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U.S. Department of Health and Human Services

Animal & Veterinary

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FOI Summary Aquacalm

Date of Index Listing:  June 3, 2009                   

FREEDOM OF INFORMATION SUMMARY

Original Request for Addition to the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species

MIF 900-002

Aquacalm

Metomidate Hydrochloride

Ornamental Finfish

“For use as a sedative and anesthetic in ornamental finfish”

Requested by:

Western Chemical Inc.

TABLE OF CONTENTS

I.       GENERAL INFORMATION

II.     EFFECTIVENESS AND TARGET ANIMAL SAFETY

A.  Findings of the Qualified Expert Panel

B.  Literature Considered by the Qualified Expert Panel

III.    USER SAFETY

IV.    AGENCY CONCLUSIONS

A.  Determination of Eligibility for Indexing

B.  Qualified Expert Panel

C.  Marketing Status

D.  Exclusivity

E.   Attachments

I.             GENERAL INFORMATION:

 

A.  File Number:MIF 900-002
B.  Requestor:

Western Chemical Inc.

1269 Lattimore Rd.
Ferndale, Washington  98248

Drug Labeler Code:  050378

C.  Proprietary Name(s):AQUACALM
D.  Established Name(s):Metomidate hydrochloride
E.  Pharmacological Category:Anesthetic/sedative
F.   Dosage Form(s):Soluble powder

G.  Amount of Active Ingredient(s):

 

Each gram contains 1000 mg metomidate hydrochloride powder
H.  How Supplied:Opaque 30 cc or 120 cc bottles containing 1, 5, 10, or 50 g of the product.
I.    How Dispensed:Over-the-counter (OTC)
J.   Dosage(s):

For sedation:  0.1 to 1.0 ppm

For anesthesia:  1.0 to 10.0 ppm

K.  Route(s) of Administration:Immersion
L.  Species/Class(es):Ornamental finfish
M. Indication(s):For use as a sedative and anesthetic in ornamental finfish

 

II.          EFFECTIVENESS AND TARGET ANIMAL SAFETY:

In accordance with 21 CFR part 516, a qualified expert panel evaluated the target animal safety and effectiveness of AQUACALM for immersion use as a sedative and anesthetic in ornamental finfish to determine whether the benefits of using AQUACALM for the proposed use outweigh its risks to the target animal.  The members of the qualified expert panel were:

James D. Bowker, M.S. Biological Sciences, U.S. Fish and Wildlife Service;

Craig A. Watson, M.S. Aquaculture, University of Florida; and

Michael O. Frinsko, M.S. Wildlife Ecology (Aquaculture), North Carolina State University.

A.    Findings of the Qualified Expert Panel:

Based on a thorough review of the literature, results from investigational new animal drug (INAD) studies and their own personal, extensive experience with this drug, the expert panel concluded that AQUACALM is both effective and safe for use as a sedative and anesthetic in ornamental finfish.  Species of ornamental finfish tested include:

Scientific Name

  1. Aequidens portalegrensis
  2. Pterophyllum sp.
  3. Poecilia sphenops
  4. Pomacentrus caeruleus
  5. Trichogaster trichopterus sumatranus
  6. Gyrinocheilus aymonieri
  7. Archocentrus nigrofasciatus
  8. Gnathonemus petersii
  9. Pomatoschistus sp.
  10. Carassius auratus auratus
  11. Oryzias latipes
  12. Xenomystus nigri
  13. Cyprinus carpio carpio
  14. Thayeria boehlkei
  15. Xiphophorus maculatus (Günther)
  16. Poecilia latipinna
  17. Rasbora trilineata
  18. Xiphophorus hellerii
  19. Trichogaster trichopterus
  20. Pomacentrus melanochir
  21. Danio rerio

The expert panel also reviewed information pertaining to use in food producing species as supportive evidence of the safety and effectiveness of use of this product in ornamental finfish species.  Because the indexed product is only for use in ornamental finfish, specific information relating to food producing finfish species is not included in this summary.

