Addison's Disease - Including treatment with Percorten - USA (Zycortal - UK)

[Jo CIMDA]

An Addison's Up-date

The Basics: Hypoadrenocorticism – the correct term for Addison's – is caused by the adrenal glands, situated near the kidneys, failing to secrete enough glucocorticoid (primarily cortisol) and mineralocorticoid (primarily aldosterone) hormones.  In the majority of cases both types of hormone are affected.  Less commonly the problem is not with the adrenal glands but with the pituitary gland.  The pituitary secretes a hormone called adrenocorticotrophic hormone (ACTH), which regulates the adrenal secretion of cortisol and has little effect on aldosterone.  In these cases of secondary Addison's only glucocorticoid secretion is generally affected.  The secretion of aldosterone is regulated by a number of factors, but the most important is the level of potassium ions in the serum.  By far the most common cause of primary adrenal failure is autoimmune disease, but it can be the result of granulomatous disease, hemorrhage, inflammation, infarction (due to interrupted blood supply), cancer or the deposition of amyloid tissue in the adrenal glands.  Immune mediated destruction of the adrenal glands often occurs in conjunction with other autoimmune endocrine diseases such as thyroiditis (hypothyroidism), diabetes mellitus or hypoparathyroidism.  Lesions of the hypothalamus or pituitary can result from a tumor or other space occupying lesion.  Drugs given to treat hyperadrenocorticism (Cushing's disease) – mitotane, trilostane or ketoconazole – can result in Addison's due to adrenal destruction/suppression, in the case of mitotane this is not reversible, but adrenal function will usually rebound once the patient stops taking the other two drugs.  Ketoconazole is also given to treat fungal infections.  Corticosteroids, such as prednisone, suppress an animal's normal adrenal production and release of glucocorticoids, as well as causing adrenal atrophy.  This can happen within a few days, and abrupt termination of these drugs can result in symptoms of Addison's, and is by far the most common cause of secondary Addison's disease.  The biggest risk is from the long acting glucocorticoid drugs, which can suppress adrenal function for five to six weeks. 

Diagnosing Addison's is complicated by the wide range of presenting symptoms.  In some dogs there will be acute collapse, while in others symptoms come on gradually and may wax and wane, so that the owner is not really aware how sick the dog was until treatment shows a significant improvement.  85 or 90% of adrenal hormone reserves have to have been depleted before a dog will show clinical signs, and usually some stress then triggers the onset of illness.  Lack of glucocorticoids can produce loss of appetite, vomiting, lethargy/depression, weakness, weight loss, diarrhea, blood in the stool (melena), shivering, increased urination and drinking, as well as abdominal pain.  Not all dogs will show all these symptoms.  When the mineralocorticoids are also affected signs tend to be more severe with dehydration, shock and collapse accompanying the other signs.  Gastrointestinal hemorrhage and seizures (due to low blood sugar and electrolyte imbalances) are less common signs.  Heart rate slows, and pulses become weak, in some cases the heart may stop beating and death may be the first symptom. 

Blood work can be equally confusing.  The hematocrit can be increased by dehydration or show anemia. In about 20-30% of cases white cell counts will be elevated, especially eosinophil and lymphocyte numbers, a so called stress leukogram, due to decreased glucocorticoids.  If aldosterone is deficient there will be significant electrolyte abnormalities with reduced sodium and chlorine and increased potassium, calcium and phosphate.  The role of aldosterone is to increase retention of sodium and water by the kidneys.  Without it, urine is dilute and the animal easily dehydrated.  Lack of aldosterone also results in hydrogen ion retention and a mild acidosis.  Albumin (protein), cholesterol and glucose levels tend to be low, while liver enzymes may be elevated.

One study showed that 24% of dogs diagnosed with Addison's did not have classic electrolyte abnormalities, and the percentage may be higher in some breeds.  These atypical cases may be due to secondary Addison's – affecting only the pituitary or hypothalamus – or occur because the areas of the adrenal glands producing glucocorticoids only or primarily have been affected. While some cases of atypical Addison's go on to include diminished mineralocorticoid production, by no means all of them will.  Dogs with atypical Addison's tend to be older, have had a longer duration of symptoms prior to diagnosis, and be low in protein and cholesterol.

