Public Release Summary

on the evaluation of the new active constituent triptorelin acetate in the product Elanco Ovugel (Triptorelin Acetate) Gel for intravaginal use in sows.
APVMA Product Number 69700

© Australian Pesticides and Veterinary Medicines Authority 2016
ISBN	978-1-925390-37-7 (electronic)
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Director Public Affairs and Communication
Australian Pesticides and Veterinary Medicines Authority
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KINGSTON ACT 2604 Australia
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This publication is available from the APVMA website: www.apvma.gov.au.

Contents
Preface
About this document
Making a submission
Further information
1	Introduction
2	Chemistry and manufacture
2.1	Active constituent properties
2.2	Product
2.3	Recommendation
3	Toxicological assessment
3.1	Public health aspects and toxicology summary
3.2	Evaluation of toxicology
3.3	Public health standards
3.4	Conclusion
4	Residues assessment
4.1	Recommendations
5	Assessment of overseas trade aspects of residues in food
6	WORKER health and safety assessment
6.1	Worker health and safety summary
6.2	Conclusion
7	Environmental assessment
7.1	Introduction
7.2	Conclusion
8	Efficacy and safety assessment
8.1	Evaluation of efficacy data
8.2	Evaluation of target animal safety data
8.3	Conclusions
9	Labelling requirements
Abbreviations
Glossary
 
Preface
The Australian Pesticides and Veterinary Medicines Authority (APVMA) is the Australian Government regulator with responsibility for assessing and approving agricultural and veterinary chemical products prior to their sale and use in Australia.
In undertaking this task, the APVMA works in close cooperation with advisory agencies, including the Department of Health and Ageing, Office of Chemical Safety (OCS), Department of the Environment (DotE), and State Departments of Primary Industries.
The APVMA has a policy of encouraging openness and transparency in its activities and of seeking community involvement in decision making. Part of that process is the publication of Public Release Summaries for products containing new active constituents.
The information and technical data required by the APVMA to assess the safety of new chemical products, and the methods of assessment, must be consistent with accepted scientific principles and processes. Details are outlined in the APVMA’s regulatory guidelines.
This Public Release Summary is intended as a brief overview of the assessment that has been conducted by the APVMA and the specialist advice received from its advisory agencies. It has been deliberately presented in a manner that is likely to be informative to the widest possible audience thereby encouraging public comment.
About this document
This is a public release summary.
It indicates that the Australian Pesticides and Veterinary Medicines Authority (APVMA) is considering an application for registration of an agricultural or veterinary chemical. It provides a summary of the APVMA’s assessment, which may include details of:
•	the toxicology of both the active constituent and product
•	the residues and trade assessment
•	occupational exposure aspects
•	environmental fate, toxicity, potential exposure and hazard
•	efficacy and target animal safety.
Comment is sought from interested stakeholders on the information contained within this document.

Making a submission
In accordance with sections 12 and 13 of the Agvet Code, the APVMA invites any person to submit a relevant written submission as to whether the application for registration of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows should be granted. Submissions should relate only to matters that the APVMA is required, by legislation, to take into account in deciding whether to grant the application. These matters include aspects of public health, occupational health and safety, chemistry and manufacture, residues in food, environmental safety, trade, and efficacy and target animal safety. Submissions should state the grounds on which they are based. Comments received that address issues outside the relevant matters cannot be considered by the APVMA.
Submissions must be received by the APVMA by close of business on 12 July 2016 and be directed to the contact listed below. All submissions to the APVMA will be acknowledged in writing via email or by post.
Relevant comments will be taken into account by the APVMA in deciding whether the product should be registered and in determining appropriate conditions of registration and product labelling.
When making a submission please include:
•	contact name
•	company or group name (if relevant)
•	email or postal address (if available)
•	the date you made the submission.
All information judged by the APVMA to be confidential commercial information (CCI) contained in submissions will be treated confidentially.
Written submissions on the APVMA’s proposal to grant the application for registration that relate to the grounds for registration should be addressed in writing to: 
Enquiries
Registration Management and Evaluation 
Australian Pesticides and Veterinary Medicines Authority
PO Box 6182
Kingston ACT 2604

Phone:	+61 2 6210 4701
Fax:	+61 2 6210 4721
Email:	enquiries@apvma.gov.au
Further information
Further information can be obtained via the contact details provided above.
Further information on public release summaries can be found on the APVMA website: www.apvma.gov.au.

1	Introduction
The Australian Pesticides and Veterinary Medicines Authority (APVMA) has before it an application from Elanco Animal Health A division of Eli Lilly Australia Pty Ltd for registration of a new product, Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, containing the new active constituent, triptorelin.
This publication provides a summary of the data reviewed and an outline of the regulatory considerations for the proposed registration of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, and approval of the new active constituent, triptorelin.
Triptorelin is a synthetic analogue of gonadotropin releasing hormone (GnRH). Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows is gel product for intravaginal use in sows containing 100 µg/mL triptorelin (as triptorelin acetate). The proposed use is for the synchronisation of time of insemination in weaned sows to facilitate a single fixed-time artificial insemination in sows.
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows will be packaged in 52.5 mL bottles (containing 26 x 2 mL doses) and presented in single bottles and cartons of 6 x 52.5 mL bottles.
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows is registered in the USA and Canada.
The APVMA seeks public comment on the product outlined in this document prior to the product being registered for use in Australia. The APVMA will consider all responses received during the public consultation period in deciding whether the product should be registered and in determining conditions of registration and product labelling.

