Switching from Epiphen to Pexion

RE: Switching from Epiphen to Pexion

Lucy Fleming — Fri, 14 Aug 2015 15:40:44 GMT

[quote user="Anthony Todd"]PS Nobody can tell me how the "recommended dose rate" is arrived at, and my citation suggests that, in babies, it is arrived at by favourable effect and more than that is not necessarily toxic as seems to be suggested here.[/quote]

Well, I would tend to say that it is the same in dogs...I would imagine there were studies of some sort regarding the dose that reduced seizure frequency in dogs. I would use that as a starting point, and monitor for seizure reduction. I've certainly tested some which have come back with a phenobarb level below the 'therapeutic range' but as they have been seizure free we have made no changes (our results actually come back from the lab with a statement to that effect!). I'm not sure anyone has suggested anything different (like aiming for a particular serum level? I would say most aim for a particular clinical effect and use serum levels to see why that may not be happening or that the expected risk of side effects is not unacceptable)

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 17:31:33 GMT

Andrew, Ha, I tried but can't see how to get the whole thing.... saved me from a red face yet again....

RE: Switching from Epiphen to Pexion

Robin Grimmer — Thu, 13 Aug 2015 17:22:47 GMT

Back to the OP. I spoke to BI re Pexion and they say it is not recommended with pre existing liver disease and there is possibility of destabilising during switch over. I spoke to Vetoquinol re Epiphen and liver disease. The serum phenobarbitone was only 22. They couldn't help me so have referred me to AHT so waiting for their reply. In the meantime the dog is doing well clinically and is almost seizure free, so will likely just carry on as we are!

RE: Switching from Epiphen to Pexion

Andrew Kent — Thu, 13 Aug 2015 17:16:06 GMT

[quote user="Anthony Todd"]

Sorry, the abstract wasn't clear to me on that point, but I accept that is what it says.

[/quote]

I agree it wasn't entirely clear and its not available online - I just had to do it the old fashioned way and dig the paper out in the library.

Andy

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 16:01:57 GMT

Sorry, the abstract wasn't clear to me on that point, but I accept that is what it says.

RE: Switching from Epiphen to Pexion

Andrew Kent — Thu, 13 Aug 2015 15:47:38 GMT

[quote user="Anthony Todd"]Sorry Andrew but I think your citation only shows that giving pheno to dogs with preexisting or co-existing liver disease exaggerates the effects of the phenobarb as the abstract suggests that the liver disease was preexisting.[/quote]

It doesn't suggest that. In this study the median duration of phenobarb treatment in the dogs was 39 months before onset of hepatic disease. All dogs had been appropriately monitored over that time and, aside from the expected enzyme induction, had shown no previous indication of impaired hepatic dysfunction.

The point of the study was to show that there was a strong association between serum pheno levels and toxicity - i.e. if you are above a certain level you may be more likely to get toxicity.

I dont understand why this should be such an alien concept - it is true of almost every pharmacological agent that we use - give enough of it and it becomes toxic. Just some drugs have a more narrow therapeutic window than others.

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 14:54:55 GMT

Sorry Andrew but I think your citation only shows that giving pheno to dogs with preexisting or co-existing liver disease exaggerates the effects of the phenobarb as the abstract suggests that the liver disease was preexisting.

[quote user="Andrew Kent"]The medical records of 18 dogs that had hepatic disease and received phenobarbital as an anticonvulsant for 5 to 82 months were reviewed.[/quote]

I think we'd all agree that the effects of barbiturates in dogs with liver disease are exaggerated but whether the barbiturates cause the liver disease doesn't seem clear to me from your citation nor is it supported by my citation??

PS Nobody can tell me how the "recommended dose rate" is arrived at, and my citation suggests that, in babies, it is arrived at by favourable effect and more than that is not necessarily toxic as seems to be suggested here.

RE: Switching from Epiphen to Pexion

Andrew Kent — Thu, 13 Aug 2015 14:13:57 GMT

[quote user="Anthony Todd"]

Sorry, but there's also this:

J Vet Intern Med. 2000 Mar-Apr;14(2):165-71.

