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FDA New Animal Drug Application for Prascend Sept 2011

 
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PostPosted: Sat Jun 23, 2012 5:43 pm    Post subject: FDA New Animal Drug Application for Prascend Sept 2011  Reply with quote

FDA New Animal Drug Application for Prascend Sept 2011:

http://www.fda.gov/downloads/Anim...s/FOIADrugSummaries/UCM280354.pdf

Suggests a review of literature supports a starting dose of 2 mcg/kg with a dose range of 2-4 mcg/kg once daily (2 mcg/kg = 1mg for a 500 kg horse, 4 mcg/kg = 2 mg for a 500 kg horse), but acknowledges that in the literature doses from 0.6 to 10 mcg/kg were used.  Whilst many horses do appear to do well on these doses, there are horses on doses up to 10 mg/day (ECIR Group).

The USP 2007
http://vetmed.tamu.edu/common/docs/public/aavpt/pergolide.pdf
recommends a starting dose of 2 mcg/kg, increasing to 6-10 mcg/kg if no response is seen, and cites research using doses of 3 mg (Sgorbini et al. 2004, Munoz et al. 1996), 1.7-5.5 mcg/kg (Donaldson et al. 2002), 4-5 mg (Williams 1995).

An effectiveness study was carried out using 122 horses aged 10 to 35 diagnosed with PPID by presence of regional hirsutism plus either ACTH 50 pg/ml or more or DST cortisol 1 mcg/dl or more (Nov to Jan).  All horses, regardless of their symptoms or diagnostic test results, were started on 2 mcg/kg BW Prascend per day.

There is no mention of the initial dose being tapered, so presume it was introduced at 2 mcg/kg.

At day 90 all horses had diagnostic tests repeated.  42% of the horses still had abnormal results (ACTH > 50 pg/ml, DST cortisol > 1 mcg/dl), and had their dose of Prascend doubled to 4 mcg/kg BW.

Treatment success was based on either an improvement in endocrine testing plus a slight improvement in clinical signs or no improvement in endocrine testing but a reasonable improvement in clinical signs.  The clinical signs graded were hirsutism, hyperhidrosis, polyuria/polydipsia, abnormal fat distribution and muscle wasting.

76% were considered treatment successes at day 180 (58% on 2 mcg/kg BW, 42% on 4 mcg/kg BW, following their results at day 90).  8 horses died during the 180 days due to worsening of pre-existing conditions (laminitis, dental disease, septic tenosynovitis) or colic.

32% of horses showed improvement in hirsutism at day 90, 89% at day 180.
27% showed improvement in hyperhidrosis at day 90, 42% at day 180.
31% showed improvement in PU/PD at day 90, 34% at day 180.
21% showed improvement in abnormal fat distribution at day 90, 33% at day 180.
36% showed improvement in muscle wasting at day 90, 46% at day 180.

Only 20 horses had ACTH monitored.  Mean baseline ACTH was 73.53 pg/ml, decreasing to 51.12 pg/ml at day 90 and 45.08 pg/ml at day 180.
73.53 pg/ml is not a high ACTH level for a horse with PPID – it’s perhaps not surprising that these low doses of pergolide appeared to be effective.  It would be interesting to see how effective these doses were on horses with much higher ACTH concentrations.

93 horses had DST cortisol monitored.  Mean baseline DST cortisol was 3.12 mcg/dl, decreasing to 1.39 mcg/dl at day 90 but then increasing to 1.47 mcg/dl at day 180.  (NB if horses were included in the trial in January, 180 days later may have been in July, so going into the seasonal rise – this may have affected test results at 180 days).

Mean insulin was 483 pmol/L (69.6 µIU/ml) before treatment, decreasing to 319 pmol/L (45.9 µIU/ml) but remained above the reference range (300 pmol/L (43.2 µIU/ml)).

Although lab dependent, fasting insulin > 20 µIU/ml is generally considered indicative of insulin resistant and therefore not normal.  The fact that mean insulin remained above the reference range after treatment with Prascend  implies that the dose was not sufficient to control insulin resistance - a higher dose may have had a greater effect.  Controlling insulin resistance, and therefore the risk of laminitis, is surely one of the main aims of treating PPID.

