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8 hours in the 5X group. The lowest recorded individual heart rate was 60 beats/minute and occurred in the 5X dose group (2 cats). Cardiac arrhythmias characterized by isolated junctional escape complexes with episodes of junctional escape rhythm were observed during periods of low heart rate or following sinus pauses in all dexmedetomidine dose groups. In most cases the arrhythmia was no longer observed after 1 to 2 hours. Atrioventricular block was not observed. Incidences of arrhythmias were not related to dose; however, more cats were affected by cardiac arrhythmias on the third day of treatment, compared to the frst two days of the study. The decrease in respiratory rate, but not the duration, was dose dependent. The rectal temperature decreased in all dexmedetomidine-treated groups, with the lowest temperatures in the 5X group at 8 hours on all three days. Two cats vomited (40 and 120 mcg/kg). Corneal opacity was noted in all dexmedetomidine-dose groups, was transient, related to dose and duration of sedation, and was attributed to lack of lubrication with decreased blinking during sedation. Hematology and blood chemistry were unaffected by treat- ment. Injection site tolerance was good, with mild infammatory lesions representative of the IM injection procedure. Gross and histological examination of all other tissues did not reveal any abnormalities related to DEXDOMITOR administration. Dexmedetomidine demonstrated dose dependent effects related to its pharmacology when administered IM to healthy cats at doses up to fve times the recommended dose. Feline acute tolerance study: IM DEXDOMITOR was administered once at 10X (400 mcg/kg) the recommended dose of 40 mcg/kg to 3 female and 3 male 7 month old cats. No mortality was observed. Sedation was observed within 15 minutes of dosing and lasted for at least 4 hours with full recovery noted between 8 and 24 hours after dosing. Transient observations of corneal dehydration and opacity, miosis, pale skin and gingiva, salivation, and watery ocular discharge were observed in some animals. Vomiting was observed 7 to 11 hours after dosing in all but one animal. Decreases in heart rate accompanied by prolonged PQ and QT intervals were most pronounced 2 to 4 hours after dosing. No atrioven- tricular (AV) blocks or escape rhythms were noted. In one cat, incidental and reversible premature junctional complexes were seen at 1 and 2 hours after dosing which were considered secondary to bradycardia. Slightly lower respiratory rate and reduced rectal temperature were observed 4 to 8 hours after dosing. Observations had returned to normal by 24 hours after dosing. Mild infammatory lesions observed histologically at the injection site were representative of the IM injection procedure. No treatment related changes were observed in hematology. Mild elevations in some clinical ALT, AST, and CK, were observed 24 hours after dosing, with a trend towards recovery by 48 hours. Total protein, albumin and globulin levels were slightly lowered in one cat 48 hours after dosing. STORAGE INFORMATION: Store at controlled room temperature 15-30°C (59-86°F). Protect from freezing. HOW SUPPLIED: DEXDOMITOR is supplied in 10-mL, multidose vials containing 0.5 mg of dexmedetomidine hydrochloride per mL. DEXDOMITOR 0.1 mg/mL is supplied in 20-mL, multidose vials with flling volume of 15 mL containing 0.1 mg of dexmedetomidine hydrochloride per mL. DEXDOMITOR and DEXDOMITOR 0.1 are trademarks of Orion Corporation. Mfd by: Orion Pharma Orion Corporation Espoo, Finland August 26, 2013 BRIEF SUMMARY: See package insert for full prescribing information NADA #141-033, Approved by FDA (atipamezole hydrochloride) Sterile Injectable Solution—5.0 mg/mL Dexmedetomidine and Medetomidine Reversing Agent For intramuscular use in dogs only CAUTION: Federal law restricts this drug to use by or on the order of a licensed veterinarian. INDICATIONS: Antisedan is indicated for the reversal of the sedative and analgesic effects of Dexdomitor (dexmedetomidine hydrochloride), and Domitor (medetomidine hydrochloride) in dogs. CONTRAINDICATIONS: Since atipamezole is always used concomitantly with dexmedetomidine or medetomidine, it should not be used in dogs with the following conditions: cardiac disease, respiratory disorders, liver or kidney diseases, dogs in shock, severely debilitated dogs, or dogs stressed due to extreme heat, cold or fatigue. Administration of atipamezole is contraindicated in dogs with a known hypersensitivity to the drug. Developed and manufactured by: Distributed by: Div. of Pfzer Inc NY, NY 10017 Zoetis Inc. Kalamazoo, MI 49007 Distributed by: 15 minutes after dosing in one of twelve dogs. Second degree atrioven- tricular (AV) blocks were observed in one of twelve dogs. 3X dose group: At 3 times the recommended dose, the duration of sedation was between two and eight hours. During sedation, muscle twitches occurred, and temperature, respiratory rate, and heart rate decreased in all dogs. The pupillary light refex was transiently decreased for up to 90 minutes in four of twelve dogs. Vomiting was seen in two of twelve dogs. One dog experienced frst and second degree AV blocks; second degree AV block was observed in three of twelve dogs. Elevated concentrations of alanine aminotransferase (ALT) were observed in one dog, without histological changes to the liver. 