JG, LaMoreaux L, Garofalo E, Pierce M, US Gabapentin Study Group 88/89. Gabapentin monotherapy: I. An 8-day, double-blind, dosecontrolled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49:739 – 45. 11. Beydoun A, Fischer J, Labar DR, Harden C, Cantrell D, Uthman BM, Sackellares JC, Abou-Khalil B, Ramsay RE, Hayes A, Greiner M, Garofalo E, Pierce M, US Gabapentin Study Group 82/83. Gabapentin monotherapy: II. A 26week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49:746 –52. 12. Leiderman D, Garofalo E, LaMoreaux L. Gabapentin patients with absence seizures: Two double-blind, placebo controlled studies. Epilepsia 1993;34(suppl 6):45. 13. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alph2delta subunit of a calcium channel. J Biol Chem 1996;271:5768 –76.
J EPILEPSY, VOL. 11, NO. 3, 1998 135
Evaluation of Gabapentin in an Outpatient and Office-based Sample of Epilepsy Patients Cynthia L. Harden, Syed Hosain, Blagovest Nikolov, and Douglas R. Labar
A retrospective analysis of charts of patients who received gabapentin (GBP) as adjunctive anticonvulsant therapy in its first year of marketing, between March 1994 and April 1995 was conducted to evaluate patterns of use, side effects, and efficacy in the general epilepsy population. Ninety patients (45 men, 45 women) with an average age of 33.5 years (range: 7 months–78 years) were included. Average GBP dosage was 1700 mg/day; 46 patients took ,1800 mg, and 44 patients took Ä1800 mg/day. Duration of GBP treatment ranged from 1 month–14 months. Patients took an average of 1.7 concurrent antiepileptic drugs while on GBP. A total of 13 patients were on GBP monotherapy, four at the outset joined by nine others during the study. Gabapentin was associated with improvement as assessed by reduction of seizure frequency in 69 patients (77%). Sixty patients (67%) who reported no side effects had a mean GBP dosage of 1900 mg/day (median: 2000 mg/day). The 30 patients who experienced side effects had a mean GBP dosage of 1600 mg/day (median: 1500 mg/day). Gabapentin was discontinued in 21 patients, six because of side effects, nine because of lack of efficacy, and six because of a combination of both. Gabapentin was used in more difficult patients with intractable epilepsy and was generally well tolerated. Higher doses were not associated with more side effects, suggesting that GBP-related side effects may not be dose-related. Key Words: Epilepsy—Seizures—Gabapentin—Adjunctive therapy. © 1998 by Elsevier Science Inc. All rights reserved.
Approximately 25%– 41% of patients with epilepsy are not satisfactorily controlled with currently available antiepileptic drugs AEDs (1). Several facReceived September 24, 1996; accepted October 28, 1996. From the Comprehensive Epilepsy Center, New York Hospital-Cornell University Medical Center, New York, NY, U.S.A. Address correspondence and reprint requests to Dr. Cynthia Harden, Comprehensive Epilepsy Center, Room K-615, New York Hospital-Cornell University Medical Center, 525 East 68th Street, New York, NY 10021, U.S.A. J. Epilepsy 1998;11:130 –135 © 1998 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
tors have an impact on the effectiveness of AEDs, including type of epilepsy, correct identification of seizure type, selection of appropriate drug therapy, optimization of AED therapy, balancing efficacy with adverse effects, choice of monotherapy or polytherapy, compliance, and needs of individual patients (2). It is current practice to add one or more AEDs to the treatment regimen when one AED is not adequate for seizure control. Although no major new drugs for the treatment of epilepsy were available in the United States from 1978 –93 (3), since 1993,
0896-6974/98/$19.00 PII S0896-6974(97)00140-0
GABAPENTIN IN EPILEPSY PATIENTS
gabapentin (GBP), lamotrigine, topiramate, and tiagabine were approved for by the FDA for very similar uses, which are as adjunctive therapy in treating partial seizures in adults. Gabapentin is a novel AED that has efficacy in treating partial seizures. It was approved in 1994 for adjunctive treatment of partial seizures with or without secondary generalitzation in adults and children 12 years of age and older. In three large, double-blind, placebo-controlled, add-on studies, GBP has been shown to be effective in treating partial onset seizures, with and without secondary generalization (4 – 6). Patients enrolled in these studies were intractable to treatment with standard AEDs and were required to have had a minimum of four partial seizures per month prior to receiving add-on therapy with GBP. The protocols of these standard clinical trials mandated inclusion of a patient population that was difficult-to-treat and greatly impaired. The effectiveness of GBP has not been studied in the larger pool of less intractable seizure patients reflective of those treated in an office setting. Moreover, the side effects reported by patients treated in general practice may be different from those observed in the group with more intractable seizures, because patients in research settings are instructed to report all side effects, while those in clinical settings may only report the most debilitating, drug-related side effects. The less intractable, presumably higher functioning group may have different sensitivities to side effects and find specific side effects more or less limiting than the intractable population. The aim of this study was to evaluate the use of GBP in a sample of patients from the presumably less intractable, general epilepsy population, including patterns of use, side effects, and efficacy. This review also offers the opportunity to assess the severity of epilepsy in the postmarketing population in whom GBP is being used.