2	Chemistry and manufacture
2.1	Active constituent properties
The chemical active constituent triptorelin acetate has the following properties:
Common Name (ISO):	Triptorelin acetate	
IUPAC Name:	L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolyl-glycinamide, acetate salt	
ChemiCal Abstract Name:	Luteinizing hormone-releasing factor (swine), 6-D-tryptophan, acetate (1:?)	
CAS Registry Number:	160296-12-8	
Empirical Formula:	C64H82N18O13·C2H4O2	
Molecular Weight:	1371.6	
Physical Form:	Powder	
Colour:	White to off-white	
specific optical rotation:	[α]D20 = -69.0 (1% in 1% acetic acid)	
Solubility:	Free soluble in acetic acid; soluble in water and DMF; practically insoluble in acetone and chloroform	
maximum absorption:	282 nm (5x10-3% in DMF)	
Structural Formula:	See below	

2.2	Product 
Dose form 
Gel for intravaginal use
Formulation type 
Gel
Level of active 
100 µg/mL triptorelin (as triptorelin acetate)
Physical properties—appearance
The product is a thin clear to slightly hazy gel.
Storage and stability
The applicant provided the results of real time and accelerated stability testing conducted using samples stored in the proposed commercial containers. The results indicated that the formulated product is expected to be stable for the duration of the proposed shelf life when stored between 2°C and 8°C (Refrigerate, Do Not Freeze) in the proposed commercial packaging.
Packaging
The product will be packaged in 52.5 mL amber glass vial with stopper and seal. Based on the storage stability results, the product is not expected to have an adverse effect on the packaging and the packaging is not expected to have an adverse effect on the product.
2.3	Recommendation 
The APVMA evaluated the chemistry and manufacturing aspects of triptorelin. All the information (including the physico-chemical properties, spectral identification, manufacturing and quality control aspects, impurity formation, active constituent specification, stability, batch analysis data, analytical methods and packaging information) necessary for the approval of this new active constituent has been provided. The APVMA is satisfied that the application requirement is met.
The APVMA evaluated the chemistry and manufacturing aspects of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows. All the information (including formulation process, composition and form of constituents, product specifications, stability data, analytical methods, product containers and label) necessary for registration of the product has been provided. The APVMA is satisfied that the application requirement is met.

