Label: TZED (TILETAMINE HYDROCHLORIDE AND ZOLAZEPAM HYDROCHLORIDE)- tiletamine and zolazepam injection

Dogs: Tzed is indicated in dogs for restraint and minor procedures of short duration (30 min. avg.) requiring mild to moderate analgesia. Minor surgery is considered to be laceration repair, draining of abscesses, castrations and other procedures requiring mild to moderate analgesia. (See Dogs under Dosage and Administration.) Tzed administered intravenously is indicated in dogs for induction of anesthesia followed by maintenance with an inhalant anesthetic.

Cats: Tzed is indicated in cats for restraint or for anesthesia combined with muscle relaxation.

Dogs:

Intramuscular (IM) For Restraint and Minor Procedures of Short Duration Requiring Mild to Moderate Analgesia:

In healthy dogs, an initial intramuscular dosage of 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) Tzed is recommended for diagnostic purposes; 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg) for minor procedures of short duration, such as treatment of lacerations and wounds, castrations and other procedures requiring mild to moderate analgesia. When supplemental doses of Tzed are required, such individual supplemental doses should be less than the initial dose, and the total dose given (initial dose plus supplemental dose or doses) should not exceed 12 mg/lb (26.4 mg/kg). The maximum safe dose is 13.6 mg/lb (29.92 mg/kg). (See Animal Safety.) Results from Tzed anesthesia in dogs will be more satisfactory if the procedures are completed within one hour and if the procedures can be completed following single dose administration. In order to maintain at least a 2× margin of safety in dogs, the use of this product is limited to procedures that call for low doses (see Indications). Studies show that there is variation in response to different dosages of tiletamine and zolazepam and that low doses do not give adequate levels of anesthesia, and in some instances do not give adequate analgesia, for extensive procedures.

Intravenous (IV) For Induction of Anesthesia Followed by Maintenance with an Inhalant Anesthetic:

In dogs, for induction of anesthesia, administer Tzed intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) body weight to effect. Tzed should be administered slowly, over 30-45 seconds; after approximately 30-60 seconds, the dog's level of consciousness, muscle relaxation, and jaw tone should be assessed to determine the ability to intubate. If after waiting 60 seconds the dog's level of anesthesia is not sufficient for successful intubation, additional Tzed may be administered; the total dose should not exceed 2 mg/lb (4.4 mg/kg) body weight.

Cats:

In healthy cats, an initial Tzed dosage of 4.4 to 5.4 mg/lb (9.7 to 11.9 mg/kg) IM is recommended for such procedures as dentistry, treatment of abscesses, foreign body removal and related types of surgery; 4.8 to 5.7 mg/lb (10.6 to 12.5 mg/kg) for minor procedures requiring mild to moderate analgesia, such as repair of lacerations, castrations and other procedures of short duration. Initial dosages of 6.5 to 7.2 mg/lb (14.3 to 15.8 mg/kg) are recommended for ovariohysterectomy and onychectomy. When supplemental doses of Tzed are required, such individual supplemental doses should be given in increments that are less than the initial dose, and the total dose given (initial dose plus supplemental doses) should not exceed the maximum allowable safe dose of 32.7 mg/lb (72 mg/kg). (See Animal Safety.)

General Dosing Information: Fasting prior to induction of general anesthesia with Tzed is not essential; however, when preparing for elective surgery, it is advisable to withhold food for at least 12 hours prior to Tzed administration. As with other injectable anesthetic agents, the individual response to Tzed is somewhat varied, depending upon the dose, general physical condition and age of the patient, duration of the surgical procedure, and any preanesthetics used. Therefore, recommendations for dosage regimens cannot be fixed absolutely. Specific dosage requirements must be determined by evaluation of the health status and condition of the patient and of the procedure to be performed.

Recovery varies with the age and physical condition of the animal and the dose of Tzed administered. Recovery is extended with high dose or multiple injections, particularly in cats.

