May 2017 FAQs
March 2017 FAQs
What is the role of bezlotoxumab in treating Clostridium difficile infections?
What is the role of bezlotoxumab in treating Clostridium difficile infections?
Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients.1 C. difficileis a spore-forming, toxin-producing, gram-positive, obligately anaerobic bacillus that usually causes infections in patients with disruption in normal colonic microflora due to recent antibiotic use. Many antibiotics have been associated with increased risk of C. difficile infection (CDI) including clindamycin, cephalosporins, and fluoroquinolones although all antibiotics carry some risk. Antimicrobial use is the most modifiable risk factor as appropriate antimicrobial stewardship has been shown to decrease CDI rates.2 Other risk factors include underlying illness, advanced age, and use of various antacid agents.1,2Infection control measures such as handwashing initiatives and contact isolation play an important role in decreasing the transmission of CDI.
Infections related to C. difficile substantially increase the burden on the healthcare system. Excess hospital costs for CDI management in the United States were estimated at $3.2 billion between the years 2000 and 2002.2 Infection rates and severity have increased in recent years, and more recent estimates suggest the excess hospital costs may be up to $4.8 billion for acute care facilities alone.3
The treatment of CDI is outlined in the guidelines published jointly by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). 2 According to the 2010 version of these guidelines, metronidazole is the treatment of choice for the initial episode of mild-to-moderate CDI. Oral vancomycin is the first-line option for patients presenting with severe CDI as their initial episode. Patients with severe, complicated infection may be treated with a combination of parenteral metronidazole and oral vancomycin. Rectal vancomycin is administered in patients with suspected ileus. In patients with a first recurrence of CDI, the guidelines recommend the same regimen used in the initial episode; however, the severity of the disease should be reassessed. Metronidazole should not be used for multiple recurrent infections as the risk of neurotoxicity increases with prolonged therapy. Second or later recurrences of CDI are treated with tapered or pulsatile oral vancomycin regimens. No guidance is provided for patients who need to remain on the inciting antibiotic throughout the CDI.
Considering the poor outcomes of these infections, especially recurrent infections, and the burden on the healthcare system, novel treatment strategies are being explored. One such strategy is the administration of monoclonal antibodies against the toxins produced by C. difficile as passive immunity.4 This strategy builds on the correlation between increased antibodies against toxin A and toxin B and protection against recurrent CDI.
MODIFY I and MODIFY II
MODIFY I and MODIFY II were double-blind, randomized, placebo-controlled, phase 3 trials evaluating the efficacy and safety of actoxumab and bezlotoxumab.4 These human monoclonal antibodies bind and neutralize C. difficile toxin A and toxin B, respectively.
The studies were conducted in 30 countries at 322 sites.4 Participants were adults with initial CDI or recurrent CDI who were receiving standard of care oral antibiotics (metronidazole, vancomycin, or fidaxomicin at the discretion of their treating physician) for 10 to 14 days. CDI was defined as 3 or more unformed bowel movements in 24 hours with a positive C. difficile toxin stool test.
Patients were randomized to a single 60-minute infusion of placebo, bezlotoxumab 10 mg/kg, or bezlotoxumab 10 mg/kg plus actoxumab 10 mg/kg.4 In MODIFY I patients were also randomized to actoxumab 10 mg/kg as a single agent, but this was discontinued for MODIFY II due to lack of efficacy and increased mortality in that group. Participants recorded unformed bowel movements for 80 to 90 days after the infusion. Any new episode of diarrhea was monitored through telephone contact or at follow up visits. The primary endpoint was recurrent CDI during the 12-week follow-up. Safety parameters included infusion reaction monitoring for 24 hours, laboratory tests for 4 weeks, and recording of serious adverse events through week 12. The modified intention-to-treat population (mITT) was used for efficacy analysis and included those who received the study infusion, had a baseline stool test that was positive for C. difficile toxin, and received the standard of care antimicrobials before or within 1 day of the study infusion.
A total of 2655 patients underwent randomization, and 2559 were treated and included in the mITT population.4 Over half of the patients were women, and the median age was 66 years. Patients with 1 or more recurrence or those with severe infection were spread equally among groups. Standard of care antimicrobial choice was also proportionally spread – metronidazole and vancomycin were used for nearly all patients with a small percentage (<4%) in each group receiving fidaxomicin. The cure, recurrence, and global cure rates for bezlotoxumab and placebo are described in the Table. Recurrence was significantly improved with bezlotoxumab in both studies. However, cure rates were not significantly improved in either study and global cure rates were only improved in MODIFY II. The addition of actoxumab did not improve efficacy.