Effects of long-term phenobarbital treatment on the liver in dogs.

Müller PB1, Taboada J, Hosgood G, Partington BP, VanSteenhouse JL, Taylor HW, Wolfsheimer KJ.

And cherry picking gives this:

These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.

...

I can't work out whether the dogs in your citation were on phenobarb concurrently with their liver disease and cancer or whether this developed after the phenobarb started.

[/quote]

I think we have all agreed that phenobarbitone induces liver enzyme elevation and that is not the same as being toxic.

However hepatotoxicity is reported in dogs on phenobarbitone (as the paper I posted previously shows) usually at doses that are excessive.

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 12:40:06 GMT

Sorry, but there's also this:

J Vet Intern Med. 2000 Mar-Apr;14(2):165-71.

Effects of long-term phenobarbital treatment on the liver in dogs.

Müller PB1, Taboada J, Hosgood G, Partington BP, VanSteenhouse JL, Taylor HW, Wolfsheimer KJ.

And cherry picking gives this:

...

I can't work out whether the dogs in your citation were on phenobarb concurrently with their liver disease and cancer or whether this developed after the phenobarb started.

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 12:27:27 GMT

[quote user="Anthony Dennison"]

Couple of issues with you using this paper Anthony.

1) Its in babies. Generally this means there is another cause of the seizures compared to the majority of cases we see in veterinary medicine, which are idiopathic.

2)Its in babies. Not animals.

[/quote]

Sorry]

As I said, all I was trying to get across was the idea that the dosage of pheno [and probably most drugs] is determined, not by toxicity, but by reaching the desired effect, as in the paper I quoted.

Nothing to do with aetiology.

What seems to be to be happening in this thread is the conviction that any blood level over the recommended therapeutic dose is, by definition, toxic.

It should really just be an indication of [probably] an adequate or effective dose, not necessarily of impending toxicity.

[Could be helpful in ensuring that the beast is actually getting the bloody stuff as well!!]

I do realise that babies may be different from dogs and that injections may give higher blood levels.

[Gee, I'll bet the injections hurt unless they were I/V]

RE: Switching from Epiphen to Pexion

Andrew Kent — Thu, 13 Aug 2015 11:37:29 GMT

[quote user="Anthony Todd"]I still can't see why a dose over this rate is therefore, no argument but no evidence, "toxic" just that it is a higher dose-rate than usually stops fits in the dog [that's if the study has ever been done][/quote]

Its based on a few older studies, an example of which is below, where the majority of dogs that developed toxicity to phenobarb had serum levels greater than 40 mcg/ml.

J Am Vet Med Assoc. 1991 Oct 15;199(8):1060-6.

Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989).

Dayrell-Hart B1, Steinberg SA, VanWinkle TJ, Farnbach GC.

Author information

Abstract

The medical records of 18 dogs that had hepatic disease and received phenobarbital as an anticonvulsant for 5 to 82 months were reviewed. Clinical signs included sedation and ataxia in all dogs, 5 dogs were also anorectic, 2 had coagulopathy, 3 were icteric, and 5 had ascites. Serum biochemical analysis revealed serum albumin concentration less than or equal to 2.2. g/dl in 12 dogs, serum alkaline phosphatase activity greater than or equal to 169 U/L in 18 dogs, serum alanine transaminase activity greater than or equal to 57 U/L in 15 dogs, and total bilirubin concentration greater than or equal to 1 mg/dl (in the absence of lipemia) in 7 dogs. Serum phenobarbital concentration was greater than or equal to 40 micrograms/ml in 12 of 17 dogs. Sulfobromophthalein excretion was prolonged in 8 of 10 dogs. Preprandial serum bile acid concentrations were high in 8 of 10 dogs, and 2-hour postprandial serum bile acid concentrations were high in 9 of 10 dogs. Two of 4 dogs tested had resting plasma ammonia concentrations greater than 200 mg/dl. An ammonia tolerance test was performed on 2 other dogs; both had ammonia concentration greater than or equal to 200 mg/dl in the plasma 30 minutes after receiving 100 mg of ammonium chloride/kg of body weight, PO. Nine dogs died, 1 was euthanatized, and necropsies were performed on these 10 dogs. Biopsies and necropsies of 6 dogs revealed chronic hepatic fibrosis with nodular regeneration (cirrhosis). One dog had hepatocellular carcinoma and mild cirrhosis. In 1 dog, after phenobarbital had been withheld, necropsy revealed complete recovery of the previously observed lesions.

