Morphine Sulphate Injection 1mg/Ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Morphine Sulphate Injection 1mg/ml
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of sterile solution for injection contains 1mg Morphine Sulphate.
3. PHARMACEUTICAL FORM
Solution for injection.
Clear, colourless liquid, practically free from particles, contained in a Type I glass 10-ml pre-filled syringe.
4. CLINICAL PARTICULARS
4.1. Therapeutic Indications
Morphine Sulphate Injection 1mg/ml is indicated for the relief of severe pain. It is indicated for use as a loading dose prior to continuous or patient-controlled analgesia.
4.2. Posology and Method of Administration
By intramuscular, subcutaneous or intravenous injection.
Morphine Sulphate Injection 1mg/ml should not be diluted before use.
Dose and dosage regimen depends on the severity of the pain and should be titrated against the individual patient’s requirements. A typical loading dose range and lock out time for a 70kg adult are:
Loading dose - 5-15mg over 30 minutes
then 2.5- 5.0mg every hour
With a lock out time of 5-10 minutes
Due attention should be paid to the caution mentioned below and the possibility of side effects such as respiratory depression.
For Adults and children over 12 years
Doses of up to 10mg have been given by slow intravenous injection, as a loading dose for continuous or patient-controlled infusion. For continuous Intravenous administration maintenance doses have generally ranged from 0.8 to 80mg per hour, although some patients have required and been given much higher doses. Similar doses have been given by continuous subcutaneous infusion.
Children under 12 years
This formulation is not recommended for use in children under 12 years.
In the Elderly
The dose of morphine should be reduced in elderly patients and titrated to provide optimal pain relief with minimal side effects. Morphine clearance decreases and half-life increases in older patients.
In patients with disturbed Renal function
Caution should be exercised in the use of Morphine in patients with renal dysfunction i.e. renal failure, because such patients can show signs of overdose following conservative dosage regimens.
In patients with Impaired Liver Function
Caution should be exercised in the use of Morphine in patients with impaired liver function e.g. cirrhosis as this condition is likely to affect elimination. The dose therefore should be carefully titrated to provide optimal pain relief.
4.3. Contraindications
Respiratory depression, coma, obstructive airways disease, acute abdomen, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors (MAOIs) or within two weeks of discontinuation of their use. Morphine Sulphate Injection should be avoided in patients with raised intracranial pressure or head injury as this interferes with respiration and neurological assessment due to the effect on the pupils. Also in patients with convulsive disorders or acute alcoholism.
4.4. Special Warning and Precautions for Use
Hypotension, hypothyroidism, asthma (avoid during attack), and decreased respiratory reserve; pregnancy and breast-feeding; may precipitate coma in hepatic impairment (reduce dose but many such patients tolerate morphine well); reduce dose in renal impairment, elderly and debilitated (reduce dose); dependence (severe withdrawal symptoms if withdrawn abruptly).
4.5. Interactions with other medical products and other forms of interaction
The depressant effects of morphine are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics and sedatives, tricyclic anti-depressants, and phenothiazines. Opioid analgesics with some antagonistic activity, such as buprenorphine, butorphanol, nalbuphine, or pentazocine, may precipitate withdrawal symptoms in patients who have recently used pure agonists such as morphine. The actions of opioids may in turn affect the activities of other compounds.
Opioid Analgesics
Alcohol: enhanced sedative and hypotensive effect.
Anti-Arrhythmics: delayed absorption of mexiletine.
Antidepressants: CNS excitation or depression (hypertension or hypotension) if pethidine and possibly other opioid analgesics given to patients receiving MAOIs (including moclobemide).
Anxiolytics and Hypnotics: enhanced sedative effect.
Cisapride: possible antagonism of gastro-intestinal effect.
Domperidone andMetoclopramide: antagonism of gastro-intestinal effects.
Dopaminergics: hyperpyrexia and CNS toxicity reported with selegiline.
Ulcer-healing drugs: cimetidine inhibits metabolism of opioid analgesics notably pethidine (increased plasma concentration).
No Data Held
4.6. Pregnancy and Lactation
Morphine Sulphate should be given with great care during pregnancy and whilst breastfeeding. The administration of morphine during labour may cause respiratory depression in the newborn infant. Morphine is excreted in the breast milk in small quantities and may cause adverse effects.
4.7. Effects on Ability to Drive and Use Machines
Morphine may cause drowsiness and patients should not drive or operate machinery.
4.8. Undesirable Effects
In normal doses the commonest side effects of morphine and other opioid analgesics are nausea, vomiting, constipation, drowsiness and confusion. Tolerance generally develops with long-term use, but not to constipation. Micturition may be difficult and there may be ureteric or biliary spasm. In addition, there is also an antidiuretic effect. Dry mouth, sweating, facial flushing, vertigo, bradycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, changes of mood, hallucinations and miosis also occurs. These effects tend to occur more commonly in ambulant patients than in those at rest in bed and in those without severe pain. Raised intracranial pressure occurs in some patients. Muscle rigidity has been reported following high doses. The euphoric activity of morphine and similar compounds has led to their abuse.
Larger doses of morphine produce respiratory depression and hypotension, with circulatory failure and deepening coma. Convulsions may occur, especially in infants and children. Rhabdomyolysis progressing to renal failure has been reported in overdosage. Death may occur from respiratory failure. Toxic doses vary considerably with the individual and regular users may tolerate large doses. The triad of coma, pinpoint pupils and respiratory depression is considered indicative of overdosage; dilatation of the pupils occurs as hypoxia develops.
Pulmonary oedema after overdosage is a common cause of fatalities among opioid addicts.
