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Repeatable. Reliable. Relax.
Resource Guide
Alfaxan® Resource GuideContents
1. What is Alfaxan®? 4
1.1 Active ingredient 4
1.2 Mode of action 4
1.3 History 5
1.4 Product specification 7
1.5 Features 8
1.6 Pharmacokinetics 10
1.7 Pharmacodynamics 10 1.7.1 Anaesthesia 10 1.7.2 Cardiorespiratory profile: effect on blood pressure 11 1.7.3 Cardiorespiratory profile: effect on respiratory rate 12
1.8 Safety in cats 13
1.9 Safety in dogs 14
2. The Anaesthetic Process in Veterinary Practice 15
2.1 Anaesthesia: Important principles 15 2.1.1 Anaesthesia is not routine 15 2.1.2 Phases of anaesthesia 16 2.1.3 Patient risk assessment 17 2.1.4 Pre-operative assessment and equipment check 18
2.2 Premedication 20 2.2.1 General principles 20 2.2.2 Premedication agents 21
2.3 Induction of anaesthesia 22 2.3.1 The ideal induction agent 22 2.3.2 Alfaxan® dosage 23
2.4 Maintenance of anaesthesia 24 2.4.1 Maintenance with Alfaxan® 24
2.5 Peri-operative analgesia 25
2.6 Recovery 26
3. Summary 27
4. References 28
5. Summary of Product Characteristics 31
Repeatable. Reliable. Relax.
4 5
1.3 History
The anaesthetic properties of steroids have been known for more than 70 years. In the 1940s the Hungarian born endocrinologist Hans Selye showed that reversible unconsciousness could be produced in rats administered intraperitoneal injections of large quantities of steroid hormones.[4] Of the steroids injected, pregnanedione was the most potent and devoid of hormonal activity.[5] In 1955 P’An and colleagues reported that a close structural analogue of pregnanedione, hydroxydione, was more potent and safer than the thiobarbiturate, thiopentone.[6] However, hydroxydione was not an ideal anaesthetic induction agent as it produced a delayed induction of up to three minutes and had to be solubilised in an alkaline pH causing venous thrombosis. Further research on the structure/activity relationship of neurosteroids showed that manipulation of the 3 and 21 carbon positions altered anaesthetic potency.[7, 8] Eventually, the active molecule 3-hydroxy-5-pregnane-11, 20-dione (alfaxalone) was discovered by the Glaxo UK Pharmacology Department. Similar to the barbiturates, benzodiazepines, propofol and isoflurane, it is thought that the main mechanism of action is through the gamma-aminobutyric acid type A (GABAA) receptor, which belongs to a superfamily of ligand gated, pentameric, ion-pore-forming, cell surface receptors found in neurones and other excitable cells (see Figure 3).[9]
Figure 3. GABAA receptor and known ligands 1.2 Mode of action
Alfaxalone produces anaesthetic effects via enhancement of gamma-aminobutyric acid sub-type A (GABAA) receptor-mediated neurotransmission. GABAA receptors are widely distributed throughout the mammalian Central Nervous System (CNS). GABA is the major inhibitory amino acid transmitter of the mammalian CNS and receptors are present on almost half of all neurones .[3] GABA acts by opening a pore in the receptor allowing the in-flow of chloride ions, causing hyperpolarisation. Alfaxalone’s enhancement of GABA’s effects prevents development of action potentials and stops impulse transmission.
Figure 2. Mode of action
1. What is Alfaxan®? 1.1 Active ingredient
Alfaxan® Anaesthetic Injection (referred to throughout as Alfaxan®) contains the neuroactive steroid molecule alfaxalone (3--hydroxy-5--pregnane-11, 20-dione) and is registered for use in dogs and cats for both the induction and maintenance of anaesthesia. Although alfaxalone is a steroid molecule it does not bind to sex hormone, glucocorticoid or mineralocorticoid receptors (i.e. nuclear receptors).[1, 2]
Figure 1. Alfaxalone
For more information visit www.alfaxan.co.uk
Alfaxalone
F
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
N
F
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
N
F
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
NF
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
N F
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
N
F
F
F
FCl
O F
HNO S
O
NH
OH
N
N
O
O
OH
Cl
N
H3CO
N
ThiopentalR – (+) – Etomidate
Propofol
Ethanol
Diazepam
Isoflurane
Extracellular Extracellular
Intracellular Intracellular
Resting GABA tone Alfaxalone augmented hyperpolarisation
Cl- ions GABA Alfaxalone
GABAA receptor
6 7
Alfaxalone was later combined with alfadolone (21-acetoxy-3-hydroxy-5--pregnane-11, 20-dione), Cremophor EL and sodium chloride to yield formulation CT1341. The alfadolone was placed in the formulation to improve the solubility of the alfaxalone.[10] Child et al performed a battery of pharmacological tests on CT1341 in laboratory animals and found it offered significant advantages over the other injectable anaesthetics as it had a higher margin of safety, it was non-irritant to tissues including veins, it was compatible with the adjuvant and pre-anaesthetic drugs, it did not accumulate and it produced a pleasant anaesthetic experience for the patient.[11] In the early 1970s, CT1341 was introduced as an intravenous (IV) anaesthetic induction agent for humans (Althesin) and as an IV and intramuscular anaesthetic (Saffan) for cats and monkeys. Saffan was not licensed in dogs because in dogs polyoxyethylated emulsifying agents like Cremophor EL cause histamine release and potential anaphylaxis.[12] In an effort to remove the side effects observed with drug carriers like Cremophor EL, Brewster et al found that alfaxalone and other drugs could be solubilised in safe carriers like hydroxypropyl-beta-cyclodextrin (HP-ϐ-CD).[13, 14]
In 2000 alfaxalone was formulated by Jurox Pty Limited in 2-HPCD as an anaesthetic for intravenous injection as Alfaxan®. HPCD is inert, does not cause histamine release and is excreted in its parent form through the kidneys.[15]
The product is approved for the induction and maintenance of anaesthesia in dogs and cats internationally; including Australia, New Zealand, South Africa, Canada, France, Germany, Republic of Ireland, Spain, Belgium, United Kingdom and the United States of America.
1.4 Product specification
Alfaxan® is a 1% (10 mg/mL) aqueous solution of alfaxalone in hydroxypropyl-beta-cyclodextrin (HP-ϐ-CD). The solution has a pH of 6.5 – 7.0 and does not contain a preservative. It is a clear, colourless, sterile solution for injection, presented in 10 mL single use vials. Alfaxan® should be stored in the outer carton at room temperature, avoiding freezing. Any solution remaining in the vial following withdrawal of the required dose should be discarded.
Figure 4. Encased alfaxalone. Artistic rendering of beta-cyclodextrin.
