Inhalation vapour, liquid.
Clear, almost colourless, volatile liquid, with a characteristic fruity odour.

PENTHROX should be self-administered under supervision of a person trained in its
administration, using the hand held PENTHROX Inhaler.
One bottle of 3 mL PENTHROX to be vaporised in a PENTHROX inhaler. On
finishing the 3 mL dose, another 3 mL may be used. Dose of PENTHROX should not
exceed 6 mL in a single administration. Methoxyflurane may cause renal failure if the
recommended dose is exceeded. The lowest effective dosage of PENTHROX to
provide analgesia should be used.
Onset of pain relief is rapid and occurs after 6 – 10 inhalations. Patients should be
instructed to inhale intermittently to achieve adequate analgesia. Patients are able to
assess their own level of pain and titrate the amount of PENTHROX inhaled for
adequate pain control. Continuous inhalation provides analgesic relief for up to 25-
30 minutes. Intermittent inhalation may provide longer analgesic relief. Patients should
be advised to take the lowest possible dose to achieve pain relief.
The frequency at which PENTHROX can be safely used is not established.
Administration on consecutive days is not recommended and the total dose to a patient
in a week should not exceed 15 mL (see section 4.4).
Method of Administration
Instructions on the preparation of the PENTHROX Inhaler and correct administration
are provided in the Figures below.

1
Ensure the Activated Carbon (AC) Chamber is
inserted into the dilutor hole on the top of the
PENTHROX Inhaler.
2
Remove the cap of the bottle by hand.
Alternatively, use the base of the PENTHROX
Inhaler to loosen the cap with a ½ turn. Separate
the Inhaler from the bottle and remove the cap by
hand.
3
Tilt the PENTHROX Inhaler to a 45° angle and
pour the total contents of one PENTHROX bottle
into the base of the Inhaler whilst rotating.
4
Place wrist loop over patient’s wrist. Patient
inhales through the mouthpiece of the
PENTHROX Inhaler to obtain analgesia. First
few breaths should be gentle and then breathe
normally through Inhaler.
5
Patient exhales into the PENTHROX Inhaler.
The exhaled vapour passes through the AC
Chamber to adsorb any exhaled methoxyflurane.
6
If stronger analgesia is required, patient can
cover dilutor hole on the AC chamber with finger
during use.

7
Patient should be instructed to inhale
intermittently to achieve adequate analgesia.
Continuous inhalation will reduce duration of
use. Minimum dose to achieve analgesia should
be administered.
8
Replace cap onto PENTHROX bottle. Place used
PENTHROX Inhaler and used bottle in sealed plastic
bag and dispose of responsibly.

Use as an anaesthetic agent. Hypersensitivity to PENTHROX or any fluorinated anaesthetic. Malignant hyperthermia: patients with known or genetically susceptible to malignant hyperthermia or a history of severe adverse reactions in either patient or relatives. Patients who have a history of showing signs of liver damage after previous methoxyflurane use or halogenated hydrocarbon anaesthesia. Clinically significant renal impairment. Altered level of consciousness due to any cause including head injury, drugs, or alcohol. Clinically evident cardiovascular instability. Clinically evident respiratory depression.

