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ADVICE SUMMARY
APPLICATION FOR REGISTRATION OF A CHEMICAL PRODUCT
Product name: VETORYL 120 MG CAPSULES
Applicant: DERMCARE-VET PTY LTD
Product number: 60618
Application number: 38577
Purpose of Application and Description of Use: Registration of a 120mg/capsule trilostane encapsulated granule product for the treatment of pituitary
dependant and adrenal dependant hyperadrenocorticism (Cushing's syndrome) in dogs, in conjunction with the approval of the new
active trilostane (HATR/60618).
Active Constituent(s): TRILOSTANE
Regulatory Decision:
To grant the application subject to the following conditions:
Standard Conditions of Registration/Approval
For full conditions, refer to http://www.apvma.gov.au/advice_summaries/adv_summaries.shtml.
«appl_num» Page 1 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
ADVICE
Australian Government Department Of Health And Ageing, Office Of Chemical Safety
The Office of Chemical Safety (OCS) of the Department of Health and Ageing has assessed the toxicological risk aspects of trilostane in Vetoryl 120mg
Capsules (60618) as the primary product. Vetoryl 60mg Capsules (60619) and Vetoryl 30mg Capsules (60620) are secondary applications for registration of
products and the advice is relevant to these appklications. Trilostane has a low acute oral toxicity and is expected to be of low acute dermal and inhalational
toxicity, the product(s) are thus expected to have low acute oral, dermal and inhalational toxicity. In chronic studies, the main organs affected were the liver
and the adrenal glands. Trilostane was not carcinogenic in mice or rats nor was trilsotane considered to be an in vivo mutagen. Reproduction and developmental
studies showed that maintenance of pregnancy was affected by of continued administration through pregnancy. The label has been amended to mititgate the
risks.
The report was forwarded to the National Drugs and Poisons Schedule Committee (NDPSC), which considered the application and decided that trilostane be a
new entry to Schedule 4 of the Poisons Schedule.
The OCS report recommends that from a toxicological viewpoint, the approval of the active constituent trilostane be supported; the registration of Vetoryl
120mg Capsules (60618) is supported. No ADI or ArfD was required to be set for trilostane, as the product is for use in non-food producing species only. First
Aid Instructions were recommended.
Data relied on to provide the advice
Inherited
Data Data Author(s) Title Date Data Type Data Sub-type Authorising Application
No Source* Party No.
7667 S Lape H. Win 24,540 - summary of antihypertensive 4 May Metabolism and Laboratory Animals Applicant
activity in the renal, spontaneous, and adrenal- 1967. Kinetics
regeneration hypertensive rat. Progress Report:
Endocrinology.
7666 S Harding H., Fairburn A comparison of the effects of Trilostane and 8 Aug Metabolism and Laboratory Animals Applicant
M and Shane H.P. Spironolactone or urinary electrolytes in 1978. Kinetics
frusemide-treated intact rats and
deoxycorticosterone acetate (DOCA)-treated
adrenalectomised rats. Progress Report:
Endocrinology
7691 S Baker, J. F., Disposition of Trilostane in the Rat and Monkey. 1980 Metabolism and Laboratory Animals Public
Benzinger, D., Kinetics
Chalecki, B. W.,
«appl_num» Page 2 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
C1emens, S., Fritz, A.,
O'Melia, P.E.,
Shargel, L. and
Edelson, J.
7665 S Harding H.R., The reversal of frusemide-induced kalurensis 23 Oct Metabolism and Laboratory Animals Applicant
Fairburn M.E., associated with the reduction of Aldosterone and 1975. Kinetics
Creange J.E., Atkins Corticosterone in the rat by Win 24,540.
D., Warren C. and Progress Report: Endocrinology.
Potts G.O.
7689 S Davison C., Kline R., Distribution and Excretion Studies with Carbon 20 Feb Metabolism and Laboratory Animals Applicant
Biddlecome C. and Labelled Win 24,540. 1975. Kinetics
Fritz A.
7664 S Harding H.R., Tymon The reversal of frusemide-induced urinary 22 May Metabolism and Laboratory Animals Applicant
T. and Potts G.O. potassium loss by Win 24,540. Progress Report: 1974. Kinetics
Endocrinology.
7687 S Baker J.F. Biotransformation of Win 24,540 in the Rhesus 6 Dec Metabolism and Laboratory Animals Applicant
Monkey ll. Excretion and Urinary Metabolite 1976. Kinetics
Distribution Following Oral Administration
7663 S Harding H.R., Gauven Increased urinary excretion and potassium 3 Apr Metabolism and Laboratory Animals Applicant
B.R. and Potts G.O. retention in sodium deficient rats given Win 1970. Kinetics
24,540 orally. Progress Report: Endocrinology
7685 S Shargei L., Balfour Plasma Kinetics and Excretion of (14C) Win 17 Jun Metabolism and Laboratory Animals Applicant
K.G. and Fritz A. 24,540 in the Monkey after Intravenous 1975. Kinetics
Medication.
7662 S Harding H.R., Rogers Screening of Win 24,540 for effects of urinary 28 Oct Metabolism and Laboratory Animals Applicant
JE. and McConnell N electrolytes (SC415). Progress Report: 1965. Kinetics
Endocrinology.
7683 S McGee J.P. and Shaw Factors affecting the intestinal absorption of 1991 Metabolism and Laboratory Animals Public
P.N. trilostane in rats Kinetics
7661 S Creange J.E. Soloff Reversible inhibition by Win 24,540 of 18 Sep Metabolism and Laboratory Animals Applicant
M.S. and Potts G.O. aldosterone excretion in rats maintained on a low 1969 Kinetics
sodium diet. Progress Report: Endocrinology.
7681 S Suzuki, M., Mori, Y., Study on metabolites of Trilostane, an inhibitor 1979 Metabolism and Laboratory Animals Public
Tsuboi, M. and of Adrenal steroidogenesis. Kinetics
Tatematsu, A.
7660 S Creange J.E. and Effect of Various Derivatives and Metabolites of 1 Jun Metabolism and Laboratory Animals Applicant
Anzalone AJ Win 24,540 on 3ß-hydroxysteroid 1979 Kinetics
dehydrogenase Activity In Vitro on Pregnancy in
Rats (SC417B) and on General Endocrine
«appl_num» Page 3 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Balance in Female Rats (SC413C). Progress
Report: Endocrinology.
