2015 Fall CE for the Upstate 9/20/2015. Seizure Management in the Dog: Options Beyond Phenobarbital

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1 Seizure Management in the Dog: Options Beyond Phenobarbital Upstate Veterinary Specialists Fall 2015 CE September 20, 2015 Rennie Waldron, DVM, DACVIM (Neurology) Objective Outline Zonisamide, Levetiracetam Mechanism of action Pharmacokinetics Literature Patient selection Follow-up, monitoring Additional AEDs Conclusions 1

2 Phenobarbital PROS Efficacy, Efficacy, Efficacy! 60-93% BID CONS Side effects Rising Cost Injectable Historically most affordable Requires careful monitoring Other AEDs Why should we consider alternatives for monotherapy & add-on therapy? Cost Side effects Pharmacoresistant epilepsy Akc.org 2

3 Zonisamide Synthetic, sulfonamide-based anticonvulsant 1, 2 benzisoxazole-3-methanesulfon-amide dailymed.nlm.hih.gov Mechanism of Action Broad, exact MOA unknown Inhibition of voltagedependent sodium channels Inhibition of T-type calcium channels Modulation of dopaminergic system Acceleration of GABA release Protect from free oxygen radicals 3

4 FDA approved in 2000 Use in Humans Adjunctive therapy in the treatment of partial seizures in adults with epilepsy Wilfong et al., Neuropsych Disease & Treatment, 2006 Monotherapy in Humans Fujii et al Kumagai et al Hayakawa et al Seki et al Bauluc et al Study Design Prospective Prospective Prospective Prospective Multicenter, randomized, double-blind, non-inferiority trial Seizure Type Partial Partial & generalized Partial & generalized Partial & generalized Partial N Results 68% seizure free 72% seizure free 66% seizure free 82% seizure free 79.4% seizure free > 26 wks Bauluc et al, Lancet Neurol, 2012 Kumagai et al, Jpn J Psych Neurol, 1991 Hayakawa et al, J Jpn Epilep Soc, 1994 Seki et al, Seizure,

5 Pharmacokinetics in Dogs Parameter Matsumoto et al Boothe et al Fukunaga et al T max 2-3 h 2.75 h Bioavailability 68% +/- 12% Protein Binding 40% Elimination 83% renal 70% renal Elimination t 1/2 14 h 17 h h Starting dose: 5-10 mg/kg PO q12h Therapeutic dose range: ug/ml Matsumoto et al, Arzneimittelforschung, 1983 Boothe et al, J Vet Pharm Therap, 2008 Fukunaga et al, J Vet Pharm Therap, 2010 PB decreases: C max Elimination t 1/2 Bioavailability Higher starting dose (10 mg/kg) 5

6 N = 12 dogs, pharmacoresistant IE ZON 5-10 mg/kg q12h 58% positive responders Reduction or elimination of other AEDs in 75% N = 11 dogs, pharmacoresistant IE ZON 10 mg/kg q12 17m to evaluate long-term seizure control, SE 80% positive responders 6

7 N = 10 with IE ZON as first-line, 5-15 mg/kg q12h 60% positive responders Significant decrease in seizure frequency Side Effects Few sedation, ataxia, decreased appetite Dewey et al 50%: ataxia, transient vomiting, lethargy, KCS von Klopmann et al 54%: transient ataxia, sedation Idiosyncratic hepatotoxicity 7

8 Hepatotoxicity Case 1 9 yr, FS Rottweiler 3 wks after ZON initiated: vomiting, inappetence, icterus ZON discontinued clinical recovery normal liver enzymes 8wks later Case 2 4 yr, MC Boston Terrier Similar presentation 10d after initiating ZON Euthanized Necropsy: severe, subacute, massive panlobular hepatic necrosis Schwartz et al, J Vet Med Sci, 2011 Miller et al, J Vet Intern Med, 2011 Monotherapy Patient Selection Young dog with idiopathic epilepsy + no hx of bad cluster seizures, status epilepticus Structural disease elderly dog with brain tumor, dogs with meningoencephalitis **Owner concerned about SE + prefers BID administration** Cervera et al. VRUS