Renal disease
Methoxyflurane causes significant nephrotoxicity at high doses. Nephrotoxicity is also
related to the rate of metabolism. Therefore factors that increase the rate of metabolism
such as drugs that induce hepatic enzymes can increase the risk of toxicity with
methoxyflurane as well as sub-groups of people with genetic variations that may result
in fast metaboliser status (see section 4.5). Nephrotoxicity is thought to be associatedwith inorganic fluoride ions, a metabolic break-down product. Toxicity in the past
when used as an anaesthetic agent has been determined to be associated with serum
levels greater than 40 μmol/L. Following a single dose of 3 mL serum levels did not
exceed 10 μmol/L.
Despite this safety margin the lowest effective dose of methoxyflurane should be
administered, especially in the elderly or patients with other known risk factors of renal
disease. In addition, methoxyflurane should be cautiously used in patients diagnosed
with clinical conditions that would pre-dispose to renal injury.
Liver disease
Methoxyflurane is metabolised in the liver, therefore increased exposures in patients
with hepatic impairment can cause toxicity. PENTHROX must not be used in patients
who have a history of showing signs of liver damage after previous methoxyflurane use
or halogenated hydrocarbon anaesthesia. PENTHROX should be used with care in
patients with underlying hepatic conditions or with risks for hepatic dysfunction (such
as enzyme inducers - see also section 4.5).
It has been reported that previous exposure to halogenated hydrocarbon anaesthetics
(including methoxyflurane when used in the past as an anaesthetic agent), especially if
the interval is less than 3 months, may increase the potential for hepatic injury.
Cautious clinical judgement should be exercised when PENTHROX is to be used more
frequently than on one occasion every 3 months.
Cardiovascular system depression / Use in elderly
Potential effects on blood pressure and heart rate are known class-effects of high dose
methoxyflurane used in anaesthesia and other anaesthetics. They do not appear to be
significant at the analgesic doses. There is no particular pattern to the patients’ systolic
BP levels after methoxyflurane administration as an analgesic across age groups.
However, as the risk may potentially be increased for older people with hypotension
and bradycardia, caution should be exercised in the elderly due to possible reduction in
blood pressure.
Central nervous system effects
Secondary pharmacodynamic effects including potential CNS effects such as sedation,
euphoria, amnesia, ability to concentrate, altered sensorimotor co-ordination andchange in mood are also known class-effects. Self-administration of methoxyflurane in
analgesic doses will be limited by occurrence of CNS effects, such as sedation.
Additionally, the CNS effects can be a risk factor for potential abuse.
Occupational exposure
Healthcare professionals who are regularly exposed to patients using PENTHROX
inhalers should be aware of any relevant occupational health and safety guidelines for
the use of inhalational agents. To reduce occupational exposure to methoxyflurane, the
PENTHROX Inhaler should always be used with the Activated Carbon (AC) Chamber
which adsorbs exhaled methoxyflurane. Multiple use of PENTHROX Inhaler without
the AC Chamber creates additional risk. Elevation of liver enzymes, blood urea
nitrogen and serum uric acid have been reported in exposed maternity ward staff in
delivery wards when methoxyflurane was used in the past in obstetric patients at the
time of labour and delivery.
Frequent repeated use
Due to the limitations on the dose of PENTHROX (maximum - 6ml) and the duration
of pain relief, PENTHROX is not appropriate for providing relief of break-through
pain/exacerbations in chronic pain conditions. PENTHROX is also not appropriate for
relief of trauma related pain in closely repeated episodes for the same patient.
Butylated hydroxytoluene
PENTHROX contains the excipient, butylated hydroxytoluene (E321), a stabiliser.
Butylated hydroxytoluene may cause local skin reactions (e.g. contact dermatitis), or
irritation to the eyes and mucous membranes. See section 6.1.

The metabolism of methoxyflurane is mediated by the CYP 450 enzymes particularly
CYP 2E1 and to some extent CYP 2A6. It is possible that enzyme inducers (such as
alcohol or isoniazid for CYP 2E1 and phenobarbital or rifampicin for CYP 2A6)
which increase the rate of methoxyflurane metabolism might increase its potential
toxicity and they should be avoided concomitantly with methoxyflurane.
Concomitant use of PENTHROX with CNS depressants, such as opioids, sedatives or
hypnotics, general anaesthetics, phenothiazines, tranquillisers, skeletal muscle
relaxants, sedating antihistamines and alcohol may produce additive depressant
effects. If opioids are given concomitantly with PENTHROX, the patient should be
observed closely, as is normal clinical practice with opioids.
Concomitant use of methoxyflurane with medicines (e.g. contrast agents and some
antibiotics) which are known to have a nephrotoxic effect should be avoided as there
may be an additive effect on nephrotoxicity. Antibiotics with known nephrotoxic
potential include tetracycline, gentamicin, colistin, polymyxin B and amphotericin B.
It is advisable to avoid using sevoflurane anaesthesia following methoxyflurane
analgesia, as sevoflurane increases serum fluoride levels and nephrotoxicity of
methoxyflurane is associated with raised serum fluoride.
There are no reported drug interactions when used at the analgesic dosage (3 – 6 mL).

When methoxyflurane was used for anaesthesia at the higher doses of 40 – 60 mL,
there were reports of:
a) Drug interaction with hepatic enzyme inducers (e.g. barbiturates) increasing
metabolism of methoxyflurane and resulting in a few reported cases of
nephrotoxicity. There is insufficient information to show whether enzyme
induction affects liver damage after an analgesic dose of methoxyflurane.
b) Reduction of renal blood flow and hence anticipated enhanced renal effect when
used in combination with drugs (e.g. barbiturates) reducing cardiac output.
c) Class effect on cardiac depression which may be enhanced by other cardiac
depressant drugs, e.g. intravenous practolol during cardiac surgery.

