SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Mediject® Morphine Sulphate Auto-Injector 10 mg in 1ml.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1ml solution contains 10mg Morphine Sulphate.

3    PHARMACEUTICAL FORM

Solution for injection.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the management of moderate to severe pain

4.2.    Posology and Method of Administration

Dose:

Adults:

The Auto-Injector delivers a fixed dose of 10mg morphine sulphate which will generally provide adequate analgesia for a 70kg adult.

Onset of analgesia is usually within 5 to 20 minutes and peak analgesia will be reached in one hour. Although a single injection will usually provide appropriate relief for most individuals of normal stature, individuals who do not obtain adequate pain relief after 30 minutes may require a second dose.

The Auto-Injector is not intended for repeat administration, but if repeated doses must be given using the device, the usual adult dosage for repeated administration is one Auto-Injector (10mg morphine sulphate) every four hours as needed to control the pain.

Children:

Not for use in children under the age of 14 years or weighing less than 40 kg. Elderly:

The pharmacodynamic effects of morphine in the aged are more variable than in the younger population. Older patients will vary widely in the effective initial dose, rate of development of tolerance and the frequency and magnitude of associated adverse effects. Use of this product in the aged should be accompanied by the appreciation of the increase risks involved with its use in this population.

Renal and hepatic impairment:

Since a dose reduction may be necessary, Mediject® Morphine Sulphate AutoInjector should not be administered to patients with renal and hepatic impairment.

Method of administration:

For intramuscular use.

1.    Remove injector from protective outer sleeve.

2.    Remove red safety pin.

3.    Place the yellow end on patient's outer thigh and hold firmly.

4.    Press opposite end with thumb and hold for 5 seconds.

4.3. Contra-indications

Known hypersensitivity to morphine, to sulphates or other excipients.

Acute respiratory depression (see section 4.4 below), acute or severe asthma.

Morphine Sulphate Injection should be avoided in patients with raised intracranial pressure, who are comatose or who have a significant head injury. In addition to the impairment of respiration morphine affects pupillary responses which are important in neurological assessment (see section 4.4 below).

Phaeochromocytoma (risk of pressor response to histamine release).

4.4. Special Warnings and Precautions for Use

The Morphine Sulphate Auto-Injector system was developed for use under conditions which require an automatic injection device. It carries a low risk of inadvertent intravascular injection and injection site reactions and it is preferable to deliver morphine by syringe if conditions permit.

Head injury and intracranial pressure

Morphine sulphate should be used with caution in patients with increased intracranial pressure or with head injury. Pupillary changes (miosis) from morphine as well as adverse effects (vomiting, bradycardia) may obscure the existence, extent, and course of intracranial pathology.

Pulmonary disorders

Care is urged in using this drug in patients who have a decreased respiratory reserve (e.g. chronic obstructive airways disease, cor pulmonale, kyphoscoliosis or paralysis of the phrenic nerve). Morphine sulphate should be used with caution in patients with acute or severe bronchial asthma, chest wounds, upper airway obstruction, or in any other acute or chronic pulmonary disorder because of the known risk of acute respiratory failure following morphine sulphate administration in such patients.

Hypotensive effect

The administration of morphine sulphate may result in severe hypotension in an individual whose ability to maintain his or her blood pressure has been compromised by blood loss or shock. In addition, morphine sulphate may produce orthostatic hypotension (syncope) in ambulatory patients and make it difficult for such patients to walk if necessary for medical evacuation.

Renal or hepatic disease

Morphine may have a prolonged duration and cumulative effect in patients with kidney or liver dysfunction.

Use in abdominal conditions, gastrointestinal obstruction or paralytic ileus

The administration of morphine may obscure the diagnosis or clinical course in patients with abdominal conditions. However, analgesia should not be withheld for these reasons in cases of severe pain.

Use in biliary disorders

Therapeutic administration of morphine sulphate may result in smooth muscle hypertonicity which can aggravate or induce biliary colic.

Exposure, hypothermia, immersion and shock

Caution must be used when injecting any opioid intramuscularly into chilled areas or in patients with hypotension or shock, since impaired perfusion may prevent complete absorption; if repeated injections are administered, an excessive amount may be suddenly absorbed if and when normal circulation is re-established.

Drug dependence

As with all potent opioids which are ^-agonists, tolerance, psychological and physical dependence to morphine may occur. Individuals with a prior history of opioid or other substance abuse would be considered to be at a greater risk. Care must be taken to avert withdrawal in patients who have been maintained on parenteral or oral narcotics. Withdrawal symptoms may occur when morphine is discontinued abruptly or upon administration of a narcotic antagonist.

Morphine should be used with caution and in reduced dosage in patients who are concurrently receiving other narcotic analgesics, general anaesthetics, phenothiazines, other tranquillisers, sedative-hypnotics, tricyclic antidepressants, and other CNS depressants (including alcohol). Respiratory depression, hypotension and profound sedation or coma may result.