Materials and Methods The study was performed by a retrospective analysis of all charts for patients who received GBP after it became available in pharmacies in March 1994. Study enrollment ended April 1995. The patient population for this study was drawn from the Comprehensive Epilepsy Center, an outpatient epilepsy clinic at New York Hospital-Cornell University Medical Center in New York City, and from all
associated private neurology practices. Patients were excluded if follow-up efficacy or tolerability data were lacking or if they were lost to follow-up after starting GBP treatment. Information about patient demographics, seizure history, prior or concomitant treatment with AEDs, GBP dose titration, duration of GBP treatment, reported side effects, seizure reduction, and use of healthcare resources such as office visits and emergency room visits were entered into an IBM-compatible computer database for analysis. Tolerability ratings were based on patient reports of side effects and were coded as ‘‘excellent’’ if the patient reported no side effects, ‘‘good’’ if insignificant, mild side effects were reported, ‘‘fair’’ if dose-limiting or activity-limiting side effects occurred, and ‘‘poor’’ if the side effect was a reason for stopping GBP. All reported side effects were included in the analysis. Insignificant side effects were those judged mild in severity, not requiring dose reduction of GBP. Seizure calendars with careful seizure counts were not used in this study, so the assessment of GBP’s overall effectiveness was based on patients’ subjective reports compared with the period prior to starting GBP. An effectiveness rating of ‘‘much better’’ was used for patients with a dramatic seizure reduction and a reported improvement in activities of daily life, ‘‘better’’ was used for any lesser improvement in seizures. Ratings of either ‘‘worse’’ or ‘‘much worse’’ resulted in discontinuing GBP due to seizure exacerbation.
Results Ninety patients (45 men, 45 women) with a mean age of 33.5 years (range: 7 months–78 years) were included in this retrospective analysis. Eighty-five patients had partial epilepsy, and five had generalized epilepsy. Seizure etiology is shown in Table 1. Patients reported taking an average of 2.4 AEDs prior to starting GBP. However, this estimate probably is low, since the data collection methods allowed for a maximum of three previous AEDs to be entered into the database. In order of decreasing frequency of use, patients had taken phenytoin, carbamazepine, valproate, felbamate, phenobarbital, and mysoline before GBP was used. Prior to starting GBP, 46 patients had discontinued one or more AEDs due to lack of efficacy, and 47 had one or more previous AEDs discontinued due to side effects. Additionally, 18 patients had felbamate disJ EPILEPSY, VOL. 11, NO. 3, 1998 131
C. L. HARDEN ET AL.
Table 1. Etiology of seizures (n 5 90) Etiology
Table 2. Tolerability of GBP (n 5 90)
Number of patients (%)
Physician rating
Number of patients (%)
Mean (median) (mg/d)
Range (mg/d)
40 (44%) 10 (11%) 10 (11%) 9 (10%) 8 (%) 4 (4%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 3 (3%)
Excellent Good Fair Poor
36 (40%) 24 (27%) 18 (20%) 12 (13%)
2000 (2000) 1700 (1800) 1700 (1500) 1500 (1500)
500–3600 600–2800 600–2400 600–3000
Cryptogenic etiology Traumatic brain injury Congenital malformation Vascular etiology Perinatal injury Neoplastic etiology Febrile etiology Brain infection Alcohol abuse Tuberous sclerosis Idiopathic
continued following reports of aplastic anemia associated with felbamate. After GBP was started, 33 patients stopped taking a total of 37 additional AEDs: for 18 of the 37 AEDs, the discontinued drug was felbamate. This suggests that when felbamate was discontinued due to the possible negative sequelae associated with its use, GBP was added. Prior to initiation of GBP, the mean seizure frequency including simple partial seizures was approximately 16 per month. Forty-four patients had experienced fewer than four seizures per month. The maximum seizure frequency was an estimated 320 simple partial seizures per month in one patient.
