How to Manage Hyperthyroid Cats that Become Resistant to Methimazole

I have a 19-year old female DSH cat who was diagnosed with hyperthyroidism 5 years ago. I chose not to do the radioactive treatment because that treatment required her being away for several days. I didn't want to do surgery to remove the thyroid gland because she was very weak at the time of the initial diagnosis. 

Therefore, I have been treating her with methimazole over all these years. Initially, her daily dosage was 5 mg (divided twice daily). Over the years, it has become necessary to increase this first up to 10 mg/day, then to 15 mg (daily doses divided into 2-3 doses per day). This 15-mg dosage was effective at controlling her hyperthyroidism for a short time, but now her serum thyroid value is high again. Because of the persistent hyperthyroidism, many of her clinical signs have returned. She has lost weight, despite the fact that her appetite has increased.  I have just increased the methimazole dose up to 10 mg twice a day (20 mg/day) but this still does not appear to be helping.  Now I am worried about the effects of the medicine on her kidneys.

Do cats just become accustomed to the methimazole and always need an increasing amount?  How high can we go with the dosage of the methimazole?  

Thank you. 

My Response: 

This scenario that you are describing isn't that uncommon in cats treated with methimazole on a long-term basis. All hyperthyroid cats, as you may know, have one or more thyroid adenomas (benign thyroid tumors), which will continue to grow larger with time (1-7).

Thyroid scans of hyperthyroid cats, illustrating that all of these cats will have a thyroid tumor that will continue to grow larger over time. In some cats, these tumors will become very large or huge, which can lead to "resistance" to methimazole.

How methimazole works to control hyperthyroidism
Methimazole and other antithyroid drugs work by being taken up by the thyroid tumor where the drugs inhibit thyroid hormone production and secretion (1-4,7). Therefore, most hyperthyroid cats will require higher dosages of methimazole to inhibit thyroid hormone secretion as their goiters become larger and the thyroid tumor volume increases.

The methimazole does not change the tumor pathology and cannot stop the tumor from growing (5,6).  In some of these cats, the thyroid adenoma also may transform into a thyroid carcinoma as the disease progresses (6,8). Again, methimazole does nothing to the tumor pathology and cannot stop this from happening.

Why methimazole may become ineffective with time
In answer to one of your questions, hyperthyroid cats do not just become accustomed to the methimazole and need an increasing amount. There is a good explanation for the dose increases and why the drug will fail to work in some cats, especially in those treated chronically.

After use of medical treatment for a number of months to years, many hyperthyroid cats will have fairly large palpable goiters (thyroid enlargement). Because of the large goiter size, these cats can be difficult to regulate and make euthyroid, even when very high daily doses of oral or transdermal methimazole are administered (7). The reason for this is simple— with time, we just can't give a dose of methimazole that is high enough to block thyroid secretion from all of the thyroid tumor cells. In other words, the cat just has too much thyroid tumor tissue and thyroid oversecretion can no longer be adequately suppressed by the methimazole.

How high can we go with the methimazole dose in this cat?
So, what do you do?  The dose of methimazole needed to control hyperthyroid cats is based on what it takes to lower the serum T4 concentration into the reference range, so there is not an upper limit to what methimazole dosage can be used. I've gone as high as 30 mg per day in some cats, although the incidence of side effects tends to be higher as you raise the dose (7). So in your cat, I would continue to raise the dose up to 25 mg and then 30 mg/day, as needed. If this fails to completely control the hyperthyroidism, addition of other drugs such as beta-adrenergic blockers (e.g., atenolol) and/or L-carnitine could also be considered (9, 10).

If your cat was younger, I would strongly recommend definitive therapy (i.e., surgery or radioiodine) in order to remove or destroy the thyroid tumor(s). However, at 19-years of age, that may no longer be feasible, depending on your cat's overall clinical condition.

My Bottom Line:
The underlying cause of hyperthyroidism in all affected cats is a hyperfunctional thyroid tumor. Unless surgically removed or irradiated with radioiodine, these thyroid tumors will tend to grow larger with time, as the disease progressed. If methimazole is used as initial treatment, the drug may eventually become ineffective, even when higher dosages of the drug are used.

Overall, I believe that we should be curing the thyroid tumor in the hyperthyroid cat with definitive treatments, not just controlling the hyperthyroid state for the rest of the cat's life with methimazole. In most hyperthyroid cats, especially those that are young to middle-aged, the use of surgical thyroidectomy or radioiodine are, therefore, the treatments of choice. I do not generally recommend using methimazole on a long-term basis, unless we don't believe that the cat will live for another couple of years. Both surgery and radioiodine can be more difficult in cats with large goiters and severe hyperthyroidism, so early definitive therapy is always best.

References:

1. Peterson ME. Hyperthyroid diseases In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Fourth ed. Philadelphia: WB Saunders Co, 1995;1466-1487.
2. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
3. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. Manual of Canine and Feline Endocrinology Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;199-203.
4. Peterson ME. Hyperthyroidism in cats In: Rand JS, Behrend E, Gunn-Moore D, et al., eds. Clinical Endocrinology of Companion Animals. Ames, Iowa Wiley-Blackwell, 2013;295-310.
5. Gerber H, Peter H, Ferguson DC, et al. Etiopathology of feline toxic nodular goiter. Vet Clin North Am Small Anim Pract 1994;24:541-565.  
6. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
7. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 ACVIM Forum; 2011 June 15–19; Denver, CO. American College of Veterinary Internal Medicine, pp 104–106.
8. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. J Vet Intern Med 2012;26:1523.
9. Peterson ME. Alternative medical treatments for hyperthyroid cats. Conference Proceedings North American Veterinary Conference (NAVC) Conference 2012: Small Animal & Exotics Proceedings 2012;852-858.
10. Peterson ME. Alternative Medical Treatments for Hyperthyroid Cats. Animal Endocrine Clinic blog, September 13, 2012.

What's the Human Risk Associated with Handling of Thyroid Medications?

Maybe I am missing something here, but I have a question about the human risk associated with handling thyroid medications. Why do you state that owners should be careful when handling and cutting methimazole tablets (Tapazole of Felimazole) because of the human safety concerns (1,2), when I can find no mention that we should use any precautions when handling or cutting L-thyroxine (L-T4) tablets?  I've heard that we should wear gloves when handling methimazole tablets or applying methimazole transdermally to the cat's ear, but no one has ever mentioned the need for gloves with L-T4 tablets.

So why is handling L-thyroxine any less of a concern than handling methimazole? Do they not both have the same potential to affect human thyroid levels? If handling methimazole can lower a human's thyroid levels, why wouldn't handling an L-thyroxine preparation potentially lead to hyperthyroidism?

