Zoletil

Description

ZOLETIL (tiletamine and zolazepam for injection) is a nonnarcotic, nonbarbiturate, injectable anesthetic agent indicated for use in dogs and cats. It is composed of equal parts by weight of tiletamine hydrochloride and zolazepam hydrochloride. Tiletamine hydrochloride is chemically defined as 2-ethylamino-2-2-thienyl-cyclohexanone hydrochloride, classified as an arylaminocycloalkanone dissociative anesthetic. Zolazepam hydrochloride is identified as 4-o-fluorophenyl-6, 8-dihydro-1,3,8-trimethylpyrazolo 3,4-e 1,4 diazepin-7 1H-1-hydrochloride, which is a nonphenothiazine diazepinone with minor tranquilizing properties. When 5 mL of diluent is added, the resulting solution contains 50 mg of tiletamine base, 50 mg of zolazepam base, and 57.7 mg of mannitol per milliliter, with a pH range of 2 to 3.5.

Uses and Indications

ZOLETIL is indicated for use in dogs for restraint and minor procedures of short duration, averaging 30 minutes, that require mild to moderate analgesia. Such minor surgical procedures include laceration repair, draining of abscesses, castrations, and other interventions necessitating mild to moderate analgesia. Additionally, ZOLETIL, when administered intravenously, is indicated for the induction of anesthesia in dogs, followed by maintenance with an inhalant anesthetic.

In cats, ZOLETIL is indicated for restraint or for anesthesia in conjunction with muscle relaxation.

Dosage and Administration

For dogs, the recommended dosage for intramuscular (IM) administration for restraint and minor procedures requiring mild to moderate analgesia is as follows: an initial dosage of 3 to 4.5 mg/lb (6.6 to 9.9 mg/kg) is advised for diagnostic purposes. For minor procedures, the dosage should be increased to 4.5 to 6 mg/lb (9.9 to 13.2 mg/kg). Supplemental doses must be less than the initial dose, and the total dose (initial plus supplemental) should not exceed 12 mg/lb (26.4 mg/kg). The maximum safe dose is established at 13.6 mg/lb (29.92 mg/kg).

For intravenous (IV) administration aimed at the induction of anesthesia, the induction dosage is set at 1-2 mg/lb (2.2-4.4 mg/kg) of body weight, administered slowly over a period of 30-45 seconds. It is essential to assess the level of consciousness, muscle relaxation, and jaw tone after 30-60 seconds. If the level of anesthesia is deemed insufficient after 60 seconds, additional ZOLETIL may be administered, ensuring that the total dose does not exceed 2 mg/lb (4.4 mg/kg) of body weight.

In cats, the initial dosage for IM administration is recommended at 4.4 to 5.4 mg/lb (9.7 to 11.9 mg/kg) for procedures such as dentistry, treatment of abscesses, and foreign body removal. For minor procedures requiring mild to moderate analgesia, a dosage of 4.8 to 5.7 mg/lb (10.6 to 12.5 mg/kg) is appropriate. For specific procedures such as ovariohysterectomy and onychectomy, the initial dosages should be increased to 6.5 to 7.2 mg/lb (14.3 to 15.8 mg/kg). Supplemental doses should be administered in increments less than the initial dose, with the total dose (initial plus supplemental) not exceeding 32.7 mg/lb (72 mg/kg).

Contraindications

The use of ZOLETIL is contraindicated in dogs and cats with pancreatic disease due to the potential for exacerbating the condition. Additionally, ZOLETIL should not be administered to dogs and cats with severe cardiac or pulmonary dysfunction, as it may worsen these conditions.

Due to the unknown teratogenic potential of ZOLETIL, its use is contraindicated in pregnant bitches or queens at any stage of pregnancy. Furthermore, ZOLETIL is contraindicated for use during Cesarean sections because of the risk of respiratory depression in the newborn.

Warnings and Precautions

Use of ZOLETIL is restricted to dogs and cats only. When administering ZOLETIL for the induction of anesthesia, it is imperative that patients are continuously monitored throughout the procedure. Facilities must be equipped to maintain a patent airway, and provisions for artificial ventilation and oxygen supplementation should be readily available.