Table. Results of the bezlotoxumab and placebo groups in Modify I and II.4,5
MODIFY I Bezlotoxumab Placebo Adjusted difference (95% CI) Curea 77.5% 82.8% -5.3 (-10.9, 0.3); p=0.0643 Recurrenceb 17.4% 27.6% -10.1 (-15.9, -4.3); p=0.0007 Global curec 60.1% 55.2% 4.8 (-2.1, 11.7); p=0.1722 MODIFY II Curea 82.5% 77.8% 4.8 (-0.9, 10.4); p=0.0962 Recurrenceb 15.7% 25.7% -9.9 (-15.5, -4.3); p=0.0006 Global curec 66.8% 52.1% 14.6 (7.7, 21.4); p<0.0001 Pooled data Curea 80.0% 80.3% -0.3 (-4.3, 3.7); p=0.8832 Recurrenceb 16.5% 26.6% -10 (-14.0, -6.0); p<0.0001 Global curec 63.5% 53.7% 9.7 (4.8, 14.5); p=0.0001 aCure was defined as no diarrhea for 2 consecutive days after completion of antibiotic.
cGlobal cure was defined as initial cure with no recurrence during the 12 week follow-up.
Infusion-related reactions including nausea, headache, and pyrexia were the most common adverse events reported, and the incidence was similar among groups.4 Of note, serious adverse events and death were reported more frequently in the actoxumab monotherapy group, resulting in the early discontinuation of this arm at the interim analysis.
MODIFY I and II were well-designed, randomized controlled trials with baseline demographics equally distributed among the groups and use of guideline-recommended antibiotics for CDI treatment. These studies also have various limitations. Although agents recommended in the guidelines for the treatment of CDI were included, selection of the treatment agent was left to provider discretion resulting in potential bias. In addition, very few patients received fidaxomicin which has been shown to lower recurrence rates compared with vancomycin; thus, the efficacy of this combination is unknown.6,7 The interval of time between symptom onset and infusion of the antibodies varied widely. Therefore, it is difficult to determine the utility of bezlotoxumab for diarrhea severity and duration for the CDI episode.
In conclusion, the role of these medications and others that target CDI recurrence needs to be better defined. As discussed by various experts, the price associated with novel treatment strategies will make widespread adoption prohibitive.5,6 These agents would be best utilized for patients at high risk of recurrence, but it is difficult to identify these patients. Although scoring tools for severity of CDI and cure at end of treatment have been validated, no scoring tool exists for recurrence risk.8 This potential tool would help clinicians assess which patients would most benefit from bezlotoxumab. Factors currently associated with recurrence include advanced age and previous recurrence, but more data are needed to assess other factors and develop a scoring tool. Updates to the CDI guidelines are expected in the summer of 2017 and will potentially incorporate information on bezlotoxumab as well as other novel treatment strategies.9
- Gerding DN, Johnson S. Clostridium difficile infection, including pseudomembranous colitis. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130§ionid=79734123. Accessed April 10, 2017.
- Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
- Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-834.
- Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.
- Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection [supplemental appendix]. N Engl J Med. 2017;376(4):305-317. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1602615/suppl_file/nejmoa1602615_appendix.pdf. Accessed April 21, 2017.
- Bartlett JG. Bezlotoxumab – a new agent for Clostridium difficile infection. N Engl J Med. 2017;376(4):381-382.
- Cook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55 (Suppl 2):S93-S103.
- Jacobson SM, Slain D. Evaluation of a bedside scoring system for predicting clinical cure and recurrence of Clostridium difficile infections. Am J Health Syst Pharm. 2015;72(21):1871-1875.
- Clostridium difficile. Infectious Diseases Society of America website. http://www.idsociety.org/Organism/. Accessed April 24, 2017.
Sana Said, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago
The information presented is current as of April 21, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
What is the evidence for use of high-dose vitamin C in critically ill patients?
What is the evidence for use of high-dose vitamin C in critically ill patients?
