Bhatti et of. BMC Veterinary Research (2015) 11:176
`DOI 10.1186/s12917-015-0464-z
`
`CORRESPONDENCE
`
`(3:c
`Veterinary Research
`
`Open Access
`
`International Veterinary Epilepsy Task Force gcms'
`consensus proposal: medical treatment of
`canine epilepsy in Europe
`
`Sofie F.M. Bhatti", Luisa De Risio2, Karen Munana3, Jacques Penderis4, Veronika M. Steins, Andrea TipoIds,
`Mette Berendt6, Robyn G. Farquhar', Andrea Fischer8, Sam Long9, Wolfgang Loscherm, Paul JJ. Mandigers",
`Kaspar Matiasek12, Akos Pakozdy13, Edward E. Patterson14, Simon Platt's, Michael Podell16, Heidrun Potschka17,
`Clare Rusbridge18''9 and Holger A. Volk2°
`
`Abstract
`
`In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years.
`Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used
`initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when
`treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED
`treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for
`dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature,
`2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe,
`and 3) reflects the authors' experience. With this paper it is aimed to provide a consensus for the management of
`canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition
`to treating the underlying cause, if possible.
`
`Keywords: Dog, Epileptic seizure, Epilepsy, Treatment
`
`Background
`In Europe, the number of antiepileptic drugs (AEDs) li-
`censed for dogs has grown considerably over the last
`years. Nevertheless, the same questions remain, which
`include, 1) when to start treatment, 2) which drug is best
`used initially, 3) which adjunctive AED can be advised if
`treatment with the initial drug is unsatisfactory, and 4)
`when treatment changes should be considered. In this
`consensus proposal, an overview is given on the aim of
`AED treatment, when to start long-term treatment in
`canine epilepsy and which veterinary AEDs are currently
`in use for dogs. The consensus proposal for drug treatment
`protocols, 1) is based on current published evidence-based
`literature [17], 2) considers the current legal framework of
`the cascade regulation for the prescription of veterinary
`
`• Correspondence: sofie.bhatti@ugentbe
`'Department of Small Animal Medicine and Clinical Biology, Faculty of
`Veterinary Medicine, Ghent University, Salisburylaan 133, Merelbeke 9820,
`Belgium
`Full list of author information is available at the end of the article
`
`drugs in Europe, and 3) reflects the authors' experience.
`With this paper it is aimed to provide a consensus for the
`management of canine idiopathic epilepsy. Furthermore,
`for the management of structural epilepsy AEDs are in-
`evitable in addition to treating the underlying cause, if
`possible.
`At present, there is no doubt that the administration
`of AEDs is the mainstay of therapy. In fact, the term
`AED is rather inappropriate as the mode of action of
`most AEDs is to suppress epileptic seizures, not epilep-
`togenesis or the pathophysiological mechanisms of epi-
`lepsy. Perhaps, in the future, the term anti-seizure drugs
`might be more applicable in veterinary neurology, a term
`that is increasingly used in human epilepsy. Additionally,
`it is known that epileptic seizure frequency appears to
`increase over time in a subpopulation of dogs with un-
`treated idiopathic epilepsy, reflecting the need of AED
`treatment in these patients [63].
`In our consensus proposal on classification and termin-
`ology we have defined idiopathic epilepsy as a disease in
`
`BiolVled Central
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`O 2015 Bhatti et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License
`(httcr.acreativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,
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`creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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`Bhatti et al. WC Veterinary Research (2015) 11:176
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`Page 2 of 16
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`its own right, per se. A genetic origin of idiopathic epilepsy
`is supported by genetic testing (when available) and a gen-
`etic influence is supported by a high breed prevalence
`(>2 %), genealogical analysis and /or familial accumulation
`of epileptic individuals. However in the clinical setting
`idiopathic epilepsy remains most commonly a diagnosis of
`exclusion following diagnostic investigations for causes of
`reactive seizures and structural epilepsy.
`
`Aims of AED treatment
`The ideal goal of AED therapy is to balance the ability
`to eliminate epileptic seizures with the quality of life of
`the patient. Seizure eradication is often not likely in
`dogs. More realistic goals are to decrease seizure fre-
`quency, duration, severity and the total number of epi-
`leptic seizures that occur over a short time span, with
`no or limited and acceptable AED adverse effects to
`maximize the dog's and owner's quality of life. Clinicians
`should approach treatment using the following paradigm
`[23, 76, 91, 92,120]:
`
`- Decide when to start AED treatment
`- Choose the most appropriate AED and dosage
`- Know if and when to monitor serum AED
`concentrations and adjust treatment accordingly
`- Know when to add or change to a different AED
`- Promote pet owner compliance
`
`When to recommend maintenance AED treatment?
