1 October 2012

Merck Animal Health introduces Incurin™ (estriol) Tablets

New product offers a simple, natural solution for female canine urinary incontinence.

SUMMIT, NJ—October 1, 2012 – Merck Animal Health announces the availability of Incurin, a new FDA-approved treatment for canine urinary incontinence in spayed females, which features convenient once-a-day dosing and a proven efficacy and safety profile. Incurin will be available for veterinary customers to order on October 1, 2012.

Incurin is unique in that the starting dose is the same for all female dogs—two 1-mg tablets once daily. Incurin may also be titrated down to the lowest effective dose. In an efficacy study of spayed dogs, 51 percent of dogs treated with Incurin were titrated down to doses less than 2 mg daily. Of these dogs, 99 percent were shown to be improved or continent by six weeks.1

The active ingredient in Incurin, estriol, is a naturally occurring, short-acting estrogen. Estriol can help restore estrogen levels in spayed dogs to support a dog’s natural processes for maintaining urethral tone for urinary control. It differs from most other estrogens because it binds with estrogen receptors for a short time. Estriol has a nuclear retention time of one to four hours compared to estradiol and DES, which have a nuclear retention time of six to 24 hours.2 The shorter retention time of estriol limits undesirable side effects associated with long-term estrogen-receptor binding, such as bone marrow suppression.3,4

“With one daily starting dose and one tablet size to stock, Incurin provides veterinarians a new option for the treatment of canine urinary incontinence in spayed females that simplifies dosing and offers a natural estrogen solution with reduced risk of long-term, estrogen-related side effects,” said John Janelli, Associate Director, Marketing, Merck Animal Health.

Estriol has been shown to be effective and well tolerated in clinical trials and has been effectively and safely used worldwide for more than 12 years.1

Incurin is indicated for the control of estrogen-responsive urinary incontinence in ovariohysterectimized dogs. The most common side effects associated with Incurin treatment under field conditions included loss of appetite, vomiting, excessive water drinking, and swollen vulva. The safety and effectiveness of Incurin Tablets have not been evaluated in dogs less than 1 year of age, intact female dogs, male dogs, dogs used for breeding, or lactating dogs. Incurin is contraindicated in dogs showing polyuria secondary to polydipsia, or in pregnant dogs. Please see full prescribing information for complete details.

AboutMerck Animal Health

Today's Merck is a global healthcare leader working to help the world be well. Merck Animal Health, known as MSD Animal Health outside the United States and Canada, is the global animal health business unit of Merck. Merck Animal Health offers veterinarians, farmers, pet owners and governments one of the widest ranges of veterinary pharmaceuticals, vaccines and health management solutions and services. Merck Animal Health is dedicated to preserving and improving the health, well-being and performance of animals. It invests extensively in dynamic and comprehensive R&D resources and a modern, global supply chain. Merck Animal Health is present in more than 50 countries, while its products are available in some 150 markets. For more information, visit www.merck-animal-health.com.

MEDIA CONTACTS
Melissa Smith
melissas@circahealthcare.com

Kelly Goss
kelly.goss@merck.com

References:

  1. Incurin™ (estriol) Tablets for Dogs [Freedom of Information Summary]. Summit, NJ: Intervet, Inc.; 2011.
  2. Clark JH, Hardin JW, McCormack SA. Mechanism of estrogen agonists and antagonists. J Anim Sci. 1979;49:46–65.
  3. Incurin™ (estriol) Tablets for Dogs [package insert]. Summit, NJ: Intervet, Inc.; 2011.
  4. Clark JH, Markaverich BM. The agonistic and antagonistic actions of estriol. J Steroid Biochem. 1984;20(4B):1005–1013.

MEDIA BACKGROUNDER
Incurin™ (estriol) Tablets

1. What causes urinary incontinence in female dogs?

Urethral sphincter mechanism incompetence (USMI) is the most common cause of urinary incontinence in adult female dogs and is more prevalent after spaying. Studies have found that up to 20 percent of spayed female dogs are affected by USMI, and 90 percent of female dogs with USMI have been spayed.1,2

Incontinence usually develops two to four years after the dog has been spayed.3 Risk factors for developing urinary incontinence include medium or large body size and breed.4 At-risk breeds include Boxer, Doberman Pinscher, English Springer Spaniel, German Shepherd, Giant Schnauzer, Irish Setter, Old English Sheepdog, Rottweiler, and Weimaraner.3 Tail docking is also suspected to be a contributing risk factor for urinary incontinence.