My Response: 

Methimazole and L-thyroxine are totally different drugs, with different patterns of absorption and metabolism. Methimazole is a potent antithyroid drug whereas L-thyroxine is a synthetic form of natural thyroid hormone.

Methimazole
As you state, we must be careful when cutting methimazole tablets or applying transdermal methimazole since either form of methimazole could potentially be absorbed via human skin (1,2). Methimazole is a human teratogen (i.e., the drug may cause birth defects) and crosses the placenta concentrating in the fetal thyroid gland. Besides being a safety issue in pregnant women or women who may become pregnant, the drug should not be handled by lactating women because methimazole is transferred in breast milk at a high rate.

The same precautions pertain regardless of what methimazole product is used, i.e., the veterinary brand-name Felimazole preparation or a human brand-name or generic product. The methimazole tablets should not be cut with our bare hands. We want to wash our hands after administering the medication to minimize skin and oral contamination; repeated and chronic exposure could pose a risk.

L-Thyroxine
As compared to methimazole, L-thyroxine is not absorbed well from the skin. Results of two studies found that the hormone is not absorbed into the systemic circulation to have an effect on all tissues of the body (3,4). In support of that, of the few dogs that I have evaluated on transdermal L-T4, none have responded to the transdermal replacement therapy with a rise in serum T4 concentrations (5). I know that some compounded pharmacies will sell transdermal preparations of L-T4 but I do not believe that they actually work. Ask for some actual data and you will get none!

So go ahead and cut all the L-T4 pills that you want. It will not get absorbed unless you ingest the hormone supplement so you should still wash your hands to remove any residual L-T4 residue from your hands.

References:

1. Peterson ME. Methimazole-Handling Precautions for Cat Owners. Blog post, Animal Endocrine Clinic, September 2, 2012.
2. Felimazole-Coated Tablets. Product insert. Available at: www.dechra-us.com/files/dechraUSA/downloads/Product%20inserts/Felimazole.pdf 
3. Padula C, Pappani A, Santi P. In vitro permeation of levothyroxine across the skin. Int J Pharm 2008 12;349:161-165. 
4. Padula C, Nicoli S, Santi P. Innovative formulations for the delivery of levothyroxine to the skin. Int J Pharm 2009;372:12-16.
5. Peterson ME. Alternative Dosage Forms of L-Thyroxine for Hypothyroid Dogs. Blog post, Insights into Veterinary Endocrinology, March 28, 2012.

Can Methimazole Cause Anemia in Hyperthyroid Cats?

I am very concerned about my 14-year old male DSH cat. He was diagnosed in the spring with hyperthyroidism and has been treated with oral methimazole (Tapazole). 

 After the first 6 months of treatment, I brought him back to my vet because I was concerned about how skinny he was (very little weight gain on the medication). The vet tested him and increased the Tapazole dosage. He said not to be concerned unless he continued to lose weight.

Now, 2 months later, my cat's weight has held steady on the increased dose of methimazole, but he still remained so skinny that I brought him back for another recheck— even though he wasn't losing weight. It turned out he has developed anemia, so severe that he needed a blood transfusion. He had a bone marrow biopsy, which was consistent with a regenerative anemia. Now my vet wants to just wait and redo his CBC to see how he is in another week.

Because we aren't sure if the methimazole caused the anemia, he isn't putting him back on it right now. He recommended trying Hill's y/d. I tried it (just one can), but my cat isn't keen on it (won't eat it), and he is skinnier than ever now so I don't have the luxury of giving it a chance — I don't want to risk him starving to death!

Now that he's been off the methimazole for about a month. I am really worried about him because he's lost even more weight.

My questions include the following:

1. Can a cat with anemia or recovering from anemia still be a candidate for radioiodine treatment?
2. Can a severely underweight cat be treated for radioiodine treatment? He's only 5 pounds now!
3. If my cat has been off of the methimazole for a month, how much time do we have to get him treated again for his hyperthyroidism? Do we need to restart the methimazole before we do the radioiodine treatment? I'm worried he'll die before I can get it properly addressed. 
4. If I do go for the radioiodine treatment, will he have to wait for a period of time to be treated, since he's eaten a bit of y/d?

Thank you so much!

My Response:

Sorry to hear that your cat isn't doing well. Although rare, antithyroid drugs, including methimazole, can produce hematologic abnormalities, including hemolytic anemia in cats (1-5).  If the drug is responsible for the anemia in your cat, it should never be restarted because that would be life-threatening.

Even if we forget about the anemia for a moment, it is certainly clear that methimazole has not been an effective treatment in your cat. Feeding a low-iodine diet (y/d) might help if he would eat it (many cats won't) but that too is less likely to be successful in cats with severe, chronic, or advanced hyperthyroidism.

Treatment with radioiodine would probably the best treatment, but we would need to be certain that the anemia is resolving before moving forward with this treatment. Anemia is a sign, not a diagnosis in itself. If the methimazole isn't causing it, we need to figure out what is responsible, since that is a sign of serious disease. The good news is that if it is regenerative, that suggests that the bone marrow will be able to respond once the insulting factor (e.g., methimazole) has been removed. Nonregenerative, aplastic anemia is a rare but very serious complication of methimazole treatment in man (5,6), which has only been reported in 1 cat (7); let's hope that this is not the case in your cat.

If the anemia resolves and doesn't recur now that your cat is off the methimazole, I would strongly consider the radioiodine treatment. To do that treatment, we do NOT need to pretreat a cat with methimazole; in fact, we like to have owners stop the drug 1-2 weeks prior to I-131 treatment. Feeding a small amount of y/d will not interfere with the treatment. And finally, severely underweight cats with hyperthyroidism certainly can be treated with radioiodine. Since it's likely that your cat's thyroid tumor may be larger than the average hyperthyroid cat, a larger dose of radioiodine might be needed.

References:

1. Peterson ME, Hurvitz AI, Leib MS, et al. Propylthiouracil-associated hemolytic anemia, thrombocytopenia, and antinuclear antibodies in cats with hyperthyroidism. J Am Vet Med Assoc 1984;184:806-808. 
2. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. J Vet Intern Med 1988;2:150-157. 
3. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
4. Peterson ME. Hyperthyroid diseases In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Fourth ed. Philadelphia: WB Saunders Co, 1995;1466-1487.
5. Yamamoto A, Katayama Y, Tomiyama K, et al. Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis. Thyroid 2004;14:231-235. 
6. Edell SL, Bartuska DG. Aplastic anemia secondary to methimazole-case report and review of hematologic side effects. J Am Med Womens Assoc 1975;30:412-413. 
7. Weiss DJ. Aplastic anemia in cats - clinicopathological features and associated disease conditions 1996-2004. J Feline Med Surg 2006;8:203-206. 
8. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014 (in press).

