This information is intended for use by health professionals

1. Name of the medicinal product

Morphine Sulfate Injection BP 2mg/ml

2. Qualitative and quantitative composition

Morphine Sulfate BP

0.2 % w/v

Sodium Chloride BP

0.9 % w/v

Water for Injections BP

To

1ml

3. Pharmaceutical form

Sterile solution for Injection containing 2mg/ml Morphine Sulfate BP in a clear glass

( Type 1 ) vial of 50 and 100ml.

4. Clinical particulars
4.1 Therapeutic indications

Morphine Sulfate Injection BP 2mg/ml is indicated for the relief of both acute and chronic severe pain, where continuous analgesia is required over several days following major surgical procedures, by Patient Controlled Analgesia (PCA).

4.2 Posology and method of administration

The product should not be diluted before use.

For Adults

By slow intravenous injection in Patient Controlled Analgesia (PCA)

The dose and dosage regimen depends on the severity of the pain and should be titrated against the individual patient requirements. A typical loading dose, dose range and lock out time for a 70kg adult (Dollery - Therapeutic Drugs) is:- Loading dose - 5-15mg over 30 minutes then 2.5- 5.0mg every hour with a lock out time of 5-10 minutes

In the Elderly

The dose of morphine should be reduced in the elderly patient 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 Sulfate 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 warnings 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 Interaction with other medicinal 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 activites of other compounds.

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 and Metoclopramide: 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).

4.6 Fertility, pregnancy and lactation

Morphine Sulfate should be given with great care during pregnancy and whilst breast feeding. The administration of morphine during labour may cause respiratory depression in the new-born 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.

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

Side effects associated with parenteral Morphine by PCA administration are dose related, in several small clinical studies* the following percentage incidence were found :

Constipation 13 - 70%, Sedation 51%, Mental clouding 6-41%, Dry mouth 20-33%, Respiratory depression 1-18%, Hallucinations 15%, Dizziness 2-3%, Nausea & vomiting 13-57%, Drowsiness 20%, Itching 6-28%, Accommodation problems 13%, Sedation 13-69%, Fever 29%, Muscle spasms 7%, Urinary retention 52%.

Other side effects include slow heart beat, palpitations, cold sensation, restlessness and mood changes. Raised intracranial pressure rarely occurs in patients. The euphoric activity of morphine and similar compounds has led to their abuse.

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. Anaphylactic reactions following intravenous injection have been reported.

Continuous Intravenous Morphine Infusions for Terminal Pain Control: a retrospective review - G J Stuart et al

Drug Intelligence & Clinical Pharmacy 1986, v.20, pp 969-972

Patient Controlled Analgesia with Extradural Morphine or Pethidine -S.Sjostrom et al BR. J. Anaesth 1988, 60, 358-66

Patient Controlled Analgesia. R K Parker et al Jama 1991 v.226 no.14 1947-1952

An Evaluation of Morphine and Oxymorphone Administered via PCA or PCA Basal Infusion in Postcesarean- Delivery Patients R. Sinatra et al Anaesthesiology 1989, 71,pp 502-507

Patient-Controlled Analgesia: a randomised, prospective

Comparison between two commercially available PCA pumps and conventional analgesic therapy for post operative pain. B R Hecker et al Pain 1988, 35, 115-120

IV Infusion of Opioids for Cancer Patients Clinical Review and Guidelines for Use - R K Portenoy et al Cancer Treatment Reports 1986, 70, 575-581

4.9 Overdose

Signs of morphine toxicity and overdosage include pinpoint pupils, respiratory depression, and hypotension. Circulatory failure and deepening coma may occur in more severe cases

Treatment of Morphine Overdosage

In the treatment of known or suspected opioid overdosage, an initial dose of naloxone hydrochloride 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 overdosage 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 0.1 to 0.2mg to avoid precipitating withdrawal symptoms.

In children, the usual antagonism, an intravenous infusion of naloxone hydrochloride has been (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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Morphine, a phenanthrene derivative and the principal alkaloid of opium, is an opioid analgesic with agonist activity at μ opioid receptors and, to a lesser extent, κ receptors. It acts mainly 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

There have been many studies on the pharmacokinetics of morphine following administration by various routes and methods. They include administration by the buccal route, controlled-release oral preparations, the rectal route, continuous subcutaneous compared with intravenous infusion, and the intraspinal route.

Osborne et al studied the pharmacokinetics of morphine administered by 5 different routes - intravenous bolus injection and oral, sublingual, buccal, and sustained-release buccal tablets - with particular reference to morphine-6-glucuronide, the active metabolite. This metabolite occurred in large quantities after intravenous administration and plasma concentrations rapidly exceeded those of morphine.

L.E. Mather studied and produced the following pharmacokinetic data for parenteral morphine.

Plasma Binding = 35%

Blood/Plasma Concentration ratio = 1.1

Total Body Clearance = 0.9-1.5 e/ml

Apparent volume of Distribution = 100-300 l

Elimination shelf life = 1.4-4.0 h

5.3 Preclinical safety data

There are no pre-clinical 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 BP

Water for Injections BP

6.2 Incompatibilities

Morphine salts are sensitive to changes in pH and morphine is liable to be precipitated out of solution 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 sulfate solution;

Chlorpromazine hydrochloride injection - precipitation was considered to be due to chlorocresol present in the morphine sulfate injection;

Frusemide - precipitate noted one hour after admixture with morphine sulfate solution;

Heparin sodium - incompatibility has been reported from straightforward additive studies. More recent study indicated that morphine sulfate and heparin sodium were only incompatible at morphine sulfate concentrations greater than 5mg per ml and that this incompatibility could be prevented by using 0.9% sodium chloride solution as the admixture diluent rather than water;

Pethidine hydrochloride - incompatibility has been noted following admixture with morphine sulfate.

Prochlorperazine edisylate - immediate precipitation was attributed to phenol in the morphine sulfate injection formulation.

Promethazine hydrochloride - cloudiness was reported to develop when 2.5mg of promethazine hydrochloride was drawn into a syringe containing morphine sulfate 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 sulfate 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

6.4 Special precautions for storage

Store below 25°C. Protect from light

6.5 Nature and contents of container

Type 1 glass vial with halobutyl rubber stoppers and aluminium overseal.

50 and 100ml solution containing 2mg/ml of Morphine Sulfate BP

6.6 Special precautions for disposal and other handling

For single dose use only. Not for multidose use. The product should be used immediately the integrity of the rubber septum is breached. Any solution remaining at the end of the session should be discarded or returned to the pharmacy.

7. Marketing authorisation holder

Aurum Pharmaceuticals Ltd

Bampton Road

Harold Hill

Romford

Essex

RM3 8UG

United Kingdom

8. Marketing authorisation number(s)

PL 12064/0008

9. Date of first authorisation/renewal of the authorisation

21/05/1996

10. Date of revision of the text

09/05/2014