7679 S Schane H.P., Potts Inhibition of ovarian, placental, and adrenal 1978 Metabolism and Laboratory Animals Public
G..O and Creange J.E. steroidogenesis in the rhesus monkey by Kinetics
trilostane.
7659 S Creange J.E. and IP 24540: Lack of effect of trilostane on in vitro 23 Aug Metabolism and Laboratory Animals Applicant
Schane H.P. conversion of cholesterol to pregnenolone or 1977. Kinetics
conversion of progesterone to corticoid
hormones. Progress Report: Endocrinology.
7677 S Harding H.R., Reduction in blood glucose levels in alloxan 11 Mar Metabolism and Laboratory Animals Applicant
Schanck G., Diamond diabetic rats following oral treatment with Win 1977. Kinetics
D. and Schane H.P. 24,540 (trilostane). Progress Report:
Endocrinology.
7658 S Creange J.E, Norton Relative lack of effect on ovarian progestin 9 Oct Metabolism and Laboratory Animals Applicant
LF, Soloff M.S. and production. Progress Report: Endocrinology. 1969. Kinetics
Potts G.O.
7672 S Schane H.P., Hormonal activity of Win 24,540 (4a, 5a-epoxy, 1 Oct Metabolism and Laboratory Animals Applicant
Anzalone A.J. and 17ß-hydroxy-3-oxoandrostane-2-carbonitrile). 1975. Kinetics
Potts G.O Progress Report: Endocrinology.
7671 S Bentley H and Aceto Screening of Win 24540 for effects on 09/2005 Metabolism and Laboratory Animals Applicant
M reserpine-induced eyelid ptosis in mice. Kinetics
7641 S Ryan W.T. and Potts Effect of Win 24,540 on Experimentally induced 1963 Metabolism and Laboratory Animals Applicant
G.O. urinary nitrogen loss (SC411-D). Kinetics
7669 S Brown TG Screening of Win 24540 for cardiovascular 09/2005 Metabolism and Laboratory Animals Applicant
effects in monkeys. Kinetics
7656 S Creange J.E. and Potts Kinetics of the blockade by Win 24,540 of rat 9 Oct Metabolism and Laboratory Animals Applicant
G.O. adrenal 3ß-hydroxysteroid dehydrogenase. 1978. Kinetics
Progress Report: Endocrinology
7690 S Shargei L, Balfour Distribution and Excretion of (14C) Win 24,540 26 Mar Metabolism and Laboratory Animals Applicant
KG and Fritz A in Rat and Monkey. 1975. Kinetics
7655 S Creange J.E., Ryan Win 24540: The Effect of Three months Oral 13 Nov Metabolism and Laboratory Animals Applicant
WT, and Potts G.O. Administration of Win24540 to Rats Upon 1967. Kinetics
Various Organ weights, Upon Plasma and
Adrenal Corticosterone Content, Upon Urinary
Excretion of 17-Ketosteroids and Corticoids and
Upon Activity of the 3ß-hydroxysteroid
Dehydrogenase-Isomerase System in
Subsequently Isolated Testicular Microsomes
Progress Report: Endocrinology.
«appl_num» Page 4 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
7688 S Baker J.F., Jensen Biotransformation of Win 24,540 in the Rhesus 28 Jun Metabolism and Laboratory Animals Applicant
A.F., O'Melia P.E., Monkey III. Isolation and Structural Study of the 1978. Kinetics
Hlavac A. and Three Major Urinary Metabolites.
Clemans S.
7650 S Ryan W.T., Reckman Effect of Win 24,540 (4a, 5a-epoxy, 17ß- 12 Oct Metabolism and Laboratory Animals Applicant
J. and Potts G.O hydroxy-3-oxoandrostane-2-carbonitrile) alone 1965. Kinetics
and in combination with ACTH on plasma
corticosteroid levels of the mature male guinea
pig. Progress Report: Endocrinology.
7684 S McGee, J.P., and The pharmacokinetics of Trilostane and Keto- 1992 Metabolism and Laboratory Animals Public
Shaw, P.N. trilostane in an interconverting system in the rat. Kinetics
7649 S Ryan W.T., Reckman Effect of Win 24,540 on the weights of the 29 Mar Metabolism and Laboratory Animals Applicant
J. and Potts G.O adrenal and thymus upon the urinary excretion of 1965. Kinetics
17-ketosteroids and l7-ketogenic steroids in
response to ACTH. Progress Report:
Endocrinology
7680 S Shargei L., Balfour Blood levels and Excretion of Radioactivity by 20 Jun Metabolism and Laboratory Animals Applicant
K.G., Chalecki B.W. Rat after Intravenous Medication. 1975 Kinetics
and Fritz A.K.
7648 S Ryan W.T. and Potts The effects of Win 24,540 (4a, 5a-epoxy, 17ß- 7 Apr Metabolism and Laboratory Animals Applicant
GO. hydroxy-3-oxoandrostane-2-carbonitrile) on the 1964. Kinetics
organ weights of the intact mature male guinea
pig. Progress Report: Endocrinology.
7673 S Potts GO and Bentley Screening of Win 24540 for antifertility activity 09/2005 Metabolism and Laboratory Animals Applicant
DL in rats Kinetics
7647 S Harding H.R., Effect of the induction of liver tryptophan 12 Oct Metabolism and Laboratory Animals Applicant
Maxstadt J.1. and pyrrolase in cold stressed rats. Progress Report: 1964. Kinetics
Potts G.O. Endocrinology.
7668 S Friemann, J.A. and Effects of Trilostane in Normotensive and 1985 Metabolism and Laboratory Animals Public
Muller, K.M. Hypertensive rats Kinetics
7646 S Harding H.R., Duration of blocking on the induction of liver 31 Aug Metabolism and Laboratory Animals Applicant
Maxstadt J.J. and tryptophan pyrrolase by ACTH. Progress Report: 1964 Kinetics
Potts G.O. Endocrinology.