Gabapentin Use The duration of treatment with GBP ranged from 1 month–14 months. Patients who did not take GBP for at least 1 month were not included. The median length of treatment during the study period was 8 months, and one patient stopped GBP after 1 month. Fifty-five patients were followed for 8 months or more. The mean dose of GBP reached at stabilization or prior to discontinuation was 1700 mg/day; the median dose was 1800 mg/day. Fortysix patients took ,1800 mg/day and 44 patients took Ä1800 mg/day. Doses ranged from 500 –3600 mg/day. In those who discontinued GBP treatment, the mean dose was 1600 mg/day, the median dose was 1200 mg/day, and doses ranged from 500 –3600 mg/day. Four patients initially took GBP as monotherapy. The remaining 86 patients were taking an average of 1.7 concomitant AEDs; 15 patients took three concomitant AEDs, 33 took two concomitant AEDs, and 38 took one concomitant AED. Concommittent 132 J EPILEPSY, VOL. 11, NO. 3, 1998
AEDs were carbamazepine in 39 patients, phenytoin in 26, valproate in 26, felbamate in 21, phenobarbital in 15, primidone in 10, lamotrigine in five, acetozolamide in two, clonazepam, lorazepam, vigabatrin, nitrazepam and methsuximide in one each. Four of the 86 patients eventually achieved GBP monotherapy, for a total of eight patients taking GBP monotherapy. The mean dose of these eight patients was 2100 mg/day.
Side Effects Overall tolerability was rated by physicians as excellent in 36 patients, good in 24, fair in 18, and poor in 12 patients (Table 2). As shown in Table 2, patients who had fair or poor tolerability had lower mean GBP dosages than those with excellent or good tolerability. Sixty patients (67%) reported no significant side effects. The mean GBP dose for these 60 patients was 1900 mg/day (median 2000 mg/day). Twentyeight patients took ,1800 mg/day, and 32 took Ä1800 mg/day. Forty-three adverse events (AEs) were reported in the remaining 30 patients who were taking a mean GBP dose of 1600 mg/day (median 1500 mg/day). Twenty of the 30 patients had one complaint (Table 3). In the eight patients who achieved monotherapy, tolerability was rated as excellent in five patients and good in three patients. The most commonly reported side effect was sedation, which occurred in 15 patients; carbamazepine was a comedication in five of these patients, phenytoin was a comedication in six, and five were also taking phenobarbital. Ten of the 15 patients who reported sedative side effects were taking more than one additional AED; seven were on two additional AEDs, and three taking three additional AEDs. The remaining five were taking one additional AED. Three patients complained of dizziness; all three were taking carbamazepine. Two out of the three patients who reported headache were taking phenytoin. None of the three patients with reported weight gain were taking valproate: one was on GBP
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Table 3. Significant side effects of GBP (n 5 30 patients) Side effect Sedation Dizziness Headache Weight gain Mental clouding Diarrhea Blurred vision Body/joint aches Nausea Fever Depression Rash Ankle edema Decreased libido Tremulousness Antispasticity Urinary frequency Increased bruising
Number reported (% of patients reporting) 15 (17%) 3 (3%) 3 (3%) 3 (3%) 3 (3%) 2 (2%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%) 1 (1%)
monotherapy, one was taking felbamate and phenytoin, and one was taking carbamazepine. In addition to sedation, dizziness, headache, and weight gain, other significant side effects were mental clouding in three patients, body or joint aches in two, diarrhea in two, blurred vision in two, and nausea, fever, depression, rash, ankle edema, increased bruising, tremulousness, antispasticity, urinary frequency, and decreased libido in one patient each. Of the eight patients with more than one AE, four patients had two complaints, three had three complaints, and one had four complaints. Gabapentin was discontinued due to side effects alone in 12 patients (mean GBP dose: 1500 mg/day; median: 1500 mg/day) and due to side effects combined with lack of efficacy in six patients (mean GBP dose: 1300 mg/day; median: 1800 mg/day). Of the patients with side effects as the sole reason for discontinuing GBP, five patients discontinued because of central nervous system side effects such as sedation and mental clouding (mean GBP dose: 900 mg/day; range: 600 –1600 mg/day). The remaining seven patients discontinued due to more idiosyncratic reactions including rash, fever, ankle edema, joint pain, and weight gain. No specific AED combination was associated with any of the most frequently reported side effects. One patient who was taking valproate and warfarin had elevation of liver function tests after GBP was initiated, which resolved after GBP was stopped. Gabapentin does not undergo hepatic metabolism, suggesting that this side effect was unre-
lated to GBP; therefore, this patient was not included in Table 3. One patient with partial complex seizures was hospitalized because of side effects while taking GBP; this patient complained of nausea, mild fever (documented at 37.9°C), and diarrhea. She was hospitalized due to the severity of her complaints, and while in the hospital gradually improved as GPB was discontinued. All laboratory tests were normal and she was discharged in good condition. She was gradually changed to methsuximide for seizure treatment. This patient had a history of developing a lupus-like reaction to carbamazepine associated with a positive ANA test, was allergic to phenytoin, and was in general poorly tolerant of AEDs.