`Definitive, evidence-based data on when to start AED
`therapy in dogs based on seizure frequency and type is
`lacking. As such, extrapolation from human medicine may
`be possible to provide treatment guidelines. Clinicians
`should consider the general health of the patient, as well
`as the owner's lifestyle, financial limitations, and comfort
`with the proposed therapeutic regimen. Individualized
`therapy is paramount for choosing a treatment plan. As a
`general rule, the authors recommend initiation of long-
`term treatment in dogs with idiopathic epilepsy when any
`one of the following criteria is present:
`
`- Interictal period of < 6 months (i.e. 2 or more
`epileptic seizures within a 6 month period)
`- Status epilepticus or cluster seizures
`- The postictal signs are considered especially
`severe (e.g. aggression, blindness) or last longer
`than 24 hours
`- The epileptic seizure frequency and/or duration
`is increasing and/or seizure severity is
`deteriorating over 3 interictal periods
`
`In humans, the decision regarding when to recommend
`AED treatment is based on a number of risk factors
`(e.g. risk of recurrence, seizure type, tolerability, adverse
`
`effects) [42, 115]. In people, clear proof exists that there is
`no benefit initiating AED treatment after a single unpro-
`voked seizure [42], but there is evidence to support start-
`ing treatment after the second seizure [43, 108]. In dogs,
`long-term seizure management is thought to be most suc-
`cessful when appropriate AED therapy is started early in
`the course of the disease, especially in dogs with a high
`seizure density and in dog breeds known to suffer from a
`severe form of epilepsy [12-14]. A total number of z 10
`seizures during the first 6 months of the disease appeared
`to be correlated with a poor outcome in Australian Shep-
`herds with idiopathic epilepsy [132]. Furthermore, recent
`evidence exists that seizure density is a crucial risk factor,
`experiencing cluster seizures, and being male is associated
`with poor AED response [84].
`A strong correlation exists in epileptic people between
`a high seizure frequency prior to AED treatment and
`poor AED response [16, 34, 59]. Historically, this has
`been attributed to kindling, in which seizure activity
`leads to intensification of subsequent seizures [117].
`However, there is little clinical evidence that kindling
`plays a role in either dogs [54] or humans [111] with re-
`current seizures. In humans, a multifactorial pathogen-
`esis is suggested [14, 52]. Recent epidemiologic data
`suggest that there are differences in the intrinsic severity
`of epilepsy among individuals, and these differences in-
`fluence a patient's response to medication and long-term
`outcome. Additionally, evidence for seizure-associated
`alterations that affect the pharmacodynamics and
`pharmacokinetics of AEDs have been suggested [99].
`Breed-related differences in epilepsy severity have been
`described in dogs, with a moderate to severe clinical
`course reported in Australian Shepherds [132], Border
`Collies [49, 84], Italian Spinoni [24], German Shepherds
`and Staffordshire Bull Terriers [84], whereas a less se-
`vere form of the disease has been described in a different
`cohort of Collies (mainly rough coated) [77], Labrador
`Retrievers [7] and Belgian Shepherds [45]. Consequently,
`genetics may affect the success of treatment and may ex-
`plain why some breeds are more predisposed to drug re-
`sistant epilepsy [3, 77].
`
`Choice of AED therapy
`There are no evidence-based guidelines regarding the
`choice of AEDs in dogs. When choosing an AED for the
`management of epilepsy in dogs several factors need to
`be taken into account (AED-specific factors (e.g. regula-
`tory aspects, safety, tolerability, adverse effects, drug inter-
`actions, frequency of administration), dog-related factors
`(e.g. seizure type, frequency and aetiology, underlying
`pathologies such as kidney/hepatic/gastrointestinal prob-
`lems) and owner-related factors (e.g. lifestyle, financial cir-
`cumstances)) [23]. In the end, however, AED choice is
`often determined on a case-by-case basis.