Methimazole-induced Overgrooming in Cats

Methimazole-induced facial excoriation in a hyperthyroid cat

I have a 13-year old male DSH cat with hyperthyroidism. He's being treated with methimazole but I can't seem to really get an answer from my vet (or my online searching) as to a side effect I think he is having related to the methimazole treatment. 

Have you seen cats excessively groom and/or fur pull as a side effect of the drug? I've read where that shows up as a side effect of hyperthyroidism, but not the medicine. 

My cat only started doing this (fur pulling mostly) once he was put on 7.5mg/day of methimazole. It's so excessive that three weeks ago, I decided to stop the meds and switch him to Hill's Y/D food. That was a mistake as he lost way too much muscle weight and began to look emaciated. Plus, he had a horrible squeaking noise in his intestines! (I did gradually transition the food over a week, but the GI sounds still persisted).

I now have him back on his normal diet of Orijen Cat food (dry) and Blue Spa Turkey (wet). Anyway, he is 3 days back on the methimazole, eating well and regaining weight. But of course, on the second day of restarting the meds, he started fur pulling again.

I'm at a loss.... wondering if you have run across this ever and have any advice? Thank you so much for your time.

My Response:

This certainly sounds like your cat is having an allergic skin reaction to the methimazole. We don't see this very often in cats or humans treated with methimazole, but drug-induced cutaneous reactions can develop in association with almost any drug in the susceptible patient (1-3).

In cats, we see this most frequently around the head and neck area, and these self-induced excoriations will commonly become quite severe (see photo of cat above) (4). In these cases, we generally are forced to stop the drug and use another form of therapy.

In your cat, the fact that the "fur pulling" resolved after stopping the drug and now has recurred once you have restarted the drug is diagnostic for a cutaneous drug allergy. In this case, it doesn't sound life threatening, but if he were my cat, I would treat him with either radioiodine or surgery and get him off this drug —the pruritis must be making him very uncomfortable.

References: 

1. Svensson CK, Cowen EW, Gaspari AA. Cutaneous drug reactions. Pharmacological Reviews 2001;53:357-379. 
2. Khan DA. Cutaneous drug reactions. Journal of Allergy and Clinical Immunology 2012;130:1225-1225 e1226.  
3. Otsuka F, Noh JY, Chino T, et al. Hepatotoxicity and cutaneous reactions after antithyroid drug administration. Clinical Endocrinology 2012;77:310-315. 
4. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157. 

Hyperthyroidism in Cats: Past and Upcoming Topics

As you know, if you have been following this blog, I've spent much of the last few months writing about the diagnosis and treatment of hyperthyroidism, the most common endocrine disorder of the cat.

For my next series of posts, I'm getting back to this series to discuss the next treatment option — namely,  radioactive iodine (radioiodine; I-131), which is considered by most to be the treatment of choice for most cats suffering with hyperthyroidism. I do plan to do a series of posts on a number of issues concerning radioiodine over the next few weeks.

But before I move on to the topics of treatment of this common feline condition, I thought I'd post links to the hyperthyroid topics I've covered thus far:

• Do All Hyperthyroid Cats Have a Thyroid Tumor? Is It Thyroid Cancer? 
• Why Has Hyperthyroidism in Cats Reached Epidemic Levels? 
• Top 10 Signs of Hyperthyroidism in Cats 
• Top 12 Physical Exam Findings in Cats with Hyperthyroidism 
• Hypertension (High Blood Pressure): A Common Problem in Cats 
• Diagnosing Hyperthyroidism in Cats: Routine Testing Procedures 
• Diagnosis of Hyperthyroidism in Cats: Serum T4 Concentrations 
• Diagnosis of Hyperthyroidism in Cats: Serum T3 Concentrations 
• Diagnosis of Hyperthyroidism in Cats: Serum Free T4 Concentrations 
• Diagnosis of Hyperthyroidism in Cats: Serum Free T4 (Part 2) 
• Diagnosis of Hyperthyroidism in Cats: Serum Free T3 Concentrations 
• Diagnosis of Hyperthyroidism in Cats: Serum TSH Concentrations 
• Diagnosis of Hyperthyroidism: T3 Suppression Test 
• Diagnosis of Hyperthyroidism: TRH Stimulation Test 
• Diagnosis of Hyperthyroidism: Thyroid Scintigraphy 
• Treatment Options and Considerations for Hyperthyroid Cats 
• Do Hyperthyroid Cats Ever Go Into Spontaneous Remission? 
• Daily Water and Fluid Requirements and Needs for Hyperthyroid Cats 
• Diet and Nutritional Management of Hyperthyroid Cats 
• Treating Cats with Hyperthyroidism: Antithyroid Drugs 
• Antithyroid Drug Treatment for Hyperthyroidism: Brand Name, Generic, or Compounded Drug? 
• How to Dose and Monitor Hyperthyroid Cats on Methimazole 
• Thyroid Tumors Grow Progressively Larger in Most Hyperthyroid Cats Treated with Methimazole 
• Methimazole-Handling Precautions for Cat Owners 
• Alternative Medical Treatments for Hyperthyroid Cats 
• Treating Cats with Hyperthyroidism: Surgical Thyroidectomy 
• Surgical Thyroidectomy in Cats: Thyroid and Parathyroid Anatomy 
• Surgical Thyroidectomy for Cats with Hyperthyroidism: Preoperative Preparation 
• Thyroid Imaging for Preoperative Staging of Hyperthyroid Cats 
• Surgical Thyroidectomy for Cats with Hyperthyroidism: Intraoperative Considerations 
• Thyroidectomy for Cats with Hyperthyroidism: Surgical Procedure 
• Thyroidectomy for Cats with Hyperthyroidism: Surgical Techniques 
• Complications of Thyroidectomy in Cats: Postoperative Hypocalcemia 
• Complications of Thyroidectomy in Cats: Postoperative Hypothyroidism 
• Complications of Thyroidectomy in Cats: Persistent Hyperthyroidism & Relapse 

My next post on feline hyperthyroidism (entitled, Treating Hyperthyroid Cats with Radioiodine: The Pros and Cons) will go up within the next week; then I'll continue with I-131 treatment issues, with a post once a week.

Would Methimazole Be More Effective Given 3 Times Daily?

I have a hyperthyroid cat being treated with methimazole who is difficult to control. Are there any studies comparing the effectiveness of methimazole given 3 times daily (8 hours) versus twice daily?

I know that the plasma half-life of the drug is relatively short so it makes sense to me that giving the medication more frequently should be more effective.

My Response:

It is clear that twice daily administration of methimazole to cats with hyperthyroidism works much better than only once daily administration (1). No studies have been done in hyperthyroid cats to evaluate the effect of methimazole three times daily.