7686 S Baker J.F., Chalecki Biotransformation in the Rhesus Monkey: I 11 Jun Metabolism and Laboratory Animals Applicant
B.W., O'Melia P.E. Isolation and preliminary identification of the 1976. Kinetics
and Clemans S. major urinary metabolites following oral
administration of Win 24,540-14C.
7645 S Maxstadt J. and The effect of the adrenal blocking agent Win 16 Jun Metabolism and Laboratory Animals Applicant
Harding H.R. 24,540 (4,5 epoxy, 17-hydroxy-3-oxoandrostan- 1964. Kinetics
«appl_num» Page 5 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
2carbonitrile) on the induction of liver
tryptophan pyrrolase (TPO) by ACTH and
cortisol. Progress Report: Endocrinology.
7678 S Zacek M Effect of Win 24540 and Win 31540 on in vitro 9 Mar Metabolism and Laboratory Animals Applicant
prostaglandin dehydrogenase from rat stomach. 1978. Kinetics
Progress Report: Endocrinology.
7644 S Ryan W.T. and Potts Effects on separate and concurrent 16 Jun Metabolism and Laboratory Animals Applicant
G.O administration of Win 24,540 and ACTH to 1964. Kinetics
Immature and Mature Hypophysectomised Male
Rats. Progress Report: Endocrinology.
7682 S Mori, Y., Tsuboi, M, Studies on the metabolism of Trilostane, an 1981 Metabolism and Laboratory Animals Public
Suzuki, E., Saito,A. inhibitor of Adrenal steroidogenesis. Kinetics
and Ohnishi, M.
7670 S Martin R and Aceto Influence of ACTH (adrenocorticotrophic 6 Oct Metabolism and Laboratory Animals Applicant
MD hormone) plus Win 24540 on the overt 1967. Kinetics
behaviour of the rat.
7692 S Robinson, D.T., The Bioavailability and Metabolism of 1984 Metabolism and Laboratory Animals Public
Earnshaw, R.J., Trilostane in Normal Subjects, A Comparative Kinetics
Mitchell, R., Powles, Study Using High Pressure Liquid
P., Andrews, R.S. and Chromatographic and Quantitative Cytochemical
Robertson, W.R. Assays
7643 S Ryan W.T., Reckman Effect of Win 24,540 on adrenal ascorbic acid 25 Nov Metabolism and Laboratory Animals Applicant
J. and Potts G.O concentration and corticosteroid concentrations 1965. Kinetics
of plasma and adrenals of the ACTH rat.
Progress Report: Endocrinology.
7642 S Ryan W.T. and Potts Effects on Rat Plasma and Adrenal 31 Jan Metabolism and Laboratory Animals Applicant
G.O Corticosterone Responses to an Acute ACTH 1964 Kinetics
Challenge. Progress Report: Endocrinology
7657 S Creange J.E. and IP24540: Kinetics of trilostane action: a re- 26 Sep Metabolism and Other Information Applicant
Schane H.P. examination. Report: Progress Report: 1978 Kinetics
Endocrinology.
7699 S Gumaer K.L. and Acute Oral Tolerance Study in Mongrel Dogs 17 Apr Toxicology Acute Oral Studies, Applicant
Drobeck H.P. Treated Orally with Win 24,540. 1969. Active
7697 S Duprey L.P., Drobeck Acute Oral Toxicity of Win 24,540 in the Mouse 19 Jan Toxicology Acute Oral Studies, Applicant
H.P., Filler R.N. and and Rat. 1970. Active
Farinacci J.V.
7698 S Rennie M., Gumaer Acute Oral Tolerance Study in New Zealand 31 Jul Toxicology Acute Oral Studies, Applicant
K1 and Drobeck H.P. White Rabbits with Win 24,540. 1967. Active
7740 S Brean W.G. and A Twenty-four Month Oral Carcinogenicity 30 Mar Toxicology Carcinogenicity Applicant
«appl_num» Page 6 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Rinehart W.E Study of Win 24,540 in Rats. Project No 75- 1979. Studies
1285. Final Report
7739 S Hogan G.K. and An Eighteen Month Oral Carcinogenicity Study 19 Sep Toxicology Carcinogenicity Applicant
Rinehart W.E. of Win 24,540 in Mice. Project No. 76-1694. 1979. Studies
Final Report:
7703 S Owen S.D., Donikian Chronic Oral Administration of Win 24,540 to 1 Nov Toxicology Chronic Studies Applicant
M.R., Wiland J., Albino Rats for 18 months. 1976.
Fabian R.J. and
Drobeck H.P.
7708 S Donikian M.R., Owen Oral Administration of Win 24,540 to Rhesus 1 Jun Toxicology Chronic Studies Applicant
S.D., Gumaer KI and Monkeys for One Year 1976.
Drobeck H.P.
7704 S Creange J.E. and Adrenal Blocker: Circulating Corticosterone and 29 Jun Toxicology Chronic Studies Applicant
Schane H.P. Aldosterone Levels in Albino Rats after 18 1976
Months of Daily Oral Treatment with Win
24,540.
7676 S Benziger D. and Effects of Win 24,450 on microsomal protein 15 Dec Toxicology Chronic Studies Applicant
Chalecki B. and hepatic drug metabolising enzymes in the 1975.
monkey. Progress Report: Endocrinology.
7651 S Creange J.E., Harding Plasma cortisol and electrolyte levels in monkeys 24 May Toxicology Chronic Studies Applicant
H.R. and Schane H.P. during chronic treatment with Win 24,540. 1976.
Progress Report: Endocrinology
7730 S Owen S.D., Brown Oral Administration of Win 24,540 to Pregnant 09/2005 Toxicology Developmental Applicant
G.L., Clemens G.R., New Zealand White Rabbits: Assessment of (Teratology) Studies
Bradford J.C., Neidl teratogenic potential.
M.J. and Drobeck
H.P.
7728 S Owen S.D., Bradley Oral Administration of Win 24,540 to Pregnant 19 Dec Toxicology Developmental Applicant
D.J., Hunt C.E., Albino Rats-Second Experiment. 1974. (Teratology) Studies
Bradford J.C. and
Drobeck H.P.
