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  1. Minor Use/Minor Species

FOI Summary Ovaprim

Date of Index Listing: March 17, 2009 

FREEDOM OF INFORMATION SUMMARY

ORIGINAL REQUEST FOR ADDITION TO THE INDEX OF LEGALLY MARKETED UNAPPROVED NEW ANIMAL DRUGS FOR MINOR SPECIES

MIF 900-001

OVAPRIM

Salmon Gonadotropin Releasing Hormone analog + Domperidone
Injectable Solution
Ornamental Finfish Broodstock

“For use as a spawning aid in ornamental finfish broodstock”

Requested by:

Western Chemical Inc.

TABLE OF CONTENTS

  1. GENERAL INFORMATION: 

  2. EFFECTIVENESS AND TARGET ANIMAL SAFETY:

    1. Findings of the Qualified Expert Panel:
    2. Literature Considered by the Qualified Expert Panel:
  3. USER SAFETY:

  4. AGENCY CONCLUSIONS:

    1. Determination of Eligibility for Indexing:
    2. Qualified Expert Panel:
    3. Marketing Status:
    4. Exclusivity:
    5. Attachments:
  1. GENERAL INFORMATION:
     
    1. File Number: MIF 900-001
    1. Requestor: Western Chemical Inc.
      1269 Lattimore Rd.
      Ferndale, Washington  98248

      Drug Labeler Code: 050378

    1. Proprietary Name(s): OVAPRIM
    1. Established Name(s: Salmon gonadotropin releasing hormone analog (sGnRHa) + domperidone
    1. Pharmacological Category: Spawning agent
    1. Dosage Form(s):  Injectable
    1. Amount of Active Ingredient(s): SGnRHa 20 µg/mL; domperidone 10 mg/mL
    1. How Supplied: OVAPRIM is packaged ready for use in a sterile liquid form.  It comes in self-sealing 10 mL vials.
    1. How Dispensed: Over-the-counter (OTC)
    1. Dosage(s): A general dose of OVAPRIM is 0.5 mL per kilogram of body weight.  This dose may vary among species and water temperatures.
    1. Route(s) of Administration: Intraperitoneal or intramuscular injection
    1. Species/Class(es): Ornamental finfish broodstock
    1. Indication(s): For intraperitoneal or intramuscular use as a spawning aid in ornamental finfish broodstock

  2. EFFECTIVENESS AND TARGET ANIMAL SAFETY:

    In accordance with 21 CFR part 516, a qualified expert panel evaluated the target animal safety and effectiveness of OVAPRIM for intraperitoneal or intramuscular use as a spawning aid in ornamental finfish broodstock to determine whether the benefits of using OVAPRIM for the proposed use outweigh its risks to the target animal.  The members of the qualified expert panel were:

    Roy P. E. Yanong, VMD, University of Florida;
    John D. Baldwin, Ph.D., Florida Atlantic University; and
    Craig Adam Watson, M.Aq., University of Florida.

    1. FINDINGS OF THE QUALIFIED EXPERT PANEL:
       

      Based on a thorough review of the literature and their own personal, extensive experience with the compound, the expert panel concluded that OVAPRIM is both effective and safe for use as a spawning aid in ornamental finfish broodstock.

      OVAPRIM has been shown to be effective and safe in numerous ornamental finfish species in the refereed scientific literature (II.B.).  In addition, OVAPRIM has a 20 year history of safe and effective use in a wide variety of ornamental finfish species, representing groups commonly raised by U.S. ornamental fish producers.

      Many years of research investigating hormonal triggers for ovulation and spermiation went into the development of OVAPRIM (Sherwood et al., 1983; Peter et al., 1985; Peter et al., 1986; and others).  Although sGnRHa alone is effective for inducing ovulation and spermiation in numerous species, some groups also require the dopamine blocker domperidone to prevent inhibition of spawning activity. 