A sodium:potassium ratio of less than 27 or 28 is strongly indicative of Addison's disease, but it is only useful in dogs with mineralocorticoid involvement.  In these cases it is a powerful diagnostic tool, but not absolutely accurate (~95%). Care should be taken particularly in cases in which one electrolyte is significantly affected (high potassium, low sodium) while the other is well within the normal range or even high normal for sodium).  In cases of atypical Addison's the sodium:potassium ratio is generally completely normal, and levels of sodium and potassium well with reference ranges.

Imaging is of little value.  In typical Addison's you will generally see a smaller than normal heart and liver and narrowing of cardiac blood vessels.  The adrenal glands may also appear small, but this is subjective.  Elevated potassium will produce characteristic changes in the EKG, but are not diagnostic.  A basal cortisol of <2 micrograms/dl is 100% predictive of Addison's but not diagnostic.  To diagnose Addison's you need an ACTH stimulation test.  In this test the dog's basal serum cortisol is measured.  He is then injected with a dose of synthetic ACTH and the level of cortisol is recorded again an hour later.  (One dose of dexamethasone can have been administered prior to the test if necessary to treat a dog in crisis.) In dogs with Addison's (typical or atypical) pre and post cortisol levels are usually less than 1 mcg/dl, but should definitely be below the lab's reference range. This range can vary depending upon the laboratory doing the testing, but is usually <5mcg/dl.  Inadequate response will also be seen in dogs that have been treated for Cushing's or with glucocorticoids.  Some dogs with sex-hormone secreting adrenal tumors may also fail to respond.  The ACTH hormone is not terrifically stable, and loss of activity of the ACTH used may lead to a false diagnosis.  A borderline post ACTH level of cortisol should be retested in four to eight weeks to see if the dog was in the early stages of adrenal failure.

In cases of atypical Addison's, measuring serum ACTH can determine whether the disease is adrenal (primary, normal ACTH levels) or secondary (pituitary, subnormal levels).  The former are more likely to progress to full-blown Addison's disease, and electrolyte levels should be tested at regular intervals.  In one study of 11 dogs with atypical Addison's, only one developed mineralocorticoid deficiency although 9 of the 11 had primary (adrenal) disease, however.  Measuring plasma aldosterone does not appear to be helpful in reaching a diagnosis or distinguishing different types of Addison's disease. 

Treating Atypical Addison's disease:  Conservatively between 5 and 10% of dogs with primary hypoadrenocorticism only have a glucocorticoid deficiency.  Symptoms tend to be relatively mild and in most cases look like a gastrointestinal upset with weight loss, vomiting, loss of appetite, and – especially in small lean dogs – low blood sugar.  The ACTH stimulation test should be run in any dog with vague waxing and waning clinical signs, general malaise and weight loss. If the ACTH stimulation test result is consistent with Addison's but sodium and potassium levels are normal – atypical Addison's – glucocorticoid supplementation should be given as 0.2 to 0.4 mg/kg prednisolone a day, and electrolyte levels and general health should be monitored every three to four months for a year.  If sodium or potassium concentrations or both become abnormal the disease has probably progressed to typical Addison's.  Some veterinarians advocate measuring serum aldosterone concentrations pre and post ACTH stimulation for confirmation, but this test is not yet widely available, and has not proven particularly accurate.  Atypical Addisonian's should not receive mineralocorticoids.

Treating an Addisonian Crisis:  During an Addisonian crisis time is of the essence.  If Addison's disease is suspected in a previously undiagnosed dog in extremis, blood and urine samples should be collected for a complete blood count, serum biochemistry, serum cortisol and urinalysis prior to any treatment.  The dog is then given synthetic ACTH for the ACTH stimulation test, and blood collected an hour later for cortisol evaluation.  (If synthetic ACTH is not available it is more important to stabilize the dog, and run this test later.)  During the hour, shock doses of 0.9% sodium chloride (fluids) are given to resolve the loss of blood volume and blood pressure.  The glucocorticoid dexamethasone is given intravenously (as it doesn't affect the ACTH stim test result as oral prednisone or prednisolone would).  The dog should be kept warm to prevent or resolve hypothermia.   Mineralocorticoids are also given.  It is preferable to give desoxycorticosterone pivalate (DOCP, Percorten V) intramuscularly.  Even given daily Percorten does not produce adverse effects in healthy dogs, and so it can safely be given in suspected cases of Addisonian crisis even if this proves not to be the problem.  (Giving the drug subcutaneously is contraindicated in dehydrated dogs, which dogs in Addisonian crisis typically are, due to poor absorption.)  Florine-f – fludrocortisone acetate – may be substituted if Percorten is not available.  It has both mineralocorticoid and glucocorticoid activity, but has to be given orally and dogs in Addisonian crisis usually have significant gastrointestinal upset – vomiting, gastric bleeding – limiting assimilation.  Percorten also corrects electrolyte abnormalities better than Florine-f. After one or two hours replacement fluids are reduced to maintenance levels.  If the dog has not responded well within 24 hours, the diagnosis should be reevaluated.