Efficacy Addition of GBP to the regimen allowed discontinuation of another AED in one-third of the study population. Overall efficacy was rated as much better in eight patients (9%), better in 61 (68%), worse in 20 (22%), and much worse in one patient (1%). All patients who had worsened seizure control were discontinued from GBP. Of the 15 patients in whom GBP was stopped due to lack of efficacy alone, the mean dose was 1700 mg/day (median: 1500 mg/day; range: 500 –3600 mg/day). Lack of efficacy was a supplemental reason, along with side effects, for discontinunation in an additional six patients (mean GBP dose: 1200 mg/day; median: 1800 mg/day). Eight patients had emergency room visits due to seizure; nine patients were hospitalized due to seizures. Gabapentin was used in two patients with symptomatic generalized epilepsy with seizure improvement reported for both; these patients had static encephalopathy and suffered multiple seizure types. Additionally, GPB was used in three patients with idiopathic primary generalized epilepsy, because AEDs indicated for treatment of this condition were poorly tolerated or ineffective in these patients. Electroencephalograms were consistent with this diagnosis in all three patients; two of three had seizure histories consistent with Juvenile Myoclonic Epilepsy (JME). The JME patients both had improvement in myoclonus with GBP, and neither patient achieved monotherapy. However, one patient was able to reduce the valproate dose and the other remained on phenytoin without change. J EPILEPSY, VOL. 11, NO. 3, 1998 133
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Discussion This review suggests that in its first year of release, GBP was used in a highly intractable patient population, similar to the premarketing study population. In these 90 difficult-to-treat patients, most (77%) reported some reduction in seizure frequency. This high rate of perceived improvement is consistent with a seizure-reducing effect of GBP, but also may have been produced by, perhaps in part, improved AED compliance with the addition of a new medication, or placebo effect. Elevations in concomitant AED levels would not explain improvement, as GPB does not interact with other AEDs. Gabapentin was very well tolerated, with tolerability rated as excellent or good in 73% of patients. The majority of AEs, particularly the most common one of sedation or sleepiness, occurred at low GBP doses. This suggests that if side effects do not occur at low doses when the drug is started, a dose escalation to higher doses (.1800 mg/day) may be accomplished with little worry about the onset of dose-related side effects. The side effects reported by the study population were similar to those reported in the premarketing studies, with no surprising deviation from the adverse event profile previously described (4 – 8). Titration of GBP doses above 1800 mg/day appears to be associated with a low risk of side effects. Our study indicates that side effects, especially sedation, are more likely to occur at lower doses, and suggest that if sedation does not occur at a low dose, it will not appear with higher doses. Although some of the patients in our retrospective study achieved doses of nearly 3600 mg/day, further evaluation is necessary to determine the usefulness of GBP at doses in the highest range. The doses of GBP used in this study reflect the lower doses used immediately after its availability. It is possible that greater efficacy could have been achieved in the patients who discontinued due to lack of efficacy if higher doses had been used. However, recent data does suggest that doses of GBP , 1800 mg/day are adequate for patients with milder epilepsy and that patients with more difficult to control seizures require titration to doses . 1800 mg/day (9). Two open-label studies suggest that GBP is safe, well-tolerated, and effective in patients with drugresistant partial and secondarily generalized epileptic seizures over the long-term, for a period of at least 4 years (7,8). In the first study, 25 patients were followed for 4 years in an open-label study, using 134 J EPILEPSY, VOL. 11, NO. 3, 1998
GBP as add-on therapy after a 3-month, doubleblind, placebo-controlled phase (7). Twelve patients responded to GBP, while no benefit was seen in the remaining 13 patients. Seven patients took GBP for more than 4 years (median follow-up time: 54 months). Five of the seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the initial 25 patients who entered the study. The authors concluded that GBP was effective in the long-term treatment of patients with partial and secondarily generalized epileptic seizures, and that GBP was safe and well tolerated as long-term treatment. The second study included 23 patients with intractable, partial-onset seizures following a blinded, placebo-controlled, add-on, dose efficacy study (US Gabapentin Study No. 5) (8). Nine patients had no