Clinical signs of female canine urinary incontinence include:

  • Urinary dribbling
  • Involuntary loss of urine
  • Signs of discomfort or behavioral changes
  • Scalding of the skin or severe eczema
  • An offensive odor (in severe cases)

2. What role does estrogen play in urinary incontinence?

The increased prevalence of USMI in spayed female dogs may be partly attributed to the decrease in endogenous estrogen production that accompanies spaying. In unspayed female dogs, a decrease in circulating estrogen concentration during the proestrus and estrus stages of the estrous cycle was found to correlate with a decrease in maximum urethral closure pressure.5 Similarly, increased urethral closure pressure in unspayed female dogs has been found to coincide with higher circulating levels of 17β-estradiol during the proestrus and estrus stages of the estrous cycle.6

As shown in human health, a decrease in circulating estrogen levels is associated with a loss in the tone in the lower urogenital tract, particularly in the internal sphincter muscle that surrounds the urethra. In addition, decreased circulating estrogen levels appear to reduce bladder storage capacity and reduce the sensitivity of target tissues to sympathetic stimulation. These effects may contribute to involuntary leakage of urine.

Therefore, estrogens may affect continence by a number of mechanisms. In spayed female dogs with USMI, estrogens have been used to restore the normal tone of the urethra, presumably by improving the sensitivity to endogenous α-adrenergic stimulation.7,8

3. Why has estrogen therapy in dogs created some controversy?

Large doses of estrogens with long binding times have been associated with long-term, estrogen-related side effects, such as bone marrow suppression.9 Due to its long receptor binding time, diethylstilbestrol (DES), a synthetic compound, has been linked to both short- and long-term side effects, such as behavior changes, attractiveness to male dogs, and bone marrow suppression.9–11 Estrogens with a long receptor binding time can inhibit the differentiation of the canine pluripotent stem cells, resulting in neutropenia, anemia, and thrombocytopenia.9,12 DES is only available through veterinary compounding pharmacies, as the human product used by veterinarians in the past has been removed from the market due to safety concerns.

4. How does estriol differ from other estrogens used to treat urinary incontinence in dogs?

Estriol is a naturally occurring metabolite of 17β-estradiol and estrone that has a high affinity for receptors in cells of the lower urogenital tract. Estriol differs from other estrogens, such as 17β-estradiol and DES, because of its short receptor binding time of the nuclear-bound receptors, making it short-acting.13

Because estriol disassociates from receptors after a short binding period, this limits the undesirable effects on skeletal muscle growth and bone marrow suppression associated with long-term estrogen-receptor binding.13,14 Estriol has a nuclear retention time of one to four hours, whereas estradiol and DES have a nuclear retention time of six to 24 hours.15

There are two factors that serve to improve the safety of estriol. First, it has a shorter half-life due to rapid absorption and clearance and does not accumulate during repeated oral administration to dogs.14–16 Second, it has a short binding time at the estrogen receptor.14

5. What is the method of action for estriol?

Estriol, like other estrogens and estrogenic compounds, binds to estrogen receptors found in the muscle cells of the urethra. Estrogen-receptor complexes migrate to the cells’ nuclei, where they bind to the target gene of the DNA, increasing the overall synthetic activity of the tissue, such as the synthesis of new α-adrenergic receptors.7,8 These new receptors then migrate to the surface of the cell. The estrogen-receptor complex unbinds from the DNA and migrates out of the nucleus. The estrogen-receptor complex breaks apart and the estrogen is conjugated in the liver while appearing to undergo enterohepatic circulation.17–19 Metabolites are excreted mainly in the urine.20

6. What is the safety profile for Incurin?

There was no evidence of bone marrow suppression in a target animal study at five times the maximum label dose (10 mg daily) given to dogs for six months. Bone marrow smears evaluated microscopically, and the myeloid to erythroid (M:E) cell ratios were comparable between dogs that received 10 mg of estriol per day and those treated with placebo.21

Estriol was shown to be well tolerated in a long-term field study (up to 1,396 days) involving 324 client-owned spayed female dogs. Based on the relatively low frequency and mildness of the adverse events and their level of association with estriol, no safety concerns associated with longer-term use of the product were observed.21

Estriol has been safely used worldwide in dogs for more than 12 years. In post-market pharmacovigilance data collected from the United Kingdom, France, Germany, the Netherlands, Switzerland, and New Zealand between the years 2000 and 2010 by Merck Animal Health, adverse reactions were rare. Of reported reactions, vulvar swelling, attractiveness to male dogs, gastrointestinal signs, and localized or generalized hormonal pattern alopecia were the most common observations.21,22

7. How is Incurin administered?

Dosing for estriol is not dependent upon body weight. All dogs receive an initial dose of 2 mg once per day, regardless of size. After urinary incontinence is controlled, the lowest effective daily dose of estriol can be determined to help reduce the risk of any side effects. This can be done by decreasing the dose in a step-wise manner from 2 mg once daily to 1 mg once daily, then 0.5 mg once daily, depending upon the response of the individual dog. There should be a minimum of seven days between each dose adjustment, following the initial 14 days on 2 mg a day. Once the lowest daily dose that controls urinary incontinence is identified, the dose may be decreased further by administering once every two days.13