Maintenance therapy:  Electrolyte levels of dogs treated with DOCP should be checked 2 weeks after the initial dose, and then at weekly intervals.  This is necessary to determine the appropriate dose between DOCP injections.  Once either potassium rises above laboratory normals or sodium drops below the laboratory reference range, or both, it is time for the next shot.  This interval can range from every two to every 8 weeks.  Novartis, the manufacturer of Percorten, recommends an initial dose of 1mg/lb body weight, but I find most dogs of Beardie size or larger do well with an initial dose of 0.5 mg/lb.  If electrolyte levels are still normal after four weeks an even smaller dose can be given the next time.  Maintenance doses can be given either subcutaneously or intramuscularly, so owners should be able to give the shots themselves to lower their costs once the dog is stabilized.  While Florine-f can be used for maintenance treatment, it does not stabilize sodium and potassium concentrations as effectively as Percorten and is more expensive for dogs weighing more than 25 lbs.  With stable dogs it is only necessary to recheck electrolytes every four to six months or if the dog becomes ill. Because Percorten has no glucocorticoid activity it is necessary to give prednisolone (Beardies tolerate the artificial drug better than prednisone) at a dose of 2.5 or 5 mg every day or every other day.  The dose must be increased if the dog is stressed or if a stressful situation is anticipated.  In this case increase the prednisolone dose two or three days before the anticipated stress – travel, visitors, hospitalization, etc. 

While Addison's is not a disease anyone would wish for, most dogs are well maintained and can expect a fairly normal life span and other diseases are usually responsible for their deaths.  Owners become especially keyed into their dogs and recognize situations that cause their dog stress and tweak drug doses accordingly.  One of the biggest risks now seems to be that anytime the dog appears not to be functioning optimally owners increase medication dose, often without consulting their veterinarian.  This response seems to be encouraged by the Internet Addison's groups.  As a result I have seen a lot of dogs over-medicated several fold.  If your dog is taking more than the recommended dose of either Percorten or Florine-f (0.015-0.2 mg/kg/day, although I have maintained Addisonian Beardies well on doses as low as 0.1 mg a day), do consider the possibility that your dog is being over-medicated.  Fortunately, there is less risk of this happening if the dog is getting Percorten injections. 

Linda Aronson, DVM   

 

 

[Jo CIMDA]

People who are looking after a dog with Addison's disease should be aware that the treatment in the UK is changing. 

A product called Zycortal is to replace Florinef. It is an injectable mineralocorticoid and it is usually given about once a month. The UK vets will have to get used to this form of replacement mineralocorticoid, so they will be learning too. 

This is not a new treatment for Addison's because it has been used under the name of  Percorten-V in the USA for a long time but it has not available in the UK unless shipped over by special licence.  Clearly, they now have got a licence to use this in the UK.  It does seem to control Addison's well once the optimum dose is established for the individual dog.

As far as I know Addisonian humans still use Florinef so it will be produced.  The problem is when a new drug comes on the market licenced for veterinary use the vet is obliged to use it,  and not the human equivalent drug without good reason and permission from the VMD (Veterinary Medicines Directorate) although that is not mentioned in the extract below.

Percorten-V is sometimes known as DOCP.  This is only a mineralocorticoid, unlike Florinef which has mineralocorticoid and a small amount of glucocorticoid (prednisolone).  This means that a glucocorticoid supplementation still has to be given and this might be on a daily basis or an every other day basis, depending on the requirements of the dog.  Also, additional pred will still have to be given in stressful situations.