Pharmacokinetics studies of methimazole in cats document that the drug has a relatively short elimination half-life in the circulation— the average serum half-life of methimazole is only 6-7 hours (2,3). Therefore, one might think that giving the drug 3 or even 4 times a day might be more effective in normalizing the high serum T4 and T3 concentrations in cats with hyperthyroidism. However, most cat owners would not be thrilled about medicating their cat at 6- to 8-hour intervals, and fortunately, administrating methimazole more than twice a day should not ever be necessary.

After absorption, methimazole circulates in the plasma and gets taken up by the cat's thyroid tumor where the drug acts to block thyroid hormone secretion. Because methimazole is concentrated in the thyroid after administration, the intrathyroidal residence time of the drug is considerably longer than serum half-life. In studies of human patients, an intrathyroidal residence time of 24 hours or longer has been documented (4-6). Therefore, the "duration of action" of methimazole within the thyroid tumor becomes much more valuable than does the serum half-life in determining dosing schedules.

Bottom Line

The serum elimination half-life of the methimazole is relatively short in cats, but the residence time of the drug within the thyroid gland is much longer.

Although giving methimazole 3 times a day is not contraindicated, it's probably not going to help any more than simply giving a higher dose twice a day because the residence time appears to be longer than 12 hours in all hyperthyroid cats.

Methimazole is available as the human preparation, Tapazole, as well as the veterinary formulation, Felimazole.

References:

1. Trepanier LA, Hoffman SB, Kroll M, et al. Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. J Am Vet Med Assoc 2003;222:954-958.    
2. Trepanier LA, Peterson ME, Aucoin DP. Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism. Res Vet Sci 1991;50:69-74. 
3. Trepanier LA, Peterson ME, Aucoin DP. Pharmacokinetics of intravenous and oral methimazole following single- and multiple-dose administration in normal cats. J Vet Pharmacol Ther 1991;14:367-373. 
4. Okuno A, Yano K, Inyaku F, et al. Pharmacokinetics of methimazole in children and adolescents with Graves' disease. Studies on plasma and intrathyroidal concentrations. Acta Endocrinol (Copenh) 1987;115:112-118. 
5. Jansson R, Dahlberg PA, Johansson H, et al. Intrathyroidal concentrations of methimazole in patients with Graves' disease. J Clin Endocrinol Metab 1983;57:129-132. 
6. Huang G. Relation between the dosage of methimazole and its intrathyroidal concentrations. Zhonghua Yi Xue Za Zhi 1991;71:301-303, 322. 

Methimazole-Handling Precautions for Cat Owners

Methimazole is considered by most veterinarians to be the antithyroid agent of choice when using drugs to control feline hyperthyroidism (1,2).

For many years, veterinarians prescribed methimazole to cats "off-label," using either a generic or brand-name product (Tapazole and Northyx) designed for human use (3-5).  A methimazole product specifically licensed for treatment of cats with hyperthyroidism (Felimazole, Dechra Veterinary Products) was only first released in 2009 (6).

In addition to methimazole tablets, transdermal methimazole gels are also commonly used in hyperthyroid cats, particularly in fractious cats or in those that develop GI side effects from the oral methimazole drug (7,8). Such transdermal preparations are not FDA-approved but are widely available through compounding pharmacies.

Is Methimazole a Safe Drug to Handle?
Label warnings on Felimazole (9), the form of the drug actually made and licensed for cats, points out the potential risks of methimazole in humans handling the drug. Many owners and veterinarians are not aware of the potential dangers associated with the "casual handling" of this drug.

The Felimazole label has a section on “Human Warnings” that reads as follows (9):

Human warnings

Not for use in humans. Keep out of reach of children. For use in cats only. 

Wash hands with soap and water after administration to avoid exposure to drug. 

Do not break or crush tablets. Wear protective gloves to prevent direct contact with litter, feces, urine, or vomit of treated cats, and broken or moistened tablets. Wash hands after contact with the litter of treated cats. Methimazole is a human teratogen and crosses the placenta concentrating in the fetal thyroid gland. There is also a high rate of transfer into breast milk. Pregnant women or women who may become pregnant, and nursing mothers should wear gloves when handling tablets, litter or bodily fluids of treated cats. Methimazole may cause vomiting, gastric distress, headache, fever, arthralgia, pruritus, and pancytopenia. In the event of accidental ingestion/overdose, seek medical advice immediately and show the product label to the physician. 

What's the Issue Here?
The major issue is oral absorption of residual drug (powder, dust) on a person's hands rather than direct absorption through the human skin. However, methimazole potentially can be absorbed through human skin as well, since the transdermal product in well-absorbed in most cats.

Methimazole is a human teratogen (i.e., the drug may cause birth defects) and crosses the placenta concentrating in the fetal thyroid gland. Besides being a safety issue in pregnant women or women who may become pregnant, the drug should not be handled by lactating women because methimazole is transferred in breast milk at a high rate.

The same precautions pertain regardless of what methimazole product is used, i.e., the veterinary brand-name Felimazole preparation or a human brand-name or generic product.  The methimazole tablets should not be cut with our bare hands. We want to wash our hands after administering the medication to minimize skin and oral contamination; repeated and chronic exposure could pose a risk. Special attention should be given to the potential for unwitting human exposure through cat’s bodily fluids and excretions, including the feces, urine, and vomitus.

Bottom Line: 

• Methimazole, in any form, should be handled with some caution. 
• Wash hands with soap and water after handling drug. 
• Do not break, cut, or crush tablets. 
• Wear protective gloves when handling litter, feces, urine, or vomit of treated cats.
• Wear gloves when handling broken or moistened tablets. 
• Wash hands after contact with the litter of treated cats.
• Wear gloves or finger cots when applying transdermal methimazole.
• Keep all forms of methimazole out of reach of children.
• Pregnant women and nursing mothers should not handle methimazole, if possible 

These warning may be overkill, but it's always best to be careful, especially if one is pregnant. Absorption through intact skin is probably minimal, but transfer of the "powder" from the methimazole tablet or transdermal gel into the mouth, nose, or eyes might be significant over time. So never forget to washes you hands after touching the methimazole tablets or gel.