8 9
1.5 Features
When Alfaxan® is administered as recommended the following will be observed:
• smooth induction,[16, 17]
• no pain on injection,[18]
• rapid onset of anaesthesia,[19, 20]
• no tissue irritation if inadvertently given peri-vascularly,[21]
• excellent muscle relaxation,[19, 20]
• minimal disruption to cardio-pulmonary function or vascular system parameters,[19, 20]
• stress free recovery.[19, 20, 22]
Alfaxan® has a wide safety margin, with animals receiving significant overdoses (20 mg/kg dogs; 25 mg/kg cats) requiring only ventilation to allow recovery with no residual effects.[19, 20]
Alfaxan® is rapidly eliminated from the body[23] and is registered for use as an anaesthetic maintenance agent. Studies have shown that repeated, supra-clinical doses of Alfaxan® administered IV at 10 mg/kg dogs (5X)[24] and 25 mg/kg cats (5X)[25] every 48 hours for three doses did not result in any deleterious effects. It can be used with confidence repeatedly over consecutive days.
Alfaxan® is also registered for use as a maintenance anaesthetic agent and produces clinically acceptable anaesthetic quality and haemodynamic values when used as a constant rate infusion (CRI).[26]
Alfaxan® is compatible for use with routine premedicant medications.[16, 17, 27, 28]
9
10 11
1.6 Pharmacokinetics
After a single dose of Alfaxan®, alfaxalone is metabolised rapidly in the liver and eliminated in the bile and urine, with the drug being completely cleared from the body within a few hours after administration.[29] Table 1 shows the pharmacokinetic parameters of alfaxalone in both dogs and cats after a single dose administered at the clinically recommended dose rate.[30]
Table 1. Pharmacokinetic parameters of alfaxalone in dogs and cats[30]
Parameter Dog (n = 8) 2 mg/kg
Cat (n = 8) 5 mg/kg
Mean volume of distribution at steady state 2.4 L/kg 1.8 L/kg
Mean terminal plasma elimination half life 25 minutes 45 minutes
Mean total body clearance 59.4 mL/kg/min 25.1 mL/kg/min
1.7 Pharmacodynamics
1.7.1 Anaesthesia
After intravenous (IV) administration of Alfaxan® the duration of unconsciousness seen in patients will vary depending on the patient’s physical state, concurrent medications and the dose of alfaxalone administered. As a general guide, with no noxious stimuli, healthy un-premedicated cats administered 5 mg/kg of Alfaxan® IV will remain anaesthetised for approximately 25 minutes[19] and healthy un-premedicated dogs administered 2 mg/kg of Alfaxan® IV will remain anaesthetised for approximately 10 minutes.[20] If required, anaesthesia may be prolonged by administration of maintenance gaseous agents (such as isoflurane) or further administration of Alfaxan®. Concurrent sedative and analgesic medications can be expected to decrease the dose requirements for Alfaxan® and alter the duration of resulting anaesthesia.
1.7.2 Cardiorespiratory profile: effect on blood pressure
Patients induced with Alfaxan® maintain clinically acceptable blood pressure parameters.[31, 32]
140
130
120
110
100
90
80
70
Syst
olic
Blo
od P
ress
ure
(mm
Hg)
Premed RecoveryPeriod
MaintenancePeriod
Mean of observed systolic blood pressures by anaesthetic period
(Canine Multisite Clinical Trial)[31]
Alfaxan® induction– premedication, isoflurane
maintenance(n = 90 dogs)
Alfaxan® induction– premedication, Alfaxan®
maintenance)(n = 46 dogs)
150
140
130
120
110
100
90
80
70Premed
Syst
olic
Blo
od P
ress
ure
(mm
Hg)
RecoveryPeriod
MaintenancePeriod
Mean of observed systolic blood pressures by anaesthetic period
(Feline Multisite Clinical Trial)[32]
Alfaxan® induction– premedication, isoflurane
maintenance(n = 86 cats)
Alfaxan® induction– premedication, Alfaxan®
maintenance(n = 70 cats)
1.7.3 Cardiorespiratory profile: effect on respiratory rate
Patients that are anaesthetised with Alfaxan® breathe spontaneously and maintain clinically acceptable respiratory rates.[31, 32]
50454035302520
1015
5Premed
Res
p R
ate
(bre
aths
/min
)
RecoveryPeriod
MaintenancePeriod
ImmediatePost Induction
Mean of observed respiratory rates by anaesthetic period
(Canine Multisite Clinical Trial)[31]
Alfaxan® induction– premedication, isoflurane
maintenance(n = 90 dogs)
Alfaxan® induction– premedication, Alfaxan®
maintenance(n = 46 dogs)
50454035302520
1015
5
Res
p R
ate
(bre
aths
/min
)
Premed RecoveryPeriod
MaintenancePeriod
ImmediatePost Induction
Mean of observed respiratory rates by anaesthetic period
(Feline Multisite Clinical Trial)[32]
Alfaxan® induction– premedication, isoflurane
maintenance(n = 86 cats)
Alfaxan® induction– premedication, Alfaxan®
maintenance(n = 70 cats)
1.8 Safety in cats
Acute tolerance to overdose of Alfaxan® has been demonstrated up to five times the recommended dose of 5 mg/kg in the cat (25 mg/kg), with animals requiring only ventilation to allow recovery with no residual effects.[19]
Repeated overdosing with Alfaxan® (five times the recommended dose) every 48 hours for 3 doses in cats caused no adverse effects.[25]
Alfaxan® can be used safely in kittens from 12 weeks of age.[59]
Alfaxan® does not cause tissue irritation after peri-vascular, subcutaneous or intramuscular injection.[18, 21, 34] (Alfaxan® is licensed for intravenous administration only and these studies purely indicate that no adverse event should be expected if it is administered by any other route accidentally.)
13 12
14 15
1.9 Safety in dogs
Acute tolerance to overdose of Alfaxan® has been demonstrated up to 10 times the recommended dose of 2 mg/kg in the dog (i.e. 20 mg/kg), with animals requiring only ventilation to allow recovery with no residual effects.[20]
Repeated overdosing with Alfaxan® (five times the recommended dose) every 48 hours for 3 doses in dogs caused no adverse effects.[22]
Alfaxan® does not cause tissue irritation after peri-vascular or subcutaneous injection.[18] (Alfaxan® is licensed for intravenous administration only and these studies purely indicate that no adverse event should be expected if it is administered by any other route accidentally.)
Alfaxan® can be used safely in puppies from 12 weeks of age[59] and prior to canine caesarean section.[36]
Research has demonstrated Alfaxan® can be used safely in sighthounds.[27]
2. The Anaesthetic Process in Veterinary Practice 2.1 Anaesthesia: Important principles
2.1.1 Anaesthesia is not routine
General anaesthesia must NOT be considered a routine procedure, because no two animals are the same. Using the terminology ‘routine’ can imply that if something is done the same way every time, the same outcome can be expected. Individual animals vary in physiologic status and responses to medications; this should be considered before anaesthetising a patient.
