ISFM Protocol: An update on a treatment of feline infectious peritonitis in the UK (Updated November 2021)

By Yaiza Gomez Mejias posted 26 Nov, 2021 08:08

  

Sam Taylor BVetMed(Hons) CertSAM DipECVIM-CA MANZCVS FRCVS, Séverine Tasker BVSc BSc DSAM PhD DipECVIM-CA FHEA FRCVS, Danielle Gunn-Moore BSc(Hon), BVM&S, PhD, MANZCVS, FHEA, FRSB, FRCVS, Emi Barker BSc BVSc PhD PGCertTLHE DipECVIM-CA MRCVS, Stephanie Sorrell BVetMed(Hons) MANZCVS DipECVIM-CA MRCVS


In August 2021 remdesivir (Figure 1) became legally available to UK vets for the treatment of feline infectious peritonitis (FIP) in cats. Since that time many cats and kittens have been treated and are still being treated successfully. As with any novel formulation, with experience, adjustments are made in protocols and given the recent release (November 2021) of oral GS-441524 (50 mg tablets) from a specials manufacturer in the UK (Figure 2), this article has been created to support practitioners in the use of remdesivir and GS-441524 in the management of FIP. Treatment may need to be tailored to the individual cat based on response, compliance and client finances. Specific protocols are listed below but will not be appropriate for all.


    Figure 1: Remdesivir for intravenous or subutaneous injection            
         
        








  Figure 1: Injectable remdesivir for intravenous or subcutaneous injection.  


gs

   Figure 2: Oral GS-154424  tablets 
                                                                                                                                                                                                    

Treatment protocols  
Drug dosages have increased from previous recommendations, based on the experience of our Australian colleagues who have treated over 600 cats. Although some cats responded to the previously recommended lower dosages, they found that recurrence at, or towards the end of, the 84-day
(12-week) treatment period was possible, resulting in the need for extension of the treatment at a higher daily dosage. This was ultimately more expensive than if the treatment course had been started at a higher dosage.
 
When using remdesivir and/or GS-441524, treatment options now include a 12-week course of injectable remdesivir, transition from injectable remdesivir to oral GS-441524 or an entirely oral
GS-441524 protocol. Suggested dosages, benefits and limitations of each protocol are provided below. Remdesivir cannot be given orally. Recommended drug dosages (Table 1) depend upon clinical presentation (ie, whether there is an effusion present or not and whether there is ocular and/or neurological involvement). This is due to variation in the tissue penetration of the drugs. Where there is doubt, use of the higher dosage is preferable.
 
Please note that the dosages of oral GS-441524 provided here are higher than quoted in some publications – these publications have used ‘black market’ preparations of so-called GS-441524 in which the amount of active agent given to the cats was not confirmed. The dosages provided here are based on experience using an oral preparation of known GS-441524 content. Thus, extrapolation is not applicable to other oral preparations where the active component and/or its concentration are not known or given by the manufacturer.

 
Combined injectable and oral treatment protocols:
The decision on when to move from injectable remdesivir to oral GS-441524 may depend on the cat’s tolerance of injections (or oral administration of tablets), formulation price differences (including cost of needles, syringes, sharps disposal, wastage) and owner preferences and finances.
 
Experience suggests this transition can be made between 7 and 14 days of starting remdesivir intravenous (IV) or subcutaneous treatment. The change can be made directly; remdesivir is given one day and GS tablets started the next day.

The protocol chosen will depend on the severity of the FIP disease in the cat. Dosages are shown in Table 1.