5X dose group: At 5 times the recommended dose, the duration of sedation was between four and eight hours. Muscle twitches, decreases in temperature, respiratory rates, and heart rates were seen in all dogs. No pupil response was noted in six of twelve dogs (IV) for up to 1.5 hours; decreased transient pupillary light refex was seen for up to 60 minutes in two of twelve dogs (IM). Vomiting was seen in one of twelve dogs. First and second degree AV blocks were observed in one of twelve dogs. Elevated concentrations of ALT were observed in 3 of 12 dogs, without histological changes to the liver. Dexmedetomidine demonstrated dose dependent effects related to its pharmacology when administered IV or IM to healthy dogs at doses up to fve times the recommended dose. Canine safety study with an anticholinergic: In another laboratory safety study, one of three doses of an IM anticholinergic drug or saline was administered 10 minutes before, at the same time, or 15 minutes after 500 mcg/m 2 IM dexmedetomidine. The anticholinergic drug was given for the prevention or treatment of dexmedetomidine-induced reduction in heart rate. In a crossover design, 18 dogs were used in a total of 72 trials, to evaluate the safety of dexmedetomidine used with an anticholinergic drug. Dogs were instrumented for the accumulation of continuous ECG data. The following arrhythmias were recorded during the study (some dogs experienced more than one arrhythmia). Table 8: Arrhythmias recorded during the canine laboratory safety study* Type of arrhythmia Number of dogs (of 18) Second degree AV block 18 Supraventricular tachycardia (SVT) or SVPCs 16 Ventricular escape beats 16 Ventricular premature contractions 14 Third degree AV block 6 Idioventricular rhythm 1 Paroxysmal VT 1 Ventricular bigeminy; SVPCs; pulse alternans 1 Junctional escape beat 1 * Table does not relate arrhythmias to the presence or absence of anticholinergic The occurrence of arrhythmias was not related to the presence or absence of the anticholinergic drug. Arrhythmias were transient (although frequent over time in some dogs), returning toward base- line levels within 55 minutes after dexmedetomidine. No dogs required treatment related to these arrhythmias, and none of these arrhythmias persisted or adversely affected the overall clinical status of any dog in the study. Dexmedetomidine without anticholinergic: Without the anticholinergic drug, and in addition to arrhythmias, dexmedetomidine produced clinically relevant sedation accompanied by a statistically signifcant reduction in heart rate, respiratory rate, cardiac output, pulmonary arterial temperature, and mixed venous oxygen tension. A statistically signifcant increase in arterial blood pressure, pulmonary capillary wedge pressure, central venous pressure, and systemic vascular resis- tance was noted. No dogs experienced hypotension. Dexmedetomidine tended to increase pulmonary vascular resistance. Dexmedetomidine alone had no statistically signifcant effect on mean pulmonary arterial pressure, arterial pH, arterial carbon dioxide tension, and arterial oxygen tension. Dexmedetomidine plus anticholinergic: Either of the two higher anti- cholinergic doses was effective in the prevention or treatment of the dexmedetomidine-induced reduction in heart rate. Anticholinergic (higher doses) given after dexmedetomidine caused marked increases in the occurrence of various cardiac arrhythmias, especially second degree AV block. When the higher doses of anticholinergic drug were given at the same time or 15 minutes after dexmedetomidine, large increases in heart rate (p<0.01) and blood pressure (p<0.05) were seen. Increases were dose related; the highest anticholinergic dose elicited more frequent arrhythmias and larger increases in heart rate and blood pressure. In conclusion, moderate doses of anticholinergic drug given prior to dexmedetomidine performed best for the prevention of dexmedetomidine- induced reduction of heart rate in dogs. The routine use of anticholinergics given simultaneously with, or after dexmedetomidine, is not recom- mended. Feline safety study: In a multiple dose safety study, DEXDOMITOR was administered intramuscularly (IM) at 1X, 3X, and 5X (40, 120, and 200 mcg/kg) the recommended dose of 40 mcg/kg on 3 consecutive days to healthy cats, 6 to 8 months old. A control group received the product vehicle as a placebo (0X). No mortality was observed. The depth and duration of sedation was