A particular stage of anesthesia can be achieved using many different drug dose/duration combinations.  For example, different stages of anesthesia can usually be achieved using the same dose but altering the exposure duration.  On one end of the spectrum, it is possible to achieve light sedation using a very low anesthetic dose and prolonged exposure duration.  On the other end of the spectrum, it is possible to achieve the same stage of light sedation using a much higher anesthetic dose but with a very short exposure duration.  Inherent differences within a species of finfish, let alone differences between fish species, in which it may take several seconds to many minutes longer to sedate fish to the same stage of anesthesia, make it very difficult to identify one dose/duration combination to achieve a pre-determined stage of anesthesia.  Lastly, time to induce the desired stage of anesthesia in a particular fish species, and time to recover, may depend upon several environmental conditions, such as water temperature and pH.  As such, it is desirable to use an anesthetic within a pre-determined range of safe and effective doses and monitor the fish until they reach the desired stage of sedation. 

There are three general uses of immobilization of ornamental fishes:  sedation, loss of equilibrium, and anesthesia.

Sedation (light and deep sedation) of fish is used for visual evaluation, photography, and transport.  Collectors and appraisers often sedate fish for enhanced viewing and photography.  Photography is a tool for ornamental fish breeders, wholesalers, retailers, and exhibitors to display the fish’s virtues and value.  Fish health professionals desire to sedate fish to better evaluate such things as:  reproductive status, skin and fin condition, and presence of certain ectoparasites.  Another important use may be the need to sedate fish for ease of handling, prior to and during both capture and transport.  In general, it is believed that sedated fish survive extended periods of confinement during transport better than non-sedated fish.

Loss of fish equilibrium is desired to facilitate the capture and handling of fish for numerous management and husbandry purposes.  Without the use of anesthetics, fish typically become stressed and display increased excitability during routine attempts to capture them.  Whether by hand or using nets, this type of harsh handling often results in damage to fish skin and fins, and in extreme cases, can even result in fish death.  In addition, increased physiological stress can negatively affect fish maturation and spawning and contribute to disease outbreaks.  Common handling practices include: egg and milt collection, measuring fish length/weight, and measuring features important to ornamental fish breeders and collectors.

Anesthesia of fish is used primarily to improve survival involved with surgical and other invasive procedures.  Different stages of anesthesia are also desired for other reasons, such as when fish are (1) temporarily held in inhospitable environments (e.g., hypoxic, extreme temperature), (2) transferred from one environment to another, and (3) calmed as part of broader research activities.

Different investigators will commonly sedate fish to the same stage of anesthesia, but will use different numerical stage descriptors and/or descriptions to define the same stage of anesthesia.  The descriptors developed by Schoettger and Julin (1967) are useful.

Stage of anesthesiaDescriptorVisual cues
1Light sedationPartial loss of reaction to external stimuli
2Deep sedationPartial loss of equilibrium; no reaction to external stimuli
3aTotal loss of equilibriumFish usually turn over but retain swimming ability
3bTotal loss of equilibriumSwimming ability stops, but fish responds to pressure on the caudal peduncle
4AnesthesiaLoss of reflex activity; no reaction to strong external stimuli
5Medullary collapseRespiratory movement ceases

AQUACALM has been used in Canada and other countries outside the U.S. as a sedative and anesthetic in ornamental fish for over 15 years (Canada Drug Identification Number 00824240).  Metomidate hydrochloride is a rapid acting, water-soluble, non-barbiturate hypnotic (Mattson and Riple 1989, Thomas and Robertson 1991, Knoph 1995) that does not have analgesic properties (Godefroi et al. 1965).  It is considered to have excellent application in fish and other poikilotherms (Stoskopf and Arnold 1984).  Metomidate hydrochloride is thought to exert its activity by being absorbed from the water via the gills into the bloodstream where it produces its sedation or anesthetic effect on the central nervous system.

