Efficacy and Safety of Levetiracetam as an Adjunctive to Carbamazepine and Phenytoin for treating Focal Seizures in Indian Patients

Introduction

Nearly 60% of all the epilepsies are attributed to focal seizures. Nearly one-third of these patients do not respond to monotherapy and essentially require a combination therapy for better seizure control. Carbamazepine (CBZ) and phenytoin (PHT), the first-line drugs for treatment of focal seizure have a narrow therapeutic index necessitating their plasma drug concentration monitoring. Moreover, they are also inducers of CYP enzymes leading to drug interactions. An ideal add-on AED should therefore be safer with a better pharmacodynamic and pharmacokinetic profile to minimize drug-drug interactions and adverse events. Levetiracetam (LEV) has good safety profile, lesser drug interactions and does not require plasma monitoring making it a better choice for adjunctive therapy.

Aim

To compare the efficacy and safety of LEV as an adjunctive to CBZ and PHT in treatment of focal seizures

Patient Profile

• Patients with focal seizures with or without secondary generalization treated at Neurology out-patient department super-speciality hospital (PMSSY) in Bengaluru, India (n=60, age: 18-65 years)
• All patients were receiving CBZ or PHT for last 3 months and were experiencing at least 1 and not more than 14 focal seizure episodes per month for last 3 months

Methods

Study Design

• Prospective, open label, comparative study

Treatment strategy

• Levetiracetam was given as an adjunctive at a dose of 20-50 mg/kg/day to patients receiving either CBZ monotherapy (dose: 10-30 mg/kg/day) or PHT monotherapy (dose: 3-6mg/day)
• Dose of LEV was titrated subsequently depending on treatment response and tolerability.

Outcomes

• Seizure count
• Responder rate (percentage of patients with = 50% reduction from historical baseline)
• Seizure freedom rate (percentage of patients who did not experience focal seizures during the entire 12-week treatment period)
• Adverse events
• Quality of life (QOL) as assess using Quality of Life in Epilepsy 10p questionnaire (QOLIE- 10p)
• Adherence to medication

Follow-up Visits

• Conducted at week 4, 8 and 12

Results

• The mean age of the study population was 33.38 years and 63% were males. Fourteen patients had a history of febrile seizures (CBZ group; n=8 and PHT group; n=6).
• Mean seizure count per month at baseline was 1.96 and 2.03 in CBZ and PHT groups, respectively.
• At the end of week 12, the mean seizure count had reduced to 0.2 per month and 0.07 per month in the CBZ and PHT groups, respectively (between group difference was statistically non-significant; p = 0.65). Nevertheless, the difference was significant within their groups, at every follow-up visit (Table 1)

• At week 4, CBZ group had 22 responders, the number increased to 27 at the end of the study. The PHT group had 22 responders at week 4, by end of the study all patients responded. 
• Seizure free rate for both groups was 23 and 19 patients at week 4, 27 and 28 patients at week 12. Seizure freedom from historic baseline was observed in 20 and 17 patients in the CBZ and PHT groups, respectively.
• Few minor adverse events including; headache, giddiness, tiredness and slurring of speech were observed in both groups during the study, but none of them required hospitalization or treatment discontinuation.
• The QOLIE- 10p score decreased in both CBZ (baseline score; 36.7, decreased to 32.2) and PHT (baseline score 35.7, decreased to 31.8) groups, indicating improved QOL. All though the between group differences were not significant, within groups differences were significant (p<0.001).
• Adherence to medication during the study period was satisfactory.

Conclusions

• Levetiracetam given as an adjunctive resulted in more than 50% reduction in seizure count from baseline in 90% patients treated with CBZ and in 100% of patients treated with PHT.
• The seizure count, QOL between groups across different time periods did not differ significantly when levetiracetam was used as add-on to both the drugs.
• Levetiracetam can be a better add-on to focal seizures patients who were not controlled with monotherapy.

Biomed Pharmacol J 2020; DOI: 10.13005/bpj/1898.