9 Patient Selection Add-on therapy Are other anticonvulsants maximized? Remember higher dose with PB Avoid Hepatic, renal dysfunction Hx cluster seizures, status epilepticus Monitoring, Follow-Up CBC, Chemistry every 6-12 months Therapeutic drug monitoring Not routinely performed for this AED Consider if unsatisfactory control, adding another agent mg/dl for guidance Trough ideal Auburn, Cornell 9

10 Zonisamide - Conclusions Sulfonamide-based anticonvulsant 5-10mg/kg BID Affordable Few side effects Monitoring not as important as with PB Good choice for add-on therapy and first-line agent in the right patient (anecdotal evidence) Levetiracetam (Keppra) (S)-α-ethyl-2-oxo-1- pyrrolidine acetamide Structurally unrelated to other anticonvulsants Trade name Keppra dailymed.nlm.hih.gov 10

11 Mechanism of Action Unique Brain specific binding site Synaptic vesicle protein 2A (SV2A) Modulate calciumdependent exocytosis of excitatory NTs? Lynch et al, PNAS, 2004 Noyer et al, E. J. Pharm, 1995 Mendoza-Torreblanca, et al, Eur J. Neuroscience, 2013 Adjunctive treatment Use in Humans Partial seizures in adults, children 4yr and older 3 large trials: median % reduction in seizures 18-40% Children 1m and older Myoclonic seizures, juvenile myoclonic epilepsy Primary generalized tonic-clonic seizures in adults and children with idiopathic generalized epilepsy IV formulation approved in 2006 Cereghino et al, Neurology, 2000 Shorvon et al, Epilepsia, 2000 Ben-Menachem et al, Epilepsia,

12 Monotherapy Ben-Menachem et al Alsaadi et al Brodie et al Study Design Mulicenter, double-blind, placebo-controlled, parallelgroup trial Retrospective Multicenter, double-blind, non-inferiority, parallel-group trial Methods Converted to monotherapy First-line or converted LEV or Carbamazepine monotherapy N Results 73.8% median reduction in partial seizure frequency 38% seizure free, 44% >50% reduction in seizures 73% seizure free at 6m, 57% at 12m Ben-Menachem et al, Epilepsia, 2000 Alsaadi et al, Seiz-Euro J Epilep, 2005 Brodie et al, Neurology, 2007 Pharmacokinetics in Dogs Dewey et al Patterson et al Moore et al Route, Frequency IV, single dose IV IM PO PO, single, q8h Dose (mg/kg) 60 mg/kg mg/kg mg/kg Elimination t 1/2 4 h 3 h 3 h Bioavailability 100% for IM, PO T max Starting dose: 20 mg/kg PO q8h Therapeutic dose range: 5-45 ug/ml 40 min for IM 81 min for PO Dewey et al, JVEC, 2008 Patterson et al, J. Vet Pharmacol, 2008 Moore et al, AVJR,

13 PB decreases: C max Elimination t 1/2 PB increases: Oral clearance LEV dose adjustments N = 22 dogs with pharmacoresistant IE Retrospective, n = 8 LEV mg/kg q8h added 64% positive responders Prospective, n = 14 57% positive responders after 2m at 10 mg/kg q8h Longer-term follow-up 67% increase in seizure frequency and days after 4-8m Honeymoon effect 13

14 N = 19 dogs, status epilepticus or cluster seizures IV diazepam first Randomized to IV LEV (30 or 60 mg/kg) or placebo Responder rate LEV: 56% Placebo: 10% N = 34 dogs, pharmacoresistant IE 2 treatment periods LEV 20 mg/kg PO q8h or placebo 4 week washout Crossover 22/34 completed study **No significant difference in seizure frequency during LEV administration compared to placebo** 14

15 Retrospective N = 52 dogs 29 continuous treatment 23 pulse therapy 69%: 50% or > reduction seizure freq 15%: seizure free Pulse Therapy for Cluster Seizures First Seizure or Pre-ictal Signs 60 mg/kg PO 20 mg/kg q8h For 3 days vs. Sz free for 48 hours Packer et al. BMC Vet Res

