# Tacrolimus Ointment.



## Kylie- (Mar 14, 2011)

Hi,

My dog was recently prescribed Tacrolimus Ointment (0.02%) due to issues with the eyes not being able to produce tears. I was researching about the ointment to see that there has been concern over a possible link to Tacrolimus and cancer? Should I look elsewhere for another medication, or is it safe? 

I'd greatly appreciate a reply.


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## [email protected] (Nov 18, 2013)

Tacrolimus is a relative new drug to the veterinary world. It comes from a class of medications called "calcineurin inhibitors," and it is used most frequent for treating keratoconjunctivitis sicca (also known as KCS or dry-eye). Less commonly this medicine is used topically to treat for allergies (atopy) and for some of the autoimmune skin diseases (discoid lupus erythematosus, pemphigus erythematosus, etc.). In human medicine this medication is used orally for similar conditions at massively higher dosages.
The link between cancer and Tacrolimus was observed in humans following organ transplantation, who were taking very high dosages orally. This effect has been reproduced in mice, using a topical (skin) application model, but again at extremely high dosages. The issue appears to be related to how much of the mediation is absorbed systemically. Using Tacrolimus topically in the eye, there is no systemic absorption. Using the medication topically on the skin at normal application levels, there is no demonstrable systemic absorption. Using the medication topically on the skin at 25 times the normal application level the drug can be detected systemically and there would be a small increased risk of cancer. 
Philosophically all medications pose a certain amount of risk and should not be used unless the risk (and potential side effects) are warranted. Since your dog has KCS (dry-eye), he is at risk of chronic discomfort, inflammation, secondary eye infections, and ultimately severe changes to the corneas and/or vision loss. In mild cases you can treat with artificial tears (available over-the-counter), which are available in both a cream form and a liquid (eyedrop) formulation. If these are not sufficient (and usually they are not) then your choices are Cyclosporine Ophthalmic or Tacrolimus. Cyclosporine used to be widely available as a compounded medication and was relatively affordable. Recently it has been almost impossible to find it in this form and even the big national compounding pharmacies have stopped making it. There is still a commercial form of Cyclosporine available (a cream called Optimmune) which is very good, but also relatively expensive. If you are still concerned about using Tacrolimus you could ask your vet about Optimmune. Personally I am very comfortable with the minimal (non-existant?) risk of cancer that the ophthalmic form of his medication creates. Over the past six months I have transitioned all of my patients with dry-eye to either Tacrolimus or Optimmune. There has been at least one study to show that Tacrolimus is at least as effective as Cyclosporine, and may also be effective in those patients who are resistant to the effects of Cyclosporine.