Intramuscular injection in dogs and cats:

There may be pain on injection. This is especially prevalent in cats.

Following a single, deep intramuscular injection of Tzed in cats and dogs, onset of anesthetic effect usually occurs within 5 to 12 minutes. Muscle relaxation is optimum for approximately the first 20 to 25 minutes after Tzed is administered, and then diminishes.

Repeated doses increase the duration of the effect of Tzed but may not further diminish muscle tone. The quality of anesthesia with repeated doses varies because the ratio of the two components within the animal's body changes with each injection. This is due to the difference in the rates of metabolism and elimination of the two components. The quality of anesthesia will be improved and more predictable if the entire dose is given as a single injection rather than in several doses. The best method of evaluating the depth of Tzed anesthesia is to monitor the patient for deliberate conscious response to nociceptive stimuli.

If adequate anesthesia is not produced by the recommended dosage regimen, supplemental anesthesia or another agent is indicated. This includes the use of barbiturates and volatile anesthetics. When used concurrently with Tzed the dosage of these agents should be reduced.

For Restraint and Minor Procedures of Short Duration Requiring Mild to Moderate Analgesia

Respiratory depression may occur following administration of high doses of Tzed. If at any time respiration becomes excessively depressed and the animal becomes cyanotic, resuscitative measures should be instituted promptly. Adequate pulmonary ventilation using either oxygen or room air is recommended as a resuscitative measure.

Adverse reactions reported include emesis during emergence, excessive salivation, transient apnea, vocalization, erratic recovery and prolonged recovery, excessive tracheal and bronchial secretions when atropine sulfate was not given before anesthesia, involuntary muscular twitching, hypertonicity, cyanosis, cardiac arrest, pulmonary edema and muscle rigidity during surgical procedures. Central nervous system stimulation and convulsions have also been reported. Tachycardia frequently occurs, particularly in the dog. This rise in heart rate usually lasts about 30 minutes. Either hypertension or hypotension may also occur. Insufficient anesthesia has been reported in dogs.

Death has been reported in dogs and cats following tiletamine and zolazepam administration.

Intravenous Induction of Anesthesia followed by Maintenance with Inhalant Anesthesia in Dogs

In a field study to assess the effectiveness and safety of tiletamine and zolazepam administered intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) for the induction of anesthesia followed by maintenance with inhalant anesthesia in dogs, 144 dogs were intravenously administered tiletamine and zolazepam (See Effectiveness). Sixteen adverse reactions occurred during the study: nystagmus (5), emesis (4), diarrhea (2), and one occurrence each of hypersalivation, urticarial, anorexia, hyperthermia, and lethargy. All adverse reactions resolved by the end of the study.

Physiologic abnormalities related to general anesthesia were transient and not severe.

Post-induction apnea (time from induction to first inspiration ≥30 seconds) was observed in 49.3% of dogs across all treatment groups with a mean duration of one minute. The highest overall frequency and duration of post-induction apnea was in the alpha2-agonist + opioid groups.

Overall, 36 dogs received assisted ventilation. Assisted ventilation was needed most frequently early in the procedure (at procedure start, possibly after an apneic period) then decreased in frequency as the procedure continued.

Sixteen dogs experienced oxygen saturation (SpO2) ≤90 mmHg: 7 in the alpha2-agonist + opioid groups, 6 in the phenothiazine + opioid groups, and 3 in the opioid alone groups.

Twenty-five dogs had a temperature ≥103°F during the study, with 12 of these occurring prior to preanesthetic administration only. Of the remaining 13 dogs, 7 were in the alpha2-agonist + opioid groups, 5 were in the opioid alone groups, and 1 in the phenothiazine + opioid groups. One dog was reported with hyperthermia as an adverse reaction in the alpha2-agonist + opioid treatment groups. The dog became excitable during recovery and its temperature elevated to 105.7°F. Hyperthermia resolved with treatment of IV fluids and cooling.