3	Toxicological assessment
Triptorelin is a synthetic analogue of Gonadotropin Releasing Hormone (GnRH). Compared to natural GnRH, triptorelin has a chemical modification in the amino acid composition at position 6, replacing glycine for D-tryptophan. GnRH analogues control the release of the pituitary gonadotrophins luteinising hormone (LH) and follicle stimulating hormone (FSH). In turn LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively.
Analogues of GnRH, including triptorelin, are used as human therapeutic agents. Information for some of these was submitted by the applicant to support a position of minimal human toxicity of triptorelin acetate in its intended use. 
The data package provided by the applicant comprised three acute toxicology studies for the active (skin and eye irritation, and skin sensitisation), two acute toxicology studies for the product (skin irritation and an in vitro bovine corneal opacity and permeability assay, i.e. BCOP assay), a short-term (45-day) oral and subcutaneous toxicity study in rats, target animal safety and efficacy studies, and published journal articles. 
3.1	Public health aspects and toxicology summary
Good quality studies with triptorelin demonstrate biological effect (good absorption) when administered subcutaneously or intramuscularly, but no effect (negligible bioavailability) orally. Substitution of the 
6–amino acid with D-tryptophan in native GnRH confers resistance to triptorelin from enzymatic degradation, which increases its plasma persistence and therefore therapeutic efficacy. Triptorelin is distributed into the anterior pituitary gland (biological target organ), in the liver and kidney (main inactivating organs). Parent molecule and peptide metabolites are found in urine, with metabolites also present in the intestine. 
Pharmacokinetic studies in healthy adult men indicate after intravenous bolus administration, triptorelin is distributed and eliminated according to a 3–compartmental model; corresponding half-lives are 6 minutes, 
45 minutes and 3 hours. Elimination half-lives are longer in patients with renal or hepatic insufficiency 
(6.6–7.7 hours). 
Based on the findings in the toxicological studies evaluated, the active and product are not skin or eye irritants, and the active is not a skin sensitiser. The product is expected to have low toxicity via all routes of exposure. The submitted information and information from the literature indicates negligible dermal and oral bioavailability of the active even at very high oral doses. 
Clinical applications of triptorelin include treatment of malignant neoplasms of the prostate, precocious puberty, management of endometriosis, female infertility, and uterine fibroids. Published clinical studies, in which the active is given to humans as a daily subcutaneous (s.c.) injection or monthly as an intramuscular (i.m.) depot preparation at doses ranging from 0.1 mg/day s.c. (for female infertility) to 3.75 mg/month i.m. (for prostate cancer), have shown only minimal side effects. Side effects were limited to those associated with the known pharmacological action of long term administration of GnRH and its analogues, i.e. oestrogen and testosterone deficiency resulting from long term pituitary desensitisation. These side effects were reversible within a few months of cessation of exposure. 
Uncertainties exist with respect to the potential abortifacient effects of administering triptorelin acetate parenterally to pregnant women, and the human relevance of pituitary adenomas observed in rats treated s.c. with triptorelin for 23 months. Neither of these dose routes, however, are relevant for the veterinary product.
3.2	Evaluation of toxicology
Chemical class 
Triptorelin is a synthetic analogue of Gonadotropin Releasing Hormone (GnRH). Compared to natural GnRH, triptorelin has a chemical modification in the amino acid composition at position 6, where glycine is replaced by D-tryptophan. Triptorelin is also known as D-Trp gonadotrophin releasing hormone or D-Trp luteinising hormone. GnRH analogues control the release of pituitary gonadotrophins such as luteinising hormone (LH) and follicle stimulating hormone (FSH). In turn LH and FSH stimulate gonadal production of sex steroids and gametogenesis, respectively. 
Toxicokinetics and metabolism
With respect to oral bioavailability good quality studies with triptorelin are available which demonstrate biological effect (good absorption) when administered subcutaneously or intramuscularly, but no effect (negligible bioavailability) orally. Substitution of the 6-amino acid with D-tryptophan in native GnRH confers resistance to triptorelin from enzymatic degradation, which increases its plasma persistence and therefore therapeutic efficacy. Triptorelin is distributed into the anterior pituitary gland (biological target organ), in the liver and kidney (main inactivating organs). Parent molecule and peptide metabolites are found in urine, with metabolites also present in the intestine. Pharmacokinetic studies in healthy adult men indicate after i.v. bolus administration, triptorelin is distributed and eliminated according to a 3–compartmental model; corresponding half-lives are 6 minutes, 45 minutes and 3 hours. Elimination half-life is longer in patients with renal or hepatic insufficiency (6.6–7.7 hours). 
Acute toxicity
There were no conventional oral acute toxicity studies for triptorelin acetate amongst the literature evaluated. The mode of administration, the nature of the formulation (aqueous gel) and the information available on pharmacological properties make accidental or intentional overdoses of triptorelin by the operator unlikely. In a package insert for a product approved by the US Food and Drug Agency (FDA) for the palliative treatment of advanced prostate cancer containing triptorelin pamoate (3.75 mg triptorelin), it is stated that acute toxicity studies have shown the s.c. LD50 of triptorelin to be 400 mg/kg in mice and 250 mg/kg in rats (i.e. this is approximately 7000x and 4000x, respectively, the usual human dose delivered as a slow-release formulation). 
Other studies conducted to Good Laboratory Practice (GLP) and complying with relevant guidelines have shown triptorelin acetate was not irritating to rabbit skin (Hurley 2013a), was not a skin sensitiser in an LLNA in mice (Rose 2013), and did not result in eye irritation when instilled into the rabbit eye (Hall 2013). 
Although a high score was obtained in an in vitro bovine corneal opacity and permeability (BCOP) assay for corneas treated with 20% triptorelin acetate (this would predict the substance to be a severe ocular irritant), histopathology confirmed damage was limited to the upper corneal epithelium, which according to study authors and information in the literature, is generally not predictive of lasting corneal changes in vivo (Wilt and Sheehan 2013). This conclusion is supported by the results in the in vivo eye irritation study conducted with solid (undiluted) triptorelin acetate, which showed it was not an irritant when instilled into rabbit eyes (Hall 2013). The formulated product was also shown not to be an eye irritant.
Systemic effects 
A 45-day repeat dose toxicity study was conducted with triptorelin acetate in rats following either oral gavage or s.c. injection (Heward 2011a, b). The study was conducted to GLP and, except for the study duration which in this case is unlikely to affect the outcome, complied with relevant guidelines. When administered orally at doses of 0.25, 1, or the top dose of 4 µg/kg/d, triptorelin acetate was without adverse effects. The oral NOEL in this study was therefore 4 µg/kg/d, the highest dose tested.
When administered subcutaneously in rats at both 4 and 400 µg/kg/d, various treatment-related effects were observed. These included a cessation of oestrous cycling, body weight increases, serum progesterone decreases in females, serum testosterone decreases in males, as well as microscopic findings in the ovaries and uterus of females. Additional microscopic findings confined to the high s.c. dose only were observed in the vaginas of female rats, in the testes, epididymides, prostate gland, seminal vesicles of male rats, adrenal glands of females, bone marrow and mammary glands of males and females. Overall a NOEL or NOAEL for subcutaneous administration could not be determined from this study. 
There were no sub-chronic oral toxicity studies amongst the information evaluated. These studies are typically not carried out for GnRH analogues, since peptides are largely digested and orally inactive even at very high doses.