Anaesthesia is in essence a deliberate intoxication of the CNS to render a patient unconscious, the deepest level of which is Stage IV – paralysis and death. This fact should focus the attention of all practice staff on effective pre-operative assessment and close observation of the patient from premedication to complete recovery. It also should drive the practice towards balanced anaesthesia based on the principle of ‘considered polypharmacy’. This is the thoughtful use of a number of different agents to ensure optimal anaesthesia – appropriate levels of unconsciousness, muscle relaxation and analgesia.
Successful anaesthesia and smooth recovery demands focus in the pre-anaesthetic period.
14
16 17
2.1.2 Phases of anaesthesia
The considered administration of a variety of effective agents in the premedication, induction, maintenance and recovery phases is the basis of modern anaesthetic practice.
The main phases of anaesthesia are:
2.1.3 Patient risk assessment
The American Society of Anesthesiologists (ASA) has determined a classification for the clinical status of human patients when assessed pre-operatively.[37] This is readily adoptable by veterinary practices and can be used to help tailor anaesthetic protocols to individual patients.
The veterinary surgeon or veterinary nurse should assign every patient to one of the five relevant classes at the time of pre-operative assessment to assist in the decisions of whether to anaesthetise the animal, what further investigations may be warranted and what stabilisation procedures should occur.
The five physical risk states are:
ASA Physical Status 1 A normal healthy patient
ASA Physical Status 2 A patient with mild systemic disease
ASA Physical Status 3 A patient with severe systemic disease
ASA Physical Status 4 A patient with severe systemic disease that is a constant threat to life
ASA Physical Status 5 A moribund patient who is not expected to survive without the operation
If the animal has been presented as an emergency, the letter ‘E’ can be added to the recorded stage.
It is essential that all patients are classified before any premedication is applied, and that consideration is paid to the classification in developing the patient’s anaesthetic protocol. (Adapted from American Society of Anesthesiologists, http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System)
3. Induction: Anaesthetise 4. Transition: The period where the control of anaesthesia transitions from being a result of the induction drug to a result of the maintenance drug
1. Pre-operative assessment: Patient risk assessment, stabilisation, provision of analgesia, equipment checks
2. Premedication: Sedate, provide anxiolysis and analgesia
5. Maintenance: Continue anaesthesia 6. Recovery: After care, further analgesia
2.1.4 Pre-operative assessment and equipment check
The pre-operative assessment is essential in determining an anaesthetic plan for each individual patient. A thorough history and full clinical examination should be conducted and the patient assigned to an ASA class. Particular attention should be paid to respiratory and cardiac function. The patient should be examined for concurrent diseases and any potential problems with endotracheal intubation or access to veins should be resolved. The reasons for, and effects of, any current courses of medication should be taken into account.
A vital part of the pre-anaesthetic preparation is checking the equipment, including but not limited to:
• oxygen and inhalation agent levels,
• gas line connections and valve function,
• emergency oxygen button function,
• patient breathing system selection (including a range of endotracheal tubes),
• scavenger systems,
• patient monitoring and warming devices.
All drugs and materials needed for premedication, the induction, maintenance and recovery from anaesthesia should be prepared, labelled and laid out ready to use.
Careful observation and monitoring of the patient, from preparation to recovery from anaesthesia, should be standard practice.
All aspects of the procedures, including drugs used and doses administered, as well as the patient’s physiological parameters, should be recorded and the information stored with the patient’s file.
19 18
20 21
2.2 Premedication
2.2.1 General principles
During the preparation of a patient for anaesthesia, reducing the anxiety and stress of unfamiliar surroundings is essential. This can be provided by a combination of a quiet environment, calm and experienced patient restraint and administration of sedatives and analgesics. The administration of such agents dramatically improves the quality of the anaesthetic induction, transition, maintenance and recovery periods.
The aims of premedication are to relieve stress of handling in the clinic environment; to smooth the stages of anaesthesia – induction, maintenance and recovery; to contribute to muscle relaxation and to provide analgesia. Premedication may reduce the required amounts of induction and maintenance agents.
Successful anaesthesia and smooth recovery demands focus in the pre-anaesthetic period.
Alfaxan® has been proven to be safe when used with a wide range of premedicant classes of drugs including: [16, 17, 26-28, 33, 35, 38-47]
• phenothiazines (acepromazine),
• benzodiazepines (diazepam, midazolam),
• alpha-2-adrenoreceptor agonists (xylazine, medetomidine, dexmedetomidine),
• opiates (methadone, morphine, butorphanol, buprenorphine, hydromorphone),
• NSAIDS (carprofen, meloxicam)
• anticholinergic agents (atropine),
The concomitant use of other CNS depressants will potentiate the effects of Alfaxan®, often reducing the necessary dose and influencing the duration of anaesthesia, particularly in sighthounds.[27]
Use of alpha-2-adrenoreceptor agonists such as xylazine and medetomidine may decrease the required induction dose of Alfaxan® and will markedly increase the duration of anaesthesia in a dose-dependent fashion.
Benzodiazepines offer no analgesia and should not be used as the sole premedicant as anaesthesia may be suboptimal, however they can be used safely and effectively in combination with other premedicants and Alfaxan®.
Avoid standardised blanket regimes of premedicants – each patient should be assessed and the appropriate regime of medications administered at the appropriate time for that individual.
The optimal time between administration of premedicants and induction will depend on the drugs used, the route of administration and the individual patient’s physiological status and behaviour. Premedicant drugs administered intravenously will have a more rapid onset of action than those
given by other routes. The benefits of premedication on the anaesthetic induction process are best achieved by allowing sufficient time for the premedicants to take effect.
Placement of an intravenous (IV) catheter is best practice, offering immediate access for administration of medications and fluids. Consideration should also be given to pre-oxygenation of patients, especially if there is a chance of airway obstruction (e.g. brachycephalic breeds of dogs or cats) or a potential delay between administration of the induction agent and successful connection to the anaesthetic breathing system. Pre-oxygenation can delay the onset of haemoglobin oxygen desaturation.[48]
2.2.2 Premedication agents
Characteristics of drugs used for sedation and premedication.*
Drug Time to peak sedation or effect
Duration of action Reversible? Analgesia?
Acepromazine 35-40 minutes i.m.15-20 minutes i.v.
4-6 hours No No
Medetomidine 15-20 minutes i.m.2-3 minutes i.v.
Sedation: 2-3 hoursAnalgesia: 1 hour
Yes – with atipamezole
Yes
Midazolam 10-15 minutes i.m.5 minutes i.v.
1-1.5 hours Yes – with flumazenil
No
Diazepam 10-15 minutes i.m.5 minutes i.v.
2 hours Yes – with flumazenil
No
Atropine 20-30 minutes i.m.1-2 minutes i.v.