`
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`Page 3 of 16
`
`Until recently, primary treatment options for dogs
`with epilepsy have focused mainly on phenobarbital (PB)
`and potassium bromide (KBr) due to their long standing
`history, widespread availability, and low cost. While both
`AEDs are still widely used in veterinary practice, several
`newer AEDs approved for use in people are also being
`used for the management of canine idiopathic epilepsy
`mainly as add-on treatment. Moreover, since early 2013,
`imepitoin has been introduced in most European coun-
`tries for the management of recurrent single generalized
`epileptic seizures in dogs with idiopathic epilepsy.
`Several AEDs of the older generation approved for
`humans have been shown to be unsuitable for use in
`dogs as most have an elimination half-life that is too
`short to allow convenient dosing by owners, these in-
`clude phenytoin, carbamazepine, valproic acid, and etho-
`suximide [119]. Some are even toxic in dogs such as
`lamotrigine (the metabolite is cardiotoxic) [26, 136] and
`vigabatrin (associated with neurotoxicity and haemolytic
`anemia) [113, 131, 138].
`Since the 1990s, new AEDs with improved tolerability,
`fewer side effects and reduced drug interaction potential
`have been approved for the management of epilepsy in
`humans. Many of these novel drugs appear to be rela-
`tively safe in dogs, these include levetiracetam, zonisa-
`mide, felbamate, topiramate, gabapentin, and pregabalin.
`Pharmacokinetic studies on lacosamide [68] and rufina-
`mide [137] support the potential use of these drugs in
`dogs, but they have not been evaluated in the clinical
`setting. Although these newer drugs have gained consid-
`erable popularity in the management of canine epilepsy,
`scientific data on their safety and efficacy are very lim-
`ited and cost is often prohibitive.
`
`Phenobarbital
`Efficacy
`PB has the longest history of chronic use of all AEDs in
`veterinary medicine. After decades of use, it has been
`approved in 2009 for the prevention of seizures caused
`by generalized epilepsy in dogs. PB has a favourable
`pharmacokinetic profile and is relatively safe [2, 87, 97].
`PB seems to be effective in decreasing seizure frequency
`in approximately 60-93 % of dogs with idiopathic epi-
`lepsy when plasma concentrations are maintained within
`the therapeutic range of 25-35 mg/I [10, 31, 74, 105].
`According to Charalambous et al. (2014) [17], there is
`overall good evidence for recommending the use of PB
`as a monotherapy AED in dogs with idiopathic epilepsy.
`Moreover, the superior efficacy of PB was demonstrated
`in a randomized clinical trial comparing PB to bromide
`(Br) as first-line AED in dogs, in which 85 % of dogs ad-
`ministered PB became seizure-free for 6 months com-
`pared with 52 % of dogs administered Br [10]. This
`study demonstrated a higher efficacy of PB compared to
`
`Br as a monotherapy, providing better seizure control
`and showing fewer side effects.
`
`Pharmacokinetics
`PB is rapidly (within 2h) absorbed after oral administra-
`tion in dogs, with a reported bioavailability of approxi-
`mately 90 % [2, 87]. Peak serum concentrations are
`achieved approximately 4-8h after oral administration in
`dogs [2, 97]. The initial elimination half-life in normal
`dogs has been reported to range from 37-73h after mul-
`tiple oral dosing [96]. Plasma protein binding is approxi-
`mately 45 % in dogs [36]. PB crosses the placenta and
`can be teratogenic.
`PB is metabolized primarily by hepatic microsomal en-
`zymes and approximately 25 % is excreted unchanged in
`the urine. There is individual variability in PB absorption,
`excretion and elimination half-life [2, 87, 97]. In dogs, PB
`is a potent inducer of cytochrome P450 enzyme activity in
`the liver [48), and this significantly increases hepatic pro-
`duction of reactive oxygen species, thus increasing the risk
`of hepatic injury [107]. Therefore PB is contraindicated in
`dogs with hepatic dysfunction. The induction of cyto-
`chrome P450 activity in the liver can lead to autoinduction
`or accelerated clearance of itself over time, also known as
`metabolic tolerance, as well as endogenous compounds
`(such as thyroid hormones) [40, 48]. As a result, with
`chronic PB administration in dogs, its total body clearance
`increases and elimination half-life decreases progressively
`which stabilizes between 30-45 days after starting therapy
`[97]. This can result in reduction of PB serum concen-
`trations and therapeutic failure and therefore, monitor-
`ing of serum PB concentrations is very important for
`dose modulation over time.