RE: Switching from Epiphen to Pexion

Anthony Dennison — Thu, 13 Aug 2015 11:06:34 GMT

[quote user="Anthony Todd"]

The relationship of the initial phenobarbital dose to weight, gestational age, blood level, and seizure control was studied in 39 neonates. The blood level was proportional to the dosage per kilogram, and was not related to weight or gestational age. Seizures remitted only at blood phenobarbital concentrations above 16.9 pg per milliliter. Therapeutic levels can be achieved by the intravenous or intramuscular administration of 16 to 23 mg per kilogram of phenobarbital.

From:

doi: http://dx.doi.org/10.1212/WNL.29.11.1445Neurology November 1979 vol. 29 no. 11 144

Which I interpret as "the therapeutic dose rate is the minimum dose which was about right for stopping the fits in 39 babies" and I guess that the dose rate was decided in the dog after a similar experiment or research, if it was was ever done.

[/quote]

There's a difference between serum levels and the amount administered via injection. Couple of issues with you using this paper Anthony.

1) Its in babies. Generally this means there is another cause of the seizures compared to the majority of cases we see in veterinary medicine, which are idiopathic.

2)Its in babies. Not animals.

RE: Switching from Epiphen to Pexion

Thomas Johnson — Thu, 13 Aug 2015 10:56:33 GMT

[quote user="Anthony Todd"]

We have got no evidence of genuine phenobarbitone toxicity, just the idea that if the blood level is above the "recognised" therapeutic level it must be toxic and the dose rate must be reduced.

There seems to be evidence that phenobarb is a pretty non-toxic drug, in reasonable dosages [I know enough will kill anything]

Still confused [and I wonder how many dogs are now still fitting or worse because of this sanction?]

[/quote]

The therapeutic range for phenobarbital given by Idexx is very wide at 10-40mg/L. I generally find that when I blood sample a dog with presumed idiopathic epilepsy that is being effectively treated with phenobarbitone I get a result between 10 and 20mg/L. If the result is below 10mg/L, but the dog is not having seizures, then I wouldn't increase the dose.

If the dog's seizures are not being controlled by the phenobarbitone and the blood levels are less than 40mg/L, then I will consider increasing the dose. My understanding is that once you get serum concentrations over 40mg/L there are two concerns, one is that there is an increased risk of side-effects, the other is that if it's not working at that dose, further increases are unlikely to make it more effective.

Also you generally need to give a very big dose to achieve serum levels over 40mg/L. The starting dose from the Epihen datasheet is 1-2.5mg/kg twice daily. Until recently I was treating a 20kg dog with 180mg twice daily, so 9mg/kg twice daily. Its serum levels were just below 40mg/L. So using an upper limit of 40mg/L is unlikely to stop you giving big doses of phenobarbitone if necessary

RE: Switching from Epiphen to Pexion

Anthony Todd — Thu, 13 Aug 2015 10:22:47 GMT

[quote user="Anthony Dennison"]No - you can get liver disease if you are giving the dog toxic level of phenobarb.[/quote]

Sorry for the usual incoming accusation of "turbo posting" but this cherry picked summary from the medicos seems to summarise what I'm getting at.

From:

doi: http://dx.doi.org/10.1212/WNL.29.11.1445Neurology November 1979 vol. 29 no. 11 144

I still can't see why a dose over this rate is therefore, no argument but no evidence, "toxic" just that it is a higher dose-rate than usually stops fits in the dog [that's if the study has ever been done]

So it has nothing to do with toxicity!