Cavitte et al. (1988) studied the effects of long-term (up to 1 year) periodic intramuscular administration of a slow-release formulation containing triptorelin on testicular function in adult and adolescent dogs, and assessed the reversibility of these effects. Long term treatment led to inhibition of testicular function (atrophy of the testes and prostate, and reduced semen parameters), which was fully reversible within 1–8 months of the last treatment. Length of dosing had no marked impact on when reversibility occurred and reversibility was comparable between adults and adolescents. In a postscript to the study, the authors indicated two of the adolescent dogs from this study had fertilised two female dogs, and both had recently whelped. This supports the conclusion that fertility of the male dogs was unaffected by triptorelin treatment. 
Triptorelin is used clinically for treatment of various conditions in humans, and treatment for prostate cancer can last as long as 18 months at a time. Such clinical studies have found minimal side effects from long-term treatment, the effects being consistent with those of oestrogen or testosterone depletion.
Carcinogenicity 
According to the public assessment report from the Swedish Medical Products Agency for Moapar (11.25 mg triptorelin as triptorelin embonate) (Anon 2006b), in CD-1 mice given monthly i.m. injections of triptorelin embonate microgranules for 18 months up to a dose of 6000 µg/kg, no carcinogenic effects were observed. In rats, however, there was an almost 100% incidence of adenomas in the anterior pituitary of Sprague-Dawley rats treated with monthly intramuscular triptorelin embonate microgranules at doses of 120, 600, and 3000 µg/kg/month for 23 months. The Swedish Medical Products Agency notes the effect seems to be species-specific, and long term clinical experience has shown that similar problems do not appear in humans. It is noted the potential human exposure to the product (Ovugel) is only likely to be incidental during use and not long-term, hence it would seem systemic concentrations relative to those in rats would be very low in humans if they were to be exposed via a route that allowed absorption of biologically active triptorelin.
Genotoxicity
There were no genotoxicity study reports for triptorelin amongst the information evaluated.
Summary reports (no references provided) indicate no genotoxic potential was evident at concentrations up to the limit of toxicity or solubility in various studies with triptorelin (bacterial gene mutation, HGPRT locus test, chromosomal aberration in vitro in Chinese Hamster Ovary cells, and in vivo mouse micronucleus and bone marrow tests) (Anon 2006b, NLM 2006). EMEA (1995) indicates another GnRH analogue, buserelin, tested negative for mutagenicity. 
Reproductive and developmental toxicity 
There were no conventional reproductive or developmental toxicity study reports amongst the information evaluated.
However, NLM (2006) reports that after 60 days of treatment (dosing route not provided) followed by a minimum of 4 oestrous cycles prior to mating, triptorelin had no effect on fertility or general reproductive performance of female rats. Treatment did not elicit embryotoxicity, teratogenicity, or any effects on the development of the offspring (F1 generation) or their reproductive performance. 
According to the public assessment report from the Swedish Medical Products Agency for Moapar (11.25 mg triptorelin as triptorelin embonate) (Anon 2006b), reproductive toxicity of triptorelin was studied in rats (special fertility study, embryo-foetal development), mice (embryo-foetal development) and rabbits (special study). No adverse effects on fertility were seen in female rats receiving triptorelin acetate by s.c. injection at doses up to 200 µg/kg/d for 60 days or in female rats receiving 600 µg/kg of triptorelin acetate microspheres (slow release) by i.m. injection on days 1 and 31. There was no evidence that parental treatment with triptorelin acetate affected fertility, general reproductive performance, or behaviour of the F1 animals. 
Administration of triptorelin acetate to sexually mature female rabbits at 20 µg/kg/d by s.c. over a period of 
2 weeks prior to mating induced no effects on the ovaries (Anon 2006b). 
In humans, adverse reproductive effects (e.g. decrease or loss of fertility) have been noted after daily s.c. administration of 50 µg of another GnRH analogue (deslorelin), and higher doses (not reported) for up to 
10 weeks. However, these effects were fully reversible (EMEA 2002). 
A study by Yamazaki (1984) with a different GnRH analogue (leuprolide) in pregnant Sprague-Dawley rats suggests that a potential hazard for miscarriage may exist if triptorelin acetate is administered by particular routes to pregnant women, i.e. by routes resulting in absorption of biologically active triptorelin. It should be noted, however, the doses used in the study by Yamazaki (1984) are very high. For a 75 kg pregnant woman, the dose of 100 µg/kg body weight would equate to a bolus dose of 7500 µg (i.e. 38 times higher than the dose of triptorelin in Ovugel delivered at any one time to a sow). In addition, human case studies in which triptorelin has been administered to pregnant women at a dose of 100 µg/day have not found an abortifacient effect. 
There were no conventional developmental toxicity studies amongst the information evaluated.
However, rat and mouse studies briefly summarised by NLM (2006) and Anon (2006b) did not find evidence of embryotoxicity or teratogenicity for triptorelin. The results of a study with leuprolide in pregnant rats suggests an abortifacient effect of the GnRH analogue may be possible at high doses, however such an effect has not been found in human case studies with triptorelin at doses relevant to this application.
3.3	Public health standards
Poisons scheduling
Triptorelin is approved for therapeutic use in humans. The TGA has assessed and approved Diphereline™, Ipsen P/L (triptorelin embonate) for use in humans. The active is listed in Schedule 4 of the Australian Standard for Uniform Scheduling of Medicines and Poisons (SUSMP), with no exceptions. Ovugel for intravaginal use in sows contains 100 µg/mL triptorelin as the acetate and is classified as a Schedule 4 prescription animal drug. Based on the concentration of triptorelin and the toxicological profile of the product, this scheduling is considered appropriate. 
NOEL/ADI
The acceptable daily intake (ADI) for humans is the level of intake of a chemical that can be ingested daily over an entire lifetime without appreciable risk to health. It is calculated by dividing the overall NOEL for the most sensitive toxicological endpoint from a suitable study (typically an animal study) by an appropriate safety factor. 
Guidance from the European Medicines Agency (EMA 2012) indicates setting an ADI is only considered necessary for pharmacologically active substances, excipients or degradation products, and their metabolites which remain in food obtained from treated animals. Since triptorelin is likely to have a short elimination half-life in pigs as is the case in dogs and humans, and is administered prior to pregnancy, there will be no biologically active material in the sow by the time it is slaughtered. In addition, triptorelin has negligible oral bioavailability and should humans consume a pig within a few hours of it being dosed with triptorelin it is very unlikely persons will receive orally or systemically an active dose of triptorelin. Setting an ADI is not considered necessary.
ARfD 
The acute reference dose (ARfD) is the estimate of the amount of a substance in food or drinking water, expressed on a milligram per kilogram body weight basis, that can be ingested over a short period of time, usually in one meal or during one day, without appreciable health risk to the consumer on the basis of all known facts at the time of the evaluation.
The setting of an ARfD is not considered appropriate for triptorelin or the associated product, Ovugel, due to their low hazard profile and for the same reasons an ADI is not required. 
3.4	Conclusion
After consideration of the hazards associated with the proposed product, along with the exposure and risks expected with its use, the APVMA proposes to be satisfied that Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, containing 100 µg/mL triptorelin (as triptorelin acetate), for the synchronisation of time of insemination in weaned sows to facilitate a single fixed-time artificial insemination in sows, meets the safety criteria with regards to human health (toxicology).