I have added Linda Aronson's article about Addison's disease to the files. This gives an overview of using the injectable mineralocorticoid, and you will be able to get more information from searching the internet.

This isn't anything to become alarmed over but it will mean a new learning curve for you and your vet.

Jo


Below is an extract from a letter sent to an owner of an Addisonian dog by their vet.

As the owner of a dog with Addison's disease we are writing to inform you that there is a supply problem with Florinef tablets.  Florinef tablets are still available from human suppliers but the price has increased by 700%.  This situation is entirely out of our control.

A new veterinary licenced product, Zycortal, has recently become available.  This new  product is injectable and is given approximately every month.  Initially, regular monitoring of sodium and potassium levels will be required to ensure a smooth transition from Florinef.

We will not be stocking Florinef tablets once our current stocks run out, but we will be happy to write a prescription should you wish to carry on with this product.  However the cost increase is likely to be prohibitive.

[pp3460]

Thanks for this information Jo - I saw, only by chance, that Florinef was being stopped yesterday - Not very happy as I was at my Vets last Wednesday with Jenny and an ear infection and nothing at all was said to me - in fact I picked up 400 florinef tablets.  I am due to go back with Jenny on Wednesday so will be interested to see what they say.
I'm sure as with other owners they feel the same concern and worry over the transition for our dogs from daily tablets to a new once monthly injection - I'm very anxious having read this but very grateful to you for posting up this information as no one has said anything to me, and that concerns me a lot. 

[Jo CIMDA]

Hi

Good for you getting 400 Florinef.  I have subsequently heard that Boots are not stocking Florinef anymore, see the extract from an email to me below:

All seemed positive and working well until I took the prescription my vet gave to me to Boots. The lady I saw previously was apologetic and explained that a few days after I had been in they were instructed to remove the Florinef completely, no Boots will carry it in the future, they suggested I try the other dispensaries so I went to Sainsbury's, they said the price had been increased from £10 a hundred to £200 a hundred and they fetched their pharmacist who was distraught as her dog has Addison's and she didn't even know there was a substitute. At least I was able to tell her that.

    I then rang my vet, they were waiting to see if I was successful before having a meeting to decide what to do. Selling Florinef themselves at cost would be £185 a hundred so their decision is to stop carrying it and use the injections. They are not happy as it should be a clinical judgement not enforced by outside agencies. The cost with a dog on .8 mgs a day would be £16 per day which is a prohibitive £112 a week, even for dogs which are insured this would for some still leave a deficit or little left for any other treatments needed. Also if the gentleman in Boots is right it will probably be withdrawn anyway.     Our vets have opted reluctantly to make the change to the injection.


It seems the majority of vets are not at all happy about this enforced change and many have voiced concerns about changing to Zycortal if the dog is stable on Florinef, and has been for a while. I can't help feeling this is unethical. 

Is there anyone on the forum who knows more about this sort of procedural change enlighten us more?

FYI:  Linda Aronson, my vet friend in the US, sent this to me.  It might be useful.

Jo

"Ultimately, I think for most dogs Zycortal will control the Addison's with
fewer side-effects than the florine-f, but making everyone change over at
once is bound to cause all sorts of problems. I used to see my clients for
every fourth injection and trained them to give the i/m injections in
between, and Zycortal is given SQ so even easier for owners to administer.
You do have to fiddle a bit to begin with, but I do feel owners know their
Addisonian dogs well and can tell if they are a tad off and need a little
more pred or need the next injection.  Vet techs/nurses should be able to
deliver the shots at any rate, vets might also offer clinics if they have
enough Addisonian patients, although they rarely have more than one or at
most two patients at any given time.  I always gave one ml shots (4 mls in
the vial) and then adjusted the interval to the individual dog.  I rarely
had to retest after the first four injections.  They might need slightly
more often in the winter here, but the UK doesn't get that cold, or hot
either for that matter, and any variation usually only occurs if there is a
lot of stress in the dog's life that period."

[pp3460]

Oh gosh what a dilemma though as you said, we are being forced to make this change I have been on the Addisons Disease in Dogs page on Facebook where there are lots of comments from the UK members about this subject and some whose dogs have already moved over to Zycortal and some who are about to and are very nervous.  I'm assuming my vet doesn't yet know about it or is somehow still able to get a supply but that's bound to change - thankfully from the Facebook page I can give them some information if they don't know about it.   But it's certainly had an effect on me, I've been awake half the night.  One poor lady posted up  that her dog's been on Florinef for 11 years and doesn't want to change - it works for my Jenny now after a long time, we've finally got her stabilised on them. 