Morphine and some other opioids have a dose-related histamine-releasing effect, which may be responsible in part for reactions such as urticaria and pruritis as well as hypotension and flushing. Contact dermatitis has been reported and pain and irritation may occur on injection. Anaphylactic reactions following intravenous injection have been reported rarely.
4.9. Overdose
Signs of morphine toxicity and overdose include pinpoint pupils, respiratory depression, and hypotension. Circulatory failure and deepening coma may occur in more severe cases.
Treatment of Morphine Overdose
In the treatment of known or suspected opioid overdose, an initial dose of naloxone 0.4 to 2mg may be given intravenously and repeated if necessary at intervals of 2 to 3 minutes. If no response has been observed after a total dose of 10mg then the diagnosis of overdose with drugs other than opioids should be considered. If the patient is suspected of being physically dependent on opioids the dose may be reduced to 0.2mg to avoid precipitating withdrawal symptoms. In children, the usual initial dose of 10p,g per kg bodyweight intravenously followed, if necessary, by a larger dose of 100p,g per kg.
Alternatively, to sustain opioid antagonism, an intravenous infusion of naloxone has been suggested. Naloxone (4p,g per ml) in sodium chloride injection (0.9%) or glucose injection (5%) may be infused at a rate titrated in accordance with the patient’s response both to the infusion and previous bolus injections.
HARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Morphine is a phenanthrene derivative and the principal alkaloid of opium and is an opioid analgesic. Morphine acts as an agonist at p opioid receptors and, to a lesser extent, k receptors and mainly acts on the central nervous system and smooth muscle. Although morphine is predominantly a central nervous system depressant it has some central stimulant actions which result in nausea and vomiting and miosis. Morphine generally increases smooth muscle tone, especially the sphincters of the gastro-intestinal and biliary tracts.
5.2. Pharmacokinetic Properties
The majority of a dose of morphine is conjugated with glucoronic acid in the liver and gut to produce morphine-3-glucoronide and morphine-6-glucoronide, the latter of which is considered the active metabolite. Morphine-3-glucuronide, however, is thought to antagonise the effect of morphine-6-glucoronide. Morphine is distributed throughout the body, but is mainly found in the kidneys, liver lungs and spleen. Morphine also crosses the placenta and follows a similar distribution pattern in neonates. The mean elimination halflife for morphine is 3 hours. Morphine is bound to plasma proteins only to the extent of 25 - 35%, therefore factors that change the extent of protein binding will only have a minor effect. Approximately 60% of morphine is excreted in urine after 24 hours, of which a small proportion is free morphine (higher alkali urine) and about 60-70% ins conjugated. Up to 10% of the dose may eventually be excreted as conjugates through bile and faeces.
Morphine is also excreted in trace amounts in sweat and at levels generally less than 1% of any dose in breast milk.
5.3. Preclinical Safety Data
There are no pre-clinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Sodium Chloride Water for Injections Sulphuric acid Nitrogen
6.2.
Incompatibilities
Morphine salts are sensitive to changes in pH and morphine is liable to precipitate in an alkaline environment. Compounds incompatible with morphine salts include aminophylline and sodium salts of barbiturates and phenytoin. Other incompatibilities, sometimes attributed to particular formulations have included:.
Acyclovir sodium: precipitate noted two hours after admixture with morphine sulphate solution.
Chlorpromazine hydrochloride injection: precipitation was considered to be due to chlorocresol present in the morphine sulphate injection.
Fluorouracil: Immediate precipitate formed after admixture of fluorouracil (1-16mg/ml) with morphine sulphate (1mg/ml) in dextrose 5% or sodium chloride 0.9%.
Furosemide: precipitate noted one hour after admixture with morphine sulphate solution.
Heparin sodium: incompatibility has been reported from straightforward additive studies. More recent studies indicate that morphine sulphate and heparin sodium were only incompatible at morphine sulphate concentrations greater than 5mg per ml and that this incompatibility could be prevented by using 0.1% sodium Metabisulphite solution as the admixture diluent rather than water.
Pethidine hydrochloride: incompatibility has been noted following admixture with morphine sulphate.
Prochlorperazine edisylate: immediate precipitation was attributed to phenol in the morphine sulphate injection formulation.
Promethazine hydrochloride: cloudiness was reported to develop when 2.5mg of promethazine hydrochloride was drawn into a syringe containing morphine sulphate 8mg. Others have noted no incompatibility.
Tetracyclines: colour change from pale yellow to light green occurred when solutions of minocycline hydrochloride or tetracycline hydrochloride were mixed with morphine sulphate in 5% glucose injection.
Oral formulations: there was no evidence of incompatibility in an oral morphine mixture containing methyl and propyl hydroxybenzoates as preservatives.
6.3 Shelf life
24 Months (50ml Plastic Syringe)
18 Months (10 ml Glass Syringe)
6.4. Special Precautions for Storage
Do not store above 25°C. Keep the syringe in the outer carton.
6.5. Nature and Contents of Container
Sterile aqueous solution for injection in borosilicate glass (type I) 5ml and 10ml pre-filled syringes with a chlorobutyl elastomer syringe piston. Also available as a cyclo-olefin copolymer plastic 50ml pre-filled syringe with a halobutyl elastomer piston and tip cap.
6.6. Instruction for Use/Handling
For Single Dose Use Only. Discard any unused solution immediately and safely after initial use.
7. Marketing Authorisation Holder
Aurum Pharmaceuticals Ltd
Trading as Martindale Pharma
Bampton Road
Harold Hill
Romford
Essex
RM3 8UG
United Kingdom
8. Marketing Authorisation Number
12064/0102
9. Date of First Authorisation/Renewal of Authorisation
12th October 2004
10
DATE OF REVISION OF THE TEXT
19/05/2009