Particular caution should be exercised in cats, as pulmonary edema has been reported following the use of tiletamine and zolazepam for injection. Clinicians should be vigilant for signs and symptoms indicative of pulmonary edema, including dyspnea, lethargy, anorexia, and abnormal behavior. In severely affected individuals, fatalities have been documented. Close observation of cats is essential to ensure timely intervention and appropriate therapy if any concerning signs arise.

The primary route of excretion for both components of ZOLETIL in cats is via the urine. Consequently, the use of ZOLETIL is contraindicated in cats with renal insufficiency. Additionally, preexisting renal pathology or impairment may lead to an extended duration of anesthesia, necessitating careful consideration of renal function prior to administration.

The concomitant use of phenothiazine-derivative drugs with ZOLETIL at the indicated dosages for intramuscular (IM) injection is contraindicated, as this combination can result in significant respiratory and myocardial depression, hypotension, and hypothermia.

The safety of ZOLETIL in pregnant animals or its effects on reproduction have not been established. It is important to note that ZOLETIL crosses the placental barrier and may induce respiratory depression in neonates.

Finally, it is essential to adhere to federal regulations, which restrict the use of this drug to licensed veterinarians or under their direct order.

Side Effects

Patients receiving ZOLETIL may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Serious adverse reactions include respiratory depression, which may occur following the administration of high doses. If respiration becomes excessively depressed and cyanosis is observed, prompt resuscitative measures should be instituted. Other serious reactions reported include cardiac arrest, pulmonary edema, and death, which has been documented in both dogs and cats following the administration of tiletamine and zolazepam for injection. In cases of pulmonary edema, signs may include dyspnea, lethargy, anorexia, and abnormal behavior, with occasional fatalities in severely affected individuals.

Common adverse reactions observed in clinical settings include emesis, excessive salivation, transient apnea, vocalization, erratic recovery, prolonged recovery, excessive tracheal and bronchial secretions (notably when atropine sulfate is not administered prior to anesthesia), involuntary muscular twitching, hypertonicity, cyanosis, central nervous system stimulation, convulsions, and tachycardia, which frequently occurs in dogs and typically lasts about 30 minutes. Additionally, hypertension or hypotension may occur, and insufficient anesthesia has been reported in dogs.

In a study involving intravenous induction of anesthesia followed by maintenance with inhalant anesthesia in dogs, several adverse reactions were noted. These included nystagmus (5 occurrences), emesis (4 occurrences), diarrhea (2 occurrences), hypersalivation (1 occurrence), urticaria (1 occurrence), anorexia (1 occurrence), hyperthermia (1 occurrence), lethargy (1 occurrence), and post-induction apnea, which was observed in 49.3% of dogs across all treatment groups with a mean duration of one minute. Furthermore, 16 dogs experienced oxygen saturation (SpO2) levels of ≤90 mmHg, while 25 dogs had temperatures ≥103°F and 27 dogs had temperatures ≤96°F at various time points. Mean blood pressure (BP) of ≤60 mmHg was recorded in 59 dogs, although no adverse reactions were reported due to hypotension or hypertension. Ventricular premature depolarizations were noted in 3 dogs in the alpha2-agonist + opioid group, and transient ST depression was observed in 1 dog in the phenothiazine + opioid group.

It is important to note that athetoid movement may occur during ZOLETIL anesthesia and should not be mistaken for a lack of anesthesia or analgesia. Copious salivation may also occur, which can be managed with atropine sulfate; however, exaggerated swallowing and accumulation of saliva may lead to vomiting and retching.

Drug Interactions

There are currently no documented drug interactions associated with the use of this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists each NDC Code for Zoletil (tiletamine and zolazepam for injection) veterinary formulations. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The use of ZOLETIL is contraindicated in pediatric patients, specifically dogs and cats, with pancreatic disease, severe cardiac or pulmonary dysfunction, or those that are pregnant at any stage. ZOLETIL crosses the placental barrier and can cause respiratory depression in newborns, making its use during Cesarean sections inadvisable.

