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Date: Sunday, November 29, 2020 4:23

Release 2.58
Dormazolam® 5 mg/ml Solution for Injection for Horses
 
Species: Horses and other equidae
Therapeutic indication: Pharmaceuticals: Neurological preparations: General anaesthetics
Active ingredient: Midazolam
Product:Dormazolam® 5 mg/ml Solution for Injection for Horses
Product index: Dormazolam 5 mg/ml Solution for Injection for Horses
Withdrawal notes: The product is not authorised for use in horses intended for human consumption.
Qualitative and quantitative composition
Each ml contains: Active substance:
Midazolam 5.0 mg
Excipient(s): Benzyl alcohol (E1519) 10.0 mg
Pharmaceutical form
Solution for injection. Clear, colourless solution.
Clinical particulars
Target species
Horses
Indications for use
Intravenous co-induction of anaesthesia with ketamine for smooth induction and intubation and profound muscle relaxation during anaesthesia.
Contraindications
Do not use in in animals with severe respiratory failure.
Do not use as a sole agent.
Do not use in cases of hypersensitivity to the active substance or to any of the excipients.
Special precautions for use in animals
In case of renal or hepatic dysfunction or respiratory depression there may be greater risk associated with the use of the product. Use only according to the benefit/risk assessment by the responsible veterinarian.
Midazolam produces muscle relaxation; when used as a sole agent horses may be slightly sedated, but also restless or even agitated when they become ataxic/unstable.
Prolonged recovery time (prolonged recumbence and 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. Based on the pharmacokinetics of the active substance, care should be taken when administering repeated doses of midazolam within a 24 hour period to horses, particularly neonatal foals (i.e. foals less than 3 weeks old), obese horses and horses with hepatic impairment or conditions associated with reduced organ perfusion, due to the possibility of drug accumulation.
Care should be taken when administering the product to hypoalbuminaemic horses since these animals may have higher sensitivity to a given dose.
Before using combinations of midazolam with other veterinary medicinal products, the product literature for the other products should be observed.
Special precautions to be taken by the person administering the veterinary medicinal product to animals
Midazolam is a CNS 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 leaflet to the physician, but 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, thereby exerting a pharmacological effect on the nursing neonate. 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 or the excipients should avoid contact with the veterinary medicinal 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.
Advice to physicians: Like other benzodiazepines, midazolam commonly causes drowsiness, ataxia, dysarthria anterograde amnesia, and nystagmus. Overdose of midazolam is seldom life-threatening if the drug is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and in rare cases to coma.
Monitor the patient's vital signs and institute supportive measures as indicated by the patient's clinical state. Respiratory and haemodynamic symptoms should be treated symptomatically.
Adverse reactions
Ataxia/incoordination during recovery from anaesthesia occurs commonly.
Respiratory depression and spontaneous urination upon induction of anaesthesia occur uncommonly.
The frequency of adverse reactions is defined using the following convention:
- very common (more than 1 in 10 animals treated displaying adverse reaction(s))
- common (more than 1 but less than 10 animals in 100 animals treated)
- uncommon (more than 1 but less than 10 animals in 1,000 animals treated)
- rare (more than 1 but less than 10 animals in 10,000 animals treated)
- very rare (less than 1 animal in 10,000 animals treated, including isolated reports).
Use during pregnancy and lactation
Laboratory studies in mice, rats and rabbits have not produced any evidence of teratogenic, foetotoxic or maternotoxic effects. In humans, use of benzodiazepines during the late third trimester of pregnancy or during labour has been associated with adverse effects in the foetus/neonate, including mild sedation, hypotonia, reluctance to suck, apnoea, cyanosis and impaired metabolic response to cold stress. Midazolam is found in low quantities in the milk of lactating animals.
The safety of the veterinary medicinal product during pregnancy and lactation has not been established in the target species. Use only according to the benefit/risk assessment by the responsible veterinarian.
Interactions
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.
Amounts to be administered and administration route
For intravenous use.