It's very bad this has one been forced on us, and two not many people seem to be aware of it.

Thanks again Jo for your help and advise, and this post. 

[Jo CIMDA]

For those who want to do some research into Zycortal, the following links may be useful:

European Medicines Agency

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/veterinary/medicines/003782/vet_med_000329.jsp&mid=WC0b01ac058008d7a8

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/veterinary/003782/WC500196486.pdf

[Jo CIMDA]

Hi

As this lady's dog has been on Florinef for 11 years there may be a case for her vet to apply for dispensation, and permission may be granted for continuing the use of Florinef.  80% of dogs do well on Zycortel, so the other 20% will have to be maintained on Florinef so special circumstances will have to be catered for.

Jo

[pp3460]

thanks i'll let her know this - also useful to know for me and Jenny if she hopefully not falls into that 20% that don't take to it.  thanks again.

[Lovemedogs]

The figures for the 80% and 20% are in a sense like experimeantal probability and hence not set in stone. ZYcortal has the identical main ingredient as found in Percorten, with just the additives being slightly different and over the last 18 years of being around Addison's dogs I can honestly say there was maybe just one dog that didn't do so well on it and it was questionable whether this was due to the way the drug was administered rather than the drug itself.
One of the distinct advantages of Zycortal for people in the UK is that it is being manufactured here, so no worries about having to import it and the worries that transport might bring with it.

Pam

[Jo CIMDA]

That's really good to know Pam.  Thank you.

Below is the link to the package leaflet for Zycortal which gives all the information needed, including dosing and monitoring.


https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2c9b766a-c36b-44aa-bbd8-24fab24ca97c&audience=consumer

Jo

[pp3460]

thanks Pam that's also good to know.  I have told a few Addison's owners about this website so hoping some will visit to have a read of it too.

[Di Jordan]

Hi
My dog has been diagnosed with Addison's disease. The vet thinks it is Atypical Addison's however he has given her Zycortal as he says this will prevent near from going into Crisis. Is this correct? She had an ACTH test and her potassium and sodium levels were ok. I am worried that she has had Zycortal ( two injections) so far. Will Zycortal harm her if she is Atypical. Which appears to be the case. Although she could be a Secondary case. How can I  discover the best treatment for her. I am worried that I have allowed the vet to treat her with Zycortal and that this is wrong. Please help Thanks Di

[Jo CIMDA]

Hi Di and welcome

When you say she could be a secondary case, has your girl has medication to lower her adrenal function (eg., treatment for Cushing's)?

I knew the answer to your question but I emailed my vet friend in the US where they have used DOCP (Zycortal equivalent) for decades, because I wanted to get you a professional opinion.  Here is her reply:

"Absolutely not, there is no value to giving a dog with atypical Addison's
Zycortal.  All that an atypical Addisonian dog needs is a low dose of
prednisolone."

I hope this helps
Jo

[Jo CIMDA]

Hi Di

I just thought I would say, if the part of the adrenal gland (zona glomerulosa) that produces aldosterone (the mineralocorticoid hormone)  is still functioning, as happens in an atypical Addisonian dog, there shouldn't be a problem with giving the Zycortal, although it is not necessary and not advised.

  If hormones are given artificially the body will automatically stop production of the naturally occurring hormone because its intelligent 'feed-back' system recognises that there is no need to produce it.   As the Zycortal influence wanes the aldosterone production, and therefore the mineralocorticoid hormone, will increase responding to the supply and demand so there should not be a problem just stopping it.

Treatment with Zycortal is very expensive in comparison to a low daily dose of prednisolone. Also why put your dog through countless monitoring and stressful visits to the vet when it is not necessary. There is no sense in giving a hormone artificially and estimating the amount required, when the dog can produce the exact amount it needs naturally.

Atypical Addisonian dogs do need monitoring every few months for the first year (clinical signs and electrolytes), but after that you will only have to be concerned if you see typical clinical signs such as going off food and diarrhoea and vomiting etc.

Jo