Vitamin C, also known as ascorbic acid, is a water-soluble vitamin that acts as an antioxidant.1,2 It protects proteins, lipids, and deoxyribonucleic acid (DNA) from damage by neutralizing reactive oxygen species (ROS). For example, vitamin C donates an electron to superoxide (O2–) and peroxynitrite (ONOO–) and forms ascorbyl radical, which is a less damaging pro-oxidant. Ascorbate, a redox form of vitamin C, possesses some pro-oxidant properties at lower doses due to creation of low amounts of O2–; however, ascorbate serves as an antioxidant at higher doses.1,3
Sepsis typically presents with endothelial dysfunction, which is marked by decreased response to vasodilators and vasoconstrictors.1 Enzymatic processes involving activation of dinucleotide phosphate-oxidase and uncoupling of endothelial nitric oxide synthase (eNOS) produce ROS.3 The presence of unopposed ROS may lead to decreased production of endothelial nitric oxide, which is responsible for vasodilation and platelet aggregation and adhesion. Therefore, decreased levels of endothelial nitric oxide leads to a decline in organ perfusion and oxygenation. At the same time, uncoupled eNOS starts producing O2– and ONOO–, which are the most damaging ROS.1,3
Ascorbate prevents activation of dinucleotide phosphate-oxidase, scavenges O2– and ONOO–, and participates in catecholamine synthesis.1,4 Stabilizing dinucleotide phosphate-oxidase and reducing O2– and ONOO– lead to increased levels of nitric oxide, which could restore appropriate organ perfusion and oxygenation. Ascorbate serves as a cofactor in the production process for norepinephrine and vasopressin and aids epinephrine in activation of α- and β-adrenergic receptors.4 Ascorbate also inhibits bacterial replication and regulates macrophages in sepsis.3 Usually, patients with sepsis have low concentrations of vitamin C in blood and leukocytes. Cell consumption of vitamin C increases during sepsis, and patients experience higher turnover rate of leukocytes. These proposed mechanisms of action lead to exploring whether supplementation with vitamin C could be beneficial in patients with sepsis.
The literature regarding the use of vitamin C in patients with sepsis remains limited (see Table 1 for the identified key clinical trials). The trials exploring the use of vitamin C for this indication have small sample size, differ in study designs, and measure varying outcomes.5-7 Making a clear conclusion regarding the benefits of vitamin C in sepsis is difficult. However, these smaller trials are showing benefits with vitamin C in sepsis including decreased dose and duration of vasopressors, improved hospital mortality, and lack of adverse events.
Table 1. Key clinical trials exploring the use of vitamin C in patients with sepsis.5-7
Zabet 20165 RCT, DB, SC N=28 patients with septic shock requiring vasopressors (norepinephrine) IV ascorbic acid 25 mg/kg IV every 6 h (n=14)
Duration of therapy: 72 h
- Norepinephrine dose: 7.44 ± 3.65 mcg/min in the ascorbic acid group vs 13.79 ± 6.48 mcg/min in the placebo group (p=0.004)
- Norepinephrine duration: 49.64 ± 25.67 h in the ascorbic acid group vs 71.57 ± 1.60 h in the placebo group (p=0.007)
- Duration of ICU stay: NS differences between the 2 groups
- 28-day mortality rate: 14.28% in the ascorbic acid groups vs 64.28% in the placebo group, respectively (p=0.009)
- No adverse events identified in ascorbic acid group
Marik 20166 Retrospective N=94 patients in general ICU with severe sepsis or septic shock and procalcitonin ≥ 2 ng/mL Treatment group: IV ascorbic acid 1.5 g every 6 h for 4 days + IV hydrocortisone 50 mg every 6 h for 7 days + IV thiamine 200 mg every 12 h for 4 days (n=47)
Control group: IV hydrocortisone 50 mg every 6 h for 7 days (n=47)
Duration of therapy: 4 days (with ascorbic acid and thiamine)
- Hospital survival: 8.5% in the treatment group vs 40.4% in the control group (p<0.001)
- Duration of vasopressor: 18.3 ± 9.8 h in the treatment group vs 54.9 ± 28.4 h in the control group (p<0.001)
- Duration of ICU stay: NS differences between 2 groups
- Requirement for renal replacement therapy in acute kidney injury: 10% in the treatment group vs 33% in the control group (p=0.02)
- Change in procalcitonin over 72 h: 86.4% in the treatment group vs 33.9% in the control group (p<0.001)
- Change in SOFA scores over 72 h: 4.8 ± 2.4 in the treatment group vs 0.9 ± 2.7 in the control group (p<0.001)
Fowler 20147 RCT, phase I, DB, PC N=24 patients with severe sepsis or septic shock in medical ICU Low dose IV ascorbic acid 50 mg/kg/24 h administered every 6 h (n=8)