Table 1: Summary of dosage recommendations for remdesivir and GS-441524
Clinical presentation Remdesivir- by injection GS 441524-oral
Cats with effusions and without ocular or neurological signs 10 mg/kg q24h 10–12 mg/kg q24h
No effusion and without ocular or neurological signs 12 mg/kg q24h 10–12 mg/kg q24h
Ocular signs present (effusive and non-effusive) 15 mg/kg q24h 15 mg/kg q24h
Neurological signs present (effusive and non-effusive) 20 mg/kg q24h 10 mg/kg q12h daily (ie, 20 mg/kg given as a divided dose)


Severe disease
(anorexic, dehydrated, cat usually will be hospitalised)
  1. Initial treatment with once daily intravenous remdesivir (Table 1) for 3–4 days (ie, on days 1, 2, 3 ± 4). This provides a loading dose of the drug. On each day, dilute the remdesivir dose required to a total volume of 10 ml with saline and administer slowly over 20-30 mins manually or with a syringe driver.
  2. Follow with once daily subcutaneous remdesivir at the same dosage (Table 1) up to day 7–14.
  3. Change to once (or twice) daily oral GS-441524 (Table 1) on day 8–15, and continue until at least day 84.
 

Less severe disease
(normal hydration, eating)
  1. Initial treatment with once daily subcutaneous remdesivir (Table 1) up to day 7–14.
  2. Change to once (or twice if very high neurological dosage needed) daily oral GS-441524 (Table 1) on day 8-15, and continue until at least day 84.

Oral only treatment protocol:
An oral GS-441524 treatment only protocol is recommended if injectable not tolerated/
possible financially:
  • Once (or twice if very high neurological dosage needed) daily oral GS-441524 (Table 1) until at least day 84.
      

Potential adverse effects of remdesivir
Remdesivir seems well tolerated. However, the following adverse effects have been reported:
  • transient local discomfort/stinging on injection (see later on prevention);
  • development/worsening of a pleural effusion (not always proteinaceous) in the first 48 h of treatment, sometimes requiring drainage;
  • cats may seem depressed or nauseated for a few hours after IV administration;
  • increases in alanine aminotransferase (ALT) enzyme activity have been reported (it is unclear if this is due to underlying FIP disease or an adverse drug effect);
    • GS-441524 is given on an empty stomach (wash down with a little water) – food can be given 30 mins after treatment.
Mefloquine is given with food, otherwise vomiting often results.mild peripheral eosinophilia has been reported         



Need advice on the treatment of FIP?:
If advice is needed on the diagnosis and treatment of a suspected case of FIP, please email fipadvice@gmail.com



Options for cost limited clients – ideally, therapy should be given using the recommended formulations and dosages for as long as possible (up to 84 days) to increase the likelihood of cure. Only take the options below if absolutely necessary, as relapse may occur, which then requires longer treatment, increasing costs

  • Give oral GS-441524 treatment only for 84 days, as outlined above.
  • Give injectable remdesivir or oral GS-441524 for as many days as the owner can afford before switching to oral mefloquine 62.5 mg 2–3 times weekly (large cat, give three times a week) or 20–25 mg PO q24h (if reformulation of tablets is possible, eg, Novalabs) for completion of an
    84-day treatment protocol; mefloquine is cheaper than remdesivir and GS-441524 but more research is needed to judge its effectiveness in this situation.
  • If an increase in remdesivir dosage is required (eg, due to neurological disease appearing during treatment) but cannot be afforded, mefloquine treatment can be added as adjunct treatment. This is cheaper than remdesivir, although more research is needed to judge the effect of this combination.
  • Feline interferon omega has also been used in the period following treatment with remdesivir/GS-441524 treatment, but further research is needed on this combination to judge if it is necessary.

 

Are oral treatments given with or without food?

  • GS-441524 is given on an empty stomach (wash down with a little water) – food can be given 30 mins after treatment.
  • Mefloquine is given with food, otherwise vomiting often results.



Do not forget to support clients giving oral medications, as this can also be challenging. Direct clients to the iCatCare website for information and videos: https://icatcare.org/advice/how-to-give-your-cat-a-tablet/  

What can I do to help the owners give the subcutaneous remdesivir?

