ZOLETIL- tiletamine and zolazepam for injection injection, powder, lyophilized, for solution

ZOLETIL by

Drug Labeling and Warnings

ZOLETIL by is a Animal medication manufactured, distributed, or labeled by Virbac AH, Inc. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

CIII

100 mg/mL total (equivalent to 50 mg/mL tiletamine and 50 mg/mL zolazepam)
For Intramuscular and Intravenous Injection in Dogs
For Intramuscular Injection only in Cats

CAUTION

Federal law restricts this drug to use by or on the order of a licensed veterinarian.

DESCRIPTION

ZOLETIL® (tiletamine and zolazepam for injection) is a nonnarcotic, nonbarbiturate, injectable anesthetic agent for dogs and cats. Chemically, Zoletil for Injection is a combination of equal parts by weight of base of tiletamine hydrochloride (2-[ethylamino]-2-[2-thienyl]-cyclohexanone hydrochloride), an arylaminocycloalkanone dissociative anesthetic, and zolazepam hydrochloride (4-[o-fluorophenyl]-6, 8-dihydro-1,3,8-trimethylpyrazolo [3,4-e] [1,4] diazepin-7 [1H]-1-hydrochloride), a nonphenothiazine diazepinone having minor tranquilizing properties. The product is supplied sterile in vials. The addition of 5 mL diluent produces a solution containing the equivalent of 50 mg tiletamine base, 50 mg zolazepam base and 57.7 mg mannitol per milliliter. This solution has a pH of 2 to 3.5 and is recommended for deep intramuscular injection.

INDICATIONS

Dogs

ZOLETIL 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.)
ZOLETIL administered intravenously is indicated in dogs for induction of anesthesia followed by maintenance with an
inhalant anesthetic.

Cats

ZOLETIL is indicated in cats for restraint or for anesthesia combined with muscle relaxation.

DOSAGE AND ADMINISTRATION

The dose is determined by the total combined concentration of 100 mg/mL (see HOW SUPPLIED)

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) ZOLETIL 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 ZOLETIL 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 ZOLETIL 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
2X 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 for injection 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 ZOLETIL intravenously at 1-2 mg/lb (2.2-4.4 mg/kg) body weight to effect.
ZOLETIL 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 ZOLETIL may be administered;
the total dose should not exceed 2 mg/lb (4.4 mg/kg) body weight.

Cats

In healthy cats, an initial ZOLETIL 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 ZOLETIL 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 ZOLETIL is not essential; however, when preparing for elective surgery,
it is advisable to withhold food for at least 12 hours prior to ZOLETIL administration. As with other injectable anesthetic
agents, the individual response to ZOLETIL 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 ZOLETIL 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 ZOLETIL 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 ZOLETIL is administered,
and then diminishes.

Repeated doses increase the duration of the effect of ZOLETIL 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 ZOLETIL 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 ZOLETIL the dosage
of these agents should be reduced.

PREPARATION OF SOLUTION FOR ADMINISTRATION

To each vial add 5 mL sterile water for injection, USP. Slight agitation will facilitate complete reconstitution. The resultant
solution will contain 100 mg total ZOLETIL per one milliliter (50 mg tiletamine and 50 mg zolazepam per mL).

Discard unused solution after 4 days when stored at room temperature or after 14 days when kept refrigerated. Only use clear
solution. Color of solution may vary from colorless to light amber.

CONTRAINDICATIONS

The use of ZOLETIL is contraindicated in dogs and cats with pancreatic disease. ZOLETIL should not be used in dogs and cats
with severe cardiac or pulmonary dysfunction.

Because the teratogenic potential of ZOLETIL is unknown, it should not be used in pregnant bitches or queens at any stage
of pregnancy. Also, a study has shown that tiletamine and zolazepam for injection crosses the placental barrier and produces
respiratory depression in the newborn; therefore, its use for Cesarean section is contraindicated.

WARNINGS

FOR USE IN DOGS AND CATS ONLY.

When using ZOLETIL for induction of anesthesia, patients should be continuously monitored. Facilities for the maintenance
of a patent airway, artificial ventilation and oxygen supplementation should be available.

