Product Summary

1.    Trade Name of the Medicinal Product Morphine Oral Solution 10mg/5ml

2.    Qualitative and Quantitative Composition

Morphine Sulphate BP 0.2 % w/v

3.    Pharmaceutical Form

Oral Solution

Clinical Particulars

4.1.    Therap euti c Indi cati ons

For the relief of severe pain.

4.2 Posology and method of administration

Adults: Usual dose 10-20 mg (5-10 ml) every 4 hours.

Children 6-12 years: Maximum dose 5-10 mg (2.5-5 ml) every 4 hours.

Children 1-5 years: Maximum dose 5 mg (2.5 ml) every 4 hours.

Children under 1 year: Not recommended.

Dosage can be increased under medical supervision according to the severity of the pain and the patient's previous history of analgesic requirements. Reductions in dosage may be appropriate in the elderly, patients with moderate-severe renal or hepatic impairment, or where sedation is undesirable.

Morphine Sulphate is readily absorbed from the gastro-intestinal tract following oral administration. However, when Morphine Oral Solution is used in place of parenteral morphine, a 50% to 100% increase in dosage is usually required in order to achieve the same level of analgesia.

Respiratory depression, obstructive airways disease, acute hepatic disease, acute alcoholism, head injuries, coma, convulsive disorders and where the intracranial pressure is raised, paralytic ileus.

Concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use.

Morphine Oral Solution is contraindicated in patients known to be hypersensitive to morphine sulphate or to any other component of the product.

Morphine and some other opioids can induce the release of endogenous histamine and thereby stimulate catecholamine release making them unsuitable for use in patients with phaeochromocytoma.

Opioids are contraindicated in acute asthma exacerbations, see section 4.4 for information relating to use in controlled asthma.

4.4 Special warnings and precautions for use

Care should be exercised if morphine sulphate is given in the first 24 hours post-operatively, in hypothyroidism, and where there is reduced respiratory reserve, such as kyphoscoliosis, emphysema and severe obesity. Opioids are contra-indicated in acute asthma exacerbations. However, it has been suggested that they can be used with caution in controlled asthma.

Morphine sulphate should not be given if paralytic ileus is likely to occur (see section 4.3) or where there is an obstructive bowel disorder or prostatic hyperplasia. If constipation occurs, this may be treated with appropriate laxatives.

It is wise to reduce dosage in chronic hepatic and renal disease, myxoedema, adrenocortical insufficiency, prostatic hypertrophy or shock.

The administration of morphine may result in severe hypotension in individuals whose ability to maintain homeostatic blood pressure has already been compromised by depleted blood volume or the concurrent administration of drugs such as phenothiazine or certain anaesthetics.

Tolerance and dependence may occur. Withdrawal symptoms may occur on abrupt discontinuation or on the administration of a narcotic antagonist e.g. naloxone.

Hypersensitivity and anaphylactic reaction have both occurred with the use of Morphine Oral Solution. Care should be taken to elicit any history of allergic reactions to opiates.

4.5 Interaction with other medicinal products and other forms of interaction

Phenothiazine antiemetics may be given with morphine, but it should be noted that morphine potentiates the effects of tranquillisers, anaesthetics, hypnotics, sedatives, antipsychotics, tricyclic antidepressants and alcohol. Morphine may possibly increase plasma concentrations of esmolol.

Cimetidine inhibits the metabolism of morphine. Opioid analgesics including morphine may antagonise the actions of domperidone and metoclopramide on gastro-intestinal activity. Concomitant use of ritonavir should be avoided as the plasma concentration of morphine may be increased. The absorption of mexiletine may be delayed by concurrent use of morphine.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis, please see section 4.3.

Interactions have been reported in those subjects taking Morphine Oral Solution and voriconazole. Interactions have been reported in those taking Morphine Oral Solution and gabapentin. Both interactions suggest an increase in opioid adverse events when coprescribed, the mechanism of which is not known. Caution should be taken where these medicines are co-prescribed.

In a study involving healthy volunteers (N=12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

4.6 Pregnancy and lactation

Although morphine sulphate has been in general use for many years, there is inadequate evidence of safety in human pregnancy and lactation.

Morphine is known to cross the placenta, and is excreted in breast milk, and may thus cause respiratory depression in the newborn infant. Infants born from mothers who have been taking morphine on a chronic basis may exhibit withdrawal symptoms.

Gastric stasis and risk of inhalation pneumonia in mother during labour.

