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Oramorph Concentrated Oral Solution 20mg/Ml

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Oramorph Concentrated Oral Solution 20 mg/ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

A clear, red coloured liquid containing Morphine Sulphate 20 mg in each ml. Excipient: Amaranth (E123) 0.003% w/v.

For full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

For the relief of severe pain.

4.2 Posology and method of administration

Adults: Usual dose 10-20 mg (0.5 - 1.0 ml) every 4 hours.

Paediatric

population:

Children 13 - 18

years:

Children 6-12 years: Children 1-5 years:

Maximum single dose 5-20 mg (0.25 - 1.0 ml) every 4 hours

Maximum dose 5-10 mg (0.25 - 0.5 ml) every 4 hours. Maximum dose 5 mg (0.25 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.

When patients are transferred from other morphine preparations to Oramorph Concentrated Oral Solution dosage titration may be appropriate.

A calibrated oral dosing pipette is supplied with this dosage form for accurate and convenient dose adjustment. The required dose may be added to a soft drink immediately prior to administration.

Morphine Sulphate is readily absorbed from the gastro-intestinal tract following oral administration. However, when Oramorph 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.

4.3 Contraindications

Respiratory depression, obstructive airways disease, known morphine sensitivity, 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 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 contra-indicated in acute asthma exacerbations, see section 4.4 for information relating to use in controlled asthma.

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

4.4 Special warnings and precautions for use

Care should be exercised if morphine sulphate is given in the first 24 hours postoperatively, 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 the 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 Oramorph. Care should be taken to elicit any history of allergic reactions to opiates.

Oramorph Concentrated Oral Solution contains the excipient Amaranth (E123), which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

Phenothiazine anti-emetics 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 gastrointestinal 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 oxidise 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 oramorph and voriconazole. Interactions have been reported in those taking oramorph and gabapentin. Both interactions suggest an increase in opioid adverse events when co-prescribed, 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.

4.7 Effects on ability to drive and use machines

Morphine sulphate is likely to impair ability to drive or 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 Oramorph.

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 nausea, vomiting, constipation, drowsiness and confusion. If constipation occurs, this may be treated with appropriate laxatives.

A full list of currently known adverse reactions is presented below:

SOC Category	Side effect
Immune system disorders	Hypersensitivity reactions including anaphylaxis
Psychiatric disorders	Confusion Restlessness Mood changes Hallucinations Dependence
Nervous system disorders	Drowsiness Headache
Eye Disorders	Miosis
Ear and labyrinth disorders	Vertigo
Cardiac disorders	Bradycardia Tachycardia Palpitations
Vascular disorders	Orthostatic hypotension

	Hypothermia Facial flushing Raised intracranial pressure occurs in some patients.
Gastrointestinal disorders	Nausea Vomiting Constipation Dry mouth
Hepatobiliary Disorders	Biliary spasm
Skin and subcutaneous tissue	Urticaria
disorders	Pruritis Sweating
Musculoskeletal and connective tissue disorders	Muscle rigidity
Renal and urinary disorders	Micturition may be difficult Ureteric spasm Antidiuretic effect
Reproductive system and breast disorders	Decreased libido/potency

Reporting of suspected adverse reactions

Reporting suspected adverse reaction 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.

4.9. Overdose symptoms, emergency procedures, antidotes

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 10mg, or by an infusion of 2mg 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.

5.1. Pharmacodynamic properties

Morphine binds to opiate receptors 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 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, concentrating in the tissues. In animals it has been shown that a relatively small amount of 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

Not applicable.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Disodium Edetate Sodium Benzoate (E211)

Citric Acid anhydrous Amaranth (E213)

Purified Water

6.2.

Incompatibilities

None stated.

6.3 Shelf life

The shelf-life expiry date for this product shall not exceed three years from the date of its manufacture for unopened product. The product will be stored according to the provisions specified by the Home Office.

Discard any remaining Oramorph Concentrated Oral Solution 4 months after first opening.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original container to protect from light.

6.5 Nature and contents of container

Amber glass bottles of 30 ml and 120 ml with a tamper evident, child resistant closure with an outer overcap in high density polyethylene. A calibrated oral dosing pipette will be enclosed in the carton with each bottle.