References:

1. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
2. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
3. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157. 
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. VIN News Service. FDA green lights Felimazole to treat feline hyperthyroidism. June 11, 2009.
7. Hoffmann G, Marks SL, Taboada J, et al. Transdermal methimazole treatment in cats with hyperthyroidism. Journal of Feline Medicine and Surgery 2003;5:77-82.
8. Sartor LL, Trepanier LA, Kroll MM, et al. Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism. Journal of Veterinary Internal Medicine  2004;18:651-655.
9. Felimazole-Coated Tablets. Product insert. Available at: www.dechra-us.com/files/dechraUSA/downloads/Product%20inserts/Felimazole.pdf

Thyroid Tumors Grow Progressively Larger in Most Hyperthyroid Cats Treated with Methimazole

As I discussed in my last post (Managing Hyperthyroid Cats That Become Unresponsive to Methimazole), methimazole blocks thyroid hormone secretion from a hyperthyroid cat's thyroid tumor (usually a benign tumor). However, in cats treated with methimazole, it is quite common for hyperthyroid cats on methimazole treatment to need higher dosages of methimazole over time, as the thyroid adenoma continues to grow larger and increases its secretion of thyroid hormone (1-3).

No one has yet studied the long-term effects of nutritional management with a low-iodine diet (i.e., Hill's y/d) on thyroid tumor growth in these hyperthyroid cats. However, the same progressive growth of the thyroid tumor would be expected on a low-iodine diet, since the thyroid tumor remains and is free to continue to grow progressively larger with time.

Figure 1: Hyperthyroid cat who has developed a very large thyroid tumor after 3 years of methimazole treatment. Notice the swollen neck, which turned out to be a massive thyroid carcinoma.

After months to years of methimazole treatment, many of these cats will develop a very large, palpable thyroid tumor (Figure 1) and will become difficult to regulate, even with high daily doses of oral or transdermal methimazole (3-5). Some cats eventually become completely refractory to methimazole, so alternative treatment modalities must be considered.

With enough time and as the disease progresses, the benign thyroid adenoma characteristic of early feline hyperthyroidism can also transform into malignant thyroid carcinoma in some cats (5,6). Again, methimazole or other antithyroid drug therapy (including Hill's y/d) does nothing to the thyroid tumor pathology and cannot stop this from happening.

Radioiodine therapy can be used to successfully treat cats with all sizes of benign and malignant thyroid tumors, but is best used on cats with small benign tumors. Cats with small thyroid tumors are easier to cure with lower radioiodine doses, resulting in shorter hospitalization times.

Video Animation: Thyroid Growth on Methimazole

The animation below describes the continued growth of the initially benign thyroid tumors causing hyperthyroidism in cats during their medical management with methimazole (Tapazole).

This video was done by my colleague and friend, Dr. Michael Broome, Director of Advanced Veterinary Medical Imaging in Orange Country, California. We have been long-term collaborators on clinical research issues pertaining to cats with hyperthyroidism, and we continue to work closely together on this common disorder (4,5).




References:

1. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
2. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
3. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
4. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2012; 26:754.
5. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. Proceedings of European College of Veterinary Internal Medicine; 2012.
6. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. Journal of Feline Medicine and Surgery 2009;11:116-124.

Managing Hyperthyroid Cats that Become Unresponsive to Methimazole

Antithyroid drugs (methimazole or carbimazole) are commonly used as the primary means of long-term therapy for cats with hyperthyroidism. During chronic treatment (i.e., over a period of many weeks to years), many cats will develop a "resistance" to this medication. These cats will need progressively higher daily dosages of methimazole (or carbimazole) in order to keep serum thyroid hormone values within the normal, reference range limits (1-3).

The purpose of this post is to address the following questions:

• What's the highest methimazole dose that can be given?
• What causes this methimazole resistance during long-term antithyroid drug treatment?
• Could this be caused by thyroid cancer?
• What other treatments should be considered?

What's the Highest Methimazole Dose That Can Be Given to Cats?
There is no maximum dose of methimazole for cats.  However, when methimazole doses approach 10 to 15 mg twice daily (20-30 mg/day) and the serum T4 remains high, it is advisable to consider other treatment options (see below).

However, several issues should be first considered.

1. First, ensure that the tablets are consistently being put into the cat's mouth and that the cat is swallowing the pills. Many cats will learn to hold the pill in their mouth and spit it out later when the owner is not watching.  If the medication is given in food, it is common for cats to "eat around" the pill and not swallow it. If oral medication becomes an issue in treatment,  transdermal methimazole can be considered (4,5). 
2. Secondly, the problem may be the use of generic formulations of methimazole, which are not always as bioavailable or effective as brand-name products (Felimazole; Tapazole). A change to a brand-name product can sometimes be helpful.
3. Third, gastrointestinal problems (e.g., inflammatory bowl disease) could be affecting methimazole absorption. If the cat has chronic vomiting or diarrhea, a workup for primary intestinal disease might be required.
4. Finally, we must consider the possibility that a thyroid cancer (carcinoma) has developed, which generally is less responsive to the methimazole than benign thyroid tumors (see below).

Other than the last issue, most of these problems would have been addressed early on in the course of medical management. So these issues are typically not the cause of the methimazole resistance that we see in hyperthyroid cats treated chronically with antithyroid drugs.

Why is the Dose of Methimazole Increasing?
After methimazole (or carbimazole) is administered, the thyroid gland takes up and concentrates the antithyroid from the circulation. Once within the thyroid, methimazole works by inhibiting the production of T4 and T3 from the hyperthyroid cat's thyroid tumor (4,5).

It is imperative to understand that methimazole treatment blocks T4 and T3 production from the hyperthyroid cat's thyroid tumor but does not cure the disease. In cats treated with methimazole, the underlying cause of the hyperthyroidism (a benign thyroid tumor called an adenoma) remains intact. It is, therefore, quite common for hyperthyroid cats on methimazole treatment to need higher dosages of methimazole over time, as the thyroid adenoma continues to grow larger or increases its secretion of thyroid hormone (1-3,6).

Figure 1: Hyperthyroid cat that has developed a large thyroid tumor
after 18 months of methimazole treatment

After months to years of treatment, many of these cats will develop a very large, palpable thyroid tumor (Figure 1) and will become difficult to regulate, even with high daily doses of oral or transdermal methimazole. Some cats eventually become completely refractory to methimazole, so alternative treatment modalities must be considered.

Could This Be Thyroid Cancer?
With enough time and as the disease progresses, the benign thyroid adenoma characteristic of early feline hyperthyroidism can also transform into malignant thyroid carcinoma in some cats (7,8). Again, methimazole or other antithyroid drug therapy does nothing to the thyroid tumor pathology and cannot stop this from happening.

Figure 2: The thyroid scan on the left is from a cat that has become unresponsive to methimazole after 3 years of treatment.  This cat has massive thyroid tumors located both in the neck area but also extending well into the chest cavity (compare to normal thyroid scan on right). This is considered diagnostic for thyroid carcinoma.