Vagal inhibition: 2-3 hours
No No
Glycopyrronium 20-30 minutes i.m.2-3 minutes i.v.
Vagal inhibition: 2-3 hours
No No
Methadone, hydromorphone
20-30 minutes i.m.2-5 minutes i.v.
2-4 hours Yes – with naloxone
Yes
Morphine 20-30 minutes i.m.Not recommended i.v.
2-4 hours Yes – with naloxone
Yes
Pethidine (merperidine)
20-30 minutes i.m.Contraindicated i.v.
1-1.5 hours Yes – with naloxone
Yes
Buprenorphine 30-45 minutes i.m.12-15 minutes i.v.
6 hours Yes – with naloxone
Yes
Butorphanol 20-30 minutes i.m.2-5 minutes i.v.
1-1.5 hours Yes – with naloxone
Yes
Reproduced with permission from the BSAVA Manual of Canine and Feline Anaesthesia and Analgesia, 2nd edition, copyright BSAVA.
*Note that the duration of action of many of these drugs will vary between species and will depend on the dose administered. The times given are approximate guidelines only. For details on use please refer to individual product SPCs. Where products are not registered in the UK, veterinarians are advised to abide by the VMD guidance on the Cascade.
22 23
2.3 Induction of anaesthesia
2.3.1 The ideal induction agent
There are many lists that outline properties of an ideal anaesthetic induction agent. One example of such a list is given by Dugdale.[49] Alfaxan® exhibits most of the attributes that this list describes including:
1. Rapid onset of action[19, 20, 23]
2. Smooth induction[19, 20, 23]
3. Smooth recovery[26, 50]
4. Non-irritant[21]
5. Short duration of action[19, 20]
6. Non-cumulative[51]
7. Rapid metabolism[23, 51]
8. Non-toxic or no metabolites[52]
9. Does not cause histamine release[53, 54]
10. Minimal cardiorespiratory side effects[19, 20]
11. Produces a degree of muscle relaxation[19, 20]
12. Stable in storage[30]
13. Stable in solution[30]
14. High therapeutic index[11, 55]
In a number of studies confirming dosage, pharmacokinetics, efficacy and safety in dogs and cats the onset of anaesthesia from commencement of administration was found to be approximately 60 seconds.
Modern techniques for induction of anaesthesia indicate that optimum results are obtained if the agent is injected slowly. This effectively allows the patient to choose the dose that they require to produce unconsciousness. Alfaxan® does not cause pain on injection or excitement on induction[19, 20], so rapid bolus administration is not required.
2.3.2 Alfaxan® dosage
To optimise results with Alfaxan®, remember the following points:
• For Alfaxan® the rate of intravenous injection should result in the total dose, if required, being administered over a period of 60 seconds. This can be achieved by administering one quarter of the calculated dose every fifteen seconds.
• Administration should proceed until the patient is fully anaesthetised or the total dose has been administered. The patient’s reflexes (palpebral, limb withdrawal, corneal, gag and perineal), their vital signs and the ease of passage of the endotracheal tube, indicate the depth of anaesthesia.
• If, 60 seconds after complete delivery of this first induction dose, intubation is still not possible, one further similar dose may be administered to effect.
• As Alfaxan® is a short acting induction agent and anaesthesia can lighten, the patient may regain consciousness if the transition period is prolonged through delaying connection to maintenance systems and administration of maintenance agents.
• Once the endotracheal tube is placed, the patient should be immediately attached to the breathing system. Patients administered Alfaxan® in accordance with the above recommendations generally ventilate spontaneously and will transition to maintenance with gaseous agents quite smoothly. Should apnoea of more than 60 seconds occur, positive pressure ventilation (PPV) should be delivered to the patient.
Alfaxan® induction – intravenous dosage recommendation
DOGS CATS
UN-PREMEDICATED PREMEDICATED UN-PREMEDICATED PREMEDICATED
3 mg/kg 2 mg/kg 5 mg/kg 5 mg/kg
0.3 mL/kg 0.2 mL/kg 0.5 mL/kg 0.5 mL/kg
The dosing syringe should be prepared to contain the calculated dose. Administration should continue until the clinician is satisfied that the depth of anaesthesia is sufficient for endotracheal intubation, or the entire dose has been administered.
24 25
2.4 Maintenance of anaesthesia
2.4.1 Maintenance with Alfaxan®
Post-induction, anaesthesia may be maintained with an inhalation agent or with Alfaxan®.
Maintenance doses of Alfaxan® can be given as supplemental boluses or by constant rate infusion.
Alfaxan® has been used safely and effectively in dogs and cats for procedures lasting for up to one hour.[16, 17]
Suggested intravenous dosages for maintenance with Alfaxan®
DOGS CATS
Un-premedicated Premedicated Un-premedicated Premedicated
Dose for constant rate infusion
mg/kg/hour
mg/kg/minute
8-9
0.13-0.15
6-7
0.10-0.12
10-11
0.16-0.18
7-8
0.11-0.13
mL/kg/minute 0.013-0.015 0.010-0.012 0.016-0.018 0.011-0.013
Bolus dose for each 10 minutes maintenance
mg/kg 1.3-1.5 1.0-1.2 1.6-1.8 1.1-1.3
mL/kg 0.13-0.15 0.10-0.12 0.16-0.18 0.11-0.13
When maintaining anaesthesia with Alfaxan® the anaesthetist should monitor the patient’s anaesthetic depth and adjust the infusion rate, bolus volume or interval appropriately.
2.5 Peri-operative analgesia
In the past, pain relief was considered less important than it is today. At that time there was argument about the capacity of animals to feel pain, the advantage of pain being a natural immobilisation agent and the difficulty in assessing the degree of pain being experienced. The last point is still an issue. The most referenced method for assessing pain is the Glasgow Composite Pain Scale[56] which can become a rapid pain assessment tool in clinical practice.
It is now universally acknowledged that reduction of pain greatly assists recovery from surgery. To be most effective, pain relief should be instigated at the premedication phase, maintained across the surgery and continued into the recovery phase.
Use of analgesia prior to procedures that cause pain is known as pre-emptive analgesia.
Early administration of agents such as opioids can allay fear, stress and anxiety caused by the clinic environment, as well as reduce the required doses of anaesthetic agents used during surgery – early pain control reduces the sensitisation of neural pathways to painful stimuli. Use of adjunctive anxiolytic agents such as acepromazine or a benzodiazepine, while not necessarily delivering extra analgesic effect, can augment the effect of opiate medications by decreasing sympathetic drive in the patient.
The administration of a number of analgesic agents with different modes of action (e.g. opioids, local anaesthetics, NSAIDs) can target more than one point in the nervous system, thus making the control of pain more effective. This multimodal approach may also reduce the required dose of each agent and hence lessen undesirable side effects.