Medicines should not be used in pregnancy, especially the first trimester unless the expected benefit is thought to outweigh any possible risk to the foetus.

Morphine sulfate is likely to impair ability to drive and to use machinery. This effect is even more enhanced, when used in combination with alcohol or CNS depressants. Patients should be warned not to drive or operate dangerous machinery after taking Morphine Oral Solution.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

In routine clinical practice, the commonest side effects of morphine sulphate are respiratory depression, nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives.

Other adverse reactions include:

Cardiovascular: bradycardia, tachycardia, palpitations, orthostatic hypotension and hypothermia. Raised intracranial pressure occurs in some patients.

Central Nervous system: headache, restlessness, vertigo, mood changes, hallucinations, dependence, muscle rigidity.

Gastrointestinal: dry mouth, bilary spasm.

Genitourinary: decreased libido/potency, micturation may be difficult and there may be ureteric spasm. There is also an antidiuretic effect.

General: sweating, facial flushing and miosis.

These effects are more common in ambulant patients than in those who are bedridden.

Immune system disorders: hypersensitivity reactions including anaphylaxis. Urticaria, pruritis.

Symptoms: Signs of morphine toxicity and overdosage are likely to consist of pin-point pupils, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Convulsions may occur in infants and children. Death may occur from respiratory failure.

Treatment of morphine overdose: Administer 0.4-2 mg of naloxone intravenously. Repeat at 2-3 minute intervals as necessary to a maximum of 10 mg, or by an infusion of 2 mg in 500 ml of normal saline or 5 % dextrose (4 microgram/ml). Empty the stomach. A 0.02% aqueous solution of potassium permanganate may be used for lavage. Care should always be taken that the airway is maintained. Assist respiration if necessary. Maintain fluid and electrolyte levels, oxygen, i.v. fluids, vasopressors and other supportive measures should be employed as indicated.

Caution: the duration of the effect of naloxone (2-3 hours) may be shorter than the duration of the effect of the morphine overdose. It is recommended that a patient who has regained consciousness after naloxone treatment should be observed for at least 6 hours after the last dose of naloxone.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Morphine binds to opiate receptors, which are located on the cell surfaces of the brain and nervous tissue. This action results in alteration of neurotransmitter release and calcium uptake. It has been postulated that this is the basis of the modulation of sensory input from afferent nerves sensitive to pain.

5.2 Pharmacokinetic properties

Morphine N-methyl ¹⁴C sulphate administered orally to humans reaches a peak plasma level after around 15 minutes: levels of plasma-conjugated morphine peak at about 3 hours, and slowly decrease over the following 24 hours. After the first hour no significant differences in total plasma levels of radioactivity are seen whether administration is by intravenous, intramuscular, subcutaneous or oral route.

Morphine is a basic amine, and rapidly leaves the plasma and concentrates in the tissues. In animals it has been shown that a relatively small amount of free morphine crosses the blood-brain barrier. Morphine is metabolised in the liver and probably also in the mucosal cells of the small intestine. The metabolites recovered in the urine, in addition to free morphine, are morphine-3-glucuronide and morphine ethereal sulphate. These account for over 65 % of administered radioactivity; further radioactivity can be recovered as exhaled ¹⁴CO2.

5.3. Preclinical Safety Data

No additional pre-clinical data of relevance to the prescriber.

Pharmaceutical Particulars

6.1. List of Excipients

Sucrose, ethanol, sodium methyl hydroxybenzoate (E219), sodium propyl hydroxybenzoate (E217), disodium edetate, raspberry flavour, hydrochloric acid and purified water.

6.2.    Incompatibilities

None stated.

6.3.    Shelf Life

3 years (36 months) unopened 90 days once opened

6.4.    Special Precautions for Storage

Do not store above 25 °C

Keep container in the outer container.

6.5.    Nature and Contents of Container

Round amber glass bottles with child proof and tamper evident caps. The bottles are packed in a cardboard carton along with a patient leaflet.

Pack sizes: 100ml, 250ml, 300ml & 500ml.

6.6.    Instruction for Use/Handling None stated.

Administrative Data

Marketing Authorisation Holder

Martindale Pharmaceuticals Ltd Bampton Road Harold Hill Romford RM3 8UG United Kingdom

8. Marketing Authorization Number

PL 00156/0036

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/03/2009

10    DATE OF REVISION OF THE TEXT

08/04/2014