Dosage adjustments are necessary for geriatric patients, those in debilitated conditions, and animals with renal impairment. For healthy cats, an initial dosage of 4.4 to 5.4 mg/lb (9.7 to 11.9 mg/kg) is recommended for procedures such as dentistry and abscess treatment, while initial dosages of 6.5 to 7.2 mg/lb (14.3 to 15.8 mg/kg) are advised for ovariohysterectomy and onychectomy. The maximum safe dose for dogs is 13.6 mg/lb (29.92 mg/kg) and for cats is 32.7 mg/lb (72 mg/kg).

Care should be taken to monitor body temperature during ZOLETIL anesthesia, particularly in cats and smaller dogs, as they are at risk for heat loss. Supplemental heat may be required to prevent hypothermia. Recovery times can vary based on the age and physical condition of the animal, as well as the dosage administered, with extended recovery noted in cases of high doses or multiple injections, especially in cats. When supplemental doses are necessary, they should be administered in increments smaller than the initial dose, ensuring that the total administered dose does not exceed the maximum allowable safe dose.

Geriatric Use

Elderly patients, including those aged 65 and older, may require dosage adjustments when receiving ZOLETIL. It is recommended that the dosage be reduced in geriatric patients, as well as in those who are in a debilitated condition or have impaired renal function.

The recovery process in geriatric patients can vary significantly based on age, physical condition, and the dosage of ZOLETIL administered. Notably, recovery may be prolonged with higher doses or multiple injections, particularly in cats. Therefore, careful monitoring and consideration of these factors are essential when administering ZOLETIL to elderly patients to ensure safety and efficacy.

Pregnancy

The use of ZOLETIL is contraindicated in pregnant bitches or queens at any stage of pregnancy due to the unknown teratogenic potential. Tiletamine and zolazepam, the active components of ZOLETIL, are known to cross the placental barrier and may produce respiratory depression in the newborn. Consequently, the use of ZOLETIL for Cesarean sections is also contraindicated. The safety of ZOLETIL in pregnant animals or its effects on reproduction have not been established, and caution is advised when considering its use in females of childbearing potential.

Lactation

The safe use of ZOLETIL in lactating mothers has not been established. There is a potential for excretion of ZOLETIL in breast milk. Caution should be exercised when administering ZOLETIL to nursing mothers due to the unknown effects on the nursing infant.

Renal Impairment

Patients with renal impairment should be approached with caution when considering the use of ZOLETIL, as it is predominantly excreted by the kidneys. In cats suffering from renal insufficiency, the use of ZOLETIL is not recommended due to the potential for adverse effects. Additionally, preexisting renal pathology or impairment of renal function may lead to a prolonged duration of anesthesia, necessitating careful monitoring and potential adjustments in dosing.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in clinical trials for this medication. As such, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data regarding its safety and efficacy in this population. Regular monitoring of liver function may be warranted based on clinical judgment.

Overdosage

In the absence of specific overdosage information, it is essential for healthcare professionals to remain vigilant and prepared for potential scenarios involving overdose.

Healthcare providers should be aware that the clinical presentation of an overdose may vary depending on the substance involved and the individual patient’s characteristics. Symptoms of overdose can range from mild to severe and may include altered mental status, cardiovascular instability, respiratory distress, and gastrointestinal disturbances.

In the event of suspected overdosage, immediate medical evaluation is recommended. Healthcare professionals should assess the patient's vital signs and conduct a thorough clinical examination. Supportive care should be initiated as necessary, which may include airway management, intravenous fluids, and monitoring of vital parameters.

If specific antidotes or treatments are available for the substance involved, they should be administered according to established protocols. Consultation with a poison control center or a medical toxicologist may also be beneficial in managing the case effectively.

It is crucial to document all findings and interventions in the patient's medical record to ensure continuity of care and facilitate further management.

Nonclinical Toxicology

The teratogenic potential of ZOLETIL is currently unknown; therefore, its use in pregnant bitches or queens at any stage of pregnancy is contraindicated. Studies indicate that tiletamine and zolazepam for injection can cross the placental barrier, leading to respiratory depression in newborns. Consequently, the use of this drug for Cesarean sections is not recommended. Furthermore, the safety of ZOLETIL in pregnant animals or its effects on reproduction have not been established, and it has been observed to cause respiratory depression in neonates.