Fertility
No clinical data on effects of methoxyflurane on fertility are available. Limited data
from animal studies do no indicate any effects on sperm morphology.
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to
reproductive toxicity (see section 5.3).
Where methoxyflurane has been used for obstetric analgesia in pregnant women, there
has been a single report of neonatal respiratory depression associated with a high fetal
level of methoxyflurane. However, when low concentrations were administered, or the
duration of higher concentrations was kept short, per recommended posology,
methoxyflurane was found to have little effect on the fetus. No fetal complications were
reported to result from methoxyflurane analgesia in the mother in all the studies
completed in obstetric analgesia.
As with all medicines care should be exercised when administered during pregnancy
especially the first trimester.
Breast-feeding
There is insufficient information on the excretion of methoxyflurane in human milk.
Caution should be exercised when methoxyflurane is administered to a nursing mother.

Methoxyflurane may have a minor influence on the ability to drive and use machines.
Dizziness, somnolence and drowsiness may occur following the administration of
methoxyflurane (see section 4.8). Patients should be advised not to drive or operate
machinery if they are feeling drowsy or dizzy.

Summary of safety profile
The most common non-serious reactions are CNS type reactions such as dizziness, and
somnolence (≥1/100 to <1/10), and are generally easily reversible.
Serious dose-related nephrotoxicity has only been associated with methoxyflurane
when used in large doses over prolonged periods during general anaesthesia.

Methoxyflurane is therefore no longer used for anaesthesia. See section 4.4 under renal
disease. The recommended maximum dose for PENTHROX should therefore not be
exceeded.
Tabulated list of adverse reactions
The adverse drug reactions observed in PENTHROX clinical studies in analgesia are
listed in the table below, classified according to frequency (common ≥1/100 to <1/10;
uncommon ≥1/1,000 to <1/100).

MedDRA System Organ Class	Common ≥1/100 to <1/10	Uncommon ≥1/1,000 to <1/100
Nervous system disorders	Amnesia Anxiety Depression Dizziness Dysarthria Dysgeusia Euphoria Headache Sensory neuropathy Somnolence	Paraesthesia
Cardiac disorders	Hypotension
Eye disorders		Diplopia
Respiratory, thoracic and mediastinal disorders	Coughing
Gastrointestinal disorders	Dry mouth Nausea	Oral discomfort
General disorders	Feeling drunk	Fatigue Feeling abnormal Increased appetite Shivering
Skin and subcutaneous tissue disorders	Sweating

Post-marketing experience
Rare (≥1/10,000 to <1/1,000) reports of hepatic failure/hepatitis have been observed
with analgesic use of methoxyflurane.
Other events linked to the methoxyflurane use in analgesia (in addition to the reactions
from clinical trials listed above), including reports from the literature include:
- Nervous system disorders: drowsiness, agitation, restlessness, dissociation, affect
lability, disorientation, altered state of consciousness
- Respiratory system: choking, hypoxia, oxygen saturation decreased
- Cardiovascular system: blood pressure fluctuation
- Gastrointestinal: vomiting

- Hepatic: hepatitis, increased liver enzymes, jaundice, liver injury
- Renal: increased serum uric acid, urea nitrogen and creatinine, renal failure
- Eyes: blurred vision, nystagmus
To reports any side effect(s):
Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Other GCC States:
Please contact the relevant competent authority

Patients should be observed for signs of drowsiness, pallor and muscle relaxation
following methoxyflurane administration.
High doses of methoxyflurane cause dose related nephrotoxicity. High output renal
failure has occurred several hours or days after the administration of repeated high
analgesic or anaesthetic doses of methoxyflurane.