`A parenteral form of PB is available for intramuscular
`(1M) or intravenous (IV) administration. Different PB
`formulations are available in different countries, it should
`be emphasized, however, that IM formulations cannot be
`used IV and vice versa. Parenteral administration of PB is
`useful for administering maintenance therapy in hospital-
`ized patients that are unable to take oral medication. The
`pharmacokinetics of IM PB have not been explored in
`dogs, however, studies in humans have shown a similar
`absorption after IM administration compared to oral ad-
`ministration [135]. The elimination half-life in dogs after a
`single IV dose is approximately 93h [87].
`
`Pharmacokinetic interactions
`In dogs, chronic PB administration can affect the dispos-
`ition of other co-administered medications which are me-
`tabolized by cytochrome P450 subfamilies and/or bound
`to plasma proteins [48]. PB can alter the pharmacokinetics
`and as a consequence may decrease the therapeutic ef-
`fect of other AEDs (levetiracetam, zonisamide, and ben-
`zodiazepines) as well as corticosteroids, cyclosporine,
`
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`metronidazole, voriconazole, digoxin, digitoxin, phenyl-
`butazone and some anaesthetics (e.g. thiopental) [23, 33,
`72, 82, 130]. As diazepam is used as first-line medicine for
`emergency use (e.g. status epilepticus) in practice it should
`be emphasized to double the IV or rectal dose of diazepam
`in dogs treated chronically with PB [130]. Concurrent ad-
`ministration of PB and medications that inhibit hepatic
`microsomal cytochrome P450 enzymes such as cimetidine,
`omeprazole, lansoprazole, chloramphenicol, trimethoprim,
`fluoroquinolones, tetracydines, ketoconazole, fluconazole,
`itraconazole, fluoxetine, felbamate and topiramate may
`inhibit PB metabolism, increase serum concentration and
`can result in toxicity [10].
`
`Common adverse effects
`Most of the adverse effects due to PB are dose dependent,
`occur early after treatment initiation or dose increase and
`generally disappear or decrease in the subsequent weeks due
`to development of pharmacokinetic and pharmacodynamic
`tolerance [35, 121] (Table 1). The adverse effects include
`sedation, ataxia, polyphagia, polydipsia and polyuria. For an
`in-depth review on the adverse effects of PB, the reader is
`referred to comprehensive book chapters [23, 32, 91].
`
`Idiosyncratic adverse effects
`These effects occur uncommonly in dogs and include
`hepatotoxicity [13, 22, 39, 75], haematologic abnormalities
`(anaemia, and/or thrombocytopenia, and/or neutropenia)
`[51, 56]), superficial necrolytic dermatitis [66], potential
`risk for pancreatitis [38, 46], dyskinesia [58], anxiety [58],
`and hypoalbuminaemia [41] (Table 1). Most of these
`idiosyncratic reactions are potentially reversible with dis-
`continuation of PB. For an in-depth review on the idiosyn-
`cratic adverse effects of PB the reader is referred to
`comprehensive book chapters [23, 32, 91].
`
`Laboratory changes
`Laboratory changes related to chronic PB administration in
`dogs include elevation in serum liver enzyme activities [39,
`41, 75], cholesterol and triglyceride concentrations [41]. Alter-
`ations in some endocrine function testing may occur (thyroid
`and adrenal function, pituitary-adrenal axis) [21, 41, 128]. For
`an in-depth review on these laboratory changes the reader is
`referred to comprehensive book chapters [23, 32, 91].
`
`Dose and monitoring (Fig. 1)
`The recommended oral starting dose of PB in dogs is
`25-3 mg/kg BID. Subsequently, the oral dosage is tailored
`
`Table 1 Most common reported adverse effects seen in dogs treated with PB, imepitoin and KBr (rarely reported and/or
`idiosyncratic adverse effects are indicated in grey
`AED
`
`Adverse effects in dogs
`
`PB
`
`Imepitoin
`
`KBr
`
`Sedation
`
`Ataxia
`
`Polyphagia
`
`Polydipsia/polyuria
`
`Hepatotoxicity
`
`Haematologic abnormalities
`
`Superficial necrolytic dermatitis
`
`Potential risk of pancreatitis
`
`Dyskinesia and anxiousness
`
`I I ypoalhuminaemie
`
`Polyphagia (often transient)
`Ilyperactivity. apathy, polyuria, polydipsia. hypersalivation, somnolence.