7729 S Owen S.D., Bradford Oral Administration of Win 24,540 to Pregnant 19 Apr Toxicology Developmental Applicant
J.C., Clemens G.R. Albino Rats - Third of Three Experiments. 1976. (Teratology) Studies
and Drobeck H.P
7727 S Owen S.D., Bradley Oral Administration of Win 24,540 to Pregnant 3 Dec Toxicology Developmental Applicant
D.J., Hunt C.E., Albino Rats: Assessment of teratogenic potential. 1974 (Teratology) Studies
Bradford J.C. and
Drobeck H.P.
7731 S Le Roux P.A., Inhibition of progesterone secretion with 2002 Toxicology Developmental Public
«appl_num» Page 7 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Tregoning S.K., Zinn trilostane for mid-trimester termination of (Teratology) Studies
P.M., van der Spuy pregnancy: randomized controlled trials.
Z.M.
7735 S Mehmood Z., Connel Trilostane - Mouse Micronucleus Test. Report 10 Mar Toxicology Genotoxicity Applicant
J. and Fisher C. No: ANV 024/032477. 2003. (Mutagenicity)
Studies
7736 S Collins P In vitro Mammalian Cell Cytogentic Test: 24 Jul Toxicology Genotoxicity Applicant
Chinese Hamster Ovary Cells. Final Report: 2003 (Mutagenicity)
Study Number: FOV0002. Studies
7734 S Brusick, D.J., and Final report L5178Y - mouse lymphoma 26 Jan Toxicology Genotoxicity Applicant
Weir, R.J. mutagenicity assay 1977. (Mutagenicity)
Studies
7732 S Suzuki, S., Endo, Y., Biological effects of Trilostane in vitro on 1984 Toxicology Genotoxicity Public
Miura, Rand Iizuka, oocyte maturation and fertilization in the (Mutagenicity)
R. hamster. Studies
7733 S Brusick, D.J. and Final report L5178Y - mutogenicity plate assay 23 Dec Toxicology Genotoxicity Applicant
Weir, R.J. 1976 (Mutagenicity)
Studies
7737 S Weale P Bacterial Reverse Mutation Test. Study Number: 2002 Toxicology Genotoxicity Applicant
Final Report: Study No.: FOV0001. 9 Oct 2002. (Mutagenicity)
Sequani Limited, UK. Studies
7738 S Mehmood Z Trilostane: In vivo DNA repair (UDS) test using 10 Aug Toxicology Genotoxicity Applicant
rat hepatocytes. Report No: ANV 025/042905 2004 (Mutagenicity)
Studies
7722 S Greco DS and Corticosteroid withdrawal syndrome. 1995. Toxicology Other Information Public
Behrend EN. .
7716 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 120 mg 2005 Toxicology Other Information Applicant
Veterinary Products, capsules. From August 2004 to February 2005.
UK Arnolds Veterinary Products, UK
7723 S Gallagher J Adresten Capsules: A statistical analysis of the 2001 Toxicology Other Information Applicant
clinical data (of Ref 81: Clinical Case review
and statistical analysis).
7871 S Taylor, M.A. Expert Report on Safety, updated report for 2005 Toxicology Other Information Applicant
Mutual Recognition Procedure
7711 S Anon. Arnolds Pharmarovigilance Report. Vetoryl 60 mg 2002 Toxicology Other Information Applicant
Veterinary Products, capsules. From licensing (August 2001) to
UK February 2002. Arnolds Veterinary Products,
UK
7870 S Anon. Veterinary Assessment Report perfomed by the Veterinary 2005 Toxicology Other Information Applicant
«appl_num» Page 8 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Medicines Directorate Medicines Directorate, UK, on "Vetoryl
30,60&120mg Capsules" under the Mutual
Recognition process.
7712 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2002 Toxicology Other Information Applicant
Veterinary Products, capsules. From February 2002 to August 2002.
UK Arnolds Veterinary Products, UK
7721 S Hurley KJ Protocol for the use of trilostane in canine 09/2005 Toxicology Other Information Applicant
hyperadrenocorticism (of Ref 81: Clinical Case
review and statistical analysis).
7713 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2003 Toxicology Other Information Applicant
Veterinary Products, capsules. From August 2002 to February 2003.
UK Arnolds Veterinary Products, UK
7720 S Anon. Royal Clinical Case review and statistical analysis. 2001 Toxicology Other Information Applicant
Veterinary College, Royal Veterinary College, UK.
UK.
7872 S Anon. European The Rules governing medicinal prodcuts in the 2004 Toxicology Other Information Public
Commission European Union. Volume 6B: Ntoice to
Applicants: Presentation and contents of the
dossier for registration of Veterinary Medicinal
Products.
7764 S Kibbe AH Extracts from Handbook of Pharmaceutical 2000 Toxicology Other Information Public
Excipients.
7715 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 120 mg 2003 Toxicology Other Information Applicant
Veterinary Products, capsules. From launch (October 2002) to
UK February 2003. Arnolds Veterinary Products,
UK
7714 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2005 Toxicology Other Information Applicant
Veterinary Products, capsules. From August 2004 to February 2005.
UK Arnolds Veterinary Products, UK
7726 S Owen S.D., Brown Perinatal-Postnatal Study in Albino Rats Treated 12 Apr Toxicology Reproduction Studies Applicant
G.L., Bradford J.C., Orally with Win 24,540. 1977.
Clemens G.R. and
Drobeck H.P. (
7725 S Owen S.D., Brown Fertility and Reproductive Performance of Male 12 Nov Toxicology Reproduction Studies Applicant
G.L., Montenaro M.J., Albino Rats Treated Orally with Win 24,540. 1976.
Bradford J.C.,
Clemens G.R. and
Drobeck H.P.
7724 S Owen S.D., Bradley Fertility and Reproductive Performance of 09/2005 Toxicology Reproduction Studies Applicant
«appl_num» Page 9 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
D.J., Bradford J.C., Female Albino Rats Treated with Win 24,540.
Hunt C.E. and
Drobeck H.P.
7718 S Anon. Winthrop Evaluation of the Oral Toxicity of Trilostane. 1987 Toxicology Short-term Studies Applicant
Research Centre, (Win 24,540) After Being Administered for 3
France. Months to the Beagle Dog. Report
7700 S Owen S.D., Hunt Oral administration of Win 24,540 to Albino 30 Sep Toxicology Short-term Studies Applicant
C.E., Donikian M.R., Rats for three months. 1969.