Other patients at special risk

Morphine should be given with caution to patients with a brain tumour, a convulsive state such as status epilepticus, tetanus, strychnine poisoning, prostatic hypertrophy and hypothyroidism.

Concurrent administration of mono-amine oxidase inhibitors (MAOIs) or within two weeks of discontinuation of their use (see section 4.5).

Use in children

The safety and efficacy of morphine in neonates and children have not been established.

4.5. Interactions with other Medicaments and other forms of Interaction

Use with other CNS depressants or alcohol

The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, hypnotics, antihistamines or psychotropic drugs. Use of morphine in conjunction with other CNS active drugs may increase the risk of respiratory depression.

Morphine should be administered cautiously to avoid additive effects when other central nervous system depressants, including other narcotic analgesics, general anaesthetics, phenothiazines, tricyclic antidepressants, tranquillisers and alcohol are given concomitantly.

Morphine may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.

Mixed Agonist/Antagonist Opioid Analgesics

Theoretically, mixed agonist/antagonist opioid analgesics (e.g. pentazocine and buprenorphine) should not be administered to patients who have received or are receiving therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect or may precipitate withdrawal symptoms.

Monoamine Oxidase Inhibitors:

Monoamine Oxidase Inhibitors (MAOIs) intensify the effects of morphine and other opioid drugs which can cause anxiety, confusion and significant depression of respiration, sometimes leading to coma. Morphine should not be given to patients taking MAOIs or within 14 days of stopping such treatment.

Drug/laboratory test interactions

Because narcotic analgesics may increase biliary-tract pressure, with resultant increase in plasma amylase or lipase levels, determination of these enzyme levels may be unreliable for 24 hours after a narcotic analgesic has been given.

In addition, the Auto-Injector system may cause a mild increase in SGOT and CPK due to muscle injury at the site of injection. Morphine, like other opioids, will give a positive test for narcotics in the urine of any patient who has received it for a few days to a week, depending on the sensitivity of the assay procedure.

4.6. Pregnancy and Lactation Pregnancy:

This product should only be given to pregnant women when no safer method of controlling severe pain is available and the potential risks are acceptable when considered in terms of the clinical benefit. If this product is used in late pregnancy, personnel, equipment and drugs, (including paediatric naloxone) to resuscitate the new-born should be at hand.

This product is intended for fixed-dose administration by non-medical personnel and is not recommended for routine obstetrical analgesia.

Lactation:

Morphine crosses into breast milk in variable concentration and use of this product in nursing mothers should be guided by the relative risk of narcotic effects on the infant and the maternal need for analgesia.

4.7. Effects on Ability to Drive and Use Machines

Analgesic doses of morphine cloud judgement and impair the mental and/or physical abilities which are required for the performance of tasks such as driving a vehicle or operating machinery. The concomitant use of alcohol or other central nervous system depressants, including sedatives, hypnotics, tranquillisers, phenothiazines and antihistamines may have an additive effect.

4.8. Undesirable Effects

The major hazards of morphine, as with other narcotic analgesics, are respiratory depression and, to a lesser degree, circulatory depression; respiratory arrest, shock and cardiac arrest have occurred, particularly with overdosage, rapid intravenous administration and pre-existing hypovolaemic shock. Rarely anaphylactic reactions have been reported when morphine or other phenanthrene alkaloids of opium are administered intravenously.

The most frequently observed adverse reactions include sedation, drowsiness, light-headedness, dizziness, dry mouth, nausea, vomiting and sweating. These effects seem to be more prominent in ambulatory patients and in those who are not experiencing severe pain. Some adverse reactions in ambulatory patients may be alleviated if the patient lies down.

Other possible adverse reactions include:

Central nervous system: Euphoria, dysphoria, weakness, headache, agitation, tremor, uncoordinated muscle movements, visual disturbances, miosis, and accommodation problems, transient hallucinations and disorientation.

Gastrointestinal: Constipation, biliary tract spasm.

Cardiovascular: Tachycardia, bradycardia, palpitation, faintness, syncope and orthostatic hypotension.

Genitourinary: Oliguria, difficulty with micturition and urinary retention; an antidiuretic effect has been reported.

Allergy: Allergic reactions to opiates occur infrequently; pruritis, urticaria and other skin rashes are most common. Rarely, anaphylactic reactions have been reported following intravenous administration.

Other: Opiate-induced histamine release may be responsible for the flushing of the face, sweating and pruritis often seen with these drugs. Wheals and urticaria at the site of the injection are probably related to histamine release. Local tissue irritation, pain and induration have been reported following repeated subcutaneous injection. Morphine, like other opioids, may alter temperature regulation in susceptible individuals and will depress the cough reflex.

4.9. Overdose

Overdosage of morphine is characterised by respiratory depression, with or without concomitant CNS depression.