The Canadian registration allows use of AQUACALM in the following families of ornamental (or non-food) fish:  Siluriformes (e.g., ornamental aquarium catfish), Cyprinidae (e.g., carp, goldfish, and minnows), Poecillidae (e.g., platyfish, live-bearers), Pomacentridae (saltwater damsels), Cichlidae (e.g., cichlids), and Centrarchidae (sunfish, cold water bass).  In peer reviewed scientific literature, ornamental fish species tested include threespot gourami (Crosby et al. 2006), platyfish (Gou et al. 1995a, Gou et al. 1995b), goby (Grottum et al. 1998), elephantnose (Caputi et al. 1998), and goldfish (Massee et al. 1995).  In non-peer reviewed literature, ornamental fish species tested included yellowtail blue damsels and blue damsels (Thomas and Wofford 1985), koi (Crosby 2006, Crosby et al. 2007, Crosby 2008), blue gourami (Stoskopf and Arnold 1984, Crosby 2006, Crosby 2008), goldfish, acara, platyfish, and knifefish (Stoskopf and Arnold 1984), angelfish and hemidaka (Kyowa Hakko Kogyo Co., Ltd. 1984), and Chinese loach (Hao-ren 1984).  Evaluation of metomidate as a safe and effective anesthetic has not been restricted to ornamental fish.  In peer-reviewed scientific literature, it was found that metomidate has also been used successfully in a wide range of fish classified as “food fish” species.  

AQUACALM has also been used in the U.S. under INAD 011-348.  In 2005, AQUACALM administered at doses of 0, 0.2, 0.5, or 1.0 mg/L was used by investigators to sedate/anesthetize seven species of fish in five pilot studies involving a total of 916 individual fish.  Studies were conducted to evaluate the use of metomidate for sedation of ornamental fish during transport and its effect on mortality and fish quality post treatment.  Overall, results suggested that metomidate may benefit cichlids at 1.0 mg/L in that this dose reduced mortalities and improved appearance/behavior after shipping.  Results for all other fish species (zebra danio, three spot gourami, sailfin molly, swordtail, and penguin tetra) were the same.  In 2006, Aquacalm administered at doses of 0, 0.2, 0.5, or 1.0 mg/L was used by investigators to sedate/anesthetize three species of fish in two experiments involving a total of 4,640 individual fish.  Studies were conducted to evaluate the use of metomidate for sedation of ornamental fish during transport and the effect on mortality and fish quality post-treatment.  These results suggested that metomidate may benefit convict cichlids at levels of 1.0 mg/L, with this dose providing reduced mortalities and improved appearance/behavior after shipping.  Results for all other fish species (scissortail rasbora and black molly) were the same.  Several range-finding studies were also conducted during 2006 to determine the effective dose for use of metomidate for sedation of ornamental fish during transport.  Aquacalm was administered to koi (n = 398 fish) at doses ranging from 0.05 to 10 mg/L, and to three spot gourami (n = 354 fish) at doses ranging from 0.1 to 1.0 mg/L. 

In summary, after reviewing the available information, the qualified expert panel concluded that there is considerable evidence that AQUACALM, when used according to the label, is a safe and effective product to sedate/anesthetize a wide range of ornamental finfish species, and that the benefits of using AQUACALM for the proposed use outweigh its risks to the target animal.  