Taylor P.L. and
Drobeck H.P
7719 S Gallagher J. Adresten Capsules: A statistical analysis of the May Toxicology Short-term Studies Applicant
original tolerance study (Ref 79: Evaluation of 2001.
the Oral Toxicity of Trilostane. (Win 24,540)
After Being Administered for 3 Months to the
Beagle Dog).
7705 S Schane H.P. and Reversal and Prevention of Adrenal Hypertrophy 15 Jun Toxicology Short-term Studies Applicant
Anzalone A.J in the Rat Following Oral Administration of 1979.
Trilostane ((2a, 4a, 5a, 17ß)-4,5-Epoxy-17-
hydroxy-3-oxoandrostane-2-carbonitrile).
Progress Report: Endocrinology.
7717 S Emanuel A. Vetoryl: A 12 week oral toxicity study in beagle 16 Dec Toxicology Short-term Studies Applicant
dogs. Final Report 2002-3072. 2003.
7675 S Hemandez P. and Effect of prolonged pre-treatment with Win 24 Aug Toxicology Short-term Studies Applicant
Rogers J.E. 24,450 on the drug metabolising capacity of rats. 1967.
Report:
7758 S Belchetz, P. E., Davis, Problems with Trilostane. 1981 Toxicology Studies in Humans Public
J. C., Diver, M. J. and
Hipkin, L J.
7757 S Tueni E., Endocrine effects of Trilostane: in vitro and in 1987 Toxicology Studies in Humans Public
Devleeschouwer N., vivo studies.
Lec1ercq G., Nijs M.,
Coune A., Vermeulen
A., Paridaens R.
7760 S Winterberg, B. and Therapy of Primary Aldosteronism with 1983 Toxicology Studies in Humans Public
Vetter, H. Trilostane.
7742 S Komanicky, P., Spark, Treatment of Cushings syndrome with Trilostane 1978 Toxicology Studies in Humans Public
R.F., and Melby, J.C (Win 24,540) an inhibitor of adrenal steroid
biosynthesis.
7759 S Chu PS, Buzdar AU, Trilostane with Hydrocortisone in treatment of 1989 Toxicology Studies in Humans Public
«appl_num» Page 10 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
and Hortibagyi GN Metastatic Breast Cancer.
7744 S Hollifield, J.W., A new adrenal inhibitor effective in the treatment 1975 Toxicology Studies in Humans Public
McKenna T.J., Wolff of. primary aldosterism.
J.M., Chick W.T. and
Liddle G.W
7749 S Bianchine, JR Phase 1 Acute Tolerance study - Final clinical 09/2005 Toxicology Studies in Humans Public
summary Win 24,540.
7746 S Nomura, K., Demura, Concomitant falls of plasma cortisol and ACTH 1984 Toxicology Studies in Humans Public
H., Imaki, T., levels in a case of Cushings disease during
Miyagawa, M., Ono, treatment with Trilostane.
M., Yano, T. and
Shizume, K.
7750 S Winterberg B., Vetter Primary aldosteronism: treatment with trilostane. 1985 Toxicology Studies in Humans Public
W., Groth H.,
Greminger P., Vetter
H.
7748 S Dewis, P., Anderson, Experience with Trilostane in the treatment of 1983 Toxicology Studies in Humans Public
D.C., Bullock, D.E., Cushing's syndrome.
Earnshaw, R. and
Kelly, W.F.
7756 S Shigetomi, S., The Effect of Trilostane, a New Inhibitor of 1982 Toxicology Studies in Humans Public
Fukuchi, S., Adrenal Steroid Biosynthesis, on Blood
Haruyama, K. and Pressure, Plasma Aldosterone and other Steroid
Yamazaki, M. Hormones Serum Potassium and Plasma Renin
Activity in Primary Aldosteronism.
7762 S Semple CG, Trilostane and the normal Hypothalmic- 1982 Toxicology Studies in Humans Public
Thompson JA, Stark Pituitary-Adrenocorticoid Axis.
AN, McDonald M and
Beastall GH
7751 S Darling J.A.B. and Treatment of Cushing's Disease in Childhood 1981 Toxicology Studies in Humans Public
Frase N.C. with Trilostane.
7743 S Hollifield, J.W., A new adrenal inhibitor effective in the treatment 1975 Toxicology Studies in Humans Public
McKenna T.J., Wolff of primary aldosterism.
J.M., Chick W.T. and
Liddle G.W
7752 S Williams C.J., Barley Multicenter study of trilostane: a new hormonal 1987 Toxicology Studies in Humans Public
V., Blackledge G., agent in advanced postmenopausal breast cancer.
Hutcheon A., Kaye S.,
Smith D., Keen C.,
«appl_num» Page 11 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Webster D.J.,
Rowland C., Tyrrell
C.
7747 S Semple, C.G., Trilostane in the management of Cushings 1983 Toxicology Studies in Humans Public
Beastall, G.H., Gray, Syndrome.
C.E., and Thomson,
J.A
7753 S Dorrington-Ward, P., Trilostane as cause of Addisonian crisis. 1981 Toxicology Studies in Humans Public
Carter, C., Banks, R.,
and MacGregor, G
7745 S Nomura, K., Demura, Long term treatment of idiopathic 1986 Toxicology Studies in Humans Public
H., Horiba, N. and hyperaldosteronism using Trilostane
Shizume, K.
7763 S Anon . Sterling- Side effects of Trilostane in the treatment of 1988 Toxicology Studies in Humans Applicant
Winthrop Research post menopausal advanced breast cancer:
Institute, NY.. Analysis of side effects.
7761 S Nakada, T., Primary Aldosteronism Treated by Trilostane 1985 Toxicology Studies in Humans Public
Yoshikawa, M., 3ß-hydroxysteroid dehydrogenase inhibitor.
Kazama, T., Ishikawa,
S., Koike, H. and
Katayama, T.
7754 S Barnes, N. and Overdose of Trilostane. 1983 Toxicology Studies in Humans Public
Thomas, N.
7755 S Beardwell CG, Hormonal changes in postmenopausal women 1985 Toxicology Studies in Humans Public
Hindley AC, with breast cancer treated with trilostane and
Wilkinson PM, St dexamethasone.