Jurox recommends that peri-operative pain relief is administered in all procedures requiring anaesthesia where pain either already exists or the procedure could potentially induce noxious stimuli. Use of analgesics throughout the process ensures smooth recovery, especially as modern induction and maintenance agents are rapidly eliminated. A patient in pain that is recovering very rapidly is likely to have a poor recovery.
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2.6 Recovery
A safe and comfortable recovery is the final objective of anaesthesia.
Recovery remains the most overlooked phase of anaesthesia and rushing a recovery may not be best for the patient.
3. Summary Alfaxan® is a reliable and effective intravenous anaesthetic when used as an induction agent
in dogs and cats.[16, 17, 19-22, 24-28, 31-33, 35, 36, 38-47, 50]
Alfaxan® provides a smooth and rapid induction, a stress-free transition to maintenance anaesthesia and a smooth and uneventful recovery.[16, 17, 33, 35, 36]
Alfaxan® is rapidly eliminated from the body and does not accumulate,[26, 51] thus it can be given as the sole maintenance agent where the use of inhalation agents is not practical. Repeated administration of Alfaxan® both within a single anaesthetic session or over multiple anaesthetic sessions has been proven to be safe in both dogs and cats.[25, 26, 31-33]
Alfaxan®, when administered as a single injection has been proven to have a high therapeutic safety margin. Repeated 5x over-dosage in dogs and cats every 48 hours for three doses produced no observable adverse effects (NOAE).[24, 51]
Alfaxan® can be used with confidence in puppies and kittens greater than 12 weeks of age to provide reliable, effective and stress-free anaesthesia.[59]
Alfaxan® has been used as an anaesthetic induction agent prior to canine caesarean section, resulting in reliable and clinically acceptable vital parameters in the bitch and survival and vigour parameters in puppies.[36]
Alfaxan® has proven ideal for dental procedures either alone or in combination with an inhalation agent.[16, 17]
Alfaxan® has been shown to be an acceptable induction choice for patients that are considered high anaesthetic risk.[46]
Alfaxan® has been used by veterinarians in Australia since 2000. In small animal anaesthesia in Australia, Alfaxan® is the induction agent of choice, being used as the primary agent in over 50% of inductions in dogs and 75% of inductions in cats.[58]
When compared with alternative induction agents, Alfaxan® has been found to be reliable, effective, and consistent in observed results, providing smooth induction and event-free anaesthesia and recovery.
Alfaxan® has been the subject of over 100 papers published in peer-reviewed journals or presented at international veterinary conferences. These papers have included comparisons to other anaesthetic induction agents, safety, efficacy, administration in a diverse group of species, case reports, and use in research for other objectives. This literature can be found readily online or through contacting Jurox Technical Services.
A sobering fact: In a study of deaths associated with anaesthesia in the United Kingdom in 2008, covering 117 practices, 98,036 dogs and 79,178 cats, almost 50 per cent of canine fatalities and over 60 per cent of feline fatalities occurred in the recovery period or up to 24 hours post-surgery.[57]
While the actual numbers of fatalities were low the study authors noted:
“That nearly 50% of the postoperative deaths in this study occurred within three hours of the end of anaesthesia suggested that if closer monitoring and management of patients in this early postoperative period were instituted, then mortality might be reduced.” [57]
To achieve an optimal recovery, it is vital that the neurologic status of the patient is considered. This includes considering the effects of the medications that have been administered; minimising sound, movement and touch stimulus in the recovery period; addressing any pain that may be present; and considering the anxiety that can result from recovering rapidly from unconsciousness in an unfamiliar environment. As Alfaxan® is so rapidly eliminated from the body, extra attention to the recovery period is warranted, as animals can arouse very rapidly.
Studies have demonstrated that use of Alfaxan® as an induction and/or maintenance anaesthetic agent in combination with effective premedication resulted in uneventful induction, maintenance and recovery.[19, 20, 33, 35, 36]
28 29
References
1. Jurox and Ricera, An in vitro study evaluating the binding of alfaxalone to various nuclear receptors (Ricerca Study No. AA94464). Records in House, 2010.
2. Jurox and Ricera, An in vitro study evaluating the binding of alfaxalone to various abuse receptors (Ricerca Study No. AA94047). Records in House, 2010.
3. Roth, F.C. and A. Draguhn, GABA Metabolism and Transport: Effects on Synaptic Efficacy. Neural Plasticity, 2012. 2012.
4. Selye, H., Anaesthetic effects of steroid hormones. Proceedings of the Society for Experimental Biology, 1941. 46: p. 116.
5. Selye, H., Correlations between the chemical structure and the pharmacological actions of the steroids. Endocrinology, 1942. 46: p. 116-121.
6. P’An, S.Y., et al., General anesthetic and other pharmacological properties of a soluble steroid, 21-hydroxypregnanedion sodium succinate. J Pharmacol Exp Ther, 1955. 115(4): p. 432-441.
7. Robertson, J.D. and W. Williams, Studies on the clinical and pathological effects of hydroxydione. Anaesthesia, 1961. 16(4): p. 389-401.
8. Cocker, J.D., et al., Action of some steroids on the central nervous system of the mouse. Synthetic Methods. J Med Chem, 1964. 8(4): p. 417-425.
9. Belelli, D. and J.J. Lambert, Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci, 2005. 6(7): p. 565-575.
10. Phillipps, G.H., Structure-activity relationships in steroidal anaesthetics. J Steroid Biochem, 1975. 6(5): p. 607-613.
11. Child KJ, C.J., Dis B, Dodds MG, Pearce DR, Twissell DJ., The pharmacological properties in animals of CT1341 – a new steroid anaesthetic agent. Br J Anaesth, 1971. 43(1): p. 2-13.
12. Krantz, J.C., et al., XXVI. Pharmacodynamic studies of polyoxyalkylene derivatives of hexitol anhydride partial fatty acid esters. J Pharmacol Exp Ther, 1948. 93(2): p. 188-195.
13. Brewster, M.E., K.S. Estes, and N. Bodor, Development of a non-surfactant formulation for alfaxalone through the use of chemically-modified cyclodextrins. J Parenter Sci Technol, 1989. 43(6): p. 262-5.
14. Brewster, M.E., K.S. Estes, and N. Bodor, An intravenous toxicity study of 2-hydroxypropyl-ϐ-cyclodextrin, a useful drug solubilizer, in rats and monkeys. Int J Pharm, 1990. 59: p. 231-243.
15. Mesens, J.L., P. Putteman, and P. Verheyen, Pharmaceutical applications of 2-hydroxypropyl-beta-cylcodextrin., in New trends in cyclodextrins and derivatives., D. Duchene, Editor. 1991: Paris. p. 369-407.
16. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacy and safety of Alfaxan®-CD RTU administered to dogs for induction and maintenance of anaesthesia., in British Small Animal Veterinary Association Congress. 2005. Birmingham, UK.