What is the LD50 of phenobarb iin the dog?

We have got no evidence of genuine phenobarbitone toxicity, just the idea that if the blood level is above the "recognised" therapeutic level it must be toxic and the dose rate must be reduced.

There seems to be evidence that phenobarb is a pretty non-toxic drug, in reasonable dosages [I know enough will kill anything]

Still confused [and I wonder how many dogs are now still fitting or worse because of this sanction?]

RE: Switching from Epiphen to Pexion

Michael Woodhouse — Thu, 13 Aug 2015 09:41:15 GMT

[quote user="Andrew Kent"]You definitely need to continue the pexion whilst starting the phenobarbitone, the short half life of pexion and delay in full onset of phenobarb means if you stop pexion now the dog is likely to seizure before the phenobarb is on board.[/quote]

If the Pexion is doing nothing (or very little) for these dogs seizures how about stopping it, and going for a loading phenobarb protocol?

RE: Switching from Epiphen to Pexion

Anthony Dennison — Thu, 13 Aug 2015 09:07:46 GMT

[quote user="Anthony Todd"]So it's actually the change in liver function indicators etc rather than overt liver disease that is the basis for the dire warnings about liver toxicity and not overt liver disease?[/quote]

No - you can get liver disease if you are giving the dog toxic level of phenobarb. If you are within an acceptable dose range, there will be activation of cytochrome P450 by phenobarb - which causes a mild hepatopathy and sbsequent rise in serum liver enzymes.

You will get changes detectable by dynamic liver function tests before the dog comes in Simpsons yellow will a giant, painful liver. The dynamic testing means we can do something about liver disease before it comes untreatable.

[quote user="Anthony Todd"]

I just wanted to stop the dog fitting on the minimum dose that stopped the fits, no bloods, no problems and if they continued to fit on high [ie stupifying doses, even with KBr] then nothing helped ever and they were sadly euthanased.

This was mainly in sudden onset elderly animals as I recall.

[/quote]

Well that sounds like structural intracranial changes, like a mass of some sort if it was refractory to treatment, especially in older dogs.

RE: Switching from Epiphen to Pexion

Anthony Todd — Wed, 12 Aug 2015 13:24:56 GMT

[quote user="Robin Grimmer"]Re Liver blood tests, you're right that phenobarbitone will induce liver enzymes, so you check for markers of liver function like bile acids, albumin etc.[/quote]

So it's actually the change in liver function indicators etc rather than overt liver disease that is the basis for the dire warnings about liver toxicity and not overt liver disease?

If you read the reference I quoted:

http://livertox.nih.gov/Barbiturates.htm

It appears that the barbiturates aren't very toxic at all so, as I said, I'm confused???

This was mainly in sudden onset elderly animals as I recall.

RE: Switching from Epiphen to Pexion

Andrew Kent — Wed, 12 Aug 2015 13:17:21 GMT

[quote user="Anthony Todd"]Surely there are fitting dogs controlled perfectly on less phenobarb than the recommended "therapeutic" levels , so you may be overdosing patients unnecessarily[/quote]

Yes, thats why I said:

[quote user="Andrew Kent"]The purpose of monitoring serum levels of phenobarbitone is to avoid toxicity, not to assess efficacy. Different dogs will be controlled on different doses so we tend to gradually increase the dose until the desired control is achieved[/quote]

I don't use serum levels to monitor efficacy, I use them to avoid toxicity, not all dogs need to be up to a therapeutic levels, but we should aim to keep all dogs out of the toxic level.

[quote user="Anthony Todd"]in a patient still fitting but with "therapeutic" blood levels of pheno what do you do? Just let them fit on? Increase the dose? [my solution]? Add another agent? Still fitting, then what?[/quote]

If you have a dog that is still fitting and at the top end of the therapeutic range then increasing the pheno further is unlikely to improve efficacy but will increase the chance of toxicity, so both the most efficacious (in terms of combining different mechanisms of action) and safest thing is to add another drug.