Pharmacodynamic effects
Methoxyflurane vapour provides analgesia when inhaled at low concentrations. After
methoxyflurane administration, drowsiness may occur. During methoxyflurane
administration, the cardiac rhythm is usually regular. The myocardium is only
minimally sensitised to adrenaline by methoxyflurane. At analgesic therapeutic doses
pain relief may lead to some decrease in blood pressure. This may be accompanied by
bradycardia.
Clinical efficacy and safety
The efficacy and safety of PENTHROX was demonstrated in MEOF-001, a
randomised, double-blind, multi-centre, placebo controlled study in the treatment of
acute pain in patients with minor trauma presenting to an Emergency Department.
300 patients were recruited (149 received methoxyflurane and 149 received placebo in
a 1:1 ratio). Patients with a pain score of ≥ 4 to ≤ 7 on the Numerical Rating Scale were
eligible for the study. The mean pain scores (Visual Analogue Scale) observed at
baseline were similar in the methoxyflurane (64.8) and placebo (64.0) groups. The
primary efficacy variable, the estimated mean change in VAS pain from Baseline
to 5 min, 10 min, 15 min and 20 min, was greater for the methoxyflurane group (-
23.1, -28.9, -34.0 and -35.0 respectively) when compared to the placebo group (-
11.3, -14.8, -15.5 and -19.0 respectively). Overall, there was a highly significant
difference between the methoxyflurane and placebo group (estimated treatment
effect -15.1; 95% CI -19.2 to -11.0; p<0.0001). The greatest treatment effect was
seen at 15 minutes (estimated treatment effect of -18.5). An analysis was
undertaken where a responder was defined as a patient who experienced at least a
30% improvement from baseline VAS pain score. Results of this analysis indicated
that percentage of responders at 5, 10, 15 and 20 mins was significantly greater for
the methoxyflurane group (51.0%, 57.7%, 63.8%, 63.8%) when compared to the
placebo group (23.5%, 30.9%, 33.6%, 37.6%), with p < 0.0001 at each time-point.
A total of 126 patients (84.6%) in the methoxyflurane group experienced their first
pain relief after 1-10 inhalations in comparison to 76 patients (51%) in the placebo
group.

Absorption
Methoxyflurane has the following partition coefficients:
• a water/gas coefficient of 4.5,
• a blood/gas coefficient of 13 and
• an oil/gas coefficient of 825
Methoxyflurane enters the lungs in the form of a vapour and is rapidly transported
into the blood, therefore there is a rapid onset of analgesic action.

Distribution
Methoxyflurane has a high oil/gas coefficient hence methoxyflurane is highly
lipophilic. Methoxyflurane has great propensity to diffuse into fatty tissues where it
forms a reservoir from which it is released slowly over days.
Metabolism
Biotransformation of methoxyflurane occurs in man. Methoxyflurane is metabolised
by dechlorination and o-demethylation in the liver, mediated by CYP 450 enzymes
particularly CYP 2E1 and CYP 2A6. Methoxyflurane is metabolised to free fluoride,
oxalic acid, difluoromethoxyacetic acid, and dichloroacetic acid. Both free fluoride and
oxalic acid can cause renal damage at concentrations higher than those achievable with
single analgesic dose use. Methoxyflurane is more susceptible to metabolism than other
halogenated methyl ethyl ethers and has greater propensity to diffuse into fatty tissues.
Hence methoxyflurane is released slowly from this reservoir and becomes available for
biotransformation for many days.
Excretion
Approximately 60% of methoxyflurane uptake is excreted in the urine as organic
fluorine, fluoride and oxalic acid; the remainder is exhaled unaltered or as carbon
dioxide. Higher peak blood fluoride levels may be obtained earlier in obese than in nonobese
people, and in the elderly.

Embryo-fetal development
In studies in mice and rats, methoxyflurane crossed the placenta but demonstrated no
evidence of embryotoxic or teratogenic properties. However, delayed fetal
development (reduced fetal body weight and decreased ossification) was observed
following repeated dosing over 9 days. The no observed adverse effect level (NOAEL)
for embryo-fetal development was 0.006% - 4h/day in mice and close to 0.01% - 8
h/day in rats. The NOAELs in mouse and rat represent a 1- to 2-fold margin on a mg/kg
basis and a 0.1- to 0.3-fold margin on a mg/m2 basis versus the proposed maximum
clinical dose. As PENTHROX is not intended for daily use, the risk of delayed fetal
development is considered to be very low.
Hepatic effects
Repeated intermittent or continuous administration of subanaesthetic concentrations of
methoxyflurane has been associated with limited and commonly reversible hepatic
changes (fatty metamorphosis, elevated ALT/AST) in several species. A NOAEL has
not been established. These effects were seen at exposures considered sufficiently in
excess of those anticipated through normal clinical use of the product.

Butylated hydroxytoluene E321 (stabiliser).

Not applicable.

36 months.

Do not store above 30°C.

PENTHROX is supplied in the following presentations:
3 mL bottle with a tear off tamper-evident seal (packs of 10)
Combination pack with one 3 mL bottle, one PENTHROX Inhaler and one Activated
Carbon (AC) chamber (packs of 1).
Combination pack with one 3 mL bottle and one PENTHROX Inhaler (packs of 10)

After loading the PENTHROX Inhaler, replace cap onto PENTHROX bottle. After
use, place used PENTHROX Inhaler and used bottle in plastic bag provided, seal and
dispose of responsibly.