Once the horse is properly sedated, anaesthesia is induced by intravenous injection of:
Midazolam at a dose of 0.06 mg per kg body weight, corresponding to 1.2 ml solution per 100 kg, in combination with ketamine at a dose of 2.2 mg per kg body weight. Midazolam and ketamine may be combined and administered in the same syringe.
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.
Following a dose of 0.18 mg midazolam per kg body weight (3 times overdose) in combination with ketamine (2.2 mg/kg intravenously) after premedication with detomidine (20 µg/kg intravenously) 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 body weight (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.
The benzodiazepine antagonist flumazenil can be used to reverse effects associated with an overdose of midazolam, although clinical experience in horses is limited.
Withdrawal periods
The product is not authorised for use in horses intended for human consumption.
Pharmacological particulars
Pharmacotherapeutic group: hypnotic and sedative, benzodiazepine derivative.
ATCvet code: QN05CD08
Pharmacodynamic properties
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 CNS 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 GABAA-receptor, a ligand-gated chloride channel consisting of five subunits. Sensitivity to benzodiazepines is conferred by the presence of a γ subunit. Four types of benzodiazepine-sensitive GABAA-receptors can be further distinguished on the basis of the presence of α1, α2, α3 or α5 subunits. The α1 GABAA receptors are mainly expressed in cortical areas and thalamus, α2 and α5 GABAA receptors are largely expressed in the limbic system, and α3 GABAA 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 α1-type GABAA receptors, whereas the anxiolytic effects of benzodiazepine-receptor ligands appear to be mediated via GABAA receptors containing the α2 subunit. The myorelaxant effect of benzodiazepines also seems to be mediated by benzodiazepine-sensitive GABAA receptors other than the α1-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. When midazolam is used in combination with ketamine for co-induction of anaesthesia, time to achievement of lateral recumbency is approximately 1 minute and time to intubation is approximately 1.5 minutes.
Pharmacokinetic properties
Distribution
The disposition of midazolam following intravenous administration to horses is characterized by very rapid and relatively extensive distribution (VD is 2.14 l/kg after administration of the recommended dose). Midazolam is highly protein bound (94-97%) and rapidly crosses the blood-brain barrier.
Metabolism
Midazolam undergoes biotransformation by hepatic microsomal oxidation followed by conjunction with glucuronic acid.
Elimination
Midazolam is eliminated almost exclusively by metabolic processes. The drug has a medium blood clearance (8.8 ml/kg/min after administration of the recommended dose) and an elimination half-life of approximately 4 hours in horses.
The principal route of excretion is through the kidneys, mainly as glucuronidated metabolites.
Pharmaceutical particulars
Incompatibilities
Do not mix with any other veterinary medicinal product, except with ketamine 100 mg/ml solution for injection.
Shelf life
Shelf-life of the veterinary medicinal product as packaged for sale: 4 years
Shelf-life after first opening the immediate packaging: 28 days
Special precautions for storage
Keep the vial in the outer carton in order to protect from light.
This veterinary medicinal product does not require any special temperature storage conditions.
Immediate packaging
Colourless type I glass vials of 5 ml, 10 ml, 20 ml and 50 ml closed with a coated bromobutyl rubber stopper and aluminium cap in a carton box.
Not all pack sizes may be marketed.
Disposal
Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal product should be disposed of in accordance with local requirements.
Marketing Authorisation Holder (if different from distributor)
Le Vet Beheer BV, Wilgenweg 7, 3421 TV Oudewater, The Netherlands.
Marketing Authorisation Number
Vm 41821/4052
Significant changes
Date of the first authorisation or date of renewal
21 August 2017
Date of revision of the text
October 2018
Any other information
For animal treatment only. To be supplied only on veterinary prescription. Keep out of the sight and reach of children.
Legal category
Legal category: POM-V
Legal category description:CD(Sch 3)
GTIN
GTIN description:Dormazolam 5 mg/ml Solution for Injection for Horses 20 ml:
GTIN:08718469444106