4	Residues assessment
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, which contains 100 µg/mL triptorelin (as triptorelin acetate), is intended for inducing ovulation in sows.
The applicant has proposed that the use of triptorelin for inducing ovulation in sows is eligible for a Table 5 entry in the MRL Standard.
Requirements for a table 5 entry
Compounds are eligible for inclusion in Table 5 when:
(i)	residues do not or should not occur in foods or animal feeds; or
(ii)      residues are identical to or indistinguishable from natural food components; or
(iii)	residues are otherwise of no toxicological significance.
The requirements for a Table 5 entry for the use of triptorelin in pigs are considered below. 
Residues do not or should not occur in foods or animal feeds
Only very small quantities of triptorelin (0.2 mg) are used to induce ovulation in sows, and as pigs treated with the proposed product are used for breeding purposes, it is unlikely that they will be made available for human consumption in the short term. Additionally, unlike an injectable product, the proposed product is administered intravaginally, and as the vagina is removed at slaughter, there is no risk of humans eating an entire dose of triptorelin.
Therefore, when used according to the proposed relevant label particulars, triptorelin residues should not occur in pig commodities.
Residues are otherwise of no toxicological significance
After intravaginal administration triptorelin is absorbed and rapidly metabolised in the liver and kidneys into small peptides that have negligible biological activity. Further as triptorelin has low oral bioavailability, if commodities from treated animals are consumed, there will be negligible absorption of triptorelin by the gastrointestinal tract, and any triptorelin that is absorbed would be rapidly inactivated by the gastrointestinal enzymes. This is confirmed by the absence of toxicological and biological effects following chronic oral administration of triptorelin to rats. 
Therefore, if commodities from treated animals are consumed, triptorelin residues in these commodities will be of no toxicological significance.
Conclusion
The APVMA proposes to be satisfied that the use of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, in accordance with the recommended relevant label particulars, meets the safety criteria with regards to residues. 
4.1	Recommendations
MRL amendments
The following amendment to Table 5 of the MRL Standard is recommended to cover the use of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows in pigs.
SUBSTANCE	USE	
DELETE:		
Gonadotrophin Releasing Hormone (GnRH) and synthetic analogues [including buserelin, deslorelin, gonadorelin and salmon GnRH analogue]	Cattle: treatment of cystic ovaries; prevention of delayed ovulation; improvement of fertility rate
Horses: induction of ovulation; treatment of anoestrus
Finfish: induction of spawning in finfish broodstock
Pigs: at a dose of 0.01mg/animal for induction of ovulation
Rabbits: induction of ovulation; improvement of conception rate	
ADD:		
Gonadotrophin Releasing Hormone (GnRH) and analogues [including buserelin, deslorelin, gonadorelin, triptorelin acetate and salmon GnRH analogue]	Cattle: treatment of cystic ovaries; prevention of delayed ovulation; improvement of fertility rate
Horses: induction of ovulation; treatment of anoestrus
Finfish: induction of spawning in finfish broodstock
Rabbits: induction of ovulation; improvement of conception rate
Pigs: induction and synchronisation of oestrus	
Restraints
None required.
Withholding periods
Meat
Zero (0) days 