Pulmonary edema has been reported to occur in cats with the use of tiletamine and zolazepam for injection. Signs and
symptoms include dyspnea, lethargy, anorexia and abnormal behavior. Deaths have been reported occasionally in severely
affected individuals. Cats should be observed closely for any signs and symptoms which may suggest pulmonary edema so
that appropriate therapy may be instituted.

The principal route of excretion of both components in the cat is the urine; therefore, ZOLETIL is not recommended for use in
cats suffering from renal insufficiency.
Balance studies in dogs indicated extensive biotransformation of both components with less than 4% of the dose excreted
unchanged in the urine.

ZOLETIL is excreted predominantly by the kidneys. Preexistent renal pathology or impairment of renal function may be
expected to result in prolonged duration of anesthesia.

Phenothiazine-derivative drugs should not be used with ZOLETIL at dosages indicated for intramuscular (IM) injection because
the combination produces respiratory and myocardial depression, hypotension and hypothermia.

The safe use of ZOLETIL in pregnant animals or on reproduction has not been established. ZOLETIL crosses the placental
barrier and causes respiratory depression in the neonate.

PRECAUTIONS

The dosage of ZOLETIL should be reduced in geriatric dogs and cats, in animals in debilitated condition and in animals with
impairment of renal function. Death has occurred in both cats and dogs following intramuscular tiletamine and zolazepam
for injection administration. Preexisting pulmonary disease, renal disease (see CONTRAINDICATIONS and WARNINGS)
and shock were causally implicated at necropsy; however, death was drug attributable in at least one dog (of 1072) and one
cat (of 1095).

Intravenous tiletamine and zolazepam for injection has been demonstrated to be safe in a field study in dogs when used in
conjunction with phenothiazine-derivative drugs (acepromazine) administered at dosages from 0.04-0.06 mg/kg IM.

Cats and smaller dogs with small body masses in relation to large body surfaces should be protected from heat loss
during ZOLETIL anesthesia. Body temperature should be monitored, and supplemental heat may be required to control
hypothermia. As with other anesthetics, it is prudent to provide for hemostasis during any surgical procedure.

During ZOLETIL anesthesia, athetoid movement may occur. This athetosis should not be mistaken for lack of anesthesia nor is
it indicative of lack of analgesia. Do not give additional anesthesia in an attempt to abolish the athetoid movement. Efforts to
eliminate athetoid movement with additional doses of ZOLETIL can result in anesthetic overdosage.

ZOLETIL does not abolish laryngeal, pharyngeal, pinnal, palpebral, and pedal reflexes, and may not be adequate as the
sole anesthetic for surgical procedures in these areas. Endotracheal tubes are not well tolerated in connection with
ZOLETIL anesthesia in the cat and their use may result in impaired respiration. After removal of the tube, normal respiration
should resume.

The stimulation of surgical procedures aids in maintaining adequate ventilation. The anesthetized patient must be
monitored throughout the procedure, and if cardiopulmonary problems do occur, measures must be taken to assure that
alveolar ventilation and cardiovascular functions are maintained.

The eyes normally remain open with the pupils dilated. The use of a bland ophthalmic ointment is advisable to protect the
corneas from desiccation. The concurrent use of chloramphenicol will prolong the duration of anesthesia in cats.

Copious salivation may occur during ZOLETIL anesthesia. Ptyalism may be controlled in dogs and cats by administering
atropine sulfate, USP, 0.02 mg/lb (0.04 mg/kg) body weight (IV, IM, or SC) as concurrent medication. Exaggerated swallowing,
reflex action and accumulation of saliva may give rise to vomiting and retching.

ADVERSE REACTIONS

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

Respiratory depression may occur following administration of high doses of ZOLETIL. 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 for injection 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 for injection 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 for injection (See EFFECTIVENESS). Sixteen adverse
reactions occurred during the study: nystagmus (5), emesis (4), diarrhea (2), and one occurrence each of hypersalivation,
urticaria, 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 or for technical assistance contact Virbac AH, Inc. at 1-800-338-3659.
Visit vet-us.virbac.com for product details.