John J, Bullock D
7741 S Port CB, Bowen JM, Effects of a 3ß-hydroxysteroid dehydrogenase 2000 Toxicology Studies of Other Public
Keyes PL, Townson inhibitor on monocyte-macrophage infiltration Special Effects
DH into rat corpus luteum and on apoptosis:
relationship to the luteolytic action of prolactin.
7709 S Jungmann E., Althoff The inhibiting effect of trilostane on testosterone 1983 Toxicology Sub-chronic Studies Public
P .H., Balzer-Kuna S., synthesis. Hormonal and morphologic alterations
Magnet W., induced by sub chronic trilostane treatment in
Rottmann-Kuhnke D., rats and healthy volunteers.
Sprey R., Schwedes
D., Dsadel K.H. and
Schoffling K.
7706 S Sillence M.N. and Age- and sex-dependent stimulation of growth 1987 Toxicology Sub-chronic Studies Public
«appl_num» Page 12 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Rodway R.G. rate in rats by the adrenal inhibitor trilostane.
7707 S Jungmann E., Magnet The inhibiting effect of trilostane on adrenal 1982 Toxicology Sub-chronic Studies Public
W., Rottmann-Kuhnke steroid synthesis: hormonal and morphological
D., Sprey R., alterations induced by subchronic trilostane
Schwedes D., Usadel treatment in normal rats.
K.H. and Schoffling
K.
7701 S Donikian M.R., Owen Chronic Oral Administration of Win 24,540 in 2 Apr Toxicology Sub-chronic Studies Applicant
S.D., Fabian R.J. and Albino Rats. Six Month Interim Report. 1975.
Brobeck H.P
7710 S Jungmann E., Althoff Effects of subchronic low-dose trilostane 1983 Toxicology Sub-chronic Studies Public
P .H., Balzer-Kuna S., treatment on the hormonal response to insulin-
Magnet W., Rosak C induced hypoglycemia.
and Schoffling K.
7702 S Shargei L. and Hepatic Drug Metabolizing Enzyme Activities 10 Feb Toxicology Sub-chronic Studies Applicant
Balfour K.G. in .the Albino Rat after Six months Treatment 1975.
with Win 24,540.
Australian Government Department Of Environment, Water, Heritage and the Arts
The then Department of the Environment and Heritage (DEH) (now the Department of the Environment, Water, Heritage and the Arts) conducted a VICH Phase1
assessment as per the Environmental Impact Assessment (EIAs) for Veterinary Medicinal Products Phase 1 VICH Guideline 6, to assess the possible environmental
impact from the use of trilostane in Vetoryl 120mg Capsules (60618) as the primary product application and Vetoryl 60mg Capsules (60619) and Vetoryl 30mg
Capsules (60620) as secondary applications for registration of products. Environmental exposure will be primarily through excretion of residues in faeces and urine
of treated animals onto soil. Aquatic contamination is considered unlikely. DEH advised that although soil contamination could be quite high where an individual
animal was repeatedly contaminating, any effects on soil organisms such as earthworm or other terrestrial invertebrates or soil microorgansisms is likely to be in
isolated patches with re-colonisation from neighbouring non-contaminated soil as the compound dissipates. No reaction to the main sex steroid receptors occurs in
vertebrates but potential endocrine disruption in invertebrates is unknown. The product is manufactured overseas and the packaging will minimise accidental release
into the environment.
In considering the proposed use pattern the DEH has concluded that the environmental risk is likely to be acceptable under the proposed pattern and likely levels of
use.
«appl_num» Page 13 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
External Efficacy Reviewer
The application to approve the active constituent trilostane and register the product Vetoryl 120mg Capsules (60618), containing trilostane has been treated as
the primary application. The registration of two additional strength capsule products, Vetoryl 60mg Capsules (60619) and Vetoryl 30mg Capsules (60620)
have been considered as secondary applications.
Trilostane antagonises the activity of adrenocorticotropic hormone (ACTH) in the disease entities pituitary-dependent and adrenal-dependent
hyperadrenocortiscism (Cushing’s syndrome) in dogs. It works to block the production of the glucocorticoids (cortisol and corticosterone) and aldosterone.
An external reviewer evaluated data presented by the applicant to support safety and efficacy of the proposed product. The supportive safety data consisted of
five target animal safety studies (key margin of safety studies 7842, 7843 & 7845 plus related data elements for statistical analysis 7844, 78848 and trial
protocol 7846) and clinical field studies which were for both safety and efficacy (studies 7856 and 7845). Other data relied on were pharmacovigilance reports
from Suspected Adverse Reaction reporting (SARs) in the UK where the product has been registered for a number of years (data 7836, 7837, 7838, 7839, 7840
& 7841).
Hyperadrenocorticism is a severe, life-threatening illness due to the effects of the presence of too much cortisol on the body. Many body systems are affected.
Reduction in cortisol production (and the related chemicals cortisone and aldosterone which are all needed for homeostais) would therefore be expected to have
possible adverse effects resulting in hypoadrenocorticism should the cortisol become too low or affect the production of related chemicals. Some modifications
of the proposed product label based on findings of the safety studies were necessary to mitigate risk.
Because of absence of laboratory models for hyperadrenocorticism, efficacy studies were appropriately carried out under field conditions. The pivotal
supportive clinical field trial data (studies 7855, 7856 & 7857) to confirm dose and provide evidence of effectiveness for the treatment of
hyperadrenocorticism in dogs consisted of prospective multicentric field trials in several geographical locations and demonstrated effectiveness and safety of
trilostane in Vetoryl 120mg Capsules (60618), Vetoryl 60mg Capsules (60619) and Vetoryl 30mg Capsules (60620) administered at the label dose rate to
canine patients, presented as client-owned veterinary patients and suffering from hyperadrenocorticism. Additional related studies 7858 &7859 discuss the
results of studies 7855, 7856 & 7857). Effectiveness of therapy was measured by parameters including normalisation of clinical signs (including
polydipsia/polyuria), and improvement in cortisone-affected haematological and biochemical analysis (including post ACTH cortisol).