17. Pasloske, K., et al., A multicentre clinical trial evaluating the efficacy and safety of Alfaxan® administered to cats for induction and maintenance of anaesthesia., in British Small Animal Veterinary Association Congress. 2007. Birmingham, UK.
18. Jurox, Jurox Pharmacovigilance report JX9604-SR004. 2005.
19. Muir, W., et al., The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats. Veterinary Anaesthesia and Analgesia, 2009. 36(1): p. 42-54.
20. Muir, W., et al., Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs. Vet Anaesth Analg, 2008. 35(6): p. 451-462.
21. Heit, M.C., et al., Safety and efficacy of Alfaxan® CD RTU Administered once to cats subcutaneously at 10 mg/kg., in ACVIM. 2004.
22. Schnell, M., et al., Margin of safety of the anesthetic Alfaxan® CD RTU in dogs at 0, 1, 3 and 5X the intravenous dose of 2 mg/kg., in ACVIM. 2004.
23. Ferre, P.J., et al., Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan®-CD RTU. Vet Anaesth Analg, 2006. 33(4): p. 229-36.
24. Whittem, T. and K. Pasloske, RD9604.03-H005 Eight day target animal safety study of intravenous Alfaxan® CD RTU in dogs administered every other day. 2004, Jurox Pty Limited.
25. Pasloske, K. and T. Whittem, JX9604.07-H004 A target animal safety study in cats after administration of Alfaxan®-CD RTU as single, repeated injections on days 0, 2, and 5 at dosages of 5, 15 or 25 mg/kg. 2004, On File at Jurox.
26. Ambros, B., T. Duke-Novakovski, and K.S. Pasloske, Comparison of the anesthetic efficacy and cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-beta-cyclodextrin and propofol in dogs. Am J Vet Res, 2008. 69(11): p. 1391-8.
27. Pasloske, K., et al., Plasma pharmacokinetics of alfaxalone in both premedicated and unpremedicated Greyhound dogs after single, intravenous administration of Alfaxan® at a clinical dose. Journal of Veterinary Pharmacology and Therapeutics, 2009. 32: p. 510-513.
28. Heit, M.C., et al., Cardiovascular and respiratory safety of Alfaxan® CD RTU in cats premedicated with acepromazine, medetomidine, midazolam or butorphanol., in ACVIM. 2004.
29. Child, K.J., et al., Metabolism and excretion of CT1341 in the rat., in Steroid Anaesthesia. 1972. Royal College of Physicians, London.
30. Jurox, NADA 141-342 Alfaxan® Intravenous injectable anesthetic for use in cats and dogs. Product Insert. 2012, USFDA.
31. Pasloske, K., JX9604.03-C009 A multi-centre clinical trial in dogs evaluating the efficacy and safety of Alfaxan®-CD RTU administered to veterinary patients for induction and maintenance of anaesthesia (Study Report). 2005, Jurox Pty Limited.
32. Pasloske, K., JX9604.07-C006 A multi-centre clinical trial in cats evaluating the efficacy and safety of Alfaxan®-CD RTU administered to veterinary patients for induction and maintenance of anaesthesia (Study Report). 2005, Jurox Pty Limited.
33. O’Hagan, B., et al., Clinical evaluation of alfaxalone as an anaesthetic induction agent in cats less than 12 weeks of age. Australian Veterinary Journal, 2012. 90(10): p. 395-401.
34. APVMA, Alfaxan® Anaesthetic Injection Australian Product Insert Leaflet. 2010.
35. O’Hagan, B., et al., Clinical evaluation of alfaxalone as an anaesthetic induction agent in dogs less than 12 weeks of age. Australian Veterinary Journal, 2012. 90(9): p. 346-50.
36. Metcalfe, S., et al., A multi-centre clinical trial evaluating the efficacy and safety of Alfaxan® administered to bitches for induction of anaesthesia prior to caesarean section in 33rd World Small Animal Congress. 2008. Dublin, Ireland: WSAVA/FECAVA.
37. ASA Physical Status Classification System, Amer Soc Anesth, http://www.asahq.org/Home/ For-Members/Clinical-Information/ASA-Physical-Status-Classification-System.
38. Amengual, M., et al., An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone. Veterinary Anaesthesia and Analgesia, 2012.
39. Herbert, G.L., et al., Alfaxalone for total intravenous anaesthesia in dogs undergoing ovariohysterectomy: a comparison of premedication with acepromazine or dexmedetomidine. Veterinary Anaesthesia and Analgesia, 2012.
30 31
40. Jansen, K.S. and J.J. Uilenreel, A comparison between alfaxalone and propofol continuous rate infusions in a total intravenous anaesthesia protocol for canine surgical patients. 2009, Faculty of Veterinary Medicine, University of Utrecht.
41. Jimenez, C.P., et al., Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging. Veterinary Anaesthesia and Analgesia, 2012. 39(2): p. 151-159.
42. Maddern, K., et al., Alfaxalone induction dose following administration of medetomidine and butorphanol in the dog. Veterinary Anaesthesia and Analgesia, 2010. 37(1): p. 7-13.
43. Martinez Taboada, F. and P.J. Murison, Induction of anaesthesia with alfaxalone or propofol before isoflurane maintenance in cats. Veterinary Record, 2010. 167(3): p. 85-89.
44. Mathis, A., et al., Comparison of quality of recovery from anaesthesia in cats induced with propofol or alfaxalone. Veterinary Anaesthesia and Analgesia, 2012. 39(3): p. 282-290.
45. Murison, P.J. and F. Martinez Taboada, Effect of propofol and alfaxalone on pain after ovariohysterectomy in cats. 10.1136/vr.b4788. Vet Rec., 2010. 166(11): p. 334-335.
46. Psatha, E., et al., Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anaesthesia in dogs that are a poor anaesthetic risk. Vet Anaesth Analg, 2011. 38: p. 24-36.
47. Zaki, S., K. Ticehurst, and Y. Miyaki, Clinical evaluation of Alfaxan-CD® as an intravenous anaesthetic in young cats. Aust Vet J, 2009. 87(3): p. 82-7.
48. Weingart, S.D. and R.M. Levitan, Preoxygenation and Prevention of Desaturation During Emergency Airway Management. Annals of emergency medicine, 2012. 59(3): p. 165-175.e1.
49. Dugdale, A.H.A., Veterinary Anaesthesia: Principles to Practice. 2010: Wiley-Blackwell.
50. Martinez Taboada, F. and P.J. Murison, Induction of anaesthesia with alfaxalone or propofol before isoflurane maintenance in cats. 10.1136/vr.b4872. Vet Rec., 2010. 167(3): p. 85-89.
51. Whittem, T., et al., The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical doses. J Vet Pharmacol Ther, 2008. 31(6): p. 571-9.