Twenty-seven dogs experienced temperatures ≤96°F at one or more timepoints. Most dogs received supplemental heat during surgery.

Fifty-nine dogs had mean blood pressure (BP) values ≤60 mmHg. These values are spread among all treatment groups. No dogs were reported with adverse reactions due to hypotension or hypertension in any dose groups. Elevated or low BP values were transient.

Ventricular premature depolarizations were noted in 3 dogs in the alpha2-agonist + opioid group. This transient rhythm disturbance is not uncommon in dogs receiving alpha2-agonists or inhalant anesthetics. One dog in the phenothiazine + opioid group showed transient ST depression that could have been due to cardiac hypoxia. All dogs recovered normally.

To report suspected adverse drug events, for technical assistance or to obtain a copy of the Safety Data Sheet (SDS), contact Dechra Veterinary Products at (866) 933-2472.

For additional information about adverse drug experience reporting for animal drugs, contact FDA at 1-888-FDA-VETS or online at http://www.fda.gov/reportanimalae.

Mechanism of Action

Tzed (tiletamine and zolazepam for injection) is a rapid-acting anesthetic combination of tiletamine hydrochloride and zolazepam hydrochloride. Tiletamine hydrochloride is a dissociative anesthetic agent whose pharmacologic action is characterized by profound analgesia, normal pharyngeal-laryngeal reflexes and cataleptoid anesthesia. The anesthetic state produced does not fit into the conventional classification of stages of anesthesia, but instead Tzed produces a state of unconsciousness which has been termed "dissociative" anesthesia in that it appears to selectively interrupt association pathways to the brain before producing somesthetic sensory blockade.

Cranial nerve and spinal reflexes remain active; however, these reflexes must not be confused with inadequate anesthesia. Analgesia results from apparent selective interruption of sensory inputs to the brain and usually persists after the anesthetic effect has subsided.

Protective reflexes, such as coughing and swallowing, are maintained under tiletamine anesthesia. Other reflexes, e.g., corneal, pedal, are maintained during tiletamine anesthesia, and should not be used as criteria for judging depth of anesthesia. The eyes normally remain open with the pupil dilated. It is suggested that a bland ophthalmic ointment be applied to the cornea if anesthesia is to be prolonged.

Used alone, tiletamine hydrochloride does not provide adequate muscle relaxation for abdominal surgical procedures. When combined with zolazepam hydrochloride, good muscle relaxation is generally attained during the phase of deep surgical anesthesia.

Pharmacokinetics

The pharmacokinetics of tiletamine and zolazepam injectable solution was evaluated in 12 healthy adult Beagle dogs, following a single intravenous (IV) administration of 2.2 mg/kg bodyweight, which is equivalent to 1.1 mg/kg for both tiletamine hydrochloride and zolazepam hydrochloride. After administration of 2.2 mg/kg tiletamine and zolazepam IV, the initial mean concentration of tiletamine (C0) was 1018 ng/mL, the systemic clearance (CL) was 6223 mL/kg/h, the area under the curve to the last measured concentration (AUC 0-last) was 178 ng*hr/mL, and steady state volume of distribution (Vss) was 3250 mL/kg. The mean elimination half-life of tiletamine was 0.87 hours. For zolazepam, the mean C0 was 2594 ng/mL, CL was 1993 mL/kg/h and Vss was 604 mL/kg. The mean elimination half-life of zolazepam was 0.41 hours. The mean C0 and AUC0-t(last) were approximately 2.5 and 3 times, respectively, greater for zolazepam than for tiletamine. However, the mean half-life (T1/2) of tiletamine was approximately 2.5 times longer than for zolazepam, resulting in quantifiable plasma concentrations up to 2 hours longer.

Pretreatment with an alpha2-agonist or phenothiazine followed by inhalant isoflurane has been shown to increase in the initial concentration of both tiletamine and zolazepam.

