4.1. Therapeutic indications

Emergency relief of moderate to severe pain in conscious patients aged 6 years and older with trauma and associated pain.

4.2. Posology and method of administration

PENTHROX should be self-administered under supervision of a person trained in its administration, using the hand held PENTHROX Inhaler. It is inhaled through the PENTHROX inhaler.

The intended purpose of the Penthrox inhaler is to administer the analgesic drug Penthrox (methoxyflurane). Penthrox is poured into the device and as a patient breathes in through the device the patient inhales the Penthrox vapour. The attached Activated Carbon (AC) Chamber adsorbs the Penthrox vapour being exhaled by the patient through the Penthrox inhaler (see section 5.2).

Posology

Adults and children aged 6 years and older

One bottle of 3 ml PENTHROX as a single dose, administered using the device provided. A second bottle should only be used where needed.

The frequency at which PENTHROX can be safely used is not established (see section 4.4). The following administration schedule is recommended: no more than 6 ml in a single day, administration on consecutive days is not recommended, and the total dose to a patient in a week should not exceed 15 ml.

In adults the onset of pain relief is rapid and should commence after 6–10 inhalations. In children additional inhalations may be required. 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 of a bottle containing 3 ml provides analgesic relief for up to 25-30 minutes. Intermittent inhalation may provide longer analgesic relief. Patients should be advised to use the lowest possible dose to achieve pain relief (see section 4.4).

Renal impairment

Methoxyflurane may cause renal failure if the recommended dose is exceeded. Caution should be exercised for patients diagnosed with clinical conditions that would pre-dispose to renal injury (see section 4.4).

Hepatic impairment

Cautious clinical judgement should be exercised when PENTHROX is to be used more frequently than on one occasion every 3 months (see section 4.4).

Paediatric population

The safety and efficacy of PENTHROX in children aged 0 to 6 years has not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of Administration

For inhalation use.

Instructions on the preparation of the PENTHROX Inhaler and correct administration are provided in the Figures below.

Before use, check for foreign objects, broken or deteriorated parts. Do not use this device if any are identified.

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 and exhales PENTHROX through the mouthpiece 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

If further pain relief is required, after the first bottle has been used use a second bottle if available. Alternatively use a second bottle from a new combination pack. Use in the same way as the first bottle in step 2 and 3. No need to remove the AC Chamber. Put used bottle into the plastic bag provided.

8

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.

9

Replace cap onto PENTHROX bottle. Place used PENTHROX Inhaler and used bottle in sealed plastic bag and dispose of responsibly (see section 6.6).

The person trained in administering PENTHROX must provide and explain the Package Leaflet to the patient

4.3. Contraindications

Use as an anaesthetic agent.

Hypersensitivity to methoxyflurane, any fluorinated anaesthetic or to any of the excipients listed in section 6.1.

Malignant hyperthermia: patients who are known to be or genetically susceptible to malignant hyperthermia.

Patients or patients with a known family history of severe adverse reactions after being administered with inhaled anaesthetics.

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.

4.4. Special warnings and precautions for use

Renal disease

To ensure the safe use of PENTHROX as an analgesic the following precautions should be observed.

- Use the lowest effective dose to control pain

- Use with caution in the elderly or other patients with known risk factors for renal disease.

- Use with caution in patients diagnosed with clinical conditions which may pre-dispose to renal injury.

Methoxyflurane causes significant nephrotoxicity at high doses. Nephrotoxicity is thought to be associated with inorganic fluoride ions, a metabolic breakdown product. When administered as instructed for the analgesic indication, a single dose of 3 ml methoxyflurane produces serum levels of inorganic fluoride ions below 10 micromol/l. In the past when used as an anaesthetic agent, methoxyflurane at high doses caused significant nephrotoxicity, which was determined to occur at serum levels of inorganic fluoride ions greater than 40 micromol/l. 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).

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 (see section 4.3). 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 blood pressure 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 (CNS) effects

Secondary pharmacodynamic effects including potential CNS effects such as sedation, euphoria, amnesia, ability to concentrate, altered sensorimotor co-ordination and change 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. Whilst the possibility of CNS effects may be seen as risk factor for potential abuse, reports are very rare in post marketing use.

Respiratory depression

Respiratory depression has been reported also from analgesic doses (section 4.8). Respiration should be monitored due to the risk for respiratory depression and hypoxia.

Frequent repeated use

Due to the limitations on the dose of PENTHROX (refer to section 4.2) 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.

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. Patients should be instructed to exhale into the PENTHROX Inhaler so the exhaled vapour passes through the 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.