`
`vomiting, ataxia, apathy, diarrhoea, prolapsed nictitating membrane.
`
`decreased sight and sensitivity to sound
`Sedation
`
`Ataxia and pelvic limb weakness
`
`Polydipsia/polyuria
`
`Polyphagia
`
`Nausea, vomiting and/or diarrhea
`
`Personality changes (aggression, irritability, hyperactivity)
`
`Megancsophagus
`
`Persistent cough
`
`Increased risk of pancreatitis
`
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`Start PB 2.5 - 3 mg/kg BID
`
`Test serum drug concentrations 14 days after
`starting treatment or after a change in dose
`
`Adepsteselallit casiror
`
`rid seam rB < 33 sail
`
`Monitor complete blood cell
`count, biochemical profile, bile
`acid stimulation test, serum PB
`level at 3 months then every 6
`months. lithe dog is in
`remission or has no seizures:
`every 12 months.
`
`*Serum drug concentration < 30 mg/I increase PB dose using formula A
`*Serum drug concentration 30 - 35 mg/I start KBr therapy (see Figure 3)
`*Serum drug concentration > 35 mg/I reduce PB dose aiming for serum
`drug concentration < 35 mg/I and start KBr therapy (see Figure 3)
`
`Fig. 1 PB treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to start with
`PB (and add KBr if inadequate seizure control after optimal use of PB (Fig. 3)): in dogs with idiopathic epilepsy experiencing recurrent single
`generalised epileptic seizures; in dogs with idiopathic epilepsy experiencing cluster seizures or status epilepticus; in dogs with other epilepsy
`types. *Criteria for (in)adequate seizure control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic
`interventions in canine and feline epilepsy (94)). 1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom or
`extension of the interseizure interval to three times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1
`year); b: Achievement of partial treatment success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least
`50 % or more reduction defines a drug responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status
`epilepticus). 2. Treatment not tolerated i.e. appearance of severe adverse effects necessitating discontinuation of the AED
`
`to the individual patient based on seizure control, adverse
`effects and serum concentration monitoring.
`Because of considerable variability in the pharmaco-
`kinetics of PB among individuals, the serum concentra-
`tion should be measured 14 days after starting therapy
`(baseline concentration for future adjustments) or after
`a change in dose. To evaluate the effect of metabolic
`tolerance, a second PB serum concentration can be
`measured 6 weeks after initiation of therapy. Recom-
`mendations on optimal timing of blood collection for
`serum PB concentration monitoring in dogs vary among
`studies [23]. Generally, serum concentrations can be
`checked at any time in the dosing cycle as the change
`in PB concentrations through a daily dosing interval is
`not therapeutically relevant once steady-state has been
`achieved [62, 70]. However, in dogs receiving a dose of
`5 mg/kg BID or higher, trough concentrations were sig-
`nificantly lower than non-trough concentrations and
`serum PB concentration monitoring at the same time
`post-drug dosing was recommended, in order to allow
`accurate comparison of results in these dogs [70]. Another
`study recommended performing serum PB concentration
`monitoring on a trough sample as a significant difference
`between peak and trough PB concentration was identified
`in individual dogs [10]. The therapeutic range of PB in
`serum is 15 mg/1 to 40 mg/1 in dogs. However, it is the au-
`thors' opinion that in the majority of dogs a serum PB
`concentration between 25-30 mg/1 is required for optimal
`seizure control. Serum concentrations of more than 35
`mg/1 are associated with an increased risk of hepatotoxicity
`
`and should be avoided [22, 75]. In case of inadequate seiz-
`ure control, serum PB concentrations must be used to
`guide increases in drug dose. Dose adjustments can be cal-
`culated according to the following formula (Formula A):
`
`New PB total daily dosage in mg
`
`= (desired serum PB concentration/actual serum PB concentration)
`
`x actual PB total daily dosage in mg
`
`A dog with adequate seizure control, but serum drug
`concentrations below the reported therapeutic range,
`does not require alteration of the drug dose, as this
`serum concentration may be sufficient for that individ-
`ual. Generally, the desired serum AED concentration for
`individual patients should be the lowest possible concen-
`tration associated with >50 % reduction in seizure fre-
`quency or seizure-freedom and absence of intolerable
`adverse effects [23].