16 Side Effects Rare mild sedation, ataxia, dec appetite Dewey et al: none Hardy et al: mild ataxia Muñana et al: ataxia Patient Selection Monotherapy or adjunctive AED The very young The very old The very sedate Hepatic disease Cats No hx of status epilepticus, bad cluster seizures **Owner concerned about SE + can do TID administration** 16

17 Monitoring, Follow-Up CBC, Chemistry every 12 months Therapeutic drug monitoring Therapeutic range unknown ug/l for guidance Consider if unsatisfactory control, adding another agent Auburn, Cornell Safe to dose escalate Levetiracetam Extended Release Two canine PK studies in mg/kg BID More $ than immediate release Beasley et al. JVIM

18 Levetiracetam - Conclusions Unique MOA Favorable SE profile TID dosing standard release, BUT extended release effective Efficacy as adjunctive Monotherapy? Hospira.com Comparison of clinical outcome with zonisamide, levetiracetam or phenobarbital monotherapy in dogs with idiopathic epilepsy Inclusion criteria met n=134 Study population n = dogs excluded - lack of follow-up LEV Group n=16 LEV Group n=11 ZON Group n=35 Questionnaire Completed ZON Group n=25 PB Group n=65 PB Group n=36 18

19 Results Dogs in the PB group were younger at the time of the first seizure compared to the LEV and ZON groups (p=0.0024) Age at first seizure (years) * LEV ZON PB Antiepileptic Monotherapy Results Mean duration of therapy was similar between groups ZON: days LEV: days PB: days Seizure frequency was the most common reason for monotherapy failure in all groups 19

20 Results Dogs in the PB groups were less likely to still be on monotherapy at the time of death or end of study compared to the ZON and LEV groups (p=0.04) Number of dogs * No Yes 0 LEV ZON PB Antiepileptic Monotherapy Results Compared to the LEV and ZON groups, the PB group had a higher overall incidence of adverse effects (p=0.0001) Number of dogs * No adverse effects Adverse effects 0 LEV ZON PB Antiepileptic Monotherapy 20

21 Any adverse effect Frequency of Adverse Effects LEV (n=12) ZON (n=25) PB (n=36) P-value 17% (2) 36% (9) 78% (28) Sedation 17% (2) 32% (8) 39% (14) 0.45 Ataxia 17% (2) 12% (3) 39% (14) Polyphagia % (19) < Polydispia % (16) <0.001 Polyuria % (10) Aggression 8% (1) 4% (1) 3% (1) 0.62 Hepatotoxicit y 0 0 6% (2) 0.60 Adverse effects reported in more than one dog in the study population are included Results No difference in quality of life was identified between the treatment groups. No difference between treatment group was demonstrated for the following parameters: Seizure frequency before or after starting antiepileptic drugs Severity of cluster seizures before or after starting antiepileptic drugs 21

22 Conclusions Findings support the use of ZON and LEV as monotherapy in dogs with idiopathic epilepsy: ZON and LEV are well tolerated in dogs Incidence of adverse effects lower than previously reported Lower incidence of adverse effects than seen with PB monotherapy Results suggest that some dogs can be maintained on ZON or LEV monotherapy for a duration similar to that reached with PB Variability in length of follow-up and seizure frequency not being a primary outcome variable limit conclusions in this regard. Other Antiepileptic Drugs Potassium bromide Gabapentin Pregababalin Topiramate Felbamate Imepitoin 22

23 Aims of Treatment Maximize quality of life patient and owner Reduce seizure frequency Reduce seizure severity length, post-ictal period Improve/eliminate clusters Minimize adverse effects New Consensus Statement 2015 International Veterinary Epilepsy Task Force Consensus Reports Definitions, classification, terminology MRI protocol Therapeutic interventions, outcomes Genetic origin in purebred dogs Open access BMC Veterinary Research 23

24 Summary Phenobarbital is a great AED! BUT there are safe, effective, affordable alternatives for monotherapy and add-on therapy Consider medication, patient, AND client related factors before prescribing Questions?? 24

25 Notes: 25