      The combination of sGnRHa and domperidone has been used effectively and safely to promote ovulation and spermiation in a wide variety of families and species of fish.  In the scientific literature, freshwater species tested include the Chinese loach (Cobitidae: Paramisgurnus dabryanus) and common carp (Cyprinidae; Cyprinus carpio) (Lin et al., 1988; Haniffa et al., 2007).  The product OVAPRIM, itself, has been used successfully in the Australian eel-tailed catfish (Neosilurus ater) (Cheah and Lee, 2000); red-tailed tinfoil barb (Barbonymus altus, formerly Puntius altus) and the tinfoil barb (Barbonymus schwanenfeldii) (Mohamad-Zaini et al., 1994); Pangasius hypophthalmus (Legendre et al., 2000); the Thai mahseer (Tor tambroides and T. douronensis) (De Silva et al., 2004);  walking catfish (Clarias batrachus) (Sahoo et al., 2005); rainbow sharks (Epalzeorhynchos frenatum, formerly Epalzeorhynchos erythrurus) (Hill et al., 2005); Clown knife fish (Chitala chitala) (Sarkar et al., 2006); and a number of other ornamental finfish species (Hill et al., in press). Marine and euryhaline species described in the scientific literature for which OVAPRIM has been used safely and effectively include Arctic charr (Salvelinus alpinus) (Jansen, 1991); striped bass (Morone saxatilis) (King et al., 1994); marine porgy (Acanthopagrus latus) (Leu and Chou, 1996); Coho salmon (Oncorhynchus kisutch) and rainbow trout (Oncorhynchus mykiss) (Powell et al., 1998); Australian dhufish (Glaucosoma hebraicum) (Pironet et al., 1999); and striated frogfish (Antennarius striatus) (Yanong, 2003).

      In addition to the published scientific laboratory work cited, OVAPRIM has also been used safely and effectively in commercial ornamental fish production for many years in over 40 countries and members of the qualified expert panel have had extensive direct experience with the use of OVAPRIM in commercial production.

      OVAPRIM has been investigated under investigational new animal drug (INAD) file 010-040 for over two years through the Tropical Aquaculture Laboratory, University of Florida.  Data from the INAD studies include information on 15 Ostariophysan fishes representing a number of families, among them Cyprinidae, Characidae, Mochokidae, Loricariidae, Pimelodidae, and Cobitidae, 3 Perciforme fishes (representing Cichlidae), and several other groups (including Osteoglossidae and Helostomatidae).  Producers using OVAPRIM under this INAD have completed numerous target animal safety and effectiveness trials with koi, freshwater sharks, goldfish, cichlids, piranha, pacu, kissing gourami, a variety of catfishes, Asian arowana, and numerous other species.  Additionally, thousands of individual animals of numerous species have been induced to ovulate or spermiate by commercial aquaculturists.

      Adverse effects are also described in the INAD studies, and constitute primarily redness at the site of injection and/or change in body color at the site of injection (freshwater sharks).  The panel members believed that this was most likely due to secondary infection from surface bacteria, physical trauma/rough handling, or non-sterile methods.  Mortalities from the use of OVAPRIM are very rare but most can be attributed to secondary infections, rough handling, poor environmental water quality, or use in debilitated fish (e.g., egg-bound females).