52. Whittem, T. and K. Pasloske, JX9604.03-E013 The in-vitro metabolism and clearance of the neurosteroid, alfaxalone, by cat and dog hepatocytes at concentrations of 1, 5, 10 and 100 mg/L. 2005, Jurox In House Report.
53. Patten, B., et al., RD9604.03/01 The Safety of Alfaxalone-Cyclodextrin Complex in cats. 1998, Jurox.
54. Patten, B., et al., RD9604.03/06 The Safety of Jurox Alfaxan-CD® Anaesthetic Injection in dogs. 2000, Jurox.
55. Sear, J.W., C. Prys-Roberts, and K.C. Phillips, Age influences the minimum infusion rate (ED50) for continuous infusions of Althesin and methohexitone. Eur J Anaesthesiol, 1984. 1(4): p. 319-25.
56. Glasgow University short form composite measure pain score (CMPS-SF). 2012. http://www.gla.ac.uk/media/media_233876_en.pdf
57. Brodbelt, D.C., et al., The risk of death: the confidential enquiry into perioperative small animal fatalities. Vet Anaesth Analg, 2008. 35(5): p. 365-73.
58. Leyonhjelm, D., Anaesthesia Market Research. 2011, Jurox Pty Limited, Baron Strategic Services.
59. Summary of Product Characteristics, Alfaxan Anaesthetic Solution for Injection, UK-VMD, July 2012 revision.
Summary of Product Characteristics1. Name of the veterinary medicinal product ALFAXAN 10 mg/ml solution for injection for dogs and cats 2. Qualitative and quantitative composition Active substance: alfaxalone 10 mg/ml For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection Clear colourless solution 4. Clinical particulars 4.1 Target species Dogs and cats 4.2 Indications for use, specifying the target species As an induction agent prior to inhalation anaesthesia. As a sole anaesthetic agent for the induction and maintenance of anaesthesia for the performance of examination or surgical procedures.4.3 Contraindications Do not use in combination with other intravenous anaesthetic agents.4.4 Special warnings During recovery, it is preferable that animals are not handled or disturbed. This may lead to paddling, minor muscle twitching or movements that are more violent. While better avoided, such reactions are clinically insignificant. 4.5 Special precautions for use (i) Special precautions for use in animals The analgesic properties of alfaxalone are limited, therefore appropriate peri-operative analgesia should be provided in cases where procedures are anticipated to be painful. The safety of the veterinary medicinal product in animals less than 12 weeks of age has not been demonstrated. Transient post induction apnoea frequently occurs, particularly in dogs – see section 4.6 for details. In such cases, endotracheal intubation and oxygen supplementation should be employed. Facilities for intermittent positive pressure ventilation should be available. In order to minimise the possibility of apnoea, administer the veterinary medicinal product by slow intravenous injection and not as a rapid dose. Especially when using higher doses of the veterinary medicinal product, a dose-dependent respiratory depression may occur. Oxygen and/or intermittent positive pressure ventilation should be administered to counteract the threatening hypoxaemia/hypercapnea. This should be particularly important in risky anaesthetic cases and whenever the anaesthesia is to be carried out for a longer period of time. In both dogs and cats, the dose interval for maintenance of anaesthesia by intermittent bolus administration may require lengthening by more than 20%, or the maintenance dose by intravenous infusion may require reduction by more than 20%, when hepatic blood flow is severely diminished or hepatocellular injury is severe. In cats or dogs with renal insufficiency, doses for induction and maintenance may require reduction. As with all general anaesthetic agents: It is advisable to ensure that the patient has been fasted before receiving the anaesthetic. Additional monitoring is advised and particular attention should be paid to respiratory parameters in aged animals, or in cases where there may be additional physiological stress imposed by pre-existing pathology, shock or caesarean section. Following induction of anaesthesia, the use of an endotracheal tube is recommended to maintain airway patency. It is advisable to administer supplemental oxygen during maintenance of anaesthesia. Respiratory embarrassment may occur – ventilation of the lungs with oxygen should be considered if haemoglobin saturation with oxygen (SpO₂%) falls below 90% or if apnoea persists for longer than 60 seconds. If cardiac arrhythmias are detected, attention to respiratory ventilation with oxygen is the first priority followed by appropriate cardiac therapy or intervention. Psychomotor excitement may be encountered in a minority of dogs and cats recovering from anaesthesia with the veterinary medicinal product. Post-anaesthetic recovery should thus take place in appropriate facilities and under sufficient supervision. Use of a benzodiazepine as the sole premedicant may increase the probability of psychomotor excitement. (ii) Special precautions to be taken by the person administering the veterinary medicinal product to animals If the product comes into contact with the eyes or skin, wash off immediately with water. In case of accidental self injection seek immediate medical attention and show the product literature to the doctor. 4.6 Adverse reactions (frequency and seriousness) In clinical studies using the veterinary medicinal product, 44% of dogs and 19% of cats experienced post induction apnoea, which was defined as the cessation of breathing for 30 seconds or more. The mean duration of apnoea in these animals was 100 seconds in dogs and 60 seconds in cats. Endotracheal intubation and oxygen supplementation should therefore be employed. 4.7 Use during pregnancy, lactation or lay The safety of the veterinary medicinal product has not been established in cases where pregnancy is to be continued or during lactation. Its effects upon fertility have not been evaluated. However, studies using alfaxalone in pregnant mice, rats and rabbits have demonstrated no deleterious effects on gestation of the treated animals, or on the reproductive performance of their offspring. The product should be used in pregnant animals according to the risk-benefit assessment performed by the veterinarian. The product has been safely used in dogs for the induction of anaesthesia prior to delivery of puppies by caesarean section. In these studies, dogs were not premedicated, a dose of 1-2 mg/kg was drawn up (i.e. slightly lower than the usual 3 mg/kg dose, see section 4.9) and the product was administered as recommended, to effect. 4.8 Interaction with other medicinal products and other forms of interaction The veterinary medicinal product has been demonstrated to be safe when used in combination with the following premedicant classes:
Drug Class Examples
Phenothiazines acepromazine maleate
Anticholinergic agents atropine sulfate
Benzodiazepines diazepam, midazolam hydrochloride
Alpha-2-adrenoceptor agonists
xylazine hydrochloride, medetomidine hydrochloride
Opiates methadone, morphine sulfate, butorphanol tartrate, buprenorphine hydrochloride
NSAIDs carprofen, meloxicam