This is a more in-depth answer to your question (from "Pimecrolimus & Tacrolimus - Not a Cancer Risk," Drs. Mark Rishniw, Douglas Kemp, GiGi S. Davidson, VIN):
What evidence is there of carcinogenesis?
Tacrolimus has been shown to increase risk of neoplasia in humans taking the drug orally to prevent transplant rejection. Animal models with pimecrolimus and tacrolimus, administered orally, also showed increased risk of neoplasia.
Dermal application of tacrolimus or pimecrolimus in mice showed a dose-dependent carcinogenic effect. However, the drugs were applied in an ethanol base, and at doses that were 26 and 47 times the maximum recommended human doses (based on area-under-the-curve comparisons).
Following systemic exposure of monkeys with lymphocryptovirus to oral pimecrolimus at 31 times the maximum recommended human dose for 39 weeks immunosuppressive-related lymphoproliferative disorder was observed.
What is the evidence that they are safe?
Most of the data demonstrating carcinogenic risk has been performed in animal models using greatly excessive doses of drug, often administered orally.
Humans using therapeutic doses of these drugs topically generally had undetectable serum concentrations of drug, and tests of immune function in human patients receiving topical therapy with these drugs showed no evidence of immunosuppression.
Data from Novartis demonstrated that eight malignancies including one colon carcinoma and one squamous cell carcinoma occurred in the clinical trial patients and six malignancies occurred in patients identified from postmarketing surveillance spontaneous reports. Independent experts reviewed the available evidence and concluded that there is no evidence of a causal link between the use of pimecrolimus and the occurrence of the malignancy, based on the type, timing and site of the malignancy.
Worldwide exposure to pimecrolimus is estimated at 814,138 person-years, 520,000 person-years being in the under 10-year age group. Five million individuals have been exposed to pimecrolimus, over 19,000 of these in clinical trials. The average patient uses 75 g per year and treats for 45 days of the year. American sales of pimecrolimus amount to 6,780,000, 70% of these being new prescriptions, and for tacrolimus 2,797,000. There has been worldwide clinical trial exposure to topical tacrolimus in 19,000 adults and 7600 children. A study of 9813 patients during the U.S. clinical development of tacrolimus included 1718 person-years of exposure to tacrolimus in adults aged over 40 years. Patients were followed up for up to 3·5 years and 13 developed nonmelanoma skin cancer (eight basal cell carcinoma and five squamous cell carcinoma). The estimated incidence in these patients was between 361 and 1217 per 100,000. This compared with 533 per 100,000 in a male reference population not exposed to tacrolimus.
The lymphoma rate for tacrolimus treatment is 0·65 per 100,000, compared with an expected 22 per 100,000. Therefore, the incidence of lymphoma, particularly non-Hodgkin, is below that expected by chance in the normal population on the basis of person-years of exposure.
Non-melanoma skin cancer rates in patients on tacrolimus were no different from controls.
This data are strongly supportive of the hypothesis that tacrolimus and pimecrolimus, given topically at recommended doses, do not cause neoplasia in humans. However, as with any strongly immunosuppressive drug, caregivers should be warned to wear gloves or wash hands after handling these drugs.
What conditions can I use these drugs for?
The most common uses of tacrolimus or pimecrolimus in veterinary medicine are for atopy, keratoconjunctivitis sicca, discoid lupus erythematosus and pemphigus erythematosus. It is important to note that all veterinary applications of tacrolimus are topical (either by application to the skin or the eyes) at this time. Systemic use of tacrolimus has proven to be nephrotoxic in dogs and has not been sufficiently evaluated for systemic use in cats.
The commercially available ointment preparations (Protopic®) are not suitable for use by the ophthalmic route as they contain propylene carbonate which is a known ocular toxin. Tacrolimus for ophthalmic use will need to be prepared by a compounding pharmacy from sources other than the commercially available topical ointments.


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## Kylie- (Mar 14, 2011)

[email protected] said:


> Tacrolimus is a relative new drug to the veterinary world. It comes from a class of medications called "calcineurin inhibitors," and it is used most frequent for treating keratoconjunctivitis sicca (also known as KCS or dry-eye). Less commonly this medicine is used topically to treat for allergies (atopy) and for some of the autoimmune skin diseases (discoid lupus erythematosus, pemphigus erythematosus, etc.). In human medicine this medication is used orally for similar conditions at massively higher dosages.
> The link between cancer and Tacrolimus was observed in humans following organ transplantation, who were taking very high dosages orally. This effect has been reproduced in mice, using a topical (skin) application model, but again at extremely high dosages. The issue appears to be related to how much of the mediation is absorbed systemically. Using Tacrolimus topically in the eye, there is no systemic absorption. Using the medication topically on the skin at normal application levels, there is no demonstrable systemic absorption. Using the medication topically on the skin at 25 times the normal application level the drug can be detected systemically and there would be a small increased risk of cancer.
> Philosophically all medications pose a certain amount of risk and should not be used unless the risk (and potential side effects) are warranted. Since your dog has KCS (dry-eye), he is at risk of chronic discomfort, inflammation, secondary eye infections, and ultimately severe changes to the corneas and/or vision loss. In mild cases you can treat with artificial tears (available over-the-counter), which are available in both a cream form and a liquid (eyedrop) formulation. If these are not sufficient (and usually they are not) then your choices are Cyclosporine Ophthalmic or Tacrolimus. Cyclosporine used to be widely available as a compounded medication and was relatively affordable. Recently it has been almost impossible to find it in this form and even the big national compounding pharmacies have stopped making it. There is still a commercial form of Cyclosporine available (a cream called Optimmune) which is very good, but also relatively expensive. If you are still concerned about using Tacrolimus you could ask your vet about Optimmune. Personally I am very comfortable with the minimal (non-existant?) risk of cancer that the ophthalmic form of his medication creates. Over the past six months I have transitioned all of my patients with dry-eye to either Tacrolimus or Optimmune. There has been at least one study to show that Tacrolimus is at least as effective as Cyclosporine, and may also be effective in those patients who are resistant to the effects of Cyclosporine.
> 
> ...


