Methoxyflurane, solution, 1 x 3 mL with inhaler, Penthrox®, July 2008
Public summary document for Methoxyflurane, solution, 1 x 3 mL with inhaler, Penthrox®, July 2008
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Public Summary Documents
Product: Methoxyflurane, solution, 1 x 3 mL with
inhaler, Penthrox®
Sponsor: Medical Developments International
Limited
Date of PBAC Consideration: July 2008
1. Purpose of Application
To request an Authority Required PBS listing for the relief of pain
in wound dressings or trauma in patients aged 2-18 years or in an
Aboriginal or Torres Strait Islander (ATSI) person where alternate
treatments are unsuitable; and
To request PBS listing in the Emergency Drug (Doctor’s Bag)
Supplies.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Penthrox was TGA registered on 23 December 1992 for the following indications:
Self administration to conscious haemodynamically stable patients with trauma and associated pain, under supervision by personnel trained in its use.
Monitored conscious patients who require analgesia for the relief of pain in short surgical procedures such as change of dressings.
Note: the total maximum dose must not be exceeded
4. Listing Requested and PBAC’s View
Authority Required
For the relief of pain in wound dressings or trauma in patients
aged 2-18 years where alternate treatments are unsuitable.
For the relief of pain in wound dressings or trauma in an
Aboriginal or a Torres Strait Islander person where alternate
treatments are unsuitable.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Methoxyflurane is a volatile anaesthetic, which is now only used to
provide analgesia.
It will provide clinicians with an additional treatment option for
patients requiring rapid non - injectable, non narcotic
analgesia.
6. Comparator
The submission nominated placebo as the main comparator in
paediatric and Aboriginal or Torres Strait Islander patients.
7. Clinical Trials
The submission presented one randomised trial as the pivotal
evidence comparing methoxyflurane with placebo in patients aged
1-16 years for pain relief from upper limb fracture or
venepuncture, and 17 supplementary non-randomised studies involving
methoxyflurane as an analgesic.
The pivotal trial and the supplementary evidence published at the
time of the submission are as follows.
| Trial/First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trial (pivotal evidence) | ||
| Chin R et al (2002) | A randomised control trial of inhaled methoxyflurane pain relief, in children with upper limb fracture (Abstract) | J Paediatric Child Health 2002; 38(5): A13-A14. |
| Non-randomised studies (supplementary evidence) | ||
| Paediatrics | ||
| Aleksandrin A et al (1976) | Use of subnarcotic concentrations of methoxyflurane in children with burns. | Vestn Khir 1976;116 (5): 99-101 |
| Babl F, et al (2006) | Inhaled methoxyflurane as a prehospital analgesic in children | Emergency Medicine Australasia (2006) 18 , 404–410 |
| Babl F, et al (2007) | A pilot study of inhaled methoxyflurane for procedural analgesia in children. | Paediatric Anesthesia 2007 17: 148–53 |
| Firn S (1972) | Methoxyflurane analgesia for burns dressings and other painful ward procedures in children. | Br J Anaesth 1972; 4(5): 517-22. |
| Emergency Care Setting | ||
| Buntine P et al (2007) | Pre-hospital analgesia in adults using inhaled methoxyflurane. | Emergency Medicine Australasia (2007) 19, 509–14 |
| Komesaroff D (1979) | Serum fluoride ion levels following the administration of methoxyflurane for analgesia. | Presented at the Australian Society of Anaesthetists Annual General Meeting, Adelaide, South Australia, October 1979 |
| Virenque C et al (1975) | Methoxyflurane analgesia during evacuation of injured persons. | Anesth Analg Reanim 1975; 32(1):149-53. |
| Burns Dressings | ||
| Laird S et al (1972) | The effect of methoxyflurane analgesia on renal function in burned patients: an investigation. | Postgrad Med J 1972; 48(557): 133-7 |
| Marshall M et al (1972) | Analgesia for burns dressing using methoxyflurane. | Br J Anaesth 1972; 44(1): 80-2. |
| Packer K et al (1969) | Methoxyflurane analgesia for burns dressings: experience with the Analgizer®. | Br J Anaesth 1969; 41(12): 1080-5. |
| Packer K (1972) | Methoxyflurane analgesia for burns dressings. | Postgrad Med J 1972; 48(557): 128-32. |
| Dentistry | ||
| Dragon A et al (1967) | Methoxyflurane preliminary report on analgesic and mood-modifying properties in dentistry. | JADA 1967; 75(5): 1176-81 |
| Edmunds Det al (1975). | Inhalation sedation for conservative dentistry. A comparison between nitrous oxide and methoxyflurane. | BDJ 1975; 139(10): 398-402. |
| Josephson C et al (1974) | The Cardiff inhaler and penthrane. A method of sedation-analgesia in routine dentistry. | J Dent Ass S.Afr 1974; 29(2): 77-80. |
| Minor Surgical Procedures | ||
| Reier C (1970) | Methoxyflurane analgesia: a clinical appraisal and detailed description of stage I in man. | Anesth Analg 1970; 49(2): 318-22. |
| Pain Threshold | ||
| Siker E et al (1967) | Effect of sub-anaesthetic concentrations of halothane and methoxyflurane on pain threshold in conscious volunteers. | Anesthesiology 1967; 28(2): 337-42. |
| Tomi K et al (1993) | Alterations in pain threshold and psychomotor response associated with sub-anaesthetic concentrations of inhalation anaesthetics in humans | Br J Anaesth 1993; 70: 684-6. |
8. Results of Trials
The key results from the pivotal randomised trial are summarised in
the following tables. Changes of ≥ 4 points on the Faces Pain
Scale were considered clinically important.