As someone who does thyroid imaging and radioiodine treatment, I commonly see cats that have been treated for years with antithyroid drugs and now have very large to huge thyroid tumors. In about 10% of these cats with severe, long-standing hyperthyroidism, the diagnosis is thyroid carcinoma with extension of tumor or metastasis into the chest (Figure 2). It's quite likely that transformation of the tumor from adenoma to carcinoma has occurred in these cats. This may be the natural evolution of the disease; however, antithyroid drugs have been shown to be carcinogenic in rodents, it is possible that the drug treatment is playing a role.

Do All Hyperthyroid Cats Exhibit Progressive Growth of Their Thyroid Tumor(s)?
Fortunately, all cats do not show accelerated tumor growth on methimazole. In a few cats, the thyroid tumor grows very slowly or not at all (7). Most cats, however, definitely have an increase in thyroid size over time. And some cats show a rapid increase in size, just within a few months.

Unfortunately, in a newly diagnosed hyperthyroid cat, we have no way to determine how fast the thyroid tumor is going to grow or its potential for malignant transformation.

What Other Treatments Should Be Considered in Cats Unresponsive To Methimazole?
In cats that develop large thyroid tumors and become resistant to the effects of methimazole, we have 3 options for treatment: radioiodine, surgical thyroidectomy, or nutritional management with a low-iodine diet (Hill's y/d).  Of these 3 options, radioiodine is the treatment option of choice.

Surgery has a major advantage over methimazole and nutritional therapy because the large, potentially malignant thyroid masses are removed and the cat is potentially cured (9). However, complications of surgery are intensified in cats with large thyroid masses. First of all, these larger tumors are very vascular, may be invasive, and can bleed during the surgical procedure. This can make it difficult to identify the parathyroid glands, which must be preserved to prevent a low serum calcium from developing postoperatively. In addition, many of these cats have thyroid tumors that now extend into the thoracic cavity or have metastasized. Therefore, complete surgical removal of all thyroid tumor tissue may not be possible.

In most cats with severe hyperthyroidism and large thyroid masses, the use of nutritional management is not successful in normalizing thyroid hormone concentrations, similar to the methimazole. Even if this form of therapy did successfully lower serum T4 values to normal, the large and potentially malignant thyroid tumors remain, enabling them to continue to grow and possibly metastasize.

Although use of radioiodine is generally successful in treating cats that have been unresponsive to methimazole, these cats can be much more difficult to cure with a single dose of radioiodine than are cats with smaller thyroid tumors or recently diagnosed hyperthyroidism (1-3). Cats with huge benign or malignant tumors require much larger doses of radioiodine to ablate (10 to 30 mCi) the thyroid tumor(s) than do the typical recently diagnosed cats with mild to moderately hyperthyroidism (2 to 6 mCi).  Because these cats have been treated for months to years, they also tend to be older and have many more complications, mainly because of the concurrent diseases (e.g., renal disease) that are common in older cats.

References:

1. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
2. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
3. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. Peterson ME, Broome MR. Thyroid scintigraphic findings in 917 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2012; 26:754.
7. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. Proceedings of European College of Veterinary Internal Medicine; 2012.
8. Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. Journal of Feline Medicine and Surgery 2009;11:116-124.
9. Radlinsky MG. Thyroid surgery in dogs and cats. Veterinary Clinics of North American Small Animal Practice 2007;37:789-798.

How to Dose and Monitor Hyperthyroid Cats on Methimazole

Antithyroid drugs, including methimazole and carbimazole, are medications that treat an overactive thyroid (hyperthyroidism) by blocking the thyroid gland's ability to make thyroid hormone. Carbimazole is a "pro-drug" since, after its absorption, it is converted to "active" methimazole in the body; therefore, these drugs can be considered equivalent (1).

Over the 25 years since we first reported the use of methimazole for treatment of cats with hyperthyroidism (2), I have had repeated questions from veterinarians and cat owners about the use of once or twice-daily dosing regimes. In addition, I've had many questions regarding the best time to monitor a hyperthyroid cat's serum thyroid concentrations during methimazole treatment.

The purpose of this post is to review how these drugs actually work to lower serum T4 and T3 values. In addition, I'll provide an overview of my current protocols for dosing and monitoring hyperthyroid cats treated with these drugs.

How Do Antithyroid Drugs Work? What's the Mechanism of Action?
After administration, the thyroid gland takes up and concentrates methimazole from the circulation. Once within the thyroid, methimazole works by inhibiting the production of T4 and T3 from the hyperthyroid cat's thyroid tumor.

More specifically, methimazole blocks thyroid hormone synthesis by inhibiting thyroid peroxidase, an enzyme involved in the oxidation of iodide to iodine, incorporation of iodine into thyroglobulin, and coupling of tyrosine residues to form T4 and T3 (2-7). Methimazole does not block the release of preformed thyroid hormone, so there is generally a delay of 2 to 4 weeks  before serum T4 concentrations return to normal after initializing therapy.

It is important to remember that antithyroid drugs, such as methimazole, do not destroy the thyroid tumor, decrease it's size, or slow the progressive thyroid tumor growth that is characteristic for this disorder. Because the thyroid tumor continues to grow larger over time despite methimazole therapy, the need for higher doses should be anticipated during long term treatment in many cats (6-8).

How Long Does a Dose of Methimazole "Last" After Its Given? 
After oral administration, studies show that methimazole has a relatively short half-life in the circulation—only 2.3 hours and 4.7 hours in hyperthyroid and normal cats, respectively (9,10).  But we must remember that this drug does not work to lower T4 by remaining in the circulation. Rather, this antithyroid drug is taken up by the thyroid gland, the site where it acts to inhibit the production of thyroid hormones.  In accord with that, normal cats show sustained suppression of serum thyroid hormone concentrations for up to 24 hours after a single dose of methimazole (11), proving that this drug inhibits T4 production far beyond its known half-life in the circulation.

Unfortunately, once-daily dosing with methimazole will not be adequate in most cats with hyperthyroidism. In one study of 40 hyperthyroid cats (12), once-daily dosing was much less effective than use of twice-daily administration (the total daily dose given was the same in both groups of cats). In that study, only 54% of cats become euthyroid (i.e., normal thyroid state) after 2 weeks with once daily treatment, whereas 87% of cats became euthyroid with twice-daily administration (12).  Therefore, I strongly recommend twice daily dosing of methimazole to help ensure better control of the cat's hyperthyroid state.

If once-daily treatment is insufficient and twice-daily treatment causes compliance issues, a sustained carbimazole formulation (Vidalta, MSD Animal Health) can be tried at 10 to 15 mg, once a daily (13). However, this drug is not approved for use in the USA and is currently only available in Europe.

For more information about carbimazole and Vidalta, see my last post on Antithyroid Drug Treatment for Hyperthyroidism: Brand Name, Generic, or Compounded Drug? 