High dose IV ascorbic acid 200 mg/kg/24 h administered every 6 h (n=8)
Duration of therapy: 4 days
- Treatment-related adverse event frequency (hypotension, tachycardia, hypernatremia, nausea/vomiting): no patients withdrawn due to adverse events
- Change in SOFA scores: significant decrease in SOFA scores in both ascorbic acid groups over 4 days compared to baseline (p<0.05); faster decline in scores with the high dose ascorbic acid group compared to placebo (regression slopes -0.043 vs 0.003; p<0.01)
- C-reactive protein at 6 h: 3000 µM for the high-dose ascorbic acid group, 300 µM for the low-dose ascorbic acid group, and 15 µM for the placebo group (p<0.005 for each ascorbic acid group vs placebo)
- Procalcitonin: significantly lower at 48 h, 72 h, and 96 h for the high dose ascorbic acid group compared to the baseline
- Thrombomodulin: NS differences between the groups but trend for increased thrombomodulin in the placebo group at 36 h compared to the baseline
Abbreviations: DB=double-blinded; ICU=intensive care unit; IV=intravenous; NS=not significant; PC=placebo-controlled; RCT=randomized controlled trial; SC=single center; SOFA=Sequential Organ Failure Assessment
The consensus on dosing, drug preparation, and duration of therapy for vitamin C in sepsis is lacking.1The ideal initiation timeframe of vitamin C in patients with sepsis is unknown but the earlier administration of therapy could be more beneficial. Intravenous vitamin C is the preferred formulation as critically ill patients with septic shock may have decreased gut absorption, and the goal is to achieve higher plasma levels of vitamin C. The doses as high as 3 to 6 g per day may be necessary to improve outcomes in patients with sepsis.3 Most studies administered the divided daily dose of vitamin C every 6 h for 3 to 4 days.5-7 Zabet and colleagues prepared intravenous vitamin C by diluting ascorbic acid in 50 mL of dextrose 5% solution, which was infused over 30 min.5 Similarly, Fowler and colleagues prepared vitamin C in 50 mL polyvinyl chloride bags by using injectable formulation.7 The dilution solution was not specified but the package insert for injectable ascorbic acid states that either normal saline or glucose solution may be used for dilution.7,8 The diluted ascorbic acid was stored at 2 to 8°C for 24 hours after removing air from the infusion bags to avoid oxidation of ascorbic acid and wrapping bags in amber wraps for light protection.7 No oxidation was noted when stored at these conditions. Ascorbic acid was diluted in 100 ml of dextrose 5% or normal saline and then administered over 30 to 60 minutes in the trial performed by Marik and colleagues.6
The safety and toxicity of vitamin C are unclear but the main concerns consist of pro-oxidative effects and increased formation of calcium oxalate stones.3,9 Fowler and colleagues did not observe any adverse events when administering vitamin C at high doses to patients with sepsis.7 Theoretically, high-dose vitamin C may lead to pro-oxidant effects, and thus, disrupt the function of some cells due to increased production of hydrogen peroxide.9 A crossover study of healthy patients did not show increased levels of pro-oxidative biomarkers when vitamin C was administered in daily doses of up to 7500 mg for 6 days.10 Cautious use of vitamin C is necessary for patients at high risk for kidney stones as vitamin C increases excretion of oxalate and formation of calcium oxalate stones.3,9 Vitamin C is administered only for 3 to 4 days in the setting of sepsis, and such short duration of administration should not elevate the risk for oxalate stone formation in patients without risk factors for kidney stones.5-7,9
Prevention of dinucleotide phosphate-oxidase activation, scavenging damaging ROS, and participation in catecholamine synthesis are examples of proposed pharmacological mechanisms for vitamin C in attenuating sepsis. Low-quality evidence is available so far on using vitamin C in patients with sepsis. But the available smaller studies have revealed that high-dose vitamin C administered intravenously may decrease dose and duration of vasopressors and improve hospital mortality without increasing adverse effects. The potential safety concerns with high-dose vitamin C are pro-oxidative effects and formation of calcium oxalate stones, mainly in patients at high risk for kidney stones.
1. Berger MM, Oudemans-van Straaten HM. Vitamin C supplementation in the critically ill patient. Curr Opin Clin Nutr Metab Care. 2015;18(2):193-201.