Median change in Faces Pain Scores in the pivotal
trial
| McCaskill (manuscript) | Methoxyflurane Median score (range) | Placebo Median score (range) | Reference Median score (range) |
| Researcher assessed | |||
| Venepuncture | 0 (–10, 10) | 0 (–10, 6) | –2 (–8, 4)* |
| Fracture | 4 (2, 8)* | 2 (–2, 8) | |
| Parent assessed | |||
| Venepuncture | 0 (–10, 10) | 0 (–10, 8) | –2 (–8, 6)* |
| Fracture | 4 (0, 10)* | 2 (–4, 8) | |
| Child assessed | |||
| Venepuncture | 0 (–10, 10) | 0 (–10, 8) | –2 (–8, 10) |
| Fracture | 4 (0, 10)* | 2 (–4, 6) | |
* Significant difference p<0.05
Proportion of patients with no deterioration in faces pain
scores (Venepuncture) and with change of at least 4 in Faces Pain
Scores (Fracture) in the pivotal trial
| McCaskill (manuscript) | MF n/N (%) | Placebo n/N (%) | Ref n/N (%) | Odds Ratio (95 CI) | Risk Difference (MF vs. P) (95 CI) |
| Venepuncture group | |||||
| Researcher assessed | 18/27 (67) | 20/28 (71) | 7/18 (39) | - | –0.05 (–0.29, 0.20) |
| Parent assessed | 16/26 (62) | 21/28 (75) | 8/19 (42) | - | –0.13 (–0.38, 0.11) |
| Child assessed | 13/16 (81) | 9/17 (53) | 5/11 (45) | - | 0.28 (–0.02, 0.59) |
| Fracture group | |||||
| Researcher assessed | 18/25 (72) | 6/21 (29) | - | 6.43 (1.78, 23.3) | 0.43 (0.17, 0.70) |
| Parent assessed | 18/26 (69) | 8/24 (33) | - | 4.50 (1.37, 14.78) | 0.36 (0.33, 0.69) |
| Child assessed | 13/23 (57) | 4/20 (20) | - | 5.20 (1.32, 20.49) | 0.37 (0.2, 0.57) |
| All patients responding (Researcher assessed) | 36/52 (69) | 26/49 (53) | |||
MF= methoxyflurane, Ref = reference, P = placebo
The supportive non-randomised case series reports showed pain
relief after methoxyflurane administration in both adult and
paediatric patients, however, the lack of randomisation and control
arms in these case reports reduced the rigor of this
evidence.
The Therapeutic Goods Administration Therapeutic Goods
Administration (TGA) has reviewed the Australian registration
status of methoxyflurane, focusing on safety given nephrotoxicity
and hepatotoxicity were the reason for the Food and Drug
Administration (FDA) withdrawal. It was concluded that the risk of
clinically relevant renal impairment and overt hepatic toxicity
were very low when methoxyflurane is used as recommended in the
product Information (PI).
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The submission claimed that methoxyflurane is superior to placebo
in terms of comparative effectiveness in pain relief. The PBAC
noted that there was no clinical evidence to support efficacy in
children in other clinical settings or in the ATSI
population.