Thank you very much for the thorough reply. I will be talking with the vet about my concerns, but would like to ask you would Optimmune be a better option, or does it still pose the same risk (even though it seems the medication would have to be taken at higher doses as said above) What exactly is the difference between the two? I believe my dog would have to continue to be on whichever drug from now on and I'm hesitant because I'm not quite sure the effects for dogs using this long term. Optimmune (3.5gm) is available to me, price is not a factor as I want the best for him, so would there be one that you would recommend over the other based upon my concerns? I was reading a story of someone suspecting the medicine caused their dog to have bladder cancer and of course it made me nervous. Anymore information is appreciated!


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## [email protected] (Nov 18, 2013)

Personally I don't have a strong preference for either medication and believe both to be safe and effective. Cyclosporine has its own set of concerns (it is also a very strong immunosuppressive medication that can be used orally for organ transplantation), but all of the safety concerns occur when the medication is used systemically at very high dosages. Studies of Optimmune have shown that this medication does absorb systemically when administered in the eye, but the levels are a fraction of those obtained when the drug is given orally. (As an example, when used orally Cyclosporine is used at an average dose of 5mg/kg. A 50 lbs dog would likely receive 100 mg. The drug Optimmune is a 0.2% solution, so it is 2mg/ml. If you place 1 drop in each eye, you might administer 0.1ml total volume, hence 0.2mg total dose. Even if 100% of the drug absorbed systemically, this is still 0.2% of what the pet would receive with oral dosing.) 
I would base your decision on price, availability, and your vet's personal preference rather than on any concerns for safety. Efficacy should be similar between the two.


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## Kylie- (Mar 14, 2011)

[email protected] said:


> Personally I don't have a strong preference for either medication and believe both to be safe and effective. Cyclosporine has its own set of concerns (it is also a very strong immunosuppressive medication that can be used orally for organ transplantation), but all of the safety concerns occur when the medication is used systemically at very high dosages. Studies of Optimmune have shown that this medication does absorb systemically when administered in the eye, but the levels are a fraction of those obtained when the drug is given orally. (As an example, when used orally Cyclosporine is used at an average dose of 5mg/kg. A 50 lbs dog would likely receive 100 mg. The drug Optimmune is a 0.2% solution, so it is 2mg/ml. If you place 1 drop in each eye, you might administer 0.1ml total volume, hence 0.2mg total dose. Even if 100% of the drug absorbed systemically, this is still 0.2% of what the pet would receive with oral dosing.)
> I would base your decision on price, availability, and your vet's personal preference rather than on any concerns for safety. Efficacy should be similar between the two.


Thank you. A question I had also, he tends to rub his paw on his eyes (when they would be irritated) and whatever medication he will take, it may not be effective immediately, which means he will rub his eyes and lick his paws, which would mean injesting the ointment to some degree? I'm still on the fence about either, but if one isn't chosen he will not be better off without. Have studies been done to show any side effects of using Tacrolimus for dogs for long term?

I was also reading this about the medications "Its mechanism for doing so suppresses the immune system—specifically inhibiting T-cell proliferation and preventing the release of pro-inflammatory cytokines. T-cells are like policemen that patrol the body to stop invading bacteria, other pathogens and abnormal body cells. The latter may later develop into cancer without the intervention of T-cells."

Is there truth to this? I'm very particular about what I give my dog, he's too precious to me and I want to make sure I do everything right for him.


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## [email protected] (Nov 18, 2013)

There have been a number of studies on the safety and efficacy of Tacrolimus, including the following: "Safety and tolerability of 0.1% tacrolimus solution applied to the external ear canals of atopic beagle dogs without otitis" (Vet Dermatol. December 2010;21(6):554-65.), 
"Investigation on the clinical efficacy and safety of 0.1% tacrolimus ointment (Protopic) in canine atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over study" (Vet Dermatol. October 2004;15(5):294-303), 
"Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs" (J Am Anim Hosp Assoc. 2004 Jan-Feb;40(1):29-41) 

Most of these studies looked at the issue of the drug doing active harm. You are really asking a different question (could long-term immunosuppression increase the risk of cancer), but this is a really, really difficult question to answer since it is impossible to prove that because a pet was on an immunosuppressive drug they developed cancer. Of course, using these medications topically in the eye, the doses are so small that the question really becomes moot. Even if your dog is rubbing his eyes and licking his paws, the dosages become so small (again, 0.2% of the systemic dose) that the risk is negligible.


