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

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.

Dr. Mark Peterson Interviewed for "My Pet World" News Column About Treating a Geriatric Hyperthyroid Cat

My Pet World: Advice from the Experts

By Steve Dale, Tribune Media Services 

Q: The thyroid levels for my 21-year-old cat have recently become elevated, indicative of early stage hyperthyroidism. My veterinarian recommended a prescription diet (Hill's prescription y/d) or transdermally administered methimazole. The veterinarian believes radioactive iodine is a bit too extreme for a cat of this age.

I'm worried that my cat will find the (prescription) diet unpalatable. I'm also concerned about the side effects of transdermal medication. I'm impressed with what I've read about a natural solution called Resthyro. What's your opinion on what I should do for my feisty geriatric cat? -- N.M., Highland Park, IL

A: Dr. Mark Peterson, of New York City, is one of the world's experts on this topic, and helped create the radioactive iodine treatment you mention. Hyperthyroid disease nearly always occurs in older cats. Still, he says he understands that with a cat as elderly as yours, there are limits on what it makes sense to do. "I can see where this cat is no candidate for radioactive iodine," he commented. This treatment typically cures hyperthyroid disease, and is benign, but takes the cat away from home for several days of treatment.

Peterson says he doesn't personally see many adverse reactions to transdermal medication (delivering medication through the skin rather than a pill) for hyperthyroid disease. And he's seen a lot of hyperthyroid cats. Of course, side effects can potentially occur with any medication, but sometimes what you read on the Internet may be skewed. The pill version of methimazole may be just fine, but you no doubt know it can be hard to convince a cat to take a pill, which is why the transdermal might be preferred.

As for the new Hills prescription y/d diet, Peterson says, "It's long-term safety for real use is unknown." He's not absolutely convinced about the diet, and agrees that any diet change might be a problem for a 21-year-old pet. Still, that's a possible option.

As for Resthyro, Peterson said he has not seen much success. If you want to try the "natural" route, ask your veterinarian about L-Carnitine (a nutritional supplement available wherever vitamins and supplements for people are sold). Peterson says if your cat is mildly hyperthyroid, this may the best option worth trying, but do monitor your cat's thyroid levels. Open the capsule and sprinkle the contents on your cat's food or a special treat, such as a bit of chicken. Try starting at 250 mg daily. 

Links to Original Article:

• Chicago Tribune, http://www.chicagotribune.com/entertainment/books/sns-201112131830--tms--petwrldctnya-a20111215dec15,0,405315.story
• Hartford Courant,             http://www.gadzoo.com/hartfordcourant/Article.aspx?id=107094

About Steve Dale:
Steve Dale, pet expert and certified dog and cat behavior consultant, reaches more pet owners than any other pet journalist in America. Steve writes a twice-weekly syndicated newspaper column (Tribune Media Services).

He is also a contributing editor at USA Weekend and is the host of two nationally syndicated radio shows, Steve Dale’s Pet World and The Pet Minute, and Steve Dale’s Pet World at WLS Radio, Chicago.  To learn more, visit Steve's website at www.stevedalepetworld.com.

What are My Options for Treating My Hyperthyroid Cat?

Since remission of hyperthyroidism does not ever occur in cats, the aim of treatment is to normalize the excessive secretion of thyroid hormone by the cat's thyroid gland. Because all thyroid cats have a thyroid tumor (98% are benign but are few are malignant), a secondary aim of treatment is to remove or destroy the cat's thyroid tumor(s).

Hyperthyroidism can be treated medically, surgically, or with radioiodine. Medical treatment consists of administering antithyroid drugs (methimazole) one to three times per day. Methimazole treatment usually controls the signs of hyperthyroidism, but it is not a cure (i.e., the drug will block thyroid hormone secretion but will not remove or destroy the thyroid tumor). The drug must be given for the rest of the cat's life. Surgery cures the hyperthyroid condition by removing part or all of the thyroid gland. Radioiodine (radioactive iodine; I-131) also cures hyperthyroidism. The procedure for this treatment is simple; it is a single subcutaneous injection of a radioiodine, given much like a routine vaccine.

The advantages and disadvantages of these 3 treatment options are outlined below.


