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.

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.