In nonclinical studies, fatalities have been reported in both cats and dogs following intramuscular administration of tiletamine and zolazepam for injection. Necropsy findings implicated preexisting pulmonary disease, renal disease, and shock as contributing factors; however, at least one case of death was attributed directly to the drug in one dog (out of 1072) and one cat (out of 1095).

Animal pharmacology and toxicology assessments reveal that tiletamine and zolazepam for injection has a wider margin of safety in cats compared to dogs. Dogs have tolerated repeated intramuscular dosage regimens of 13.6 mg/lb (30 mg/kg) for eight consecutive days, which is approximately double the maximum recommended therapeutic dose. In contrast, cats have survived intramuscular dosages of up to 32.7 mg/lb (72 mg/kg) on alternate days for seven episodes, equating to 4.6 times the maximum recommended therapeutic dose for this species.

In cats, the duration of effect of zolazepam surpasses that of tiletamine, resulting in a greater degree of tranquilization than anesthetization during recovery. A slight decrease in blood pressure is noted within the first hour post-injection in cats, while heart rate and electrocardiogram readings remain unaffected. Arterial pO2 levels may decrease three minutes after injection but typically normalize within 15 to 35 minutes.

Conversely, in dogs, the duration of effect of tiletamine exceeds that of zolazepam, leading to a lesser degree of tranquilization compared to anesthetization. Following administration, a marked and persistent tachycardia is observed within two minutes after intramuscular injection of either 4.5 or 9 mg/lb (10 or 20 mg/kg). Stroke volume decreases in proportion to the increased heart rate at the 4.5 mg/lb (10 mg/kg) dose, with minimal change in net cardiac output. An initial increase in systolic blood pressure is followed by a slight drop within five minutes, with systolic pressure remaining at this decreased level throughout the anesthetic effect, while diastolic pressure continues to rise.

At a 9 mg/lb (20 mg/kg) dose, the relationship between stroke volume and heart rate becomes disproportionate, leading to a significant decrease in cardiac output. Additionally, contractility and mean blood pressure are reduced, indicating direct myocardial depression. During surgical procedures, tachycardia and hypertension may occur, potentially triggered by sympathetic responses to painful stimuli.

Postmarketing Experience

Pulmonary edema has been reported in cats following the administration of tiletamine and zolazepam for injection. Clinical signs associated with this condition include dyspnea, lethargy, anorexia, and abnormal behavior, with occasional fatalities noted in severely affected individuals. It is recommended that cats be closely monitored for any signs indicative of pulmonary edema to facilitate timely therapeutic intervention.

Deaths have been documented in both cats and dogs after intramuscular administration of tiletamine and zolazepam. While preexisting pulmonary disease, renal disease, and shock were identified as potential contributing factors at necropsy, at least one case of death was determined to be drug-related in one dog (out of 1072) and one cat (out of 1095).

Adverse reactions reported include emesis during emergence, excessive salivation, transient apnea, vocalization, erratic and prolonged recovery, excessive tracheal and bronchial secretions (notably when atropine sulfate was not administered prior to 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 observed. Tachycardia is frequently noted, particularly in dogs, typically lasting about 30 minutes, with occurrences of either hypertension or hypotension. Insufficient anesthesia has been reported in dogs.

In a field study evaluating the safety and effectiveness of tiletamine and zolazepam for injection administered intravenously at doses of 1-2 mg/lb (2.2-4.4 mg/kg) for anesthesia induction, 16 adverse reactions were recorded: nystagmus (5 cases), emesis (4 cases), diarrhea (2 cases), and one case each of hypersalivation, urticaria, anorexia, hyperthermia, and lethargy. All adverse reactions resolved by the conclusion of the study.

Post-induction apnea, defined as a duration of 30 seconds or more from induction to the first inspiration, was observed in 49.3% of dogs across all treatment groups, with a mean duration of one minute. The highest frequency and duration of post-induction apnea were noted in the alpha2-agonist + opioid groups.