    2. LITERATURE CONSIDERED BY THE QUALIFIED EXPERT PANEL:

      1. Azevedo, P. de and Canale, L. 1938. A hipofise e sua ação nas gonadas dos peixes neotropicos. Arq.Inst.Biol.S.Paulo, 9:165–86. (as cited in Robertson and Rinfret, 1957).
      2. Breton, B., Govoroun, M. and Mikolajczyk, T. 1998. GTH I and GTH II secretion profiles during the reproductive cycle in female rainbow trout: relationship with pituitary responsiveness to GnRH-A stimulation. Gen. Comp. Endocrinol. 111:38-50.
      3. Chang, J.P. and Peter, R.E. 1983.  Effects of dopamine on gonadotropin release in female goldfish, Carassius auratus. Neuroendocrinology, 36:351-357.
      4. Cheah, M.S.H. and Lee, C.L. 2000. Induced ovulation of the Australian eel-tailed catfish Neosiluris ater (Perugia) with OVAPRIM. Asian Fish. Sci. 13:87 96.
      5. Copp, D.H., Davidson, A.G.F. and Cheney, B.A. 1961. Evidence for a new parathyroid hormone which lowers blood calcium. Proc. Can. Fed. Biol. Soc. 4:17.
      6. Coy, D. H. and Schally, A. V. 1978. Gonadotrophin releasing hormone analogues. Ann. Clin. Res. 10(3):139-144.
      7. Davis, M.R. and Fernald, R.D. 1990. Social control of neuronal soma size. J. Neurobiol. 21:1180-1188.
      8. De Silva, S.S., Ingram, B., Sungan, S., Tinggi, D., Gooley, G. and Sim, S.Y. 2004. Artificial propagation of the indigenous Tor species, emparau (T. tambroides) and semah (T. douronensis), Sarawak, East Malaysia. Aquacult. Asia. 9(4):15-20.
      9. Donaldson, E. M. 1973. Reproductive endocrinology of fishes. American Zoologist. 13(3):909-927.
      10. Haniffa, M.A., Allen Benziger, P.S., Arockiaraj, A.J., Nagarajan, M. and Siby, P. 2007. Breeding behaviour and embryonic development of koi carp (Cyprinus carpio). Taiwania 52(1):93-99.
      11. Hill, J.E., Baldwin, J.D., Graves, J.S., Leonard, R., Powell, J.F.F. and Watson, C.A. 2005. Preliminary observations of topical gill application of reproductive hormones for induced spawning of a tropical ornamental fish. North American Journal of Aquaculture 67:7-9.
      12. Hill, J.E., Kilgore, K.H., Pouder, D.B., Powell, J.F.F., Watson, C.A. and Yanong, R.O.E. In press. Survey of OVAPRIMTM use as a spawning aid in ornamental fishes in the United States as administered through the University of Florida Tropical Aquaculture Laboratory (2005-2007). North American Journal of Aquaculture.
      13. Houssay, B.A. 1931. Action sexuelle de l’hypophyse sur les poissons et les reptiles. C.R. Soc. Biol. 106:377-378. (cited in Lam, 1982).
      14. Jansen, M.E. 1991. Induction of ovulation in Arctic char held under unchanging temperature and photoperiod. Prog. Fish. Cult. 55:32-34.
      15. Karten, M.J. and Rivier, J.E. 1986. Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists:  rationale and perspective. Endocrine Rev. 7(1):44-66.
      16. King, W., Thomas, P., Harrell, R.M., Hodson, R.G. and Sullivan, C.V. 1994. Plasma levels of gonadal steroids during final oocyte maturation of striped bass Morone saxatilis. Gen. Comp. Endocrinol. 95(2):178-191.
      17. Kramer, C.R., Caddell, M.T. and Bubenheimer-Livolsi, L. 1993. sGnRH-A [(D-Arg6, Pro9, NEt-)LHRH] in combination with domperidone induces gonad reversal in a protogynous fish, the bluehead wrasse, Thalassoma bifasciatum. J. Fish Biol. 42:185-195.
      18. Lam, T.J. 1982. Applications of endocrinology to fish culture. Can. J. Aquat. Sci. 39:111-137.