[quote user="Anthony Todd"]Are you basing "toxicity" purely on the elevated liver enzymes and not on overt signs of liver disease?[/quote]

No generally on other markers of hepatic function and, ideally, liver biopsy.

[quote user="Anthony Todd"]You then say "there is not always a direct relationship between dose and serum levels" so why bother even taking a sample?[/quote]

Because I can't guess, from the dose, how close a dog may be to the toxic level. A poor relationship is a better reason to check levels not a worse.

[quote user="Anthony Todd"]Certainly confusing me......[/quote]

I actually think we are basically saying the same thing here. The most important aspect of monitoring phenobarb is the clinical efficacy But, we can improve the safety and guide dose adjustments based on the serum level. They work together.

There will always be a ceiling effect to the clinical benefit of the drug so a blind dose increase is not always the answer, especially as we now have a wide variety of options for management of seizures in out patients.

Andy

RE: Switching from Epiphen to Pexion

Robin Grimmer — Wed, 12 Aug 2015 13:04:29 GMT

[quote user="Anthony Todd"]

[quote user="Andrew Kent"]So we are treating the dog, but using the levels to improve safety, as toxic levels may not be clinically apparent until the dog develops severe disease.[/quote]

Surely there are fitting dogs controlled perfectly on less phenobarb than the recommended "therapeutic" levels , so you may be overdosing patients unnecessarily and, alternatively, in a patient still fitting but with "therapeutic" blood levels of pheno what do you do? Just let them fit on? Increase the dose? [my solution]? Add another agent? Still fitting, then what?

As it appears, apart from the one case quoted which may not even have been related to the phenobarb dose, and other sources eg the PS I cited, that suggest that phenobarb isn't toxic apart from raised liver enzymes it seems far more sensible to give the dose of phenobarb which controls the fits rather than the "therapeutic dose" based on a blood value which may or may not control the fits and as you go on to say may not be related to the dose!! [see below]

Are you basing "toxicity" purely on the elevated liver enzymes and not on overt signs of liver disease?

You then say "there is not always a direct relationship between dose and serum levels" so why bother even taking a sample?

Certainly confusing me......

[/quote]

Yes there are definitely some dogs that do well on dose of phenobarbitone below the quoted therapeutic range. If a dog is well controlled then you might consider a dose reduction. This way you can often find the lowest effective dose and in some cases even withdraw treatment.

The problem is in some dogs that require very high doses of phenobarbitone and may be refractory to treatment. This is where blood levels are useful in predicting likelihood of liver damage. In these cases you wouldn't increase the dose but usually add another drug, classically KBr, but other options are available now eg leveriticam.

Re Liver blood tests, you're right that phenobarbitone will induce liver enzymes, so you check for markers of liver function like bile acids, albumin etc.

RE: Switching from Epiphen to Pexion

Anthony Todd — Wed, 12 Aug 2015 12:28:38 GMT

[quote user="Andrew Kent"]So we are treating the dog, but using the levels to improve safety, as toxic levels may not be clinically apparent until the dog develops severe disease.[/quote]

Are you basing "toxicity" purely on the elevated liver enzymes and not on overt signs of liver disease?

You then say "there is not always a direct relationship between dose and serum levels" so why bother even taking a sample?

Certainly confusing me......

RE: Switching from Epiphen to Pexion

Andrew Kent — Wed, 12 Aug 2015 10:53:45 GMT

[quote user="Anthony Todd"]

By "monitoring blood values" and ensuring "acceptable" or recommended blood values you may be overdosing, or are you saying that you won't control fitting unless you have some sort of arbitrary blood value.

Isn't this another example of treating the blood value rather than the patient?

[/quote]

The purpose of monitoring serum levels of phenobarbitone is to avoid toxicity, not to assess efficacy. Different dogs will be controlled on different doses so we tend to gradually increase the dose until the desired control is achieved. However we monitor serum levels because above a certain level the chance of toxicity increases (and we have seen hepatotoxicity when at toxic levels), and therefore a combination of drugs may be warranted.