`In animals with cluster seizures, status epilepticus or
`high seizure frequency, PB can be administered at a
`loading dose of 15-20 mg/kg IV, IM or PO divided in
`multiple doses of 3-5 mg/kg over 24-48h to obtain a
`therapeutic brain concentration quickly and then sustain
`it [10]. Serum PB concentrations can be measured 1-3
`days after loading. Some authors load as soon as possible
`(over 40 to 60 min) and start with a loading dose of 10
`to 12 mg/kg IV followed by two further boluses of 4 to 6
`mg/kg 20 min apart.
`Complete blood cell count, biochemical profile (includ-
`ing cholesterol and triglycerides), and bile acid stimulation
`
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`test should be performed before starting PB treatment and
`periodically at 3 months and then every 6 months during
`treatment. In case of adequate seizure control, serum PB
`concentrations should be monitored every 6 months. If
`the dog is in remission or has no seizures, a periodical
`control every 12 months is advised.
`
`Imepitoin
`Efficacy
`Imepitoin was initially developed as a new AED for
`humans, but, the more favourable pharmacokinetic profile
`of imepitoin in dogs versus humans led to the decision to
`develop imepitoin for the treatment of canine idiopathic
`epilepsy [102]. Based on randomized controlled trials that
`demonstrated antiepileptic efficacy, high tolerability and
`safety in epileptic dogs, the drug was approved in 2013 for
`this indication in Europe [64, 98, 122]. It has been recom-
`mended to use imepitoin in dogs with idiopathic epilepsy
`experiencing recurrent single generalized epileptic sei-
`zures, however, its efficacy has not yet been demonstrated
`in dogs with cluster seizures or status epilepticus [30]. In a
`recent randomized controlled study [122], the efficacy of
`imepitoin was compared with PB in 226 client-owned
`dogs. The administration of imepitoin twice daily in incre-
`mental doses of 10, 20 or 30 mg/kg demonstrated that the
`majority of dogs with idiopathic epilepsy were managed
`successfully with imepitoin without significant difference
`to the efficacy of PB. The frequency of adverse events (e.g.
`sedation, polydipsia, polyphagia) was significantly higher
`in the PB group [122]. In a study by Rieck et al. (2006)
`[98], dogs with chronic epilepsy not responding to PB or
`primidone received imepitoin (in its initial formulation) or
`KBr as adjunct AED and the seizure frequency improved
`to a similar degree in both groups. According to Chara-
`lambous et al. (2014) [17], there is good evidence for
`recommending the use of imepitoin as monotherapy in
`dogs with recurrent single generalized epileptic seizures,
`but insufficient evidence for use as adjunct AED. At
`present, scientific data and evidence-based guidelines on
`which AED can best be combined with imepitoin are lack-
`ing, and further research is needed. Nevertheless, at this
`moment, the authors recommend the use of PB as adjunct
`AED in dogs receiving the maximum dose of imepitoin
`and experiencing poor seizure control. According to the
`authors, in case of combined therapy with imepitoin and
`PB, it is advised to slowly wean off imepitoin over several
`months if seizure control appears successful on PB and/or
`to reduce the dose of imepitoin if adverse effects (e.g. sed-
`ation) occur (Fig. 2).
`
`Pharmacokinetics
`Following oral administration of imepitoin at a dose of
`30 mg/kg in healthy Beagle dogs, high plasma levels
`were observed within 30 min, but maximal plasma levels
`
`were only reached after 2-3h following a prolonged ab-
`sorption time [101]. The elimination half-life was found
`to be short; approximately 1.5 to 2h. However, in an-
`other study in Beagle dogs, a longer half-life (-6 h) was
`found after higher doses of imepitoin, and accumulation
`of plasma levels was seen during chronic BID treatment
`[64]. Also, it has to be considered that Beagle dogs elim-
`inate AEDs more rapidly than other dog strains [122].
`Despite the short half-life in healthy Beagle dogs, this
`pharmacokinetic profile is reported as adequate to main-
`tain therapeutically active concentrations with twice
`daily dosing in dogs [64, 122]. Imepitoin is extensively
`metabolized in the liver prior to elimination. In dogs,
`imepitoin is mainly excreted via the faecal route rather
`than the urinary route. Neither reduced kidney function
`nor impaired liver function is likely to greatly influence
`the pharmacokinetics of imepitoin [122].
