Dormazolam (Canada)

Company: Dechra

Midazolam injection, Mfr. Std.

Veterinary Use Only

Sterile

5 mg/mL

DIN 02517582

THERAPEUTIC CLASSIFICATION

Anaesthetic

Description

Dormazolam is a clear, colourless, sterile aqueous solution for intravenous injection in horses containing the benzodiazepine, midazolam.

Active Ingredient

INDICATION

For use with ketamine as an intravenous induction agent for the anaesthesia of healthy adult horses.

DOSAGE and ADMINISTRATION

Once the horse is properly sedated with a premedication agent, administer 0.06 mg/kg body weight (1.2 mL/100 kg) intravenously, in combination with ketamine at a dose of 2.2 mg/kg body weight (2.2 mL/100 kg of a 100 mg/mL ketamine solution). Midazolam and ketamine may be combined and administered in the same syringe.

Time to achievement of lateral recumbency is approximately 1.8 minutes and time to intubation is approximately 4.5 minutes.

Contraindications

Do not use in animals with severe respiratory failure.

Do not use in cases of hypersensitivity to midazolam.

CAUTIONS

In case of renal or hepatic dysfunction, or respiratory depression, there may be greater risk associated with the use of the product.

Dormazolam should not be used as the sole induction agent as it may cause restlessness or agitation.

Prolonged time to extubation may be associated with use of the product.

The safety of repeated bolus dosing (at 0.06 mg/kg) at intervals of less than 4 days has not been established.

Care should be taken when administering the product to hypoalbuminaemic horses since these animals may have higher sensitivity to a given dose.

Dormazolam should not be used in pregnant or lactating mares as the safety has not been assessed.

Midazolam potentiates the effect of some sedative and anaesthetic agents, reducing the dose required, including alpha-2-agonists (detomidine, xylazine), propofol and some inhalational agents.

Concurrent use of midazolam with antihistamines (H₂-receptor antagonists, e.g. cimetidine), barbiturates, local anaesthetics, opioid analgesics or CNS depressants may enhance the sedative effect.

In combination with other agents (e.g. opioid analgesics, inhalational anaesthetics), an increase in respiratory depression may be observed.

Erythromycin and azole antifungals (fluconazole, ketoconazole) inhibit the metabolism of midazolam, resulting in increased plasma midazolam concentrations and increased sedation.

Drugs that induce CYP450 mediated metabolism, such as rifampin, may decrease plasma concentrations and effects of midazolam.

WARNINGS

This drug is not to be used in horses intended for food.

Midazolam is a central nervous system depressant and can cause sedation and induction of sleep. Care should be taken to avoid self-injection. In case of accidental self-injection, seek medical advice immediately and show the package insert to the physician. DO NOT DRIVE as sedation and impaired muscular function may occur.

Midazolam and its metabolites may be harmful for the unborn child, and are secreted into breastmilk in small amounts. Pregnant and breastfeeding women should, therefore, take great care when handling this product and, in the event of exposure, seek medical advice immediately.

People with known sensitivity to midazolam should avoid contact with the product.

This product contains benzyl alcohol and can cause skin irritation. Avoid contact with skin. In the case of contact with skin, wash with soap and water. If irritation persists, seek medical advice. Wash hands after use.

The product can cause eye irritation. Avoid contact with eyes. If the product comes into contact with the eyes, rinse the eyes immediately with plenty of water and seek medical attention if irritation persists.

Keep out of reach of children.

OVERDOSE

The symptoms of overdose are mainly an intensification of the pharmacological effects of midazolam: drowsiness, and muscle relaxation.

In case of accidental midazolam overdose, restlessness or agitation in combination with prolonged muscle weakness may develop when the ketamine effect of the combined midazolam-ketamine anaesthesia subsides.

The benzodiazepine antagonist, flumazenil, can be used to reverse effects associated with an overdose of midazolam, although clinical experience in horses is limited.

ADVERSE REACTIONS

The following clinical signs have been reported after the use of this product:

Ataxia/incoordination during recovery from anaesthesia.

Spontaneous urination upon induction of anaesthesia.

Respiratory depression.

CLINICAL PHARMACOLOGY

Midazolam is an imidazobenzodiazepine, differing structurally from other benzodiazepines by the presence of an imidazole ring fused at positions 1 and 2 of the benzodiazepines nucleus. Midazolam exhibits similar pharmacologic actions as other benzodiazepines. The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the central nervous system are depressed by the benzodiazepines thus producing the mild sedative (in horses), skeletal muscle relaxant, and anticonvulsant effects seen.