For PBAC’s views, see Recommendations and
Reasons.
10. Economic Analysis
The submission presented a trial-based economic evaluation to
estimate the cost per additional responder, defined as a patient
who achieves a change of at least four in Faces Pain Scores. The
time horizon is limited to a single instance of analgesia.
The results of the univariate sensitivity analyses indicated that
the model was most sensitive to the analgesia response rate and
duration of consultation time.
The submission estimated the base case incremental
cost-effectiveness ratio to be less than $15,000 per responder.
Given that only the responders in the upper limb fracture group
were included in the calculation of outcome for the base case of
the economic evaluation, the estimated ICER should be interpreted
as an incremental cost per extra paediatric responder with upper
limb fracture.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients/year to
be between 10,000 – 50,000 patients in Year 5.
The financial cost/year to the PBS was estimated to be less than
$10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of methoxyflurane in the PBS
Doctor's Bag Item List only on the basis of an acceptable
incremental cost per extra paediatric responder with upper limb
fracture.
In making this recommendation, the PBAC noted that in order to be
included in the PBS Doctor's Bag Item List an item must be listed
on the PBS, but indicated that it did not consider it appropriate
for methoxyflurane to be made available as a general benefit. The
PBAC noted that the intent of a Section 85 (s85) PBS listing is
community-based access to medicines. Given the reported adverse
effects and precautions associated with the use of methoxyflurane,
the PBAC considered a s85 listing inappropriate as it would allow
for the direct supply of methoxyflurane inhaler to community-based
patients and as such has the potential for use not
under supervision by personnel trained in its use, which would be
contrary to the TGA-approved indication.
However, the PBAC noted that there is a clinical need for a rapid
onset, portable and non-narcotic analgesic for use by doctors and
nurses in the emergency community-based settings, and that drugs
may be made available as pharmaceutical benefits but be distributed
under alternative arrangements where these are considered more
appropriate. These alternative arrangements are provided for under
section 100 of the National Health Act 1953 and might be
considered appropriate for a doctor’s bag listing of
methoxyflurane.
The PBAC also noted that there are precautions and adverse effects
associated with the use of methoxyflurane, however, that when used
at analgesic doses and under supervision by personnel trained in
its use, these precautions and adverse effects are generally
without significant consequence. However, on the basis of the
observational studies presented, the PBAC expressed concern that
methoxyflurane has the potential for patients to be uncooperative
post-therapy and that this may be an issue in a community-based
setting. Disquiet was also expressed by the PBAC in response to the
report by Babl 2006 of deep sedation in 5 of 15 children under the
age of 5 years of age treated with methoxyflurane.
Overall, the Committee noted the expert advice at the hearing that
methoxyflurane inhaler has been used by Australian emergency
services in both adults and children for relief of acute pain for
over 30 years without significant concern.
The PBAC noted only one unpublished randomised controlled trial
(RCT) was presented in the submission comparing methoxyflurane
against placebo for early pain relief in children with upper limb
fracture or for venepuncture. The PBAC noted from this single
unpublished RCT (McCaskill et al) that methoxyflurane showed
statistically significant benefit in early pain relief in children
with upper limb fractures (1 to 16 years of age) but no benefit for
pain relief for venepuncture or for all trauma.
The PBAC also noted that although the submission provides a number
of non-randomised clinical studies dating back to the 1970s
supporting the use of methoxyflurane as an analgesic in a variety
of settings in both adult and paediatric patient, the lack of
randomisation and control arms in these case reports reduces the
rigor of this evidence.
Lastly, the PBAC noted that the requested listing for use in the
ATSI population had not been reviewed by the Department’s
ATSI working group, and that consideration by this group should
take place before PBAC make a final recommendation in respect of
subsidised access. However, the Committee also noted the lack of
clinical data to support the requested listing for ATSI patients
and expressed concern over the possibility for repeated use in
these patients and the associated potential for irreversible renal
failure.
Recommendation
METHOXYFLURANE, solution, 1 x 3 mL with inhaler.
Restriction: To be finalised
For Doctor’s Bag only
Maximum quantity: 1
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Medical Developments International is delighted with the
PBAC’s decision to recommend the inclusion of Penthrox in the
Emergency Drug (Doctors Bag) Section of the PBS. The availability
of this product provides the community with a safe and effective
analgesic agent for the treatment of acute pain.