So we are treating the dog, but using the levels to improve safety, as toxic levels may not be clinically apparent until the dog develops severe disease.

[quote user="Anthony Todd"]Has anyone ever seen or heard of clinically significant liver disease following any adequate dose regime of phenobarb or steroids, or is this an example of treating a blood value rather than the patient?[/quote]

I am not convinced that significant liver disease occurs in dogs with appropriate serum levels of phenobarbitone, but that is not the same an an adequate dose regime as there is not always a direct relationship between dose and serum levels.

[quote user="K Burton"]I was just about to write a post re: Pexion when I found this stream! I've got a patient with presumed idiopathic epilepsy (had Ix inc MRI) who was started on Pexion by the referral centre. It's been on Pexion since April and had no reduction at all in seizure frequency so I'm currently starting it on pheno. However myself and one of my colleagues have been given conflicting advice from the 'Pexion people' about changing over from Pexion to pheno. I was told to keep going on same dose Pexion until therapeutic pheno levels documented, then grad wean off by 25% per month (similar to the protocol for switching pheno to Pexion). One of my colleagues was told the Pexion can just be stopped as soon as pheno started, with no need to taper or wait until pheno bloods fine. Would appreciate other vet's experiences on this matter. Thanks.[/quote]

You definitely need to continue the pexion whilst starting the phenobarbitone, the short half life of pexion and delay in full onset of phenobarb means if you stop pexion now the dog is likely to seizure before the phenobarb is on board.

I would start phenobarb for 2 weeks, then check serum levels, then wean the pexion.

You may find the dog has more significant side effects whilst on both drugs (sedation, ataxia, polyphagia etc).

Andy

RE: Switching from Epiphen to Pexion

Kathryn Burton — Wed, 12 Aug 2015 10:39:36 GMT

I was just about to write a post re: Pexion when I found this stream! I've got a patient with presumed idiopathic epilepsy (had Ix inc MRI) who was started on Pexion by the referral centre. It's been on Pexion since April and had no reduction at all in seizure frequency so I'm currently starting it on pheno. However myself and one of my colleagues have been given conflicting advice from the 'Pexion people' about changing over from Pexion to pheno. I was told to keep going on same dose Pexion until therapeutic pheno levels documented, then grad wean off by 25% per month (similar to the protocol for switching pheno to Pexion). One of my colleagues was told the Pexion can just be stopped as soon as pheno started, with no need to taper or wait until pheno bloods fine. Would appreciate other vet's experiences on this matter. Thanks.

RE: Switching from Epiphen to Pexion

Anthony Todd — Tue, 11 Aug 2015 19:25:02 GMT

[quote user="robloxley"]What do you mean by 'adequate'?[/quote]

The minimum daily dose that will control the seizures, by reference to the patient rather than the blood value.

We all have seen cases that continue to fit even on unacceptably high doses of phenobarb!

Isn't this another example of treating the blood value rather than the patient?

And this doesn't answer my question, only says that excessive phenobarb may, just may, be the cause of liver disease.

We've been here before with the "steroid toxicity" where everyone in the family was dosing the dog, therefore steroids in therapeutic doses were toxic.....

RE: Switching from Epiphen to Pexion

Rob Loxley — Tue, 11 Aug 2015 18:50:33 GMT

[quote user="Anthony Todd"]Has anyone ever seen or heard of clinically significant liver disease following any adequate dose regime of phenobarb[/quote]

What do you mean by 'adequate'?; I saw a dog a few years back that was on an 'adequate' dose of pheno to control it's seizures, but presented pretty ill and yellow with a very high pheno level and sky high liver figures as the owners had just upped and upped the dose of pheno...

[quote user="Anthony Todd"]is this an example of treating a blood value[/quote]

I'm therefore keen to monitor the blood values

RE: Switching from Epiphen to Pexion

Anthony Todd — Tue, 11 Aug 2015 13:53:41 GMT

PS this seems relevant??

http://livertox.nih.gov/Barbiturates.htm