The concomitant use of other CNS depressants should be expected to potentiate the depressant effects of the veterinary medicinal product, necessitating cessation of further administration of the veterinary medicinal product when the required depth of anaesthesia has been reached. The use of one premedicant or a combination of premedicants often reduces the dose of the veterinary medicinal product required. Premedication with alpha-2-adrenoceptor agonists such as xylazine and medetomidine can markedly increase the duration of anaesthesia in a dose dependent fashion. In order to shorten recovery periods it may be desirable to reverse the actions of these premedicants. Benzodiazepines should not be used as sole premedicants in dogs and cats as the quality of anaesthesia in some patients may be sub-optimal. Benzodiazepines may be used safely and effectively in combination with other premedicants and the veterinary medicinal product. Refer to section 4.3. 4.9 Amounts to be administered and administration route Induction of anaesthesia: The induction dose of the veterinary medicinal product is based on data taken from controlled laboratory and field studies and is the amount of drug required for 9 of 10 dogs or cats (i.e. 90th percentile) to be successfully induced for anaesthesia. Dosing recommendations for induction of anaesthesia are as follows:
DOGS CATS
Un-premedicated Premedicated Un-
premedicated Premedicated
mg/kg 3 2 5 5
mL/kg 0.3 0.2 0.5 0.5
The dosing syringe should be prepared to contain the above dose. Administration should continue until the clinician is satisfied that the depth of anaesthesia is sufficient for endotracheal intubation, or until the entire dose has been administered. The necessary injection rate can be achieved by administration of one quarter (¼) of the calculated dose every 15 seconds, so that the total dose, if required, would be administered over the first 60 seconds. If, 60 seconds after complete delivery of this first induction dose, intubation is still not possible, one further similar dose may be administered to effect. Maintenance of anaesthesia: Following induction of anaesthesia with the veterinary medicinal product, the animal may be intubated and maintained on the veterinary medicinal product or an inhalation anaesthetic agent. Maintenance doses of the veterinary medicinal product may be given as supplemental boluses or as constant rate infusion. The veterinary medicinal product has been used safely and effectively in both dogs and cats for procedures lasting for up to one hour. The following doses suggested for maintenance of anaesthesia are based on data taken from controlled laboratory and field studies and represent the average amount of drug required to provide maintenance anaesthesia for a dog or cat. However the actual dose will be based on the response of the individual patient. Dosing recommendations for maintenance of anaesthesia are as follows:
DOGS CATS
Un-premedicated Premedicated Un-
premedicated Premedicated
Dose for constant rate infusion
mg/kg/hour 8 - 9 6 - 7 10 - 11 7 - 8
mg/kg/minute 0.13 - 0.15 0.10 - 0.12 0.16 - 0.18 0.11 - 0.13
mL/kg/minute 0.013 - 0.015 0.010 - 0.012 0.016 - 0.018 0.011 - 0.013
Bolus dose for each 10 minutes maintenance
mg/kg 1.3 - 1.5 1.0 - 1.2 1.6 - 1.8 1.1 - 1.3
mL/kg 0.13 - 0.15 0.10 - 0.12 0.16 - 0.18 0.11 - 0.13
Where maintenance of anaesthesia is with the veterinary medicinal product for procedures lasting more than 5 to 10 minutes, a butterfly needle or catheter can be left in the vein, and small amounts of the veterinary medicinal product injected subsequently to maintain the required level and duration of anaesthesia. In most cases the average duration of recovery when using the veterinary medicinal product for maintenance will be longer than if using an inhalant gas as a maintenance agent. 4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary Acute tolerance to overdose has been demonstrated up to 10 times the recommended dose of 2 mg/kg in the dog (i.e. up to 20 mg/kg) and up to 5 times the recommended dose of 5 mg/kg in the cat (i.e. up to 25 mg/kg). For both dogs and cats, these excessive doses delivered over 60 seconds cause apnoea and a temporary decrease in mean arterial blood pressure. The decrease in blood pressure is not life threatening and is compensated for by changes in heart rate. These animals can be treated solely by intermittent positive pressure ventilation (if required) with either room air or, preferably, oxygen. Recovery is rapid with no residual effects. 4.11 Withdrawal periods Not applicable. 5. Pharmacological properties Pharmacotherapeutic group: other general anaesthetics, alfaxalone. ATCvet code: QN01AX05. 5.1 Pharmacodynamic properties Alfaxalone (3--hydroxy-5--pregnane-11,20-dione) is a neuroactive steroid molecule with properties of a general anaesthetic. The primary mechanism for the anaesthetic action of alfaxalone is modulation of neuronal cell membrane chloride ion transport, induced by binding of alfaxalone to GABAA cell surface receptors. 5.2 Pharmacokinetic particulars The volume of distribution after a single injection of clinical doses of 2 and 5 mg/kg bw of alfaxalone in dogs and cats is 2.4 L/kg and 1.8 L/kg, respectively. In vitro cat and dog hepatocyte studies show that alfaxalone experiences both Phase I (cytochrome P450 dependent) and Phase II (conjugation dependent) metabolism. Both cats and dogs form the same five (5) Phase I alfaxalone metabolites. The Phase II metabolites observed in cats are alfaxalone sulphate and alfaxalone glucuronide, while alfaxalone glucuronide is observed in the dog. In cats, the mean terminal plasma elimination half-life (t½) for alfaxalone is approximately 45 minutes for a 5 mg/kg dose. Mean plasma clearance for a 5 mg/kg dose is 25.1 ± 7.6 ml/kg/min. In dogs, the mean terminal plasma elimination half-life (t½) for alfaxalone is approximately 25 minutes for a 2 mg/kg dose. Plasma clearance for a 2 mg/kg dose is 59.4 ± 12.9 ml/kg/min. In both dogs and cats the elimination of alfaxalone demonstrates non-linear (dose-dependent) pharmacokinetics. Alfaxalone metabolites are likely to be eliminated from the dog and cat by the hepatic/faecal and renal routes, similar to other species. 6. Pharmaceutical particulars 6.1 List of excipients Hydroxypropylbetadex; Sodium Chloride; Disodium Phosphate Anhydrous; Potassium Dihydrogen Phosphate; Sodium Hydroxide (for pH adjustment); Hydrochloric Acid, Concentrated (for pH adjustment); Water for Injections. 6.2 Incompatibilities In the absence of compatibility studies, the veterinary medicinal product must not be mixed with other veterinary medicinal products. 6.3 Shelf life Shelf life of the veterinary medicinal product as packaged for sale: 3 years. This product does not contain an antimicrobial preservative. Any solution remaining in the vial following withdrawal of the required dose should be discarded. 6.4. Special precautions for storage Do not freeze. Keep the container in the outer carton. 6.5 Nature and composition of immediate packaging Cardboard box with one glass vial of 10 ml with a bromobutyl rubber stopper and aluminium cap. 6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products Any unused veterinary medicinal product or waste material derived from such veterinary medicinal product should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Jurox (UK) Limited Second, Floor Richmond House, 105 High Street, Crawley, West Sussex, RH10 1DD, United Kingdom 8. Marketing authorisation number Vm: 25296/4000 9. Date of first authorisation 23 November 2006 10. Date of revision of the text September 2016
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