Injection with remdesivir can cause transient local discomfort. The following may help reduce discomfort and improve compliance:

  • Ensure owners use a new needle each time to withdraw the drug from the bottle. This will reduce the risk of bacterial contamination of the bottle, as well as alcohol swabbing the reusable seal top of the bottle before entry of the needle.
  • Ensure owners change the needle after withdrawing the drug from the bottle and before injection (puncturing the reusable seal will blunt the needle).
  • Needle size preference varies; some prefer a 21G needle to make injecting quicker, others find a finer 23G needle is better tolerated, so it may be worth trying both if problems arise.
  • Rotate the injection sites.
  • Have remdesivir at room temperature before administration.
  • Oral gabapentin (50­–100 mg/cat) may be helpful and/or transmucosal or subcutaneous buprenorphine given at least 30–60 mins before the remdesivir injection to induce mild sedation/analgesia.
  • The area to be injected can be clipped to help owners locate the appropriate site to inject and so that topical EMLA cream can be applied 40 mins before injection (although surface desensitisation may not help as it is usually the remdesivir under the skin that causes discomfort).
  • Ensure the full dose of injection is administered at each time-point and encourage owners to report any mishaps as this may influence decisions if relapse occurs.
  • Cats will need several weeks of treatment. Encourage owners to make the injection experience more positive by using treats (eg, Lick-e-lix, Dreamies) around the time of injection, or stroking, brushing or playing with the cat if they are less food motivated. Suggest owners spend time each day with their cat positively engaged to avoid any damage to cat–owner relationships that can reduce compliance.

NOTE ON WEIGHING CATS: It is very important to weigh cats weekly during treatment, using accurate scales – weight gain and/or growth in kittens will occur with successful treatment necessitating an increase in dose to ensure that the dosage of antiviral administered is still appropriate for the type of FIP being treated.

What should I expect during treatment?


  • In the first 2–5 days you should see an improvement in demeanour, appetite, resolution of pyrexia and reduction in abdominal (Figure 3) or pleural fluid if an effusion is present. In some cases pleural fluid can transiently worsen in the first couple of days. If the cat is at home, advise owner to measure resting respiratory rate, plus respiratory effort. Effusion typically resolves by 2 weeks.
  • If an effusion is still present at 2 weeks, consider increasing dosage to one that is greater than that being used (eg, increasing the dosage from that used for cats with effusions only).
  • Serum albumin increases and globulin decreases (ie, they normalise) over 1–3 weeks, but note that globulins can initially increase when a large volume effusion is absorbed.
  • Lymphopenia and anaemia may take longer to resolve, up to 10 weeks.
  • Mild peripheral eosinophilia is a common finding and may be a favourable marker for disease resolution, as it is in COVID patients.
  • Lymph node size reduces over a few weeks.
  • If progress is not as expected, consider reviewing the diagnosis (see below) and/or increasing dosage.                                                                          


Ascites
          
                                    Figure 3: A cat with FIP and ascites. Effusions should start to resolve over 3-5 days after staring treatment.

What do I need to monitor during treatment?

  • Ideally, serum biochemistry and haematology after 2 weeks and then monthly.
  • For cost limited clients, monitor weight/demeanour/effusions (eg, by in-house scanning)/neurological signs/key biochemical abnormalities only (eg, measuring just globulin, bilirubin or spinning microhaematocrit tube for packed cell volume/total proteins/colour of plasma).
  • ALT enzyme activity may increase – it is not clear if this is due to FIP pathology vs drug reaction, and it is not usually a reason to stop therapy. It is not known if the addition of hepatoprotective therapy (eg, SAMe) is helpful in these cases.
  • Point-of-care ultrasonography (POCUS) to monitor for effusion resolution and/or lymph node size.


If I am seeing a positive response to treatment, when do I stop treatment?

  • Not before 84 days (12 weeks).
  • Confirm resolution of previous abnormalities (clinically, POCUS, serum biochemistry and haematology).
  • Only stop treatment once the cat has been normal (clinically and on serum biochemistry and haematology) for at least 2 weeks.

 

What do I monitor after treatment?

