Grapiprant - a new medicine for dogs with osteoarthritis

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This module will help you keep up to date with new treatments. Galliprant is the brand name of a new prescription-only veterinary medicine (POM-V), which is licensed for treating ‘pain associated with mild to moderate osteoarthritis in dogs’. Galliprant comes in the form of tablets which contain the drug grapiprant (the generic name). This is a completely new type of drug for use in dogs. By doing this module you will:

  • understand how grapiprant works;

  • know how grapiprant relates to non-steroidal anti-inflammatory drugs (NSAIDs);

  • understand what we know about the safety of grapiprant in dogs

  • be aware of key information that clients need to know about grapiprant

Grapiprant belongs to a new class of drugs called piprants. It works by interfering with the actions of prostaglandins, the chemical messengers involved in the mechanism of pain and inflammation in the body. Another group of drugs that affect the action of prostaglandins in the body is the non-steroidal anti-inflammatory drugs (or NSAIDs). Meloxicam (brands include Metacam) and robenacoxib (Onsior) are examples of NSAIDs. 

Grapiprant has some similarities to NSAIDs, but you can see from the diagram below that it acts at a point further down the prostaglandin pathway (it blocks the action of prostaglandin E2 at EP4 receptors) and so it appears to have a more specific action than NSAIDs. NSAIDs, which act further up the pathway appear to have more widespread effects. For this reason, it is hoped that grapiprant might have some benefits over NSAIDs perhaps by causing fewer side effects. 

Grapiprant is a very new drug. Therefore, there has been limited experience with it and a limited amount of evidence from clinical trials. So far the evidence shows that grapiprant has a pain-relieving effect, but it has not been shown to have an anti-inflammatory effect in dogs. This is in contrast to NSAIDs which are known to have a pain-relieving and anti-inflammatory effect. 

Overall grapiprant was found to provide more pain relief than a placebo in dogs with mild to moderate osteoarthritis in a large randomised controlled trial that lasted 28 days, although not all dogs responded. (A beneficial effect should be seen within 7 days). Grapiprant has not been compared with an NSAID in a clinical trial and so we do not know how effective it is compared to an NSAID.

The most commonly reported side-effect of grapiprant is vomiting (reported in more than 10% of treated dogs). Other reported side effects are soft-formed faeces, diarrhoea and lack of appetite (reported in 1–10% of treated dogs). 

The licensed dose of grapiprant is 2mg/kg daily. In a study of the toxicity of grapiprant, the drug was given to healthy dogs at doses that are much higher than the licensed dose (at 6mg/kg and 50mg/kg daily). At these doses there were only mild gastrointestinal signs such as soft-formed faeces, faeces with mucous, and occasional blood seen in the faeces. These were more likely to occur with the higher dose. No effects were found on liver or kidney function or on blood clotting, and no damage to the stomach was found. This information is reassuring because it suggests that grapiprant might not cause the typical side effects that are associated with NSAIDs. However, it is still important to be cautious because this information is from trials in healthy dogs, and it does not tell us what happens if grapiprant is used to treat dogs with other diseases in addition to osteoarthritis.  For this reason, the summary of product characteristics (SPC) advises that grapiprant should be used with caution in dogs with liver, cardiovascular or renal dysfunction or gastrointestinal disease. Also the safety of grapiprant has not been studied in dogs aged under 9 months of age or those weighing less than 3.6kg. The SPC states that grapiprant should not be used in dogs that are pregnant, lactating or used for breeding.

The use of grapiprant in conjunction with an NSAID has not been studied and so we do not know if the two types of drug interact. It is possible that using them together might increase the likelihood of side effects. This is why the SPC for grapiprant recommends avoiding giving grapiprant to dogs at the same time as an NSAID. Also, if starting grapiprant after stopping an NSAID, there should be an appropriate gap (washout period) before starting grapiprant. 