Medical Treatment with Anti-Thyroid Drugs (Methimazole; Tapazole™; Felimazole™)

Advantages
•      Relatively inexpensive (in the short-term) compared with radiotherapy or surgery.
•      No hospitalization required.
•      No permanent hypothyroidism.
•      No hypoparathyroidism or hypocalcemia (low calcium crisis secondary to damage of parathyroid
       glands)

Disadvantages
•      The price of trade name methimazole has risen dramatically in the last few years, making the total
        cost of long-term administration equivalent to that of definitive treatments.
•      Medication must be given daily (usually twice a day). Pilling your cat several times daily can
        damage your relationship with your cat.
•      Relapses are common during long-term treatment, and some cats respond poorly to the medication.
•      Approximately 25% of cats experience side effects, especially lethargy, loss of appetite, and
        vomiting.
•      Serious complications are rare but include facial itching, liver failure, low white blood cell count,
        and anemia.
•      Continual monitoring and blood tests at 3- to 6-month intervals are necessary during long-term
        treatment. This adds to the expense of treating with methimazole.
•      The disease is not cured; the thyroid tumor continues to grow in size and may transform from a
        benign tumor to a cancerous tumor over time.

Surgical Treatment (Thyroidectomy)
Advantages
•      Usually successful; persistent hyperthyroidism rare.
•      Corrects hyperthyroid state in shortest time (1-2 days).
•      Cure of hyperthyroidism usually permanent.

Disadvantages
•      Surgery is moderately expensive.
•      Hospitalization is required (1-3 days).
•      Performing general anesthesia and surgery has inherent risks. Furthermore, these risks are increased
        in cats with heart disease, which is common in both hyperthyroid and geriatric cats.
•      This is the most technically difficult treatment option. It is often difficult to identify and completely
        remove all involved thyroid tissue, especially when the tumor is located in an ectopic location
        (outside the neck area) such as the chest cavity.
•      The parathyroid glands are little glands that lie adjacent to the thyroid that control the body’s
        calcium balance. During thyroid surgery, they may be damaged or accidentally removed, resulting
        in hypocalcemia (low calcium crisis).
•      Other serious complications may include vocal cord paralysis and Horner's syndrome caused by
        injury to the sympathetic nerve trunk in the neck.
•      If all thyroid tumor tissue is not removed, hyperthyroidism is likely to persist or recur shortly after
        surgery.

Radioiodine (Radioactive Iodine; I-131)
Advantages
•      Highest rate of cure for hyperthyroidism
•      Destroys thyroid tumors regardless of location
•      Cure of hyperthyroidism usually permanent; lowest rate of recurrence
•      Simplest treatment; single injection, usually given subcutaneously (under the skin)
•      No daily pilling
•      No anesthesia
•      No serious complications
•      Limited monitoring required after successful treatment; no ongoing therapy

Disadvantages
•      Radioiodine is moderately expensive.
•      Hospitalization is required (5 days to 2 weeks).
•      Owner cannot visit their cat during the hospitalization.
•      Most facilities require that the cat confined indoors and have limited contact with owners for a
        period of time after discharge.

Radioiodine...The Best Solution for Feline Hyperthyroidism?

Radioiodine treatment completely cures hyperthyroidism by destroying the thyroid tumor and nothing else. Over 95% of all cats treated do not need future treatment. The procedure for this treatment is simple; it is a single subcutaneous injection of a radioiodine, given much like a routine vaccine.
Radioiodine therapy has some distinct advantages over medical or surgical treatment, and virtually all authorities consider it to be the treatment of choice for hyperthyroidism. With radioiodine, there is no need for anesthesia and the risk of postoperative hypocalcemia is eliminated. Methimazole (Tapazole™ or Felimazole™) treatment is not needed. The major drawback is that after receiving radioiodine, the cat must be kept in the hospital for a period (usually 5 to 7 days). Overall, radioiodine provides a simple, effective, and safe cure for cats with hyperthyroidism, regardless of age.

Dr. Peterson was the first veterinarian to develop this procedure for use in hyperthyroid cats. He has over 30 years of experience successfully administering radioiodine therapy to cats. It is not a new or experimental treatment; Dr. Peterson has treated over 10,000 hyperthyroid cats in his long career.