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## Kylie- (Mar 14, 2011)

[email protected] said:


> There have been a number of studies on the safety and efficacy of Tacrolimus, including the following: "Safety and tolerability of 0.1% tacrolimus solution applied to the external ear canals of atopic beagle dogs without otitis" (Vet Dermatol. December 2010;21(6):554-65.),
> "Investigation on the clinical efficacy and safety of 0.1% tacrolimus ointment (Protopic) in canine atopic dermatitis: a randomized, double-blinded, placebo-controlled, cross-over study" (Vet Dermatol. October 2004;15(5):294-303),
> "Topical 0.1% tacrolimus for the treatment of discoid lupus erythematosus and pemphigus erythematosus in dogs" (J Am Anim Hosp Assoc. 2004 Jan-Feb;40(1):29-41)
> 
> Most of these studies looked at the issue of the drug doing active harm. You are really asking a different question (could long-term immunosuppression increase the risk of cancer), but this is a really, really difficult question to answer since it is impossible to prove that because a pet was on an immunosuppressive drug they developed cancer. Of course, using these medications topically in the eye, the doses are so small that the question really becomes moot. Even if your dog is rubbing his eyes and licking his paws, the dosages become so small (again, 0.2% of the systemic dose) that the risk is negligible.


Thank you again for the information you are giving! I appreciate it very much. I have one last question, being, why does these medications have to be immunosuppressive? I haven't yet delved into why they work the way they do. Would his ability to fight off anything harmful (even minor) be intact?


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## [email protected] (Nov 18, 2013)

Cyclosporine has two known mechanisms of action: 1) It increases tear production in both normal and abnormal eyes. This is believed to occur because it resembles the hormone Prolactin (it is a "Prolactin analogue") and binds to lacrimal (tear gland) Prolactin receptors. 2) It decreases inflammation by reducing the production of chemicals called interleukins. This reduces the inflammatory process ("arrests self-perpetuating lacrimal adenititis") within the tear producing glands themselves. KCS (dry-eye) is believed to result primarily from an autoimmune process within these glands. The action of Tacrolimus is not as well understood, but almost certainly it works by also reducing inflammation. This is why immunosuppressive drugs are used---because the process is inflammatory and therefore being driven by the immune system. You can also use anti-inflammatory medications (e.g. ophthalmic Prednisolone drops) but they are likely less safe and less efficacious in the long-term. 
In theory these medications only work locally, so they won't affect the pet's systemic immune response, but do reduce the local (eye) immune system. In theory this will increase the risk of eye infections, but since these pets already have very abnormal eyes and increased local mucus production, they are already at high risk for infections. Ironically when tear production increases this risk seems to diminish, even though the eye may not be able to mount a normal immune response.


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## Kylie- (Mar 14, 2011)

[email protected] said:


> Cyclosporine has two known mechanisms of action: 1) It increases tear production in both normal and abnormal eyes. This is believed to occur because it resembles the hormone Prolactin (it is a "prolactin analogue") and binds to lacrimal (tear gland) prolactin receptors. 2) It decreases inflammation by reducing the production of chemicals called interleukins. This reduces the inflammatory process ("arrests self-perpetuating lacrimal adenititis") within the tear producing glands themselves. KCS (dry-eye) is believed to result primarily from an autoimmune process within these glands. The action of Tacrolimus is not as well understood, but almost certainly it works by also reducing inflammation. This is why immunosuppressive drugs are used---because the process is inflammatory and therefore being driven by the immune system. You can also use anti-inflammatory medications (e.g. ophthalmic Prednisolone drops) but they are likely less safe and less efficacious in the long-term.
> In theory these medications only work locally, so they won't affect the pet's systemic immune response, but do reduce the local (eye) immune system. In theory this will increase the risk of eye infections, but since these pets already have very abnormal eyes and increased local mucus production, they are already at high risk for infections. Ironically when tear production increases this risk seems to diminish, even though the eye may not be able to mount a normal immune response.


