Product Name:  Sedivet 1% Injection, 20ml Vial

Note to Physician: This product contains an α₂-adrenoceptor agonist and can be absorbed by oral and dermal routes.

Precautions: The use of Sedivet 1.0% Injection with other α₂-agonists is not recommended since the effects (for example, cardiovascular changes, respiratory depression, ataxia) could be additive.

The adverse effects of Sedivet 1.0% Injection may be potentiated by the administration of other sedatives, tranquilizers, or opioids.

The use of epinephrine should be avoided since epinephrine may potentiate the effects of α₂-agonists.

Anesthetic doses should be reduced in the presence of Sedivet 1.0% Injection to avoid excessive depression of the central nervous system.

Sedivet 1.0% Injection has not been evaluated in horses with compromised cardiovascular function. The effects of bradycardia, increased vascular resistance, decreased cardiac output, and respiratory depression could be significant in horses with primary myocardial disease, or circulatory shock.

Sedivet 1.0% Injection should not be used in horses with respiratory disease, hepatic or renal disease, dehydration, or other systemic conditions of compromised health.

The effects of Sedivet 1.0% Injection have not been evaluated in horses with colic.

The effects of Sedivet 1.0% Injection have not been evaluated in pregnant mares, in horses intended for breeding, or in foals.

Adverse Reactions: As with other drugs of this class, the administration of Sedivet 1.0% Injection causes bradycardia (possibly profound), first and second degree atrioventricular heart block, and hypotension. The frequency and duration of cardiac arrhythmias have been shown to be dose related.

The following commonly occurring adverse reactions have been noted using α₂-agonists: hypertension, hypotension, bradycardia, ataxia, piloerection, sweating, muscle tremors, salivation, penile relaxation, urination (about an hour after treatment), lowering of head (causing passive congestion and swelling of face, lips, upper airways), stridor, decreased gastrointestinal motility, flatulence, and mild colic.

The potential exists, as with all α₂-agonists, for isolated incidences of excitation (paradoxical response).

Rare anaphylactic reactions have been reported, including one or more of the following: urticaria, dyspnea, edema of the upper airways and head, trembling, recumbency, and subsequent death.

Clinical Pharmacology: Romifidine is a potent α₂-adrenoceptor agonist that produces sedation and analgesia. Sedation is induced by stimulation of presynaptic α₂-receptors in the central nervous system. Administration of romifidine to conscious or anesthetized horses results in a biphasic effect on blood pressure. A transient increase in blood pressure due to peripheral vasoconstriction is followed by a compensatory vagal baroreceptor response resulting in longer lasting hypotension and bradycardia. A transient change in the conductivity of the cardiac muscle may manifest clinically as a partial atrioventricular block. Peripheral vasoconstriction may also lead to a transient reduction in gastrointestinal motility.

Effectiveness: A field study was conducted to evaluate romifidine as a sedative or a preanesthetic. Clinicians selected an appropriate dose, based on the procedure. Sedative doses ranged between 30-100 µg/kg; preanesthetic doses ranged between 40-100 µg/kg. The quality of sedation was rated as “good” or “excellent” in 18 of 23 horses. Of the remaining five horses evaluated for sedation, three were rated as “fair” and two were rated as “poor”. When used for preanesthesia, inductions were rated as “well-controlled” in 16 of 23 horses. Recoveries from anesthesia were evaluated as “satisfactory” or “excellent” in 20 of 23 horses. Two horses required more than three attempts to stand. One horse was euthanized without recovery, due to an unfavorable diagnosis unrelated to drug administration.

In a sedation dose confirmation study with a crossover design, twenty horses were used to evaluate romifidine at two doses: 40 and 120 µg/kg. Clinical assessments of depth of sedation, behavioral attitude, stance/posture, head ptosis, ear ptosis, eyelid and lip drooping were evaluated. Depth and duration of sedation were affected in a dose dependent manner. By the response of the horses to thermal noxious stimuli applied to withers and fetlock, the degree and duration of analgesia were also shown to be dose dependent. Transient physiological and clinical effects included decreased respiratory and heart rates, second degree atrioventricular block, sweating, increased salivation, stridor, penile relaxation, and a slight decrease in body temperature. Seventy-five minutes after receiving the 40 µg/kg dose, one older horse with a preexistent grade IV/VI systolic murmur, experienced ventricular tachycardia that lasted for 11.5 minutes. Another horse was diagnosed with pneumonia three days after receiving the 120 µg/kg dose of romifidine.

In a separate preanesthesia crossover study, the effectiveness of the 100 µg/kg preanesthetic romifidine dose was confirmed. Ten horses were induced with either ketamine or thiopental, followed by isoflurane maintenance anesthesia. The quality of induction, the transition to inhalant anesthesia, and the quality of anesthesia were scored as “excellent” for all horses. All horses except one stood on the first attempt (one stood on the third attempt).

Animal Safety: A toxicity study was conducted to observe the effects of a single dose of Sedivet 1.0% Injection at 360 µg/kg (3X the highest recommended dose) and 600 µg/kg (5X dose), using 3 horses per group. There were no clinically important alterations of blood gas, acid-base, hematological, or clinical chemistry values. The duration of bradycardia and second degree heart block was longer using the higher dose. Occasional periods of apnea (20 to 40 seconds) were followed by several deep successive breaths. Mild respiratory stridor was present, and horses periodically exhaled forcefully (“snorting”) in an apparent effort to clear their upper airways. The duration of sedation was dose dependent.

Horses exhibited signs of deep sedation, but would occasionally respond to environmental stimuli, only to return to deep sedation shortly thereafter. Mild sweating was observed. Urination commenced at 60-90 minutes and occurred frequently through four hours. One horse, which had been given a small amount of hay before full gastrointestinal motility had returned, showed mild abdominal discomfort twelve hours after administration of 600 µg/kg romifidine. Horses in this study were not necropsied. Toxicity study results for another product in the α₂-agonist class, showed microscopic foci of myocardial necrosis during histopathological examination in one of eight horses that received ten times the high end of the recommended dose for that product.

In another safety study, Sedivet 1.0% Injection was administered IV at doses of 120 µg/kg (1X the highest recommended dose), 360 µg/kg (3X), and 600 µg/kg (5X) for up to 3 consecutive days (9 horses per group). Sinus bradycardia (<30 bpm) and second degree heart block were most pronounced within 30 seconds to 5 minutes, gradually subsiding over two to four hours. Severe ataxia was observed in the 3X and 5X dose groups. Sweating was noted in all romifidine groups. Horses receiving the 1X dose showed an initial rise in blood pressure, followed by a return to baseline by 20-30 minutes. In the 3X and 5X groups, increases in blood pressure were seen at five minutes; returning toward baseline after 1 hour. Respiratory rates in all groups fell initially, followed by a gradual increase toward baseline values. Body temperature response varied, increasing slightly in the 1X and 3X groups, and decreasing slightly in the 5X group.

Storage Information: Store at controlled room temperature, 59-86°F (15-30°C).

How Supplied: Sedivet 1.0% Injection is supplied in 20 mL multi-dose vials containing 10 mg romifidine hydrochloride per mL.