Benzodiazepine agonists act by enhancing the inhibitory synaptic neurotransmission mediated by gamma-aminobutyric acid (GABA), through binding to the benzodiazepine binding site on the GABA_A-receptor, a ligand-gated chloride channel consisting of five subunits. Sensitivity to benzodiazepines is conferred by the presence of a gamma subunit. Four types of benzodiazepine-sensitive GABA_A-receptors can be further distinguished on the basis of the presence of alpha-1, alpha-2, alpha-3 or alpha-5 subunits. The alpha-1 GABA_A receptors are mainly expressed in cortical areas and thalamus, alpha-2 and alpha-5 GABA_A receptors are largely expressed in the limbic system, and alpha-3 GABA_A receptors are selectively expressed in noradrenergic and serotonergic neurons of the reticular activating system.

Studies with genetically modified mice have shown that the sedative and partly the anticonvulsant actions of benzodiazepines are mediated by the alpha-1-type GABA_A receptors, whereas the anxiolytic effects of benzodiazepine-receptor ligands appear to be mediated via GABA_A receptors containing the alpha-2 subunit. The myorelaxant effect of benzodiazepines also seems to be mediated by benzodiazepine-sensitive GABA_A receptors other than the alpha-1-type.

In acidic conditions (pH less than 4), the benzepine ring of midazolam is open, resulting in increased water solubility. However, at physiological pH, the ring closes and midazolam becomes lipophilic, which accounts for its rapid onset of action.

In the combined safety and pharmacokinetic study conducted on 8 healthy Thoroughbred horses, when administered intravenously in combination with ketamine (2.2 mg/kg), Dormazolam (midazolam dosage 0.06 mg/kg) demonstrated a mean (±SD) volume of distribution of 0.619 (±0.195) L/kg, a mean clearance of 8.6 (±1.47) mL/min/kg, and a mean residence time of 4.2 (±1.6) hours. These pharmacokinetic parameters were calculated using a non-compartmental model.

Midazolam is highly protein bound (94 - 97%) and rapidly crosses the blood-brain barrier.

Midazolam undergoes biotransformation by hepatic microsomal oxidation followed by conjunction with glucuronic acid.

The principal route of excretion is through the kidneys, mainly as glucuronidated metabolites.

SAFETY STUDIES

A study was conducted to assess safety of Dormazolam when administered intravenously at 3-times (0.18 mg/kg) and 5-times (0.3 mg/kg) the recommended dose of 0.06 mg/kg, in combination with ketamine (2.2 mg/kg intravenously) after premedication with detomidine (20 mcg/kg intravenously). The study included 8 horses (4 males, 4 females), aged between 1.6 and 8. 7 years, and weighing between 372 and 545 kg. Following a 3-times overdose, the following effects attributable to midazolam were observed: poor recovery (more attempts to stand, more ataxia), a slight decrease of the haematocrit, respiratory depression - evidenced by a slight decrease of the respiratory rate, a lower pO₂, a metabolic alkalosis and a slight increase of arterial pH - and a prolonged recovery. A dose of 0.3 mg midazolam per kg bodyweight (5 times overdose) using the same combination resulted in a violent recovery, i.e. horse trying to stand up, whilst still having profound muscle weakness.

EFFICACY STUDIES

Thirty-nine horses were enrolled in this multicenter, randomized, blinded, placebo-controlled field study; 19 in the placebo group and 20 in the midazolam group. Healthy intact colts over 400 kg body weight were used. All the horses were sedated with 20 mcg/kg of detomidine and 3 to 15 minutes later induction was performed with either a midazolam and ketamine combination (test group) or ketamine combined with a placebo (placebo group). The dosages were 0.06 mg/kg of midazolam and 2.2 mg/kg of ketamine. Once recumbent, tracheal intubation and routine open castration was performed after scrotal infiltration of lidocaine.

The quality of induction was significantly better in the test group compared to administration of ketamine without midazolam (placebo group) when assessed using a visual analogue and a simple descriptive scale. Intubation quality was significantly better in the test group as assessed by a visual analogue and a simple descriptive scale. The time to intubation was longer in the placebo group. The ease of surgery based on the degree of muscle relaxation scored significantly better when midazolam was included as an induction agent. Significantly more horses in the placebo (8/19) than in the midazolam (2/20) group required supplementary anaesthetic agent to enable surgery to be completed. Horses in the midazolam group remained recumbent for a longer period (longer recovery time) than the horses in the placebo group.

Physiological functions such as heart rate, respiratory rate, blood pressure, and oxygen saturation were not affected by midazolam during anaesthesia and no adverse reaction related to the test product was observed.

STORAGE

Store between 15 and 25°C in the original packaging to protect from light. Contents should be used within 28 days after first use.

PRESENTATIONS

Multidose vial of 20 mL.

Dechra Regulatory B.V., Handelsweg 25, 5531 AE Bladel, The Netherlands

Imported and distributed by: Dechra Veterinary Products Inc., 1 Holiday Avenue, East Tower, Suite 345, Pointe-Claire, Québec, Canada H9R 5N3

E5203-S.0721

CPN: 1786070.0