Initial Methimazole Dose 
The initial methimazole doses used vary depending on the cat’s pretreatment serum T4 value and the size of the thyroid tumor. In general, however, most cats are started on 1.25 mg to 2.5 mg of methimazole, administered twice daily (4-7). This dose is adjusted according to T4 measurements (see below), as well as the cat's clinical response.

In cats that fail to respond and remain hyperthyroid, the daily doses are slowly titrated upwards to lower serum T4 concentrations into the desired range.  For more information about making dose adjustments, see my blog post on: Treating Cats with Hyperthyroidism: Antithyroid Drugs.

Best Time to Collect Blood (Post-Pill) for Monitoring Cats on Methimazole?
Although one might expect that protocols for monitoring cats on methimazole would be standardized among veterinarians, this is not the case.  Some have stated that the time of serum T4 sampling in relation to the administration of the antithyroid drug is not important, even in cats on once-daily methimazole (11).

However, I strongly disagree with that recommendation. We know that the suppressive effect of methimazole on thyroid secretion is highly variable among hyperthyroid cats, depending on the severity of their disease and size of their thyroid tumor. In addition, we also know that twice daily dosing is more effective and that once daily therapy is less likely to be successful in treatment (12).

The protocol that I use for my hyperthyroid cats is to have the methimazole dosed twice a day (morning and night) and then collect the post-treatment serum T4 sample sometime during the day. Ideally, it would make the most sense to me to take the sample around 6 hours post-pill (half-way between the two methimazole administration times), but the "exact" timing does not appear to  critical.

However, I would recommend that one be consistent in the timing of the post-pill test sample. In other words, do not have your cat tested once in the morning (an hour after the methimaole was given) and then compare those results to another testing time when the sample was collected late in the afternoon (11 hours after the methimazole was administered). In other words, we should try to monitor the post-methimazole serum thyroid hormone values at the same time each hospital visit.

What's the Ideal Serum T4 Concentration for Cats on Methimazole? 
It is important to keep the serum T4 concentration within the mid-normal range and not have even mildly high or high-normal values on methimazole. For example, if the T4 reference range is listed as 0.8-4.0 μg/dl (10-50 nmol/L), my goal is maintain the T4 values between 1.5-2.5 μg/dl (20-32 nmol/L). Recent research indicates that hyperthyroidism may contribute to the development or progression of chronic renal disease in cats (14-16).  Leaving a hyperthyroid cat untreated (or poorly regulated with methimazole or carbimazole) may therefore be detrimental to long-term kidney function and is never recommended.

During long-term treatment, it is also important to avoid inducing hypothyroidism, which may be deleterious to the cat’s kidney function (25,26). If hypothyroidism is suspected, a complete thyroid panel is recommended, including determination of the serum concentrations of total T4, free T4, T3, and TSH (see my previous blog posts on diagnostic testing for more information about these tests). The findings of low serum free T4 with high TSH concentrations is diagnostic for iatrogenic hypothyroidism; in those cats, the daily dose of methimazole  should be decreased.

References:

1. Peterson ME, Aucoin DP. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science 1993;54:351–355. 
2. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157. 
3. Peterson ME: Hyperthyroidism, In: Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Fifth Edition). Philadelphia, WB Saunders Co. 2000; pp 1400-1419. 
4. Trepanier LA. Medical management of hyperthyroidism. Clinical Techniques in Small Animal Practice 2006;21:22–28.
5. Trepanier LA. Pharmacologic management of feline hyperthyroidism. Veterinary Clinics of North American Small Animal Practice 2007;37:775-788.
6. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110. 
7. Baral R, Peterson ME. Thyroid gland disorders. In: Little, S.E. (ed), The Cat: Clinical Medicine and Management. Philadelphia, Elsevier Saunders 2012;571-592. 
8. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 American College of Veterinary Internal Medicine Forum. 2011;104-106.
9. Trepanier LA, Peterson ME, Aucoin DP. Pharmacokinetics of intravenous and oral methimazole following single- and multiple- dose administration in normal cats. Journal of Veterinary Pharmacology and Therapuetics 1991;14:367–373.
10. Trepanier LA, Peterson ME. Pharmacokinetics of methimazole in normal cats and cats with hyperthyroidism. Research in Veterinary Science 1991;50:69–74.
11. Rutland BE, Nachreiner RF, Kruger JM. Optimal testing for thyroid hormone concentration after treatment with methimazole in healthy and hyperthyroid cats. Journal of Veterinary Internal Medicine 2009;23:1025-1030. 
12. Trepanier LA, Hoffman SB, Kroll M, et al. Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 2003;222:954–958.
13. Frenais R, Rosenberg D, Burgaud S, et al. Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. Journal of Small Animal Practice 2009;50:510-515. 
14. Lapointe C, Bélanger MC, Dunn M, et al. N-acetyl-beta-D-glucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism.  Journal of Veterinary Internal Medicine 2008;22:1103-1110. 
15. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domestic Animal Endocrinology 2009;36:45-56.  
16. van Hoek I, Meyer E, Duchateau L, et al. Retinol-binding protein in serum and urine of hyperthyroid cats before and after treatment with radioiodine. Journal of Veterinary Internal Medicine 2009;23:1031-1037. 
17. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. Journal of Veterinary Internal Medicine 2010;24:863-869. 
18. Williams T, Elliott J, Syme H. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. Journal of Veterinary Internal Medicine 2010;24:1086-1092. 

Antithyroid Drug Treatment for Hyperthyroidism: Brand Name, Generic, or Compounded Drug?

Methimazole and carbimazole are two antithyroid drugs that can be used in cats for pre-operative control and long-term management of hyperthyroidism (1-5). Both have a potent and reliable effect on suppressing thyroid hormone production. A related drug, propylthiouracil, often used in human medicine, is not recommended for cats because of a high incidence of serious adverse reactions (immune-mediated hemolytic anemia and thrombocytopenia) (6).

Methimazole Tablets

Methimazole is specifically licensed for treatment of feline hyperthyroidism both in the USA and Europe where the drug is supplied as 2.5- and 5-mg tablets (Felimazole, Dechra Veterinary Products) (7).  

It is also available as a brand name drug for human use (Tapazole and Northyx), as well as generic formulations (5- and 10-mg tablets).

The generic methimazole costs about a third of brand name Tapazole. Although no studies of cats comparing the efficacy of brand name vs. generic methimazole have been reported, their efficacies appear to be equivalent.

Toxicity of the human and generic methimazole develops, at least in part, because of the bitter taste of the methimazole tablet; this presumably occurs frequently in cats that may bite or crush the tablet after oral administration (1,2). With the methimazole licensed for veterinary use (Felimazole), the tablet is sugar coated, thereby avoiding the bitter taste and lessening gastrointestinal side effect in most cats.