Dogs

Preanesthesia

In a field study conducted at 6 veterinary hospitals, 144 dogs of various breeds, ranging in age from 4 months to 14 years (mean age 5 years) and body weights from 1.2- 85.5 kg, were enrolled for completion of a veterinary procedure requiring anesthesia. Dogs were preanesthetized with a phenothiazine + opioid, an opioid alone, or an alpha2-agonist + opioid at the study Investigator's discretion based on individual patient needs. Approximately 20 minutes later, dogs were intravenously administered tiletamine and zolazepam at 1-2 mg/lb (2.2-4.4 mg/kg) 'to effect' of anesthesia and were intubated. After induction, dogs received either isoflurane or sevoflurane for anesthetic maintenance for at least 30 minutes. Procedures conducted included dental prophylaxis with or without extractions (64), ovariohysterectomy (31), castration (18), and mass removal (14). Upon completion of the procedure, dogs were monitored in recovery for 4 hours, then followed at home for 2-4 days, monitoring for the presence of abnormal clinical signs.

Of 144 dogs enrolled in the study, 142 (98.6%) were successfully intubated after intravenous administration of tiletamine and zolazepam at a mean dosage of 1.2 mg/lb (2.7 mg/kg). The mean dosage range was lowest in the alpha2-agonist + opioid preanesthetic treatment group (0.9 mg/lb; 2 mg/kg) and highest in the opioid alone preanesthetic group (1.8 mg/lb; 3.9 mg/kg).

Overall induction quality evaluated on a scale of acceptable, intermediate, or unacceptable was acceptable in 131/142 (91.6%) dogs and intermediate in 12/143(8.4%) dogs. On a scale of good, fair, or poor, study participants rated the quality of recovery from anesthesia as good in 75% of dogs (118/144) and fair in 18.1% (26/144). In an overall assessment of anesthesia, considering induction, maintenance, and recovery, was scored as excellent or good in 128/144 (88.9%) of dogs. Three dogs (2.1%) were rated with an overall assessment of anesthesia as poor, and for these dogs, recovery was also rated poor. Physiologic measurements of heart rate, respiratory rate, body temperature, oxygen saturation, and blood pressure during anesthetic induction, maintenance, and recovery showed that the administration of tiletamine and zolazepam did not severely impact these variables. A variety of concomitant treatments were used during the study including intravenous fluid solutions, non-steroidal anti-inflammatory medications, antimicrobials, and antiparasitics that were consistent with routine canine practice.

Cats: In cats, the duration of effect of zolazepam exceeds that of tiletamine so that as the animal recovers there is a greater degree of tranquilization than anesthetization. There is a slight lowering of blood pressure during the first hour after injection. Heart rate and electrocardiogram readings are unaffected by tiletamine and zolazepam for injection. Arterial pO2 levels are decreased three minutes after injection but usually return to normal within 15 to 35 minutes.

Dogs: In dogs, the duration of effect of tiletamine exceeds that of zolazepam so there is a lesser degree of tranquilization than anesthetization in this species. The total effect of tiletamine and zolazepam for injection in dogs is of shorter duration than in cats.

Following administration of tiletamine and zolazepam for injection in dogs, a marked, persistent tachycardia occurs within two minutes following either 4.5 or 9 mg/lb (10 or 20 mg/kg) tiletamine and zolazepam for injection intramuscularly. Stroke volume decreases proportionately to the increased rate at the 4.5 mg/lb (10 mg/kg) dose, with little change in net cardiac output. There is an initial increase in systolic blood pressure, with a slight drop in pressure within five minutes. The systolic blood pressure remains at this decreased level throughout the duration of the anesthetic effect. Diastolic pressure increases throughout this same period. Following a 9 mg/lb (20 mg/kg) dose of tiletamine and zolazepam for injection in dogs, the relationship between stroke volume and heart rate is disproportionate, with a resultant substantial decrease in cardiac output. Contractility and mean blood pressure are decreased, indicating direct myocardial depression. Ventricular function is adequate. During surgical manipulations, tachycardia and hypertension may be observed, and may be brought on by sympathetic reaction to painful stimuli. Epinephrine is markedly less arrhythmogenic in animals under tiletamine and zolazepam for injection anesthesia than in those under halothane anesthesia.