Other data relied on as supportive of efficacy of trilostane included published data 7822, 7849, 7850, 7852, 7854, 7860,7861, 7862, 7864, 7765, 7766, 7867 &
7868 covering dose rates and comparison to currently commonly used therapy. Some of the published studies used the applicant formulation.
«appl_num» Page 14 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
In addition several pharmacological studies were relied on to support safety and efficacy of the proposed active constituent or product(s) (studies 7815, 7816,
7817, 7818, 7814, 7819, 7820 7786, 7787 & 7788). These studies covered pharmacokinetics including bioavailablity, comparative dissolution/bioequivalence,
pharmacodynamics and the effects of fasting and non-fasting administration.
Based on the advice of the external reviewer and the relied on data, use by or under supervision or direction of a veterinarian, the APVMA determines that use
of the product in accordance with label instructions would not be likely to have a significant harmful effect in target animals and that use of the product in
accordance with the recommendations for its use that the APVMA approves would be effective.
Data relied on to provide the advice
Inherited
Data Data Author(s) Title Date Data Type Data Sub-type Authorising Application
No Source* Party No.
7856 S Arnold E and Vetoryl Trilostane Capsules - A report on the 31 Jul Efficacy and Safety Efficacy Applicant
Melville-Walker S clinical efficacy and safety of Vetoryl capsules in 2003.
the treatment of canine hyperadrenocorticism
when administered once daily. Report
AVP/EA/TRILO/2002-1.
7765 S O'Connor JT Clinical, Clinicopathological and Therapeutic May Efficacy and Safety Efficacy Public
Aspects of Canine Hyperadrenocorticism in 2002
Ireland. Master of Veterinary Medicine Thesis.
7869 S Braddock, JA, Inefficiency of selegiline in treatment of canine 2004 Efficacy and Safety Efficacy Public
Church, DB, pituitary-dependent hyperadrenocorticism.
Robertson, ID,
Watson, ADJ
7862 S Neiger R and Hurley Long term efficacy and safety of trilostane for 09/2005 Efficacy and Safety Efficacy Applicant
K treatment of canine hyperadrenocorticism.
7867 S Braddock JA Medical treatment of hyperadrenocorticism in 2003 Efficacy and Safety Efficacy Public
the dog.
7861 S Neiger, R., Ramsey, Trilostane treatment of 78 dogs with pituitary- 2002 Efficacy and Safety Efficacy Public
I., O'Connor, J., dependent hyperadrenocorticism.
Hurley, K. J.,
Mooney, C.T.
7865 S Hurley KJ Trilostane in the treatment of canine 1999 Efficacy and Safety Efficacy Public
hyperadrenocorticism.
7860 S Overend M Canine Cushing's syndrome - a case report 2003 Efficacy and Safety Efficacy Public
7863 S Neiger R, Melville- Owners' perceptions of trilostane therapy for 2003 Efficacy and Safety Efficacy Public
Walker S, Petrie G, canine hyperadrenocorticism.
«appl_num» Page 15 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Gauven A, German A,
Bentley D, Holland F
and Ramsey I
7859 S Anon. . Arnolds Vetoryl clinical studies - Summary of adrenal 2004 Efficacy and Safety Efficacy Applicant
Veterinary Products, tumour cases.
UK
7868 S Braddock, JA, Trilostane treatment in dogs with pituitary- 2003 Efficacy and Safety Efficacy Public
Church, DB, dependent hyperadrenocorticism.
Robertson, ID,
Watson, ADJ
7858 S Anon. . Arnolds Determination of starting dose. (Review of the 2004 Efficacy and Safety Efficacy Applicant
Veterinary Products, data from study AVP/EA/TRILO/2002-1 -
UK Vetoryl Trilostane Capsules - A report on the
clinical efficacy and safety of Vetoryl capsules in
the treatment of canine hyperadrenocorticism
when administered once daily.).
7766 S Herrtage ME Canine Hyperadrenocorticism. 1998 Efficacy and Safety Efficacy Public
7866 S Cerundulo R, Lloyd The treatment of abnormal steroidogenesis using June Efficacy and Safety Efficacy Applicant
DH trilostane in canine adult-onset alopecia. 2002
Preliminary Report, June 2002
7864 S Neiger R Treatment of canine hyperadrenocorticism 2003 Efficacy and Safety Efficacy Public
(Cushing's disease) with trilostane
7857 S Arnold E etoryl Trilostane Capsules - A report on its 9 Mar Efficacy and Safety Efficacy Applicant
clinical efficacy and safety in treating canine 2003.
hyperadrenocorticism when administered twice
daily to dogs over 10kg. Report
AVP/EA/TRILO/2004-1.
7855 S Arnold E Vetoryl Trilostane Capsules - A report on its 2 Dec Efficacy and Safety Efficacy Applicant
clinical efficacy and safety in treating canine 2003.
hyperadrenocorticism when administered once
daily to dogs under 10 kg. Report
AVP/EA/TRILO/2003-2(F).
7818 S Green R and Jacobs S Measurement of trilostane and ketotrilostane in 2003 Efficacy and Safety Pharmacological Applicant
dog plasma samples from study GB009/01-001. Data/Studies
Study No. HFL1118/2. Final Report.
7822 S Neiger R, Hurley K 24 hour cortisol values in dogs with 2001 Efficacy and Safety Pharmacological Public
hyperadrenocorticism on trilostane. Data/Studies
7787 S Ryan WT, Reckman Studies on the effect of different drugs on the 9 May Efficacy and Safety Pharmacological Applicant
JA, Brown TG and dynamics of adrenal steroidogenisis in the 1966. Data/Studies
«appl_num» Page 16 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
Potts GO anesthetised mongrel dog. III: The effects of
Win 24,540(d) [4a, 5a-epoxy-17b-hydroxy-3-
oxoandrostane-2-carbonitrile] on adrenal
steroidogenesis: site of action. Progress Report:
Endocrinology.
7814 S Jackson M Comparative dissolution profile study for 16 Jul Efficacy and Safety Pharmacological Applicant
Vetoryl 30, 60 and 120 mg capsules. QA Report 2004. Data/Studies
No.: 362.
7819 S Moran, C Bioequivalence of Vetoryl after oral 28 Feb Efficacy and Safety Pharmacological Applicant
administration in fasted versus non-fasted dogs. 2005 Data/Studies
Study No: GB009\04-004. Report No.:
GB009\050228.