      19. Legendre, M., Slembrouck, J., Subagja, J. and Kristanto, A.H. 2000. Ovulation rate, latency period and ova viability after GnRH- or hCG-induced breeding in the Asian catfish Pangasius hypophthalmus (Siluriformes, Pangasiidae), Aquat. Living Resour. 13:145-151.
      20. Leu, M.Y. and Chou, Y.H. 1996. Induced spawning and larval rearing of captive yellowfin porgy, Acanthopagrus latus (Houttuyn). Aquaculture. 143:155-166.
      21. Lin, H.R., Van der Kraak, G., Zhou, X.J., Liang, J.Y., Peter, R.E., Rivier, J.E. and Vale, W.W. 1988. Effects of [D-Arg6, Trp7, Leu8, Pro9 NEt]-luteinizing hormone-releasing hormone (LHRH-A), in combination with pimozide or domperidone, on gonadotropin release and ovulation in the Chinese loach and common carp. Gen. Comp. Endocrinol. 69:31-40.
      22. Lin, H.R., Zhou, X.J., Van der Kraak, G. and Peter, R.E. 1991. Effects of gonadotropin-releasing hormone agonists and dopamine antagonists on gonadotropin secretion and ovulation in Chinese loach, Paramisgurnus dabryanus. Aquaculture. 95:139-147.
      23. Millar, R.P., Assefa, D., Ott. T., Pawson, A., Troskie, B., Wakefield, I. and Katz, A. 1998. GnRH and GnRH analogues: structure, actions and clinical applications. Horm. Front. Gyn. 5:77-87.
      24. Mohamad-Zaini, S., Saadon, K. and Omar, A.B. 1994. OVAPRIM – Satu teknologi baru pembiakan ikan akuarium. Prog. Fish. Res. Conf. Dept. Fish. Malaysia. 4:257-260.
      25. Mylonas, C.C. and Zohar, Y. 2001. Use of GnRHa-delivery systems for the control of reproduction in fish. Rev. Fish Biol. Fisheries. 10:463-491.
      26. Nelson, J.S. 1994. Fishes of the world, 3rd Edn., John Wiley and Sons Inc., New York.
      27. [No authors listed]. 1977. A new highly effective ovulating agent for fish reproduction. Practical application of LH-RH analogue for the induction of spawning of farmed fishes. Scientia Sinica. 20(4):469-474.
      28. [No authors listed]. 1978. The role of LH-RH in induction of spawning in grass carp (Ctenopharyngodon idellus). I. Cytological and histochemical studies of the pituitary and of the ovary. Scientia Sinica. 21(3): 390-396.
      29. Omeljaniuk, R.J., Shih, S.H. and Peter, R.E. 1987. In vivo evaluation of dopamine receptor-mediated inhibition of gonadotropin secretion from the pituitary gland of the goldfish. J. Endocrinol. 114:449-458.
      30. Palmer D.D., Burrows, R.E., Robertson, O.H. and Newman, H.W. 1954. Further studies on the reactions of adult blueback salmon to injected salmon and mammalian gonadotropins. Prog. Fish Cult. 16:88-107.
      31. Peter, R.E. and Crim, L.W. 1979. Reproductive endocrinology of fishes: Gonadal cycles and gonadotropin in teleosts. Annu. Rev. Physiol. 41:323-335.
      32. Peter, R.E., Nahorniak, C.S., Sokolowska, M., Chang, J.P., Rivier, J.E., Vale, W.W., King, J.A. and Millar, R.P. 1985. Structure-activity relationships of mammalian, chicken, and salmon gonadotropin releasing hormones in vivo in goldfish. Gen. Comp. Endocrinol. 58(2):231-242.
      33. Peter, R.E., Sokolowska, M., Nahorniak, C.S., Rivier, J.E. and Vale, W.W. 1987. Comparison of [D-Arg6, Trp7, Leu8, Pro9 NEt]-luteinizing hormone-releasing hormone (sGnRH-A), and [D-Ala6, Pro9 NEt]-luteinizing hormone-releasing hormone (LHRH-A), in combination with pimozide, in stimulating gonadotropin release and ovulation in the goldfish, Carassius auratus. Can. J. Zool. 65:987-991.