2. LexiComp Online [database online]. Hudson, OH: Lexicomp; 2017. http://online.lexi.com/lco/action/home. Accessed April 13, 2017.
3. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014;18(4):460.
4. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 2015;19:418.
5. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-100.
6. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2016; doi: 10.1016/j.chest.2016.11.036.
7. Fowler AA, 3rd, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
8. Ascorbic acid [package insert]. Rockford, IL: Mylan Institutional; 2016.
9. Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal. 2013;19(17):2129-2140.
10. Muhlhofer A, Mrosek S, Schlegel B, et al. High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur J Clin Nutr. 2004;58(8):1151-1158.
The information presented is current as April 10, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.
How does brivaracetam compare to other antiepileptic agents in treating refractory partial onset seizures (POS)?
How does brivaracetam compare to other antiepileptic agents in treating refractory partial onset seizures (POS)?
A seizure, which can be classified as partial (focal) or generalized, is a paroxysmal event that arises from excessive neuronal excitation in the brain, often due to alterations in neural membrane conductance and inhibitory circuits.1,2 The occurrence of 2 or more unprovoked seizures separated by at least 24 hours is defined as epilepsy.1,2 Epilepsy is the fourth most common neurological disorder and affects approximately 2.2 million people in the United States, and 50 million people worldwide.3,4Nearly 125,000 new epilepsy cases are diagnosed in the United States annually.2 The lifetime prevalence is about 8% and can affect individuals of all ages, but the incidence is highest among young children and older adults.3 Certain factors can precipitate seizures in susceptible individuals.2 These include, but are not limited to, infections, head injuries, stroke, sleep deprivation, emotional stress, hormonal changes, medications, and illicit drugs.
The goal of epilepsy treatment is to become completely free of seizures with minimal adverse reactions as a result of pharmacological or nonpharmacological therapy.5 Despite the availability of more than 20 effective antiepileptic drugs (AEDs), 30% to 40% of patients remain refractory to treatment. Refractory epilepsy, also referred to as drug-resistant epilepsy or intractable epilepsy, is defined as failure to become and stay seizure free despite adequate trials of 2 or more AEDs at maximally tolerated doses.3 Once the diagnosis has been made, the chance that patients will have seizure freedom following further trials of other AEDs ranges from 5% to 10%.
The 2004 American Academy of Neurology (AAN) guideline for the treatment of refractory epilepsy recommends using lamotrigine (LTG), oxcarbazepine (OXC), or topiramate (TPM) as monotherapy.6Gabapentin (GBP), levetiracetam (LEV), LTG, OXC, tiagabine (TGB), TPM, and zonisamide (ZNS) can be used as adjunctive therapy. Since the publication of the AAN guideline, newer AEDs have been approved for the treatment of refractory partial-onset seizures (POS). Vigabatrin (VGB) is approved as monotherapy, whereas perampanel (PER) and eslicarbazepine acetate (ESL) are approved as adjunctive therapy.5 Lacosamide, another newer AED is approved for the treatment of POS, but not refractory POS.5,7 However, newer literature indicates that this medication may also have a place in therapy in the adjunctive treatment of refractory POS. An analog of LEV, brivaracetam (BRV), is among the newest of the AEDs.9 Compared to placebo, BRV has demonstrated efficacy in reducing POS frequency from baseline, achieving freedom from all seizures, and attaining 50% or more reduction in seizure frequency in patients with refractory POS. 8,9,10,11 Brivaracetam was approved by the Food and Drug Administration (FDA) in February 2016 as an adjunctive therapy for the treatment of POS in individuals 16 years of age and older at doses of 50 to 200 mg/day.8
Although the newer AEDs have provided substantial improvements in terms of safety, tolerability, and pharmacokinetics, none of them have provided a cure for patients with refractory epilepsy.4Furthermore, no AED is completely without side effects and individuals with refractory epilepsy often have other concomitant comorbidities including depression, anxiety, reduced quality of life, and increased mortality.14 Therefore, there remains an unmet need in finding more effective and safer AEDs for individuals with refractory partial epilepsy.