Thank you again. Apologizes for another question, however I thought I would ask your opinion before going back to the vet today to ask the same thing. He was given Tobradex (0.3%) and was suppose to receive drops in his eyes for 7 days before recheck, in which I would have to purchase one of the other medications we've been discussing. His eyes have started to become runny/goopy. Would I have to start giving Tobradex before giving the other one, or start him on the medication for dry eye now? I think I will have to bring him to the vet today, as he may need to be looked at again.


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## Kylie- (Mar 14, 2011)

Also, I meant to ask. It may be an odd question and nothing to do with it however, would the type of dog food your dog eats play a roll in his eye condition? As in, would it cause or effect it (if not a factor) It may be coincidence, but it seems like he never had issues prior to a food switch, again though I would understand if the two have no correlation.


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## BernerMax (Mar 15, 2013)

All I can say is Wow, the depth of knowledge....
(and funny, I worked with someone who is on that orally, they are Post liver transplant thats why I peeked into this Thread...)...


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## Mr. V (Jan 28, 2010)

[email protected] said:


> Tacrolimus is a relative new drug to the veterinary world. It comes from a class of medications called "calcineurin inhibitors," and it is used most frequent for treating keratoconjunctivitis sicca (also known as KCS or dry-eye). Less commonly this medicine is used topically to treat for allergies (atopy) and for some of the autoimmune skin diseases (discoid lupus erythematosus, pemphigus erythematosus, etc.). In human medicine this medication is used orally for similar conditions at massively higher dosages.
> The link between cancer and Tacrolimus was observed in humans following organ transplantation, who were taking very high dosages orally. This effect has been reproduced in mice, using a topical (skin) application model, but again at extremely high dosages. The issue appears to be related to how much of the mediation is absorbed systemically. Using Tacrolimus topically in the eye, there is no systemic absorption. Using the medication topically on the skin at normal application levels, there is no demonstrable systemic absorption. Using the medication topically on the skin at 25 times the normal application level the drug can be detected systemically and there would be a small increased risk of cancer.
> Philosophically all medications pose a certain amount of risk and should not be used unless the risk (and potential side effects) are warranted. Since your dog has KCS (dry-eye), he is at risk of chronic discomfort, inflammation, secondary eye infections, and ultimately severe changes to the corneas and/or vision loss. In mild cases you can treat with artificial tears (available over-the-counter), which are available in both a cream form and a liquid (eyedrop) formulation. If these are not sufficient (and usually they are not) then your choices are Cyclosporine Ophthalmic or Tacrolimus. Cyclosporine used to be widely available as a compounded medication and was relatively affordable. Recently it has been almost impossible to find it in this form and even the big national compounding pharmacies have stopped making it. There is still a commercial form of Cyclosporine available (a cream called Optimmune) which is very good, but also relatively expensive. If you are still concerned about using Tacrolimus you could ask your vet about Optimmune. Personally I am very comfortable with the minimal (non-existant?) risk of cancer that the ophthalmic form of his medication creates. Over the past six months I have transitioned all of my patients with dry-eye to either Tacrolimus or Optimmune. There has been at least one study to show that Tacrolimus is at least as effective as Cyclosporine, and may also be effective in those patients who are resistant to the effects of Cyclosporine.
> 
> ...


Given that is is against VIN policy to share VIN community information without the permission of the author I hope you have taken the appropriate steps before posting this.


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## [email protected] (Nov 18, 2013)

Yes I have taken the appropriate steps, and no it isn't against VIN policy. To quote the policy: "Sharing VIN-Hosted Information with non-VIN members: Remember, VIN-Hosted Information is copyrighted by the organization that produced it. Use common sense and discretion; generally, it is acceptable to share a paragraph or article or proceedings chapter; it is not acceptable to print out an entire book or proceedings. Be sure to include all source and copyright information in the reproduced material. You may do so without permission from VIN." (underlining is added for emphasis and is not part of the original text)
I did take the precaution of contacting VIN directly over this issue. Their stand was that since this information is intended to help both veterinarians and pet owners, and since the section that I quoted was from a non-copyrighted source, quoting it in this context, with no change in the original author's meaning, and with credit given to both the authors and the source, was fully in line with both VIN policies and with the spirit of that board.


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