      34. Peter, R.E., Chang, J.P., Nahorniak, C.S., Omeljaniuk, R.J., Sokolowska, M., Shih, S.H. and Billard, R. 1986. Interactions of catecholamines and GnRH in regulation of gonadotropin secretion in teleost fish. Rec. Prog. Horm. Res. 42:513-548.
      35. Peter, R.E., Lin, H.R. and Van der Kraak, G. 1988. Induced ovulation and spawning of cultured freshwater fish in China: Advances in application of GnRH analogues and dopamine antagonists. Aquaculture. 74:1-10.
      36. Peter, R.E. and Yu, K.L. 1997. Neuroendocrine regulation of ovulation in fishes: basic and applied aspects. Reviews in Fish Biology and Fisheries. 7:173 197.
      37. Pironet, F.N., Bosc, F.A. and Jenkins, G.I. 1999. Preliminary trials of hormone-induced production of fertilized eggs in the West Australian Dhufish (Glaucosoma hebraicum, Richardson, 1845). Asian Fish. Sci. 12:119-132.
      38. Powell, J.F.F., Fischer, W.H., Park, M., Craig, A.G., Rivier, J.E., White, S.A., Francis, R.C., Fernald, R.D., Licht, P., Warby, C. et al. 1995. Primary structure of solitary form of gonadotropin-releasing hormone (GnRH) in cichlid pituitary; three forms of GnRH in brain of cichlid and pumpkinseed fish. Regul. Pept. 57:43-53.
      39. Powell, J.F.F., Krueckl, S.L., Collins, P.M. and Sherwood, N.M. 1996.  Molecular forms of GnRH in three model fishes: rockfish, medaka and zebrafish. J. Endocrinol. 150:17-23.
      40. Powell, J.F.F., Brackett, J. and Battaglia, J.A. 1998. Induced and synchronized spawning of captive broodstock using Ovaplant and OVAPRIM. Bull. Aquacult. Assoc. Can. 3:14-18.
      41. Robertson, O.H. and Rinfret, A.P. 1957. Maturation of the infantile testes in rainbow trout (Salmo gairdnerii) produced by salmon pituitary gonadotrophins administered in cholesterol pellets. Endocrinology. 60:559-562.
      42. Sahoo, S.K., Giri, S.S. and Sahu, A.K. 2005. Induced spawning of Asian catfish, Clarias batrachus (Linn.): effect of various latency periods and sGnRHa and domperidone doses on spawning performance and egg quality. Aquacult. Res. 36:1273-1278.
      43. Sarkar, U.K., Deepak, P.K., Negi, R.S., Singh, S. and Kapoor, D. 2006. Captive breeding of endangered fish Chitala chitala (Hamilton-Buchanan) for species conservation and sustainable utilization. Biodiversity and Conservation. 15:3579-3589.
      44. Schally, A.V. and Coy, D.H. 1976. Stimulatory and inhibitory analogs of luteinizing hormone releasing hormone. In: Hypothalamic Peptide Hormones and Pituitary Regulation. J.C. Porter, ed. Plenum, New York. 99-121.
      45. Schmidt, P.J., Mitchell, B.S., Smith, M. and Tsyuki, H. 1965. Pituitary hormones of the Pacific salmon. I. Response of gonads in immature trout (Salmo gairdnerii) to extracts of pituitary glands from adult Pacific salmon (Oncorhynchus). Gen. Comp. Endocrinol. 56:197-206.
      46. Sherwood, N., Eiden, L., Brownstein, M., Spiess, J., Rivier, J. and Vale, W. 1983. Characterization of a teleost gonadotropin-releasing hormone. Proc. Natl. Acad. Sci. USA. 80:2794-2798.
      47. Winberg, S., Winberg, Y. and Fernald, R.D. 1997. Effect of social rank on brain monoaminergic activity in a cichlid fish. Brain Behav. Evol. 49(4):230-236.
      48. Yanong, R.P.E., Curtis, E.W., Terrell, S.P. and Case, G. 2003. Atypical presentation of mycobacteriosis in a collection of frogfish (Antennarius striatus). Journal of Zoo and Wildlife Medicine 34(4):400-407.
         