Mild overdosage may be managed by continuous stimulation of the patient and/or frequent verbal instructions to "wake-up" or "take a deep breath".

Serious overdosage with morphine is characterised by a profound respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils and respiratory depression is strongly suggestive of opiate poisoning.

Treatment for overdose:

Primary attention should be given to the establishment of adequate respiratory exchange through maintenance of a patent airway and institution of assisted or controlled ventilation.

The narcotic antagonist, naloxone, is a specific antidote. An initial dose of 0.4 to 2 mg of naloxone should be administered intravenously, simultaneously with respiratory resuscitation.

If the desired degree of counteraction and improvement in respiratory function is not obtained, naloxone may be repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of naloxone has been administered, the diagnosis of morphine-induced toxicity should be questioned.

Intramuscular or subcutaneous administration of naloxone may be used if the intravenous route is not available. As the duration of effect of naloxone is considerably shorter than that of morphine, repeated administration may be necessary.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Opioid, ATC code: NO2AA

Morphine is the prototype of many narcotic drugs that interact predominantly with the opioid p-receptor, which are distributed throughout the CNS.

Morphine exerts its principal pharmacological effects on the central nervous system and smooth muscle, its main therapeutic actions being analgesia and sedation. It acts as a competitive agonist at p- and to a lesser extent k-receptors, resulting in analgesia, respiratory depression, euphoria, inhibition of gut mobility, physical dependence, miosis and sedation.

Morphine increase smooth muscle tone, with resultant effects on the gastrointestinal, biliary and urinary tracts.

Morphine also depresses the cough reflex. Nausea and vomiting may occur through direct stimulation of the chemoreceptor trigger zone. Morphine can cause histamine release.

5.2. Pharmacokinetic Properties

Morphine is completely absorbed following intramuscular administration and has an apparent volume of distribution ranging from 2.0 to 3.0 l/kg. The mean oral/parenteral ratio for an equivalent pain relieving effect is 3 (range 2 to 10).

Peak plasma levels for a 70kg adult following intramuscular administration of 10mg of morphine are between 20 and 100ng/ml. (The minimum effective analgesic concentration of morphine is 20 to 40ng/ml in studies of patient-controlled analgesia.) A blood-brain barrier exists for the drug, with plasma concentrations of morphine remaining higher than the corresponding CSF morphine levels following intramuscular administration.

Morphine is bound to plasma proteins only to the extent of 25 to 35%, with a mean total plasma clearance which ranges from 0.9 to 1.2 l/kg/h in postoperative patients.

The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide (45%), which is the major metabolite of morphine. Morphine-6-glucuronide is a quantitatively minor (5%) but active metabolite and has been shown to be approximately 40 time as active as morphine. The major excretion path of the conjugates is through the kidneys, with about 10% in the faeces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine.

The terminal half life in normal patients is 1.5 to 2.0 hours.

Preclinical Safety Data

Following administration to pregnant hamsters and mice, morphine, like many other opioids, has been shown experimentally to induce nervous system defects in the offspring. These may be related to hypoxaemia and subsequent hypoglycaemia. However, the evidence for these effects in man is inconclusive.

Although mutagenicity and carcinogenicity testing have not been conducted using modern testing, there are no safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC or to the experience gained in man over many years.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Benzyl Alcohol, Disodium Edetate, Dilute Sulphuric Acid, Water for Injections.

6.2.    Incompatibilities

None known.

6.3.    Shelf Life

48 months

6.4.    Special Precautions for Storage

Do not store above 25 °C.

Nature and Contents of Container

The Morphine Sulphate Auto-Injector contains 10mg Morphine Sulphate per ml.

The Auto-Injector is a pre-filled, fluoropolymer cartridge contained in an olive drab self-injecting automatic syringe body. The olive drab body is fitted with a yellow cap containing the rubber stopper at one end and a red safety pin at the other.

Each Auto-Injector is encased in a printed, flexible, sealed, waterproof, "popout" close fitting PVC sleeve. It is supplied in easy tear linked strips of six. The sleeve, with its "button-hole" and space for the casualty's name and timeblock acts as a casualty marker tag.

The components in contact with the morphine sulphate solution are made of fluoropolymer, HDPE, rubber and stainless steel.

6.6    Special precautions for disposal

The Morphine Auto-Injector contains a powerful spring-driven injection mechanism and is capable of inflicting injury if accidentally misused. The product should remain in its original container with the safety pin in place until actually in use, and in no case should the product be carried with the safety pin removed.

If the situation allows, after use the Auto-Injector should be disabled before discarding. The exposed canula should be snapped off the Auto-Injector, placed in the hole of the green activation cap and the red pin replaced in the hole.

7.    MARKETING AUTHORISATION HOLDER

Meridian Medical Technologies Ltd.

Regus House 33 Clarendon Dock Belfast

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 17545/0001

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11 March 2002

10    DATE OF REVISION OF THE TEXT

16/12/2008