There have been reports of non-serious and transient reactions such as dizziness, headache, nausea or malaise, and reports of hypersensitivity reactions to methoxyflurane or other ingredients in healthcare professionals exposed to Penthrox. Measurements of exposure levels to methoxyflurane in hospital staff showed levels significantly lower than those associated with nephrotoxicity.

4.5. Interaction with other medicinal products and other forms of interaction

The metabolism of methoxyflurane is mediated by the CYP 450 enzymes particularly CYP 2E1, CYP 2B6 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 and carbamazepine, efavirenz, rifampicin or nevirapine for CYP 2B6) which increase the rate of methoxyflurane metabolism might increase its potential toxicity and they should be avoided concomitantly with methoxyflurane.

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.

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.

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 (eg 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 (eg barbiturates) reducing cardiac output.

c) Class effect on cardiac depression which may be enhanced by other cardiac depressant drugs, eg intravenous practolol during cardiac surgery.

4.6. Fertility, pregnancy and lactation

Fertility

No clinical data on effects of methoxyflurane on fertility are available. Limited data from animal studies do not indicate any effects on sperm morphology.

Pregnancy

Studies in animals have shown reproduction 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 foetus. 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.

4.7. Effects on ability to drive and use machines

PENTHROX 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.

4.8. Undesirable effects

Summary of safety profile

The common non-serious reactions are CNS type reactions such as dizziness, and somnolence, 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.

Liver injury may occur (frequency not known), with analgesic use of methoxyflurane. See section 4.4 under liver disease.

Tabulated list of adverse reactions

The following table consists of adverse drug reactions:

- observed in PENTHROX clinical studies in analgesia

- observed with analgesic use of methoxyflurane following post-marketing experience

- linked to methoxyflurane use in analgesia found in scientific literature

The following frequencies are the basis for assessing undesirable effects:

Very common (≥1/10)

Common (≥1/100 to <1/10);

Uncommon (≥1/1,000 to <1/100);

Rare (≥1/10,000 to <1/1000);

Very rare (<1/10,000); and

Not known (cannot be estimated from the available data).

MedDRA System Organ Class

Very common

≥1/10

Common

≥1/100 to <1/10

Uncommon

≥1/1,000 to <1/100

Not known

Immune system disorders

Hypersensitivity^

Metabolism and nutrition disorders

Increased appetite

Psychiatric disorders

Euphoric mood

Anxiety

Depression

Disturbance in attention

Inappropriate affect

Verbigeration

Affect lability

Agitation

Confusional state

Dissociation^

Restlessness^

Nervous system disorders

Dizziness

Headache

SomnolenceDysgeusia

Amnesia

Dysarthria

Paraesthesia

Peripheral sensory neuropathy

Altered state of consciousness^

Nystagmus^

Eye disorders

Vision impairment

Vascular disorders

Flushing

Hypertension

Hypotension

Respiratory, thoracic and mediastinal disorders

Cough

Hypoxia

Choking^

Respiratory depression^

Gastrointestinal disorders

Nausea

Dry mouth

Oral discomfort

Oral pruritus

Salivary hypersecretion

Vomiting

Hepatobiliary disorders

Hepatic failure*

Hepatitis*

Jaundice^

Liver injury^

Skin and subcutaneous tissue disorders

Hyperhidrosis

Renal and urinary disorders

Renal failure^

General disorders and administration site conditions

Fatigue

Feeling drunk

Feeling abnormal

Chills

Feeling of relaxation

Investigations

Hepatic enzyme increased^

Blood urea increased^

Blood uric acid increased^

Blood creatinine increased^

* isolated post-marketing reports that have been observed with analgesic use of methoxyflurane

^Other events linked to methoxyflurane use in analgesia found in post marketing experience and in scientific literature

Paediatric population

The safety profile of PENTHROX in a placebo-controlled study in paediatrics (MEOF-002) aged 6 to < 18 years was consistent with the safety profile observed in adults. The majority of events were mild in intensity and non-serious with the most common being dizziness (41.3% in methoxyflurane group vs 12.0% in placebo group) and euphoric mood (12.0% in methoxyflurane group vs 0.0% in placebo group).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, anaesthetic effects may occur with signs of excessive drowsiness, (including loss of consciousness), lowering of blood pressure, respiratory depression, pallor and muscle relaxation. After Penthrox discontinuation such overdose effects usually resolve quickly often with no other intervention required but cardiorespiratory supportive measures can be implemented if necessary.

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.