dose dependent, lasting approximately 2 hours in the 1X group, 2 to 4 hours in the 3X group, and greater than HUMAN WARNINGS: Not for human use. Keep out of reach of children. Atipamezole hydrochloride can be absorbed and may cause irritation following direct exposure to skin, eyes, or mouth. In case of accidental eye exposure, fush with water for 15 minutes. In case of accidental skin exposure, wash with soap and water. Remove contaminated clothing. If irritation or other adverse reaction occurs (for example, increased heart rate, tremor, muscle cramps), seek medical attention. In case of accidental oral exposure or injection, seek medical attention. Caution should be used while handling and using flled syringes. Users with cardiovascular disease (for example, hypertension or ischemic heart disease) should take special precautions to avoid any exposure to this product. The material safety data sheet (MSDS) contains more detailed occupational safety information. To report adverse reactions in users or to obtain a copy of the MSDS for this product call 1-800-366-5288. Note to Physician: This product contains an alpha 2 -adrenergic antagonist. PRECAUTIONS: 1. Handling: Antisedan can produce an abrupt reversal of sedation; therefore, dogs that have recently received Antisedan should be handled with caution. The potential for apprehensive or aggressive behavior should be considered in the handling of dogs emerging from sedation, especially in dogs predisposed to nervousness or fright. Also, avoid situations where a dog might fall. 2. Sedation relapse: While atipamezole does reverse the clinical signs associated with medetomidine or dexmedetomidine sedation, complete physiologic return to pretreatment status may not be immediate or may be temporary, and dogs should be monitored for sedation relapse. Sedation relapse is more likely to occur in dogs that receive an alpha 2 - agonist by the IV route, compared to dogs that are sedated using the IM route. Animals should be monitored closely for persistent hypothermia, bradycardia, and depressed respiration, until signs of recovery persist. 3. Analgesia reversal: Atipamezole reverses analgesic effects as well as sedative effects. Additional procedures for the control of pain may be required. 4. Debilitated dogs: The safety of atipamezole has not been evaluated in dogs with compromised health. Geriatric, debilitated, and ill dogs are more likely to experience adverse reactions associated with the administration of alpha 2 -antagonists (as well as alpha 2 -agonists). Dogs with abnormalities associated with the cardiovascular system are especially at risk. 5. Breeding dogs: Antisedan has not been evaluated in breeding dogs; therefore, the drug is not recommended for use in pregnant or lactating dogs, or in dogs intended for breeding. 6. Minimum age and weight: Antisedan has not been evaluated in dogs less than four months of age or in dogs weighing less than 4.4 lbs (2 kg). ADVERSE REACTIONS: Occasional vomiting may occur. At times, a period of excitement or apprehensiveness may be seen in dogs treated with atipamezole. Other effects of atipamezole include hypersalivation, diarrhea, and tremors. ANIMAL SAFETY: Atipamezole was tolerated in healthy dogs receiving 10X the recommended dose and in dogs receiving repeated doses at 1, 3, and 5X the recommended dose, in the absence of an alpha 2 - agonist. Signs were dose-related and included excitement, panting, trembling, vomiting, soft or liquid feces and scleral injection. At 10X the recommended dose, increases in creatine kinase, AST, and ALT were noted. Creatine kinase also increased in 3 (of 6) dogs in the 3X treatment group. Localized skeletal muscle injury was seen at the injection site but no associated clinical signs or complications were observed. Dogs receiving the recommended atipamezole dose in the absence of medetomidine or dexmedetomidine exhibited no adverse clinical signs. In additional safety studies, adverse events were absent up to the 3X dose of atipamezole when its administration followed medetomidine or dexmedetomidine sedation. In a separate safety study using a crossover design, 5 dogs received atipamezole after dexmedetomidine (IV and IM). Dexmedetomidine's effects on blood pressure, heart rate, respiratory rate, and cardiac conduction times were reversed by atipamezole. However, heart rate and cardiac conduction times did not return to pre-dexmedetomidine values. Heart rate increases after atipamezole were closer to baseline values in dogs treated with dexmedetomidine IV (compared to IM). STORAGE INFORMATION: Store protected from light at controlled room temperature 15°–30°C (59°–86°F). HOW SUPPLIED: Antisedan is supplied in 10-mL, multidose vials containing 5.0 mg of atipamezole hydrochloride per mL. Antisedan ® , Dexdomitor ® , Dexdomitor ® 0.1, and Domitor ® are trademarks of Orion Corporation. 20114-0506_01-11_Mast_TOC_Ed_Ad.indd 3 5/24/2014 10:33:07 AM