Sixteen dogs exhibited oxygen saturation (SpO2) levels of ≤90 mmHg, with 7 in the alpha2-agonist + opioid groups, 6 in the phenothiazine + opioid groups, and 3 in the opioid alone groups. Additionally, 25 dogs had a temperature of ≥103°F during the study, with 12 of these occurrences noted prior to preanesthetic administration. Among the remaining 13 dogs, 7 were in the alpha2-agonist + opioid groups, 5 in the opioid alone groups, and 1 in the phenothiazine + opioid groups. One dog in the alpha2-agonist + opioid treatment groups was reported with hyperthermia as an adverse reaction.

Ventricular premature depolarizations were observed in 3 dogs within the alpha2-agonist + opioid group, a transient rhythm disturbance that is not uncommon in dogs receiving alpha2-agonists or inhalant anesthetics. One dog in the phenothiazine + opioid group exhibited transient ST depression, potentially attributable to cardiac hypoxia. All affected dogs recovered without complications.

Patient Counseling

Healthcare providers should inform patients that federal law restricts the use of this drug to licensed veterinarians or under their order. It is important to advise patients that fasting prior to the induction of general anesthesia with ZOLETIL is not essential; however, for elective surgeries, it is recommended to withhold food for at least 12 hours before administration.

Patients should be made aware that recovery from anesthesia can vary based on the age and physical condition of the animal, as well as the dosage of ZOLETIL administered. Recovery may be prolonged with higher doses or multiple injections, particularly in cats. Additionally, patients should be informed that there may be pain associated with the injection, which is especially common in cats.

Healthcare providers should explain that following a single, deep intramuscular injection of ZOLETIL in cats and dogs, the onset of anesthetic effect typically occurs within 5 to 12 minutes. Muscle relaxation is optimal for approximately the first 20 to 25 minutes after administration, after which it diminishes. It is crucial to note that the quality of anesthesia with repeated doses may vary, as the ratio of the drug's components within the animal's body changes with each injection. The best method for evaluating the depth of anesthesia is to monitor the patient for any deliberate conscious response to nociceptive stimuli.

If the recommended dosage regimen does not produce adequate anesthesia, supplemental anesthesia or an alternative agent should be considered. Patients should also be advised that the eyes usually remain open with dilated pupils, and the application of a bland ophthalmic ointment is recommended to protect the corneas from drying out.

Healthcare providers should inform patients that copious salivation may occur during ZOLETIL anesthesia. This ptyalism can be managed in dogs and cats by administering atropine sulfate, USP, at a dosage of 0.02 mg/lb (0.04 mg/kg) body weight via IV, IM, or SC routes as a concurrent medication. Patients should be made aware that exaggerated swallowing, reflex actions, and saliva accumulation may lead to vomiting and retching.

Continuous monitoring of the patient is essential during the use of ZOLETIL for anesthesia induction. Facilities for maintaining a patent airway, artificial ventilation, and oxygen supplementation should be readily available. Cats should be closely observed for any signs of pulmonary edema, allowing for timely intervention if necessary.

Finally, healthcare providers should emphasize that the stimulation of surgical procedures can aid in maintaining adequate ventilation. The anesthetized patient must be monitored throughout the procedure, and if any cardiopulmonary issues arise, immediate measures should be taken to ensure proper alveolar ventilation and cardiovascular function are maintained.

Storage and Handling

The product is supplied in a clear solution, which may vary in color from colorless to light amber. It should be stored at a controlled room temperature of 20° to 25° C (68° to 77° F). Unused solution must be discarded after 4 days when stored at room temperature. If the solution is kept refrigerated, it should be discarded after 14 days. It is essential to ensure that only clear solutions are utilized.

Additional Clinical Information

Dogs received intravenous administration of tiletamine and zolazepam for injection at a dosage of 1-2 mg/lb (2.2-4.4 mg/kg) 'to effect' for anesthesia. No further information is available regarding laboratory tests, abuse potential, patient counseling, or postmarketing experiences.

Drug Information (PDF)

This document includes the full labeling information for Zoletil, as submitted by Virbac AH, Inc for veterinary use. It may include dosage by species, withdrawal periods, and administration instructions.

View veterinary label (PDF)