5	Assessment of overseas trade aspects of residues in food
Triptorelin residues should not occur in foods and is of no toxicological significance if humans consume treated animals. Therefore, there are no residues related risks to Australia’s export trade in pork.
The APVMA proposes to be satisfied that use of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, in accordance with the recommended relevant label particulars, meets the trade criteria, provided the following Trade Advice statement is included on the relevant label particulars:
Trade Advice
Export slaughter interval (ESI)
Zero (0) days
6	WORKER health and safety assessment
6.1	Worker health and safety summary
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows will be supplied in 52.5 mL amber Type I glass vials with a butyl stopper and aluminium seal. Doses (2 mL/sow) are extracted from the vials by a bottle-mount applicator into an application chamber, which is connected to an infusion tube, similar to that used for sow artificial insemination. A new protective sheath is fitted over the infusion tube for each dose administration.
Artificial inseminators on pig farms are expected to be the main users of the product. The most likely route for worker exposure would be dermal contact, which could potentially occur when expelling air from the dosing apparatus prior to dosing or when replacing plastic sheaths between sows. Potential dermal exposure is also possible should the bottle-mount applicator malfunction and the dose in the chamber spills. Since PPE are recommended during the insemination process in sows to prevent the spread of disease in the herd, artificial inseminators would likely be wearing gloves, which would prevent the person from coming into dermal contact with the product when changing sheaths during application. Other routes of exposure are unlikely.
The product will not be used by members of the public. Since the packaging will be handled and disposed by trained personnel on pig farms, children are unlikely to have access to the product. Triptorelin residues are unlikely to occur in pork for consumption, as the GnRH analogue is expected to be rapidly metabolised and excreted in pig urine and faeces. Any residues potentially present in pork are likely to be biologically inactive if ingested by humans.
An operator qualitative risk assessment concluded that exposure to the product during the proposed use may occur, but would result in very low to negligible product exposure. This conclusion was based on considerations of the dose, route, frequency, and the negligible dermal absorption of peptides in general. Exposure via other routes was considered unlikely. 
Based on the outcomes of the risk assessment, First aid instructions have been recommended for the use of the product. Safety directions are not considered necessary. The proposed label for the product includes user safety information stating that pregnant women and others of childbearing age should exercise caution when handling the product, and that direct contact with the skin should be avoided. Considering the uncertainties in relation to the potential abortifacient effects of parenteral administration of triptorelin and other GnRH analogues, the user safety information is considered appropriate. The information is consistent with what appears on labels for other GnRH analogues approved for veterinary use in Australia. Warning, precautionary, re-entry or re-handling statements are not required for the product. 
6.2	Conclusion 
The APVMA proposes to be satisfied that use of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, in accordance with the recommended relevant label particulars, meets the safety criteria with regard to worker health and safety.