Carbimazole Tablets

Carbimazole is available for human use in many European countries and Japan, but this drug is not available in the USA (5,7-9). It exerts its antithyroid effect through immediate conversion to methimazole when administered orally (7,10).

In addition to regular carbimazole, a once daily controlled-release formulation (10- or 15-mg tablets) was recently licensed for cats in Europe (Vidalta, MSD Animal Health) (8,9). Pharmacokinetic studies of this controlled-release formulation have shown no pronounced concentration peak and a sustained presence of methimazole in plasma (> 24 hours) with an apparent terminal half-life of approximately nine hours after oral administration (8). Based on relative bioavailability and conversion it is estimated that 15 mg of this preparation is equivalent to approximately 7.5 mg of conventional methimazole (9).  It has been shown that administration of this drug with food significantly enhances its absorption (8). 

Compounded Antithyroid Drug Preparations

While antithyroid dugs are routinely administered orally, compliance can be problematic particularly in fractious cats or in those that develop GI side effects from the drug. One alternative means of administering antithyroid drugs is vs. transdermal administration (11-16). 

The most common transdermal vehicle used for antithyroid drug administration is pluronic lecithin organogel (PLO) (11,13,15). Another vehicle available is Lipoderm® which is less greasy than PLO and can be refrigerated. Lipoderm also appears to cause less skin irritation and may have a better ability to penetrate with drug. However, at least in humans, Lipoderm is slightly more expensive than PLO.

The transdermal gel is applied in a thin layer to the non-haired portion of the inner pinnae using a concentration approximating 5 mg/0.05-0.1ml (50-100 mg/ml).  Owners are instructed to wear exam gloves or finger cots, to apply the gel to alternate ears, and to wipe away any crusted material prior to the next dose. which prevents excess vehicle build up (3).  Transdermal methimazole is associated with fewer GI side effects than oral therapy, but some cats resent manipulation of the ear and crusting can occur between doses leading to erythema (1,2,13).

Custom transdermal formulation increases expense of antithyroid drug therapy. In addition, the efficacy and long-term stability of transdermal products can never be guaranteed.

In addition to transdermal preparations, compounding pharmacies will custom supply methimazole in a number of other preparations. The following is a list of formulations supplied by one compounding pharmacy:

• Chewable tablets
• Flavored with chicken or fish
• 4 strengths available (5 to 10 mg)
• Soft Chew Treat
• 57 strengths available
• 0.3 mg to 20 mg sizes
• Oral Suspension
• Flavored with chicken or fish
• 31 strengths available
• 1.25 mg to 40 mg sizes
• Can be combined with atenolol, famotidine, or amlodipine
• Oral Paste
• Flavored with chicken or liver
• 2 strengths available (2.5 mg/ml)
• Dose capsules
• 4 strengths available (1.25 mg to 4 mg)

Overview and Summary

When choosing an antithyroid drug formulation, it is important to consider the efficacy, shelf-life, adverse effect, and cost of the product used. All of these formulations, of course, have advantages and disadvantages.

Efficacy of antithyroid drug formulation: All formulations of methimazole and carbimazole appear to be efficacious in most cats, depending on owner and cat compliance. However, the tablets licensed for use by the FDA are considered to be the most reliable, since the company must guarantee the concentration of drug in each tablet. This is not the case with compounded formulations, where wide variability in drug concentration is likely.

Adverse effects of formulation: Side effects of the medication, especially methimazole, can be lessened in many cats by switching to brand name Felimazole or using compounded transdermal or flavored oral products (which avoid the bitter taste of the drug).

Cost of drug formulation: Generic brands are by far the cheapest, followed by brand-name tablets, then compounded oral suspensions and pastes, and finally transdermal preparations. Part of this cost is related to shorter shelf life with some of the compounded products.

References

1. Baral R, Peterson ME: Thyroid gland disorders, In: Little, SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012:571-592.
2. Mooney CT, Peterson ME. Feline hyperthyroidism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:92-110.
3. Trepanier LA. Pharmacologic management of feline hyperthyroidism.   Veterinary Clinics of North America Small Animal Practice 2007;37:775-788.
4. Peterson ME, Kintzer PP, Hurvitz AI. Methimazole treatment of 262 cats with hyperthyroidism. Journal of Veterinary Internal Medicine 1988;2:150-157.
5. Mooney CT, Thoday KL, Doxey DL. Carbimazole therapy of feline hyperthyroidism. Journal of Small Animal Practice 1992;33:228-235.
6. Peterson ME, Hurvitz AI, Leib MS, et al. Propylthiouracil-associated hemolytic anemia, thrombocytopenia, and antinuclear antibodies in cats with hyperthyroidism. Journal of the American Veterinary Medical Association 1984;184:806-808.
7. Longhofer S, Martin-Jimenez T, Soni-Gupta J. Serum concentration of methimazole in cats after a single oral dose of controlled-release carbimazole or sugar coated methimazole (thiamazole). Veterinary Therapeutics 2010;11:E1-7. 
8. Frenais R, Burgaud S, Horspool LJ. Pharmacokinetics of controlled-release carbimazole tablets support once daily dosing in cats. Journal of Veterinary Pharmacology and Therapeutics 2008;31:213-219.
9. Frenais R, Rosenberg D, Burgaud S, et al. Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidism. Journal of Small Animal Practice 2009;50:510-515.
10. Peterson ME. Comparison of the disposition of carbimazole and methimazole in clinically normal cats. Research in Veterinary Science1993;54:351–355.
11. Hoffman SB, Yoder AR, Trepanier LA. Bioavailability of transdermal methimazole in apluronic lecithin organogel (PLO) in healthy cats. Journal of Veterinary Pharmacology and Therapeutics 2002;25:189-193.
12. Hoffmann G, Marks SL, Taboada J, et al. Transdermal methimazole treatment in cats with hyperthyroidism. Journal of Feline Medicine and Surgery 2003;5:77-82.
13. Sartor LL, Trepanier LA, Kroll MM, et al. Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism. Journal of Veterinary Internal Medicine  2004;18:651-655.
14. Lecuyer M, Prini S, Dunn ME, et al. Clinical efficacy and safety of transdermal methimazole in the treatment of feline hyperthyroidism. Canadian Veterinary Journal 2006;47:131-135.
15. Hill KE, Gieseg MA, Kingsbury D, et al. The efficacy and safety of a novel lipophilic formulation of methimazole for the once daily transdermal treatment of cats with hyperthyroidism. Journal of Veterinary Internal Medicine 2011;25:1357-1365.
16. Buijtels JJ, Kurvers IA, Galac S, et al. Transdermal carbimazole for the treatment of feline hyperthyroidism. Tijdschrift voor diergeneeskunde 2006; 131:478-482.