7815 S Anon. Supplementary Information on Pharmacokinetics 21 May Efficacy and Safety Pharmacological Applicant
and Dosage in Dogs. 2001. Data/Studies
7788 S Ryan WR, Brown TG Studies on the effect of different drugs on the 13 Oct Efficacy and Safety Pharmacological Applicant
and Potts GO dynamics of adrenal steroidogenisis in the 1966. Data/Studies
anesthetised mongrel dog. IIIA: The effects of
Win 24,540(d) [4a, 5a-epoxy-17B-hydroxy-3-
oxoandrostane-2-carbonitrile] on adrenal
steroidogenesis: site of action/addendum.
Progress Report: Endocrinology.
7820 S Moran, C Pharmacokinetics of plasma trilostane and 28 Feb Efficacy and Safety Pharmacological Applicant
ketotrilostane following oral administration of 2005. Data/Studies
Vetoryl under four different regimes in dogs.
Study No: GB009\04-005. Report No.:
GB009\050228A.
7786 S Ryan WT, Brown TG, Studies on the effect of different drugs on the 14 Feb Efficacy and Safety Pharmacological Applicant
Reckman JA and Potts dynamics of adrenal steroidogenisis in the 1966. Data/Studies
GO anesthetised mongrel dog. II: The effects of the
intravenous or oral administration of Win 24,540
(d) [4,5-epoxy-17B-hydroxy-3-oxoandrostane-2-
carbonitrile] on the ACTH treated dog. Progress
Report: Endocrinology.
7816 S Green R Appendix 1: Pharmacokinetic analysis. Study 28 Sep Efficacy and Safety Pharmacological Applicant
No. HFL1118/2. 2003. Data/Studies
7817 S Doherty P Repeat oral administration of trilostane to dogs: 2 Aug Efficacy and Safety Pharmacological Applicant
collection of blood samples for pharmacokinetics 2001. Data/Studies
and analysis of cortisol. Study No. GB009\01-
001. Report No.: GB009\010802.
«appl_num» Page 17 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
7845 S Anon Royal Clinical Case review and statistical analysis. 2001 Efficacy and Safety Target Animal Safety Applicant
Veterinary College, Royal Veterinary College, UK Studies
UK.
7842 S Emanuel A Vetoryl: A 12 week oral toxicity study in beagle 16 Dec Efficacy and Safety Target Animal Safety Applicant
dogs. Final Report: 2002-3072. 2003. Studies
7846 S Hurley KJ Protocol for the use of trilostane in canine 09/2005 Efficacy and Safety Target Animal Safety Applicant
hyperadrenocorticism (of Ref 82: Clinical Case Studies
review and statistical analysis).
7841 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 120 mg 2005 Efficacy and Safety Target Animal Safety Applicant
Veterinary Products, capsules. From August 2004 to February 2005. Studies
UK Arnolds Veterinary Products, UK
7848 S Gallagher J Adresten Capsules: A statistical analysis of the 2001 Efficacy and Safety Target Animal Safety Applicant
clinical data (of Ref 84: Clinical Case review Studies
and statistical analysis).
7844 S Gallagher J. Adresten Capsules: A statistical analysis of the May Efficacy and Safety Target Animal Safety Applicant
original tolerance study (Ref 82: Evaluation of 2001. Studies
the Oral Toxicity of Trilostane. (Win 24,540)
After Being Administered for 3 Months to the
Beagle Dog).
7849 S Ruckstuhl, N. S., Nett, Results of Clinical Examinations, Laboratory 2002 Efficacy and Safety Target Animal Safety Public
C. S. and Reusch, C. Tests and Ultrasonography in Dogs with Studies
E Pituitary-Dependent Hyperadrenocorticism
Treated with Trilostane
7838 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2003 Efficacy and Safety Target Animal Safety Applicant
Veterinary Products, capsules. From August 2002 to February 2003. Studies
UK Arnolds Veterinary Products, UK
7854 S Barker EN, Campbell, A comparison of the survival times of dogs 2004 Efficacy and Safety Target Animal Safety Public
S. Tebb, A.J., Neiger, treated with either mitotane or trilostane for Studies
R. Herrtage, M.E., pituitary dependent hyperadrenocorticism.
Reid, S.W.J. and
Ramsey, I.K
7843 S Anon. Winthrop Evaluation of the Oral Toxicity of Trilostane 1987 Efficacy and Safety Target Animal Safety Applicant
Research Centre, (Win 24,540) After Being Administered for 3 Studies
France. Months to the Beagle Dog.
7852 S Eastwood JM and Prolonged hypoadrenocorticism in five dogs 2003 Efficacy and Safety Target Animal Safety Public
Elwood, C.M. treated with trilostane for pituitary dependent Studies
hyperadrenocorticism (PDH).
7837 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2002 Efficacy and Safety Target Animal Safety Applicant
Veterinary Products, capsules. From February 2002 to August 2002. Studies
«appl_num» Page 18 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
UK Arnolds Veterinary Products, UK
7840 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 120 mg 2003 Efficacy and Safety Target Animal Safety Applicant
Veterinary Products, capsules. From launch (October 2002) to Studies
UK February 2003. Arnolds Veterinary Products,
UK
7839 S Anon. Arnolds Pharmacovigilance Report. Vetoryl 60 mg 2005 Efficacy and Safety Target Animal Safety Applicant
Veterinary Products, capsules. From August 2004 to February 2005. Studies
UK Arnolds Veterinary Products, UK
7851 S Chapman PS, Kelly, Adrenal necrosis in a dog receiving trilostane for 2004 Efficacy and Safety Target Animal Safety Public
D.F., Archer, J., the treatment of hyperadrenocorticism. Studies
BrockmanD.J. and
Neiger, R
7850 S Eastwood JM, Elwood Trilostane treatment of a dog with functional 2003 Efficacy and Safety Target Animal Safety Public
CM, Hurley KJ adrenocortical neoplasia Studies
* S = Data submitted with the application
I = Data inherited (that is, referenced) from another application
«appl_num» Page 19 of 19 KP25S_F39 Version: 2 Issued: 14/08/2007