Brivaracetam, a 2-pyrrolidine derivative, is a third generation AED.15,16 The medication is a potent, highly selective, and reversible synaptic vesicle glycoprotein 2A (SV2A) ligand that binds to SV2A receptors with a 20-fold greater affinity than LEV.16 Synaptic vesicle glycoprotein 2A ligands are hypothesized to assist with the coordination of synaptic vesicle exocytosis and neurotransmitter release.4 Synaptic vesicle glycoprotein 2A receptor binding reduces excitatory neurotransmitter release and thereby enhances synaptic depression 200-fold more than LEV.16 At therapeutic doses, BRV is expected to occupy 80% to greater than 90% of SV2A receptors in the brain.
To date, 3 meta-analyses and 1 open-label exploratory study provide comparative data for adjunctive use of BRV and other AEDs in the management of refractory POS.17,18,19,20 In a meta-analysis by Zhang et al, a sub-analysis which indirectly compared the efficacy of LEV to BRV demonstrated that there were no statistically significant differences in efficacy between LEV and BRV at all doses, including 50% responder rates and seizure-freedom rates.17 However, there appeared to be a trend toward better efficacy for LEV because the risk ratios (RRs) for all LEV doses (500, 1,000, 2,000, and 3,000 mg/day) were greater than 1. Brivaracetam exhibited a significantly higher incidence of dizziness at high doses levels (BRV 150 and 200 mg/day) compared to high dose levels of LEV (3,000 mg/day; RR 0.38 [95% CI 0.18 to 0.83]; p=0.03).
In a meta-analysis by Lattanzi et al, a sub-analysis was performed to determine the efficacy of BRV based on previous use of LEV.18 The analysis showed that the efficacy of BRV was greater in the LEV-naive patients, and lower treatment effects were observed for patients who had previously taken LEV. Forty-five percent of patients had 50% responder rates in the BRV 50 mg/day group compared to 19% in the placebo group. Of note, the study observed that BRV was not effective in reducing seizure frequency by 50% or more as add-on therapy in patients concomitantly taking LEV. This suggests that using AEDs with the same mechanism of action, such as BRV and LEV, may not improve efficacy.
Aside from comparisons with LEV, BRV was indirectly compared to several other agents in a meta-analysis by Brigo et al.19 There were no significant differences for 50% responder rates and seizure-free rates between BRV compared to LCM, ESL, and PER at all doses. Adverse events were significantly lower with BRV 50 mg compared to PER 8 mg, and for BRV 200 mg compared to ESL 1,200 mg or PER 12 mg. No differences were found between BRV and LCM.
In an open-label, prospective, exploratory study of patients with POS or primary generalized epilepsy, 93.1% of patients had clinically meaningful reductions in nonpsychotic behavior adverse events (BAEs) when switched to BRV 200 mg/day after experiencing BAEs with LEV 1,000 to 3,000 mg/day.20 Of note, patients in this trial were receiving 2 or more AEDs concomitantly.
To date, there have been no randomized controlled trials directly comparing BRV to other AEDs. However, several meta-analyses indirectly comparing BRV to other AEDs and have found no major differences in clinical efficacy when the agent is used as adjunctive therapy for refractory POS.17,18,19,20Compared to other AEDs, BRV is effective at reducing seizure frequency and attaining seizure freedom status, while demonstrating a favorable safety and tolerability profile across all doses. Overall, BRV’s place in therapy (as monotherapy or adjunct) is yet to be determined. Therefore, the decision to choose BRV over other AEDs will most likely be based on factors such as side effect profile, formulation, patient population, organ impairment, and cost.
The incidence of treatment-emergent adverse events (TEAEs) is low, mostly mild-to-moderate in severity, and generally does not lead to permanent discontinuation of the drug. 17,18,19,20 Due to a lower incidence of TEAEs and idiosyncratic adverse events when compared to other AEDs, BRV may be reasonable option as adjunctive therapy for refractory POS, especially in the elderly.8 However, data for the use of BRV in the geriatric population are sparse.21 Since BRV has a lower incidence of behavioral side effects compared to LEV, BRV can also be a potential alternative for patients who experience BAEs with LEV.9 Of note, concomitant utilization of BRV and LEV did not provide additional reduction in weekly focal seizure frequency, suggesting that competition of binding sites can minimize the efficacy of BRV.
Brivaracetam is available as tablets, oral solution, and intravenous (IV) injection.21 The oral formulations may be a more suitable option for the outpatient setting, whereas the IV formulation may be useful in emergency situations, such as status epilepticus (SE).8 Although there are currently no data to support using BRV for SE, preclinical studies that have shown that BRV has a higher blood-brain permeability than LEV, resulting in faster SV2A ligand binding and ultimately resulting in more rapid onset of action.