B.     Literature Considered by the Qualified Expert Panel:
  1. Amend, D. F., B. A. Goven, and D. G. Elliot.  1982.  Etomidate: Effective dosages for a new fish anesthetic.  Transactions of the American Fisheries Society 111:337-341.
  2. Birkeland, K.  1996.  Consequences of premature return by sea trout (Salmo trutta) infested with the salmon louse (Lepeophtheirus salmonis Krǿyer): migration, growth, and mortality.  Canadian Journal of Fisheries and Aquatic Sciences 53:2808-2813.
  3. Caputi, A. A., R. Budelli, K. Grant, and C. C. Bell.  1998.  The electric image in weakly electric fish: physical images of resistive objects in Gnathonemus petersii.  The Journal of Experimental Biology 201:2115-2128.
  4.  Cardeilhac. P. T.  1985.  The use of metomidate as a sedative in the transport of tropical freshwater fish.  Report prepared for Wildlife Laboratories Inc., Fort Collins, Colorado.
  5. Couture, P., J. D. Dutil, and H. Guderley.  1998.  Biochemical correlates of growth and condition in juvenile Atlantic Cod (Gadus morhua) from Newfoundland.  Canadian Journal of Fisheries and Aquatic Sciences 55:1591-1598.
  6. Crosby, T.  2006.  Investigation of metomidate hydrochloride as a sedative for transportation of ornamental fish.  Abstract from University of Florida’s 10th Annual Graduate Student Symposium.
  7. Crosby, T. C., B. D. Petty, R. P. E. Yanong, J. E. Hill, K. H. Hartman, H. J. Hamlin, and L. J. Guillette.  2007.  Investigation of metomidate hydrochloride as a sedative for shipping of ornamental fish.  Meeting abstract: 2007 Aquaculture America Conference.
  8. Crosby, T. C.  2008.  Metomidate hydrochloride as a sedative for transportation of selected ornamental fishes.  Masters Thesis (Draft) presented to the Graduate School of the University of Florida.
  9. Crosby, T. C., J. E. Hill, C. A. Watson, R. P. E. Yanong, and R. Strange.  2006.  Effects of tricaine methanesulfonate, hypno, metomidate, quinaldine, and salt on plasma cortisol levels following acute stress in threespot gourami Trichogaster trichopterus.  Journal of Aquatic Animal Health 18:58-63.
  10. Gilderhus, P. A., and L. L. Marking.  1987.  Comparative efficacy of 16 anesthetic chemicals on rainbow trout.  North American Journal of Fisheries Management 7:288-292.
  11. Godefroi, E. F., P. A. J. Janssen, C. A. M. Van der Eycken, A. H. M. T. Van Heertum, and C. J. E. Niemegeers.  1965.  D L-1-(1-arylalkyl) imidazole-5-carboxylate esters.  A novel type of hypnotic agents.  Journal of Medicinal Chemistry 8:220-223.
  12. Grǿttum, J. A., U. Erikson, H. Grasdalen, and M. Staurnes.  1998.  In vivo 31P-NMR spectroscopy and respiration measurements of anaesthetized goby (Pomatoschistus sp.) pre-exposed to ammonia.  Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 120:469-475.
  13. Guo, F-C., L-H. Teo, and T-W. Chen.  1995a.  Effects of anaesthetics on the oxygen consumption rates of platyfish Xiphophorus maculatus (Günther).  Aquaculture Research 26:887-894.
  14. Guo, F-C., L-H. Teo, and T-W. Chen.  1995b.  Effects of anaesthetics on the water parameters in a simulated transport experiment on platyfish, Xiphophorus maculatus (Günther).  Aquaculture Research 26:265-271.
  15. Hao-ren, L.  1984.  Evaluation of Hypnodil (metomidate hydrochloride) for anesthetizing fish and shrimp.  Report prepared Lin Hao-ren, Department of Biolog. Zhongshan University, Guangzhou, P. R. China.
  16. Hedrick, M. S., and R. E. Winmill.  2003.  Excitatory and inhibitory effects of tricaine (MS-222) on fictive breathing in isolated bullfrog brain stem.  American Journal of Physiology – Regulatory, Integrative, and Comparative Physiology 284:405-412.
  17. Iversen, M., B. Finstad, R. S. McKinley, and R. A. Eliassen.  2003.  The efficacy of metomidate, clove oil, Aqui-STM, and Benzoak® as anaesthetics in Atlantic salmon (Salmo salar L.) smolts, and their potential stress-reducing capacity.  Aquaculture 221:549-566.
  18. Kehmeier, K., W. Lance, and S. Flickinger.  1985.  Efficacy of metomidate (Marinil) as a sedative and anesthetic in rainbow trout and channel catfish.  Report prepared for Wildlife Laboratories, Inc., Fort Collins, Colorado and Janssen Pharmaceutica.
  19. Kilgore, K. H., J. E. Hill, R. P. E. Yanong, and J. F. F. Powell.  2007.  Preliminary investigations into the use of metomidate hydrochloride (Aquacalm®) in ornamental cichlids.  Meeting abstract: 32nd Eastern Fish Health Workshop.
  20. Knoph, M. B.  1995.  Effects of metomidate anaesthesia or transfer to pure sea water on plasma parameters in ammonia-exposed Atlantic salmon (Salmo salar L.) in sea water.  Fish Physiology and Biochemistry 14:103-109.