`
`Pharmacokinetic interactions and adverse reactions
`There is no information on pharmacokinetic interactions
`between imepitoin and other medications. Although,
`imepitoin is a low affinity partial agonist for the benzodi-
`azepine binding site of the GABAA receptor it has not
`prevented the pharmacological activity of full benzodi-
`azepine agonists such as diazepam in the clinical setting
`(e.g. in dogs with status epilepticus) [122). Consequently,
`because the affinity of diazepam for the GABAA receptor
`is much higher than imepitoin, care should be taken in
`the emergency setting [122]. Therefore, dogs with idio-
`pathic epilepsy treated with imepitoin and presented in
`status epilepticus might require, in addition to diazepam,
`an additional AED parenterally (e.g. PB, levetiracetam).
`Mild and most commonly transient adverse reactions
`(Table 1) have been reported in dogs administered 10-30
`mg/kg BID of imepitoin in its initial formulation; polypha-
`gia at the beginning of the treatment, hyperactivity,
`polyuria, polydipsia, somnolence, hypersalivation, em-
`esis, ataxia, lethargy, diarrhoea, prolapsed nictitating mem-
`branes, decreased vision and sensitivity to sound [64, 98].
`As part of the development of imepitoin for the treat-
`ment of canine epilepsy, a target animal safety study in
`dogs was conducted [96]. Under laboratory conditions,
`healthy Beagle dogs were exposed to high doses (up to
`150 mg/kg ql2h) of imepitoin for 6 months. Clinical
`signs of toxicity were mild and infrequent and they were
`mostly CNS (depression, transient ataxia) or gastrointes-
`tinal system (vomiting, body weight loss, salivation) re-
`lated. These clinical signs were not life-threatening and
`generally resolved within 24h if symptomatic treatment
`was given. These data indicate that imepitoin is a safe
`AED and is well tolerated up to high doses in dogs
`treated twice daily [96]. However, the safety of imepitoin
`has not been evaluated in dogs weighing less than 5 kg
`or in dogs with safety concerns such as renal, liver,
`
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`Bhatti et al. BMC Veterinary Research (2015) 11:176
`
`Page 7 of 16
`
`Start imepitoin 10 -20 mg/kg BID
`
`,111111011,
`
`
`
`Staarelaskliair
`
`Increase dose 30 mg/kg BID
`
`Adaqrshe mime ccarce
`
`Maintain dose and monitor dog
`clinically and neurologically +
`monitor complete blood cell
`count and biochemical profile
`every 6 months. If the dog is in
`remission or has no seizures:
`every 12 months.
`
`Add adjunct AED (Bather research
`necessary to decide which AED can best be
`used as adjunct ABD)N
`
`in case of combined therapy with imepitoin
`and PB, it is advised to slowly wean off
`imepitoin if seizure control appears successful
`on PB and /or to reduce the dose of imepitoin
`if adverse effects (e.g. sedation) occur.
`
`Fig. 2 Imepitoin treatment flow diagram for decision making during seizure management in an otherwise healthy dog. The authors advise to
`start with imepitoin in dogs with idiopathic epilepsy experiencing recurrent single generalised epileptic seizures. *Criteria for (in)adequate seizure
`control with regard to efficacy and tolerability (see Consensus proposal: Outcome of therapeutic interventions in canine and feline epilepsy (94)).
`1. Treatment efficacious: a: Achievement of complete treatment success (i.e. seizure freedom or extension of the interseizure interval to three
`times the longest pretreatment interseizure interval and for a minimum of three months (ideally > 1 year), b: Achievement of partial treatment
`success (i.e. a reduction in seizure frequency including information on seizure incidence (usually at least 50 % or more reduction defines a drug
`responder), a reduction in seizure severity, or a reduction in frequency of seizure clusters and/or status epilepticus). 2. Treatment not tolerated i.e.
`appearance of severe adverse effects necessitating discontinuation of the AED. 'Currently there are no data available on which AED should be
`added to imepitoin in case of inadequate seizure control. At this moment, the authors recommend the use of PB as adjunct AED in dogs
`receiving the maximum dose of imepitoin and experiencing poor seizure control
`
`cardiac, gastrointestinal or other disease. No idiosyncratic
`reactions have been demonstrated so far. The routinely
`measured liver enzymes' activity do not appear to be in-
`duced by imepitoin [96]. Compared with the traditional
`b