Brivaracetam is only approved for use in individuals 16 years of age and older.21 However, there is an ongoing Phase III trial in the pediatric population.8 Unlike the other newer AEDs, BRV does not require dose adjustments for patients with impaired renal function. However, the use of BRV is not recommended in patients with end-stage renal disease undergoing dialysis since there are no data for use in this patient population.21 Similar to all other newer AEDs, dose adjustment is recommended for patients with hepatic impairment. Finally, since BRV is only available as a branded product, the medication is likely to be more expensive than most AEDs, and may not be a preferred agent on hospital formulary lists.
Direct comparative data for BRV and other AEDs in the treatment of refractory POS are lacking. Nonetheless, indirect data from meta-analyses suggest that there are no major differences in efficacy between BRV and other AEDs when used as adjunct treatment. When comparing BRV to LEV, ESL, LCM, and PER, there were no differences in efficacy outcomes, including 50% responder rates and seizure-freedom rates. However, there was a trend towards favoring LEV. Adverse events were similar between LEV and BRV, except BRV had a higher incidence of dizziness. When comparing BRV to ESL, LCM, and PER, lower adverse events were observed with high dose BRV compared to high dose ESL or PER, but there were no differences in withdrawal rates due to adverse events. Overall, BRV appears to be as effective as several newer AEDs for the treatment of refractory POS. Further clinical trials are warranted to elucidate advantages of BRV over other AEDs.
1.Lowenstein DH. Seizures and epilepsy. In: Kasper D, Fauci A, Hauser S, Longer D, James JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?sectionid=79755120&bookid=1130&Resultclick=2. Accessed March 15, 2017.
2.Rogers, SJ, Cavazos JE. Epilepsy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=689§ionid=45310490
3.Shafer PO. Epilepsy statistics. Epilepsy Foundation website. http://www.epilepsy.com/learn/epilepsy-statistics. Published October 2013. Accessed March 25, 2017.
4.Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov. 2010;9(1):68-82.
5.Ben-menachem E. Medical management of refractory epilepsy–practical treatment with novel antiepileptic drugs. Epilepsia. 2014;55(1):3-8.
6.French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62(8):1261-1273.
7.Harris JA, Murphy JA. Lacosamide and epilepsy. CNS Neurosci Ther. 2011;17(6):678-682.
8.Coppola G, Iapadre G, Operto FF, Verrotti A. New developments in the management of partial-onset epilepsy: role of brivaracetam. Drug Des Devel Ther. 2017;11:643-657.
9.Biton V, Berkovic SF, Abou-khalil B, Sperling MR, Johnson ME, Lu S. Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a phase III randomized, double-blind, placebo-controlled trial. Epilepsia. 2014;55(1):57-66.
10.Ryvlin P, Werhahn KJ, Blaszczyk B, Johnson ME, Lu S. Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;55(1):47-56.
11.Klein P, Schiemann J, Sperling MR, et al. A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial-onset seizures. Epilepsia. 2015;56(12):1890-1898.
12.French JA. Refractory epilepsy: clinical overview. Epilepsia. 2007;48(1):3-7.
13.Nair DR. Management of Drug-Resistant Epilepsy. Continuum (Minneap Minn). 2016;22(1):157-172.
14.Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70.
15.Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam. Epilepsia. 2011;52(2):264-272.
16.Rogawski MA. A New SV2A Ligand for Epilepsy. Cell. 2016;167(3):587.
17.Zhang L, Li S, Li H, Zou X. Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta-analysis and indirect comparison. Seizure. 2016;39:28-33.
18.Lattanzi S, Cagnetti C, Foschi N, Provinciali L, Silvestrini M. Brivaracetam add-on for refractory focal epilepsy: A systematic review and meta-analysis. Neurology. 2016;86(14):1344-1352.
19.Brigo F, Bragazzi NL, Nardone R, Trinka E. Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: results of an indirect comparison meta-analysis of RCTs. Seizure. 2016;42:29-37.
20.Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D’souza J. An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epilepsy Behav. 2015;52:165-168.
21.Brivaracetam [package insert]. Smyrna, GA: UCB Inc.; 2016.
Michelle Nguyen, PharmD
PGY1 Pharmacy Practice Resident
Loyola University Medical Center
The information presented is current as March 10, 2017. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.