Friday, July 27, 2012

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 formulationAll 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 formulationSide 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 formulationGeneric 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 hyperthyroidismJournal of Veterinary Internal Medicine 1988;2:150-157.
  5. Mooney CT, Thoday KL, Doxey DL. Carbimazole therapy of feline hyperthyroidismJournal 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 hyperthyroidismJournal 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.

2 comments:

none said...

Per your recommendation, we are currently using transdermal gel to see if we can avoid inappetence. However, the gel has been compounded at 10mg/mL, so the formulation is so dilute that we're having to use a huge .1mL blob of gel to get the dose of 1mg our vet prescribed. It isn't seeping in properly and drying before absorbing. Our kitty's ear fur is started to fall off in tiny little clumps.

Would it be correct to ask our vet to have the prescription re-compounded at 20mg/mL so we will only have to apply .05mL of gel to get the same 1mg of methimazole? What do you recommend?

Dr. Mark E. Peterson said...

Sounds reasonable to me. Talk to either your vet or the compounding pharmacy.