  • Advise the owner to monitor the cat closely for any clinical relapse – this monitoring should continue for 12 weeks after completion of treatment.
  • Ideally, repeat serum biochemistry and haematology 2 weeks and 1 month after stopping treatment (to detect any changes that could suggest early relapse).
  • Note that relapse can occur with clinical signs but without any significant biochemical/haematological abnormalities.

 

In the event of relapse (eg, recurrence of effusion, pyrexia, development of ocular or neurological signs, or return of hyperglobulinaemia):

  • Ensure that you are still confident that the cat has FIP – review diagnosis, look for additional pathology, consider repeat sampling (eg, external laboratory analysis of any fluid; cytology or biopsy of lymph nodes).
  • If relapse occurs during treatment – increase the dosage of remdesivir or GS-441524 and monitor as above, ensuring treatment is not stopped before the cat has been normal for at least 2 weeks. The increased dosage used will depend on the dosage the cat is on at the time of the relapse, the nature of the relapse and finances, but can increase to that recommended for neurological FIP (see earlier).
  • If relapse occurs after completion of treatment – restart treatment with remdesivir or GS-441524 at a higher dosage. The increased dosage used will depend on the dosage the cat is on at the time of the relapse and the nature of the relapse, but can be up to that recommended for neurological FIP (see earlier).
  • If it is not possible to increase the dose of remdesivir or GS-441524 (eg, the highest neurological dosage is already in use), consider use of mefloquine as an adjunct treatment (see above) while continuing remdesivir or GS-441524 treatment at the same dosage.

Neutering and routine treatments during therapy for FIP

  • Neutering is ideally performed a month after treatment is completed if the cat has responded. However, if leaving the cat unneutered is causing stress (eg, attempts to escape or distress when queens are on heat) neutering during therapy may be preferred, ideally when the cat is doing well on treatment.
  • There is no contraindication to routine worming and flea treatment for cats on remdesivir or GS-441524.
  • No information is available on vaccination of cats receiving treatment for FIP. Vaccines should be administered as normal if the cat is well during treatment, as these are still likely to be protective. For cats that have received an initial course, consider providing a third dose of vaccine after completion of FIP treatment (see WSAVA Vaccination Guidelines).
  • If veterinary procedures are necessary, clinic stays should be minimised and Cat Friendly Clinic protocols and handling implemented to avoid stress to the cat.


Adjunctive treatments

  • If the cat is on prednisolone treatment, this should be stopped while giving remdesivir or
    GS-441524, unless it is required for short-term management of specific immune-mediated disease arising as a result of FIP (eg, haemolytic anaemia).
  • Supportive therapies such as antiemetics, appetite stimulants, fluid therapy and analgesics can be given with remdesivir or GS-442415 as required.

 

Potential future updates

We are constantly learning about treatment with these drugs and advice may change in time. Other agents such as protease inhibitors (eg, GC374) and other nucleoside analogues (eg, molpurinavir) have also been trialled in cats, but are not commercially available at this time. How these agents and other immunomodulatory agents (eg, polyprenyl immunostimulant) will fit into future protocols is unknown at this time.

 

Updated 15 November 2021

Thank you to Richard Malik for his advice and assistance producing this document. 

 

FIP advice line

Sam Taylor BVetMed(Hons) CertSAM DipECVIM-CA MANZCVS FRCVS

Séverine Tasker BVSc BSc DSAM PhD DipECVIM-CA FHEA FRCVS

Danielle Gunn-Moore BSc(Hon), BVM&S, PhD, MANZCVS, FHEA, FRSB, FRCVS

Emi Barker BSc BVSc PhD PGCertTLHE DipECVIM-CA MRCVS

Stephanie Sorrell BVetMed(Hons) MANZCVS DipECVIM-CA MRCVS

 

The above specialists have come together to run the ‘FIP advice’ email address (fipadvice@gmail.com) answering queries on the new treatments on a voluntary basis and disseminating information to vets and vet nurses in the UK. So far, they have answered over 100 emails on the advice line

 

 







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27 Nov, 2021 13:31

thank you so much for sharing the new protocol to us.

A big thanks to everyone, who are involved in writing it.

Warmest regards
Qiao