Grapiprant is given by mouth. It is available as 20mg, 60mg and 100mg tablets, which can be divided. The SPC recommends a target dose of 2mg/kg body weight given as a single daily dose. The owner should be told to give the drug when the dog has an empty stomach (which means at least an hour before a meal). Giving a grapiprant tablet with food reduces and slows its absorption and so might reduce its efficacy. 

Grapiprant has not been used for longer than 28 days in clinical trials and it should only be used for longer durations after careful consideration, and with regular veterinary monitoring; the SPC suggests that intermittent treatment with grapiprant may be beneficial in some dogs because osteoarthritis signs come and go over time.

The owner may have been asked by the vet to record how their dog seems while on treatment (e.g. the dog’s demeanour, or how easily it walks up steps). Owners should be told to look out for any unwanted effects and to report these to the vet. The treatment should be reviewed after 2 weeks and, if there is no improvement, or adverse effects outweigh any benefit, the drug should be stopped. 

Grapiprant (brand name Galliprant) is a new class of drug for relieving pain in dogs with mild to moderate osteoarthritis. It is only available on veterinary prescription. A beneficial effect should be seen within 7 days, but if no effect is seen within 14 days the drug should be stopped. It may not be effective in all dogs. Its effects have not been studied in dogs with severe osteoarthritis. 

Grapiprant must be given on an empty stomach or the amount absorbed, and therefore the efficacy, may be reduced. Vomiting has been reported very commonly (in more than 10% of dogs) and soft-formed faeces, diarrhoea and lack of appetite commonly (in 1–10% of dogs).

We do not know yet how effective grapiprant is at relieving pain compared to NSAIDs. In theory grapiprant might cause fewer side effects than NSAIDs but it is too soon to be certain of this. 

For more information on using grapiprant, refer to the most up-to-date version of the SPC for Galliprant

Podcast

If you prefer, you can listen to the whole audio presentation of this module using the following podcast. Don't forget that you can also download the podcast to your iPod, music player, tablet or smartphone using the Download link on the right of the audio player.

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How we produced this module

Our modules start with a detailed outline and electronic literature search. The collaborating author on this module was Helen Barnett, a specialist in medicines evaluation. The draft is circulated unsigned to a wide range of commentators, include practising first-opinion vets, topic specialists, the companies that market any mentioned drugs and other organisations and individuals, as appropriate. They can raise points about the interpretation of evidence, ask questions that are important to clinical practice, and present alternative viewpoints. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration. 

References

Belshaw Z et al. The attitudes of owners and veterinary professionals in the United Kingdom to the risk of adverse events associated with usingnon-steroidal anti-inflammatory drugs (NSAIDs) to treat dogs with osteoarthritis. Prev Vet Med 2016; 131: 121–6.

Belshaw Z et al. Systematic review of outcome measures reported in clinical canine osteoarthritis research. Vet Surg 2016; 45: 480–7.

Brown DC et al. Ability of the Canine Brief Pain Inventory to detect response to treatment in dogs with osteoarthritis. J Am Vet Med Ass 2008; 233: 1278–83.

European Medicines Agency. Committee for Medicinal Products for Veterinary Use. CVMP assessment report for GALLIPRANT. 2017, online.[Accessed August 2018] [EPAR}

Galliprant. Summary of product characteristics (SPC). Elanco GmbH, January 2018. [Accessed August 2018].

Kirkby Shaw K et al. Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Science 2016; 2: 3–9.

Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Therap 2017; 40: 285–92.

Rausch-Derra LC et al. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res 2015; 76: 853–9.

Rausch-Derra LC et al. Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs. J Vet Pharmacol Therap 2016a; 39: 566–71.

Rausch-Derra LC et al. Prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med 2016b; 30:756–3.

Waller DG et al. Medical Pharmacology and Therapeutics, 4th edition 2014. Saunders Elsevier.

Which NSAID? Veterinary Prescriber, August 2018.

World Health Organization. Programme on International Nonproprietary Names (INN) (2016). Pre-stems: suffixes used in the selection of INN, October 2013 .

WHO Collaborating Centre for Drug Statistics Methodology. ATCVet Index 2018. [Accessed 1 November 2018].