  3. USER SAFETY:

    The product labeling contains the following information regarding safety to humans handling, administering, or exposed to OVAPRIM: 

    Care should be taken to avoid accidental contact or self-injection.  In the event of accidental self-injection, seek medical advice immediately.  Use in a well ventilated area.  Wear gloves, goggles and suitable protective clothing.  Not for use in humans.  Keep out of the reach of children. 

    Inhalation may be harmful.  If breathing becomes difficult, move to fresh air, and contact a physician. 

    Ingestion may be harmful.   If the person is conscious, wash out mouth with copious amounts of water and contact a physician. 

    Eye contact may be harmful.  In case of eye contact, flush with copious amounts of water for at least 15 minutes.  Assure adequate flushing by separating eyelids with fingers.  Contact a physician. 

    Skin contact may be harmful.  In case of skin contact, flush with copious amounts of water for at least 15 minutes.  Remove contaminated clothing and wash before re-using.  Contact a physician.

    The toxicological properties of sGnRHa have not been thoroughly investigated.  The actions are similar to luteinizing hormone releasing hormone (LHRH, Gonadotropin releasing hormone, GnRH) in humans.  LHRH is the key mediator in the liberation of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH).  LHRH may modify reproductive ability by influencing plasma gonadotropin levels and comcomitantly gonadal steroid levels.
  4. AGENCY CONCLUSIONS:

    The information submitted in support of this request for OVAPRIM for addition to the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (Index) for intraperitoneal or intramuscular use as a spawning aid in ornamental finfish broodstock satisfies the requirements of section 572 of the Federal Food, Drug, and Cosmetic Act (act) and 21 CFR part 516. 
  1. DETERMINATION OF ELIGIBILITY FOR INDEXING:

    As part of the determination of eligibility for inclusion in the Index, FDA determined that the drug for this intended use in ornamental finfish broodstock was safe to the user, did not individually or cumulatively have a significant effect on the human environment, and that the description of the methods used in, and the facilities and controls used for, the manufacture, processing and packing of the new animal drug was sufficient to demonstrate that the requestor has established appropriate specifications for the manufacture of the new animal drug.  Additionally, the requestor has committed to manufacture the drug in accordance with current good manufacturing practices (cGMP).

    The Index is only available for new animal drugs intended for use in minor species for which there is a reasonable certainty that the animal or edible products from the animal will not be consumed by humans or food producing animals and for new animal drugs intended for use only in a hatchery, tank, pond, or other similar contained man-made structure in an early, non-food life stage of a food-producing minor species, where safety for humans is demonstrated in accordance with the standard of section 512(d) of the act.  As used in the labeling of OVAPRIM, the words “ornamental fish” refer to a wide variety of finfish species maintained primarily for their appearance and do not include any fish that are consumed by humans or food-producing animals.  Because this new animal drug is not intended for use in food producing animals, FDA did not require data pertaining to drug residues in food (i.e., human food safety) for granting this request for addition to the Index.
  2. QUALIFIED EXPERT PANEL:

    The qualified expert panel for OVAPRIM met the selection criteria listed in 21 CFR 516.141(b).  The panel satisfactorily completed its responsibilities in accordance with 21 CFR part 516 in determining the target animal safety and effectiveness of OVAPRIM as a spawning aid in ornamental finfish broodstock. 
  3. MARKETING STATUS:

    In its written report, the qualified expert panel recommended that OVAPRIM be made available as an over-the-counter (OTC) product for this intended use.  The Agency agrees that this product can be marketed OTC because the product labeling contains adequate directions for use by laypersons and the conditions of use prescribed on the label are reasonably certain to be followed in practice.
  4. EXCLUSIVITY:

    Products listed in the Index do not qualify for exclusive marketing rights. 
  5. ATTACHMENTS:

    Facsimile Labeling:

10 mL vial/container, carton, and package insert

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