7	Environmental assessment
7.1	Introduction
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows containing the new active constituent triptorelin (as the acetate) is proposed for synchronisation of time of insemination and to facilitate fixed-time insemination in weaned sows. The product is administered intravaginally so that each animal receives one treatment of 2 mL of product, which provides 200 µg triptorelin. The standard environmental release scenario for treatment of intensively reared sows was considered in a Phase 1 assessment according to EMA Guideline on Environmental Impact Assessment for Veterinary Medicinal Products in support of the VICH Guidelines GL6 and GL38 (2008).
7.2	Conclusion
The standard environmental release scenario for treatment of intensively reared sows was considered in Phase 1. The predicted environmental concentration of triptorelin in soil (PEC soil initial) was 0.0052 µg/kg, which is well below the limit of concern (100 µg/kg). Therefore, it is not required that the environmental risk assessment proceed to Phase II.
The label will contain the standard disposal statement appropriate to the packaging type as follows:
Disposal
Dispose of empty container by wrapping with paper and putting in garbage.
The APVMA proposes to be satisfied that the use of Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows meets the safety criteria with regards to environment safety. 

8	Efficacy and safety assessment
Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows contains a new active constituent, triptorelin acetate. The product is applied as an intravaginal gel four days after weaning to facilitate a single fixed-time artificial insemination of sows 22 hours later. 
Triptorelin is a synthetic analogue of Gonadotropin Releasing Hormone (GnRH) with significantly greater biological activity than the natural peptide. It has not been previously assessed by the APVMA but other GnRH analogues are approved for use in swine in Australia.
8.1	Evaluation of efficacy data
The efficacy studies include non-pivotal laboratory model efficacy studies, dose determination studies, dose confirmation studies, field studies and a pivotal field study conducted in the USA in accordance with Good Clinical Practice, as well as supporting published information.
Appropriate and well-designed studies were undertaken in the USA and demonstrated the efficacy and target animal safety of 200 µg triptorelin gel in the proposed product for the proposed use. These studies were conducted in similar pork production systems to those used in Australia, and with similar genotypes of pigs. Consequently, the studies are applicable to Australian production systems.
The early non-pivotal studies were performed with developmental formulations, which were progressively improved and refined. An overview of the development of the triptorelin gel formulation was provided. Improvements in the formulation were mainly to improve product stability, with none of the formulations found to have an adverse impact on the effectiveness of the drug.
A series of pivotal and non-pivotal efficacy studies demonstrated that 200 µg of triptorelin gel in the proposed product administered intravaginally at 96 hours post-weaning advanced and synchronised ovulation. Normal fertility was achieved with a single fixed-time insemination.
Normal fertility was measured by farrowing rate (no. females delivering offspring ÷ no. females in group) and live pigs per litter (no. offspring born alive ÷ no. females delivering offspring). Piglet index was also proposed as a measure of fertility. The piglet index is the number of pigs born alive per 100 sows in the group [(Total no. piglets born live ÷ no. of females in group) x 100]. This measure provided an economic index that incorporates both the farrowing rate and litter size. The total number of piglets born alive within a group of sows is an important indicator for producers. It is also a simple and accurate measure for comparing triptorelin treated sows given fixed-time insemination to control sows bred using normal farm practice.
The series of studies demonstrated:
a)	a dose of 200 µg triptorelin was more effective at advancing ovulation to 48 hours post-treatment than 25 or 100 µg;
b)	200 µg triptorelin advanced ovulation relative to control sows whether it was given at 72, 84 or 96 hours post-weaning, although treatment at 96 hours produced the most synchrony of ovulation;
c)	Treatment 120 hours post-weaning was too late, with >60% of sows exhibiting oestrous (i.e. had already experienced an endogenous LH surge);
d)	200 µg of triptorelin in the proposed product administered 96 hours post-weaning, followed by a single fixed-time insemination 18 to 24 hours post-treatment, resulted in normal fertility;
e)	Two fixed time inseminations at 24 and 30 hours after triptorelin treatment did not improve pregnancy rates over a single insemination at 24 hours (suggesting that a single insemination at 30 hours may have been too late for optimal fertility);
f)	Treating sows with 200 µg of triptorelin 103 hours after weaning (around 3pm on day 4 post-weaning), followed by a single insemination at 15 or 18 hours following treatment (early on day 5 post-weaning) also resulted in pregnancy rates, farrowing rates and litter sizes comparable to control sows that received multiple inseminations during behavioural oestrus; 
g)	Multiple studies confirmed that treatment with 200 µg triptorelin gel 96 hours post-weaning synchronised the time of ovulation and facilitated a single fixed-time insemination approximately 
24 hours later (120 hours after weaning).
8.2	Evaluation of target animal safety data
Triptorelin is used in human medicine and is regarded as a safe and useful drug, producing relatively minor, reversible side effects associated with a reduction in sex hormones during prolonged administration.
The tolerance of the proposed product was tested in a target animal margin of safety study in pigs, with single intravaginal application at 1X and 7X the recommended dose. A 4.5% decrease in live-weight was associated with the regression of mammary tissue following weaning and some minor (non-dose related) vaginal inflammation was observed. However, no dose-related abnormalities were detected in results for serum chemistry, haematology, urinalysis, or serum endocrine function.
A review of reproductive safety parameters from a number of proof-of-concept studies demonstrated that sows treated with 200 µg triptorelin gel 96 hours post-weaning, followed by a single insemination about 
24 hours later, had pregnancy, farrowing rates and litter sizes comparable to controls. It was concluded that this demonstrated administration of the proposed product did not adversely affect fertilisation or embryo survival.
No adverse drug experiences or association with health problems have been noted in the non-pivotal or pivotal efficacy studies. Comparison of health-related observations for numerous sows treated with the proposed product in the multi-site pivotal efficacy study with sows receiving vehicle gel indicated that none of the health issues observed and recorded were associated with triptorelin treatment.
Data presented on GnRH agonists and, triptorelin acetate, together with the target animal safety study, dermal irritancy study (which demonstrated that the product can be classified as ‘non-irritating’ with no sign of dermal irritation in studies on Albino rabbits) and reproductive safety review, demonstrate that the proposed formulation presents no specific safety risks to sows when administered as proposed.
8.3	Conclusions
The APVMA proposes to be satisfied that the proposed product, Elanco Ovugel (Triptorelin Acetate) gel for intravaginal use in sows, when used according to the instructions on the approved label for its use, meets the efficacy criteria and the safety criteria with regards to target animal safety.