During tiletamine and zolazepam for injection anesthesia, the assurance of a patent airway is greatly enhanced by virtue of maintaining pharyngeal-laryngeal reflexes. During the first 15 minutes after intramuscular administration of 9 mg/lb (20 mg/kg) of tiletamine and zolazepam for injection, the respiratory rate is doubled while the tidal volume is decreased to less than one-half of control values. Arterial pO2 levels also decrease. This may be evidenced by hypoxemia and cyanosis. The pulmonary function usually returns to normal within 35 minutes after the administration of tiletamine and zolazepam for injection.

Preanesthetic Compatibility Study in Dogs

Six healthy Beagle dogs (3 males and 3 females), at least 8 months of age, ranging in body weight between 5.6 and 9.4 kg, were fitted with a telemetry device that captured systemic arterial blood pressures, electrocardiogram, and body temperature. Each dog received a total of 6 treatments with at least a 7-day washout between periods. During each period, dogs received 1 of the following 6 preanesthetics prior to the tiletamine and zolazepam administration: placebo (0.9% saline), acepromazine low dose (0.1 mg/kg body weight [BW]), acepromazine high dose (1.1 mg/kg BW), dexmedetomidine low dose (125 mcg/m2 body surface area [BSA]), dexmedetomidine high dose (375 mcg/m2 BSA), or butorphanol (0.4 mg/kg BW). Blood samples were collected at intubation, end of isoflurane administration, and after anesthesia when the dogs were able to walk. Plasma concentrations of tiletamine and zolazepam were measured using a validated method. Preanesthetic treatment with high dose acepromazine and both high and low doses of dexmedetomidine resulted in substantial increases in plasma concentrations of tiletamine and zolazepam at intubation. The increase in the tiletamine plasma concentrations was approximately 2× higher for the high dose of acepromazine and 2.7 to 4.5× higher for the low and high doses of dexmedetomidine, respectively, compared to saline. The increase in zolazepam plasma concentrations was 1.5× higher for the high dose acepromazine, and 1.8 to 2.8× higher for the low and high doses of dexmedetomidine, respectively, compared to saline.

No information on the dose-sparing of tiletamine and zolazepam was obtained during the study because the dogs were given the full initial half-dose (2.2 mg/kg) and not actually administered tiletamine and zolazepam 'to effect'. The average total dose of test article administered to the dogs was 2.6 mg/kg for the saline group and 2.2 mg/kg for the other treatment groups. One dog (saline group) required more than the initial 2.2 mg/kg bolus to achieve intubation at the first attempt.

Without preanesthesia (saline group), dogs retained a strong cough reflex, chewing motions, tachycardia and increased muscle tone during intubation. With preanesthesia, half of the dogs in the high dose dexmedetomidine group had no laryngeal reflex response to intubation and all experienced post-intubation apnea. The post-intubation apnea suggests that the 2.2 mg/kg dose of tiletamine and zolazepam was higher than necessary in some groups.

All dogs in all treatment groups achieved successful anesthetic plane following tiletamine and zolazepam administration and were intubated and induced to isoflurane anesthesia uneventfully. The quality of intubation, and occurrence and severity of adverse reactions (e.g., apnea and bradypnea) following tiletamine and zolazepam administration and intubation revealed differences among preanesthetic treatment groups. The cardiovascular and respiratory changes observed were typical of each preanesthetic medication used in combination with tiletamine and zolazepam. Acepromazine and isoflurane administration decreased arterial blood pressure. Dexmedetomidine decreased heart rate. Intubation transiently increased heart rate and/or blood pressure (sympathetic stimulations). Mild to severe respiratory depression was observed after tiletamine and zolazepam administration and each preanesthetic agent. Adverse reactions were manageable with appropriate care.