In an efficacy study, 51 percent of dogs treated with estriol were titrated down to doses less than 2 mg daily. By six weeks, 99 percent of these dogs were improved or continent.21

8. Is Incurin effective?

In an efficacy study, 93 percent of spayed dogs treated with Incurin were improved or continent by six weeks.21 And in a multi-site, masked, placebo-controlled field study, the proportion of dogs achieving treatment success was significantly greater in the group treated with Incurin than in the placebo-treated group at Day 14 (P=0.0038).21

References:

  1. Arnold S, Arnold P, Hubler M, Casal M, Rusch P. Urinary incontinence in spayed female dogs: frequency and breed disposition [in German]. Schweiz Arch Tierheilkd. 1989;131(5):259–263.
  2. Krawiec DR. Diagnosis and treatment of acquired canine urinary incontinence. Companion Anim Pract. 1989;19(8–9):12–20.
  3. Holt PE. Urinary incontinence in the bitch due to sphincter mechanism incompetence: prevalence in referred dogs and retrospective analysis of sixty cases. J Small Anim Pract. 1985;26(4):181–190.
  4. Holt PE. Urological Disorders of the Dog & Cat—Investigation Diagnosis and Treatment. London: Manson Publishing; 2008:150.
  5. Hamaide AJ, Verstegen JP, Snaps FR, Onclin KJ, Balligand MH. Influence of the estrous cycle on urodynamic and morphometric measurements of the lower portion of the urogenital tract in dogs. Am J Vet Res. 2005;66(6):1075–1083.
  6. Nickel RF. Studies on the function of the urethra and bladder in continent and incontinent female dogs. Vet Q. 1998;20 Suppl 1:S102–103.
  7. Hamaide AJ, Grand JG, Farnir F, et al. Urodynamic and morphologic changes in the lower portion of the urogenital tract after administration of estriol alone and in combination with phenylpropanolamine in sexually intact and spayed female dogs. Am J Vet Res. 2006;67(5):901–908.
  8. Larsson B, Andersson KE, Batra S, Mattiasson A, Sjögren C. Effects of estradiol on norepinephrine-induced contraction, alpha adrenoceptor number and norepinephrine content in the female rabbit urethra. J Pharmacol Exp Ther. 1984;229(2):557–563.
  9. Hart JE. Endocrine pathology of estrogens: species differences. Pharmacol Ther. 1990;47(2):203–218.
  10. Hall EJ. Use of lithium for treatment of estrogen-induced bone marrow hypoplasia in a dog. J Am Vet Med Assoc. 1992;200(6):814–816.
  11. Barsanti JA, Medleau L, Latimer K. Diethylstilbestrol-induced alopecia in a dog. J Am Vet Med Assoc. 1983;182(1):63–64.
  12. Handagama PJ, Feldman BF. Drug-induced thrombocytopenia. Vet Res Commun. 1986;10(1):1–20.
  13. Incurin™ (estriol) Tablets for Dogs [package insert]. Summit, NJ: Intervet Inc.; 2011.
  14. Clark JH, Markaverich BM. The agonistic and antagonistic actions of estriol. J Steroid Biochem. 1984;20(4B):1005–1013.
  15. Clark JH, Hardin JW, McCormack SA. Mechanism of estrogen agonists and antagonists. J Anim Sci. 1979;49:46–65.
  16. Hoeijmakers M, Janszen B, Coert A, Horspool L. Pharmacokinetics of oestriol after repeated oral administration to dogs. Res Vet Sci. 2003;75(1):55–59.
  17. Head KA. Estriol: safety and efficacy. Alt Med Rev. 1998;3(2):101–113.
  18. Kirdani RY, Sandberg AA. The fate of estriol in dogs. Steroids. 1974;23(5):667–686.
  19. Katzenellenbogen BS, Iwamoto HS, Heiman DF, Lan NC, Katzenellenbogen JA. Stilbestrols and stilbestrol derivatives: estrogenic potency and temporal relationships between estrogen receptor binding and uterine growth. Mol Cell Endocrinol. 1978;10(1):103–113.
  20. Takahashi S, Moriyama N, Yamazaki R, Kawabe K. Urodynamic analysis of age-related changes of alpha 1-adrenoceptor responsiveness in female beagle dogs. J Urol. 1996;156(4):1485–1488.
  21. Incurin™ (estriol) Tablets for Dogs [Freedom of Information Summary]. Summit, NJ: Intervet Inc.; 2011.
  22. Data on file, Merck Animal Health.