9	Labelling requirements
Signal heading:	PRESCRIPTION ANIMAL REMEDY
KEEP OUT OF REACH OF CHILDREN
FOR ANIMAL TREATMENT ONLY	
Product name:	ELANCO OVUGEL (triptorelin acetate) Gel for Intravaginal use in Sows	
Active constituent/s:	100 µg/mL triptorelin (as triptorelin acetate)	
Statement of claims:	For the synchronisation of time of insemination in weaned sows to facilitate a single fixed-time artificial insemination.	
Net contents:	52.5 mL (26 x 2 mL doses) 
6 x 52.5 mL (26 x 2 mL doses)	
Directions for Use Heading:	DIRECTIONS FOR USE	
Restraints:	-	
Contraindications:	OvuGel should not be used in sows with obvious reproductive tract abnormalities.	
Precautions:	The safety and effectiveness of the product have not been evaluated in gilts.	
Side effects:	-	
Dosage & administration:	Dosage and Administration
Warm product at room temperature for a minimum of 10 minutes prior to use.
Administer a single 2 mL dose of OvuGel intravaginally at approximately 96 hours after weaning. Sows should be inseminated 22 ± 2 hours following administration of OvuGel using standard AI techniques and should be exposed to a boar during insemination. OvuGel should be administered intravaginally at approximately 96 hours after weaning. Insert the delivery tube into the vagina so that the tip rests 1–3 cm posterior to the cervix. Use a separate sheath over the delivery tube for each sow treated. Each sow should receive a single 2 mL dose of OvuGel using standard artificial insemination (AI) techniques. Sows should be exposed to a boar during time of insemination The use of a bottle-mount applicator is recommended to ensure accurate dosing. The use of adequate sperm numbers per insemination and proper semen storage, as recommended by the semen or artificial inseminator catheter suppliers, is recommended. 
Illustrated OvuGel Directions for Use
[Diagram]—1. Allow the bottle of OvuGel to warm to room temperature for a minimum of 10 minutes.
[Diagram]—2. Locate the applicator, infusion tube, and protective sheaths to be used. Use of a multi-dose applicator set to deliver 2 mL is recommended.
[Diagram]—3. Attach the infusion tube to applicator.
[Diagram]—4. Remove foil tab from the bottle top. Invert applicator over upright bottle of OvuGel and push bottle onto the applicator.
[Diagram]—5. Compress the applicator handle fully and then release, allowing applicator chamber to fill with OvuGel.
[Diagram]—6. Tilt applicator so that infusion tube is pointed up.
[Diagram]—7. Compress and release the applicator handle causing the OvuGel within the chamber to enter the infusion tube and another dose from the bottle to refill the chamber.
[Diagram]—8. Slowly compress and release the applicator handle to displace any air in the infusion tube with OvuGel. There should now be a full dose in the infusion tube and in the applicator chamber.
[Diagram]—9. Slide the protective sheath over the infusion tube.
[Diagram]—10. Gently and slowly insert the covered infusion tube into the vagina at a slight upper angle (to avoid entry into the urethra) until you encounter mild resistance (the cervix) and then withdraw the infusion tube approximately 1–3cm.
[Diagram]—11. Compress and release the applicator handle to discharge the OvuGel dose and to allow another full dose of OvuGel to enter chamber.
[Diagram]—12. Remove the infusion tube and the protective sheath from the vagina. Dispose of the use protective sheath and replace it with a new sheath.
Repeat steps 9 through 12 for each sow receiving OvuGel.	
General directions:	-	
Withholding Period/s:	WITHHOLDING PERIOD: MEAT: Zero (0) Days.	
Trade Advice:	TRADE ADVICE: EXPORT SLAUGHTER INTERVAL (ESI): Zero (0) Days.	
Safety Directions:	- 	
First Aid:	If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 13 1126. 	
Additional user safety:	User Safety Information:
Pregnant women and others of childbearing age should exercise caution when handling this product. Scientific evidence indicates that accidental administration of triptorelin is unlikely to cause disruption of pregnancy, however, exposure to high doses could potentially lead to a disruption of the menstrual cycle. Direct contact with the skin should therefore be avoided.	
Environmental statements:	-	
Disposal:	Dispose of empty container by wrapping with paper and putting in garbage. 	
Storage:	Store between 2 and 8oC (Refrigerate, do not freeze). OvuGel should be administered within 1 hour of warming. Unused portions may be refrigerated immediately after use. The stopper may be punctured a maximum of three times. Discard unused product 28 days after the stopper is first punctured. 	
APVMA approval no.	APVMA No: 69700/61465	

Abbreviations
ac	active constituent	
ADI	Acceptable Daily Intake (for humans)	
ARfD	Acute Reference Dose	
bw	bodyweight	
d	day	
ESI	Export Slaughter Interval	
Fo	original parent generation	
g	gram	
GLP	Good Laboratory Practice	
hr	hour	
HPLC	High Pressure Liquid Chromatography or High Performance Liquid Chromatography	
i.m	intramuscular	
in vitro	outside the living body and in an artificial environment	
in vivo	inside the living body of a plant or animal	
kg	kilogram	
LD50	dosage of chemical that kills 50% of the test population of organisms	
LOEL	Lowest Observable Effect Level	
M/F	male/female	
mg	milligram	
mL	millilitre	
MRL	Maximum Residue Limit	
PEC	predicted environmental concentration	
PPE	Personal Protective Equipment	
s.c	subcutaneous	
µg	microgram	
WHP	Withholding Period	
Glossary
Active constituent	The substance that is primarily responsible for the effect produced by a chemical product	
Acute	Having rapid onset and of short duration.	
Carcinogenicity	The ability to cause cancer	
Chronic	Of long duration	
Codex MRL 	Internationally published standard maximum residue limit	
Efficacy	Production of the desired effect	
Formulation	A combination of both active and inactive constituents to form the end use product	
Genotoxicity	The ability to damage genetic material	
Leaching	Removal of a compound by use of a solvent	
Metabolism	The chemical processes that maintain living organisms	
Toxicokinetics	The study of the movement of toxins through the body	
Toxicology	The study of the nature and effects of poisons