significant improvement in seizure control and stopped GBP; the remaining 14 patients were observed while treated long-term with stable-dose GBP and concomitant AEDs. Improvement was maintained over the 4-year follow-up period. The upper dose limit of 2400 mg/day allowed by the protocol was well tolerated by 16 of 23 patients, indicating that higher dose may be tolerated in a substantial fraction of patients. The authors concluded that the upper dose limit for GBP efficacy and tolerability remains to be determined. In the current study, four patients initially took GBP alone, and four others achieved GBP monotherapy during the study period. Therefore, a total of eight patients, or approximately 10%, were stabilized on GBP monotherapy. Two recent studies of GBP used as monotherapy support its efficacy in this setting, however a clear dose-response was demonstrated only when 3600 mg/day was compared to 300 mg/day in refractory partial epilepsy patients (10,11). Therefore, it would be expected that some of our study patients could achieve monotherapy with GBP safely. Consistent with data suggesting that higher doses are needed for intractable patients (9), our monotherapy patients were taking GBP at a higher mean dose than other patients in the study. Five patients in this study had generalized epilepsy, including two with JME, who reported improvement with add-on GBP. Although this good response would not be predicted from the study of GBP in another form of primary generalized epilepsy, absence epilepsy in children (12), it may be that one form of primary generalized epilepsy cannot be ‘‘lumped’’ with another in terms of response to a new AED. Gabapentin has been shown to interact with L-type voltage dependent calcium
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channels, which is a property unique to GBP among AEDs (13). Therefore, because the pharmacology of GBP is still being discovered, the treatment spectrum may also be still expanding. In summary, according to a retrospective postmarketing analysis, GBP was used mainly in patients with intractable epilepsy. It was found to be effective and well tolerated as both adjunctive therapy and monotherapy. An unexpected finding was that side effects generally occur at doses less than 1800 mg/day and if GBP is well-tolerated at low doses, it can be escalated without further concern. Our review highlighted the benefits of GBP in the clinical settings of private practice and a hospital outpatient clinic, and the results of this analysis can be used to help understand the role of GBP therapy in clinical practice.
References 1. Btaiche IF, Woster PS. Gabapentin and lamotrigine: Novel antiepileptic drugs. Am J Health Syst Pharm 1995;52:61– 69. 2. Mattson RH. Drug treatment of partial epilepsy. In: Chauvel P, Delgada-Escueta AV, et al, eds. Advances in neurology (vol. 57). New York: Raven Press, 1992:643–50. 3. Fisher RS. Emerging antiepileptic drugs. Neurology 1993; 43(suppl 5):S12–S20. 4. UK Gabapentin Study Group. Gabapentin in partial epilepsy. Lancet 1990;335:1114 –7. 5. The US Gabapentin Study Group No. 5. Gabapentin as add-on therapy in refractory partial epilepsy: A doubleblind, placebo-controlled, parallel-group study. Neurology 1993;432:2292– 8.
6. Anhut H, Achman P, Feurerstein TJ, Sauermann W, Saunders M, Schmidt B, and The International Gabapentin Study Group. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: A double-blind, placebo-controlled study. Epilepsia 1994;35:795– 801. 7. Sivenius J, Ylinen A, Kalviainen R, Riekkinen PJ. Long-term study with gabapentin patients with drug-resistant epileptic seizures. Arch Neurol 1994;51:1047–50. 8. Handforth A, Treiman DM. Efficacy and tolerance of longterm, high-dose gabapentin: Additional observations. Epilepsia 1994;35:1032–7. 9. Morell M, McLean M, Willmore J, Lagnus-Miller Leslie, Podolnik PB, Rose-Legatt A. Efficacy of gabapentin (Neurontin) as add-on therapy for patients with partial epilepsy (abstract). Neurology 1997;48(suppl 2):A335. 10. Bergey GK, Morris HH, Rosendeld W, Blume WT, Penovich PE, Morell MJ, Leiderman DB, Crockatt JG, LaMoreaux L, Garofalo E, Pierce M, US Gabapentin Study Group 88/89. Gabapentin monotherapy: I. An 8-day, double-blind, dosecontrolled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49:739 – 45. 11. Beydoun A, Fischer J, Labar DR, Harden C, Cantrell D, Uthman BM, Sackellares JC, Abou-Khalil B, Ramsay RE, Hayes A, Greiner M, Garofalo E, Pierce M, US Gabapentin Study Group 82/83. Gabapentin monotherapy: II. A 26week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49:746 –52. 12. Leiderman D, Garofalo E, LaMoreaux L. Gabapentin patients with absence seizures: Two double-blind, placebo controlled studies. Epilepsia 1993;34(suppl 6):45. 13. Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alph2delta subunit of a calcium channel. J Biol Chem 1996;271:5768 –76.
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