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

CLINICAL PHARMACOLOGY

Mechanism of Action

ZOLETIL® (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 ZOLETIL
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 for injection, 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 for injection 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 (AUC0-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.

EFFECTIVENESS

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 for injection 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 for injection 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 131/143
(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 (108/144) 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 for
injection 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.

ANIMAL SAFETY

Tiletamine and zolazepam for injection has a wider margin of safety in cats than in dogs. Dogs have survived repeated IM
dosage regimens of 13.6 mg/lb (30 mg/kg) (maximum safe dose) for eight successive days. This is approximately two times
the maximum recommended therapeutic dose. Cats have survived IM dosage regimens of up to 32.7 mg/lb (72 mg/kg)
(maximum safe dose) on alternate days for seven episodes. This is 4.6 times the maximum recommended therapeutic dose
for cats. However, these reports should not obviate prudent anesthetic practices. Some degree of tolerance has been
reported. This tolerance appears to be species-variable.

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 pO2levels 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 for injection 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 2X higher for the high dose of acepromazine and 2.7 to 4.5X higher for the low and high doses of dexmedetomidine, respectively, compared to saline. The increase in zolazepam plasma concentrations was 1.5X higher for the high dose acepromazine, and 1.8 to 2.8X higher for the low and high doses of dexmedetomidine, respectively, compared to saline.

No information on the dose-sparing of tiletamine and zolazepam for injection 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 for injection ‘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 for injection was higher than necessary in some groups. 

All dogs in all treatment groups achieved successful anesthetic plane following tiletamine and zolazepam for injection 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 for injection 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 for injection. 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 for injection administration and each preanesthetic agent. Adverse reactions were manageable with appropriate care.

STORAGE CONDITIONS

Store at controlled room temperature 20° to 25° C (68° to 77° F). Discard unused solution after 4 days when stored at room temperature or after 14 days when kept refrigerated. Only use clear solution. Color of solution may vary from colorless to light amber.

HOW SUPPLIED

ZOLETIL (tiletamine and zolazepam for injection) is available in individual vials of 5 mL solution when reconstituted.
The addition of 5 mL diluent produces a solution containing the equivalent of 50 mg tiletamine base, 50 mg zolazepam base
and 57.7 mg mannitol per milliliter.

5 mL vial – 100 mg/mL total (equivalent to 50 mg/mL tiletamine and 50 mg/mL zolazepam) when reconstituted.

SPL UNCLASSIFIED SECTION

Approved by FDA under ANADA # 200-618

Manufactured in France for Virbac AH, Inc.

P.O. Box 162059, Fort Worth, TX, 76161

1-800-338-3659

Zoletil™ is a trademark of Virbac SA

Rev. 01/2024

© 2024 Virbac Corporation. All Rights Reserved.

005U4040210

PRINCIPAL DISPLAY PANEL

INGREDIENTS AND APPEARANCE

ZOLETIL 
tiletamine and zolazepam for injection injection, powder, lyophilized, for solution

Product Information
Product Type	PRESCRIPTION ANIMAL DRUG	Item Code (Source)	NDC: 51311-718
Route of Administration	INTRAMUSCULAR, INTRAVENOUS	DEA Schedule	CIII

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
TILETAMINE HYDROCHLORIDE (UNII: 99TAQ2QWJI) (TILETAMINE - UNII:2YFC543249)	TILETAMINE HYDROCHLORIDE	50 mg  in 1 mL
ZOLAZEPAM HYDROCHLORIDE (UNII: 45SJ093Q1N) (ZOLAZEPAM - UNII:G1R474U58U)	ZOLAZEPAM HYDROCHLORIDE	50 mg  in 1 mL

Product Characteristics
Color	white	Score
Shape		Size
Flavor		Imprint Code
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 51311-718-05	1 in 1 CARTON
1		5 mL in 1 VIAL, MULTI-DOSE

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANADA	ANADA200618	05/01/2020

Labeler - Virbac AH, Inc (131568396)

Registrant - Virbac AH, Inc (131568396)