Side effects reported included:
Decreased appetite – 33% - decreased appetite at one or more meals, usually transient and occurring during the first month of treatment, but some horses experienced sporadic inappetance throughout the study.  Only 2 horses had a temporary reduction in their dose (despite this being suggested in the UK Prascend data sheet).
Lameness – 18%
Diarrhea/loose stools – 10%.  One case of diarrhea was related to Potomac Horse Fever, the other 11 cases were mild and self-limiting.
Colic – 10% - 3 of 12 colics were severe (strangulating lipoma, large colon volvulus) and unlikely to be related to treatment with Prascend.  The other colics were mild and resolved with treatment.
Lethargy – 10%.  Lethargy was not reported in any of the horses before starting treatment, despite being a clinical sign of PPID.
Abnormal weight loss – 9% - more than half the horses experienced weight loss, but it was only considered abnormal in 9%.  2 of these horses lost between 22 and 45 kg, and 3 lost more than 45 kg.  In most cases of weight loss, the losses were noted to be healthy changes in body composition.  Perhaps explained by a reduction in insulin resistance?
Laminitis – 8% - 3 new cases and 7 pre-existing, recurring cases
Heart murmur – 8%
Death – 7% - due to worsening of pre-existing conditions (laminitis, dental disease, septic tenosynovitis) or colic.
Tooth disorder – 7%
Skin abscess – 6%
Musculoskeletal pain – 5%
Behaviour change – 5% - included kicking, aggression, agitation, nervous behaviour and increased activity.  One horse required a temporary reduction in dose due to energetic behaviour.

The study concludes that Prascend is effective for the control of clinical signs associated with PPID, and that adverse reactions include inappetance, weight loss, lethargy and behavioural changes.

No control group was used because of the ethics of not treating horses known to have PPID.  However when monitoring the side effects noted, it would surely have been useful to compare the incidence of similar clinical signs in an age/management matched non-PPID group of horses - without this, how can the clinical signs shown be attributed to the Prascend?

A further 180 day study was undertaken to evaluate the safety margin of Prascend using healthy – non-PPID – horses.  32 healthy horses aged 3 to 10 years were used.  Group 1 received no Prascend, group 2 4 mgc/kg BW, group 3 6 mcg/kg BW (1.5 x the suggestesd dose) and group 4 8 mcg/kg BW (2 x the suggested dose).  All horses started at 4 mcg/kg for 14 days, then those on the higher doses were given 6 mcg on day 15 and 8 mcg/kg on day 31.

Effects noted.
One horse had mild colic on day 3 – although in the 6 mcg/kg group, on day 3 it was receiving 4 mcg/kg.
One 6 mcg/kg horse has mildly icteric sclera (jaundiced eyes) and GGT of 74 U/L on day 90, returning to normal by day 90/180.  One control horse had GGT of 73 on day 60.
Prascend treated groups had lower mean heart rates and higher mean temperatures than the control group.  The heart rates all remained within normal range.  The temperatures all remained below 101.5’F.

The study concludes that Prascend is safe when administered at a dose of up to 4 mcg/kg once daily.  But as no adverse affects were reported in the higher dose groups, surely this study shows that Prascend is safe when administered at a dose of up to 8 mcg/kg in healthy horses?  

Are trials on healthy horses relevant to horses with PPID?  

A leading researcher suggested that he would not assume that PPID horses would be more tolerant of pergolide than normal horses, and that it is just as likely that the absence of endogenous dopamine might result in hypersensitivity of dopaminergic nerve terminals and make PPID cases even more sensitive to dopamine agonists - we simply don't know.

Pergolide is not a new treatment for PPID in horses.  It has been used since at least 1982 (Orth et al.) at recorded doses up to 10 mcg/kg without reported adverse effects.  Owners currently have their horses on higher doses than 10 mcg/kg.  In his August 2011 webinar for Prascend “Diagnostic Challenges in Equine Endocrine Disease”, Andy Durham said that different horses need different doses, it can be a question of playing around with the dose and carrying out further diagnostic testing to see if the pergolide is working.  He said that he currently had horses on anything from 1-2 mg/day up to 8 mg/day.
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PostPosted: Mon Feb 22, 2016 6:23 pm    Post subject: Reply with quote

http://www.fda.gov/downloads/AnimalV/UCM280354.pdf

In the USA BI have marketing exclusivity for Prascend for 5 years from 07 Sept 2011.

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