  21. Kreiberg, H., and J. Powell.  1991.  Metomidate sedation reduces handling stress in chinook salmon.  World aquaculture 22:58-59.
  22. Kyowa Hakko Kogyo Co., Ltd.  1984.  Evaluation of metomidate for anesthetizing fishes.  Report prepared by Kyowa Hakko Kogyo Co., Ltd. for Wildlife Laboratories, Inc., Fort Collins, Colorado.
  23. Lemm, C. A.  1993.  Evaluation of five anesthetics on striped bass.  U. S. Fish and Wildlife Service Resource Publication 196.
  24. Limsuwan, C., J. M. Grizzle, and J. A. Plumb.  1983.  Etomidate as an anesthetic for fish: its toxicity and efficacy.  Transactions of the American Fisheries Society 112: 544-550.
  25. Malmstrǿm, T., R. Salte, H. Magnus Gjǿen, and A. Linseth.  1993.  A practical evaluation of metomidate and MS-222 as anaesthetics for Atlantic halibut (Hippoglossus hippoglossus L.).  Aquaculture 113:331-338.
  26. Massee, K. C., M. B. Rust, R. W. Hardy, and R. R. Stickney.  1995.  The effectiveness of Tricaine, quinaldine sulfate and metomidate as anesthetics for larval fish.  Aquaculture 134:351-359.
  27. Mattson, N. S. and T. H. Riple.  1989.  Metomidate, a better anesthetic for cod (Gadus morhua) in comparison with benzocaine, MS-222, chlorobutanol, and phenoxyethanol.  Aquaculture 83:89-94.
  28. Neidig, C. L., D. P. Skapura, H. J. Grier, and C. W. Dennis.  2000.  Techniques for spawning common snook: broodstock handling, oocyte staging, and egg quality.  North American Journal of Aquaculture 62:103-113.
  29. Nelson, J. S.  1988.  Safety and efficacy of metomidate hydrochloride in red-eared sunfish (Lepomis sp.).  Trials conducted at BioMed Research Laboratories, Inc., Bellevue Washington.
  30. Nilssen, K. J., I. E. Einarsdottir, and M. Iversen.  1996.  Metomidate anaesthesia in Arctic char (Salvelinus alpinus L.): efficacy and changes in cortisol, glucose, and lactate levels.  In: Einarsdǿttir, I. E. (Ed.), Production of Atlantic salmon (Salmo salar) and Arctic char (Salvelinus alpinus).  A study of some physiological and immunological responses to rearing routines.  PhD thesis, NTNU, Trondheim, Norway.
  31. Olsen, Y. A., I. E. Einarsdottir, and K. J. Nilssen.  1995.  Metomidate anaesthesia in Atlantic salmon, Salmo salar, prevents plasma cortisol increase during stress.  Aquaculture 134:155-168.
  32. Parker, N. C., and F. van de Wijdeven.  1982.  Evaluation of metomidate as a new anesthetic in fish culture.  Completion Report submitted to Dr. Bill Lance, Wildlife Laboratories, Inc., Fort Collins, Colorado.
  33. Ross, L. G., and B. Ross.  2008.  Anaesthetic and sedative techniques for aquatic animals.  Blackwell Publishing.
  34. Ross, R. M., T. W. H. Backman, and R. M. Bennett.  1993.  Evaluation of the anesthetic metomidate for the handling and transport of juvenile American shad.  The Progressive Fish-Culturist 55:236-243.
  35. Sandodden, R., B. Finstad, and M. Iversen.  2001.  Transport stress in Atlantic salmon (Salmo salar L.): anaesthesia and recovery.  Aquaculture Research 32:87‑90.
  36. Small, B. C.  2003.  Anesthetic efficacy of metomidate and comparison of plasma cortisol responses to tricaine methanesulfonate, quinaldine and clove oil anesthetized channel catfish Ictalurus punctatus.  Aquaculture 218:177-185.
  37. Scordelis, P.  1977.  Evaluation of metomidate hydrochloride for anesthetizing fish.  Report prepared by Phil Scordelis, Tavolek Inc., USA.
  38. Schoettger, R. A., and A. M. Julin.  1967.  Efficacy of MS-222 as an anesthetic on four salmonids.  U.S. Fish and Wildlife Service Resource Publication 19.
  39. Stoskopf, M. K., and J. Arnold.  1984.  Metomidate anesthesia of ornamental freshwater fish.  Report prepared for Wildlife Laboratories, Inc., Fort Collins, Colorado.
  40. Thomas, P., and L. Robertson.  1991.  Plasma cortisol and glucose stress responses of red drum (Sciaenops ocellatus) to handling and shallow water stressors and anesthesia with MS-222, quinaldine sulfate and metomidate. Aquaculture 96:69-86.
  41. Thomas, P., and H. W. Wofford.  1985.  Efficacy of Marinil as a sedative for tropical marine fish: A report.  Report prepared for Wildlife Laboratories, Inc., Fort Collins, Colorado.
  42. Vanden Bossche, H., G. Willemsens, W. Cools, and D. Bellens.  1984.  Effects of etomidate on steroid biosynthesis in subcellular fractions of bovine adrenals.  Biochemical Pharmacology 33:3861-3868.
  43. Vermeer, G. K., and B. Falls.  1988.  Evaluation of metomidate as an anesthetic for common snook Centropomus undecimalis.  Meeting abstract: Symposium on the culture of red drum and other warm water fishes.  Contribution to the Marine Sciences 30:197.

