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Pharmacology of
SILEO®

(dexmedetomidine oromucosal gel)

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SILEO® (dexmedetomidine oromucosal gel) is presented in a 3 mL oral syringe that can be redosed, as needed. SILEO provides a low dose of dexmedetomidine, which calms but does not sedate the dog. The dog remains fully functional while the undesirable behaviors of noise aversion are eliminated or minimized.

Pharmacokinetics

Since dexmedetomidine is absorbed through the mucous membranes, SILEO in an oromucosal gel formulation provides a convenient mode of administration for pet owners to use at home.

Bioavailability: Oral transmucosal (OTM) administration achieves the optimum effect.

  • OTM 28%
  • Ingested* 0%
*Due to first-pass metabolism

Onset of Action: The calming effects of SILEO can be observed shortly after administration—OTM administration reaches peak plasma concentration within 0.6 hours.

Intensity of Effect: With the 28 percent OTM bioavailability, peak plasma concentration is approximately ¼ of the same dosage with IV or IM administration. This means that about ¼ of the dose of dexmedetomidine administered is absorbed. As a result, there is a dose-dependent effect on behavioral and physiological responses.

Duration of Effect: The half-life of SILEO is 0.5–3h; therefore, SILEO has a duration of effect of 2–3 hours.


Neurobiology of Noise Aversion

Noise aversion is a neurologic condition. It starts in the locus coeruleus, a cluster of noradrenergic nuclei in the brainstem, where norepinephrine is the main neurotransmitter.

The locus coeruleus and norepinephrine (LC-NE) facilitate the physiological and behavioral responses to stress, fear and anxiety, typically manifesting as fight, flight or avoidance (freezing behavior). Under normal circumstances, the response to acute stress is short-lived: all systems return back to normal when the threat subsides due to autoregulatory mechanisms. However, repeated exposure to acute traumatic stress causes repeated activation of the LC-NE system, which can lead to the development of anxiety.9 The fear and anxiety associated with noise aversion is an example of a repeated traumatic stressor of the sympathetic system.6 Therefore, using a pharmacological agent that decreases the LC-NE system is a logical approach for noise aversion.

Pharmacodynamics

Mechanism of Action10,11

The anxiolytic effect of SILEO is mediated through the locus coeruleus. Dexmedetomidine, the active substance of SILEO, is a highly potent and selective alpha-2 adrenoceptor agonist.


Dexmedetomidine binds with the alpha-2 receptors in the locus coeruleus, preventing release of norepinephrine and reducing levels of norepinephrine in the LC-NE neural pathways. Reduced levels of norepinephrine reduce the levels of anxiety and fear.


Dose-Dependent Effects on Sedation and Heart Rate

The same dosage of dexmedetomidine in a different formulation and different mode of administration produces different effects.

The dosage of SILEO is the same as the pre-anesthetic dose of DEXDOMITOR® (dexmedetomidine), but formulation and route are different, resulting in different effects on heart rate and sedation.




Sedation

This graph compares the mean sedation scores of SILEO in telemerized laboratory Beagles administered SILEO oral transmucosally compared to DEXDOMITOR administered intramuscularly, both at the 125 mcg/m2 dosage.

  • The dose-dependent effect on sedation is obvious; IM dexmedetomidine causes an expected moderate degree of sedation
  • SILEO results in minimal sedation, which reflects the lower plasma levels of dexmedetomidine

Heart Rate Reduction

The effect of SILEO on client-owned dogs was evaluated in a placebo-controlled study conducted at veterinary clinics. Heart rates were taken before and after treatment: Heart rates dropped slightly for the SILEO-treated dogs, but remained within normal range. The average heart rate for the SILEO-treated dogs was 98 bpm compared to 115 bpm for the placebo group.

  • SILEO 98 bpm
  • Placebo 115 bpm




VETERINARIAN FAQs (PDF)

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Sign in to Order** If you are a customer in Hawaii, please contact your local Zoetis Sales Representative or Hawaii Mega-Cor to place your order.

Important Safety Information:

SILEO Do not use SILEO in dogs with severe cardiovascular disease, respiratory, liver or kidney diseases, or in conditions of shock, severe debilitation, or stress due to extreme heat, cold or fatigue or in dogs hypersensitive to dexmedetomidine or to any of the excipients. SILEO should not be administered in the presence of preexisting hypotension, hypoxia, or bradycardia. Do not use in dogs sedated from previous dosing. SILEO has not been evaluated in dogs younger than 16 weeks of age or in dogs with dental or gingival disease that could have an effect on the absorption of SILEO. SILEO has not been evaluated for use in breeding, pregnant, or lactating dogs. Transient pale mucous membranes at the site of application may occur with SILEO use. Other uncommon adverse reactions included emesis, drowsiness or sedation. Handle gel-dosing syringes with caution to avoid direct exposure to skin, eyes or mouth. SILEO has not been evaluated for aversion behaviors to thunderstorms. See full Prescribing Information.

DEXDOMITOR and DEXDOMITOR 0.1 Do not use DEXDOMITOR or DEXDOMITOR 0.1 in dogs or cats, and ANTISEDAN in dogs, with cardiovascular disease, respiratory disorders, liver or kidney diseases, or in conditions of shock, severe debilitation, or stress due to extreme heat, cold or fatigue. DEXDOMITOR and DEXDOMITOR 0.1 should not be administered in the presence of preexisting hypotension, hypoxia, or bradycardia. As with all α2-adrenoceptor agonists, the potential for isolated cases of hypersensitivity, including paradoxical response (excitation), exists with DEXDOMITOR and DEXDOMITOR 0.1. The use of DEXDOMITOR and DEXDOMITOR 0.1 as a preanesthetic in dogs and cats significantly reduces the amount of induction and maintenance anesthetic requirements. Careful patient monitoring is necessary to avoid anesthetic overdose. Arrhythmias, bradycardia, apnea, emesis, convulsions, hypersalivation may occur with DEXDOMITOR and DEXDOMITOR 0.1 use. Severe dyspnea and respiratory crackles due to acute or delayed pulmonary edema could develop in cats. DEXDOMITOR and DEXDOMITOR 0.1 have not been evaluated for use in breeding, pregnant, or lactating dogs or cats; in dogs younger than 16 weeks of age or in cats younger than 12 weeks of age; or in geriatric dogs or cats. Occasional vomiting may occur with ANTISEDAN use. Rarely, a brief state of excitement or apprehensiveness may be seen in ANTISEDAN-treated dogs. Other potential side effects of α2-antagonists, such as ANTISEDAN, include hypersalivation, diarrhea, and tremors. See full Prescribing Information.

References

  • 6. Overall, K. Manual of Clinical Behavioral Medicine for Dogs and Cats. St. Louis, MO: Elsevier Health Sciences, 2013:256-264.
  • 9. Goddard AW, Ball SG, Martinez J, et al. Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety. 2010;27(4):339-350.
  • 10. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel [alpha]2-adrenergic agonist: a review of its pharmacodynamics characteristics. Drugs Future. 1993;18:49-56.
  • 11. Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg. 2005;32(3):117-127.