III.       USER SAFETY:

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

Not for use in humans.  Keep out of the reach of children.  Use in a well-ventilated area.  Wear gloves.

Inhalation may be harmful.  Remove immediately from danger zone and provide fresh air.  In case of respiratory problems or respiratory arrest, administer artificial respiration.  Keep the affected individual warm and still and contact  emergency medical help.

Ingestion may be harmful.  If the person is conscious, wash out mouth with copious amounts of water.  Contact emergency medical help.

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 emergency medical help.

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 emergency medical help.

OTHER HEALTH INFORMATION:  The toxicological properties of metomidate hydrochloride have not been thoroughly investigated.  It is thought to act on the central nervous system as an imidazole based non-barbiturate hypnotic.

  IV.       AGENCY CONCLUSIONS:

The information submitted in support of this request for AQUACALM for addition to the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (Index) for use as a sedative and anesthetic in ornamental finfish satisfies the requirements of section 572 of the Federal Food, Drug, and Cosmetic Act (act) and 21 CFR part 516. 

A.    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 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 AQUACALM, 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.

B.     Qualified Expert Panel:

The qualified expert panel for AQUACALM 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 AQUACALM as a sedative and anesthetic in ornamental finfish. 

C.    Marketing Status:

In its written report, the qualified expert panel recommended that AQUACALM 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 described on the label are reasonably certain to be followed in practice.

D.    Exclusivity:

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

E.     Attachments:

Facsimile Labeling:

1, 5, 10, and 50 gram bottle; 1, 5, and 10 gram carton; and package insert