Confidential

South Devon Healthcare NHS Foundation Trust

Summary of Product Characteristics

Morphine Sulfate Injection 1mg/ml

1. Trade name of the medicinal product

Morphine Sulfate Injection 1mg/ml

2.    Qualitative and quantitative composition

Morphine Sulfate BP 1mg/ml.

3.    PHARMACEUTICAL FORM

Solution for injection.

4. Clinical Particulars

4.1. Therapeutic Indications

Morphine Sulfate Injection is indicated for the relief of moderate to severe pain. Morphine is used especially in pain associated with cancer, myocardial infarction and surgery. Morphine also helps to relieve the anxiety and insomnia which may be associated with severe pain.

4.2. Posology and method of administration

Adults and children over 12 years:

Morphine Sulfate Injection is formulated for use by the intravenous route in Patient Controlled Analgesia (PCA) systems. PCA, which permits adjustment of dosage according to the patient’s individual needs, must only be carried out in departments and by staff who are trained and have experience of the system. Patient selection for the use of PCA must ensure that the patient is capable of understanding and following the instructions of the medical/nursing staff. The specific department or unit protocols must be covered to ensure aseptic transfer of the contents of the vial to the PCA system.

There is a considerable variation in analgesic requirements among patients and therefore individualised treatment strategies are required. Dosage should be based on the severity of the pain and the response and opiate tolerance of the patient.

Loading dose

Loading doses of typically between 1mg and 10mg (maximum 15mg) of morphine sulfate may be given by intravenous infusion over four or five minutes. The loading dose used will depend upon the patient’s diagnosis and condition.

PCA demand dose

An initial demand dose of 1mg Morphine Sulfate Injection with a lockout period of 5 to 10 minutes is recommended. Dosages may vary depending on the loading dose, the

tolerance and condition of the patient, and whether a background infusion of morphine sulfate is being given.

The patient should be specifically monitored for pain, sedation and respiratory rate during the first few hours of treatment to ensure that the dosage regimen is suitable.

The duration of treatment should be kept to a minimum, although dependence and tolerance are not generally a problem when morphine is used legitimately in patients with opioid-sensitive pain.

Use in children:

Not recommended for children under 12 years.

Use in the elderly:

Morphine doses need to be reduced in elderly patients.

4.3. Contra-indications

Morphine Sulfate Injection should not be given to patients with known hypersensitivity to morphine or other opioid preparations. Use of Morphine Sulfate Injection is also contra-indicated in patients with respiratory depression; obstructive airways disease; excessive bronchial secretions; during a bronchial asthma attack or in heart failure secondary to chronic lung disease; head injury; raised intra-cranial pressure; coma; convulsion disorders; ulcerative colitis; in presence of a risk of paralytic ileus; biliary and renal tract spasm and acute alcoholism; phaeochromocytoma.

Morphine Sulfate Injection should not be given to patients with moderate to severe renal impairment (glomerular filtration rate <20ml/min) or with severe or acute liver failure.

Morphine Sulfate Injection is contra-indicated in patients receiving monoamine oxidase inhibitors or within two weeks of discontinuing such treatment. Use of Morphine Sulfate Injection during pregnancy or lactation is not recommended.

4.4. Special warnings and precautions for use

As with other narcotics, a dose reduction may be appropriate in elderly patients, in patients with hypothyroidism, renal and chronic hepatic disease.

Morphine Sulfate Injection should be used with caution in debilitated patients and those with adrenocortical insufficiency; hypopituitarism; prostatic hypertrophy; shock; diabetes mellitus; diseases of the biliary tract; myasthenia gravis; cardiac arrhythmias; excessive obesity; hypotension and severe cardiac failure. It should also be used with caution post-operatively following total joint arthroplasty (colonic pseudo-obstruction).

Although the dependence potential is low when morphine is used legitimately for pain relief, physical and psychological dependence and tolerance may occur in susceptible individuals. Abrupt cessation of therapy after prolonged use may result in withdrawal symptoms.

4.5. Interactions with other Medicaments and other forms of Interaction

Concomitant or recent use of monoamine oxidase inhibitors with morphine is contraindicated since interactions have been reported, resulting in CNS excitation or depression with hyper- or hypotensive crises.

The CNS depressant effects of morphine are increased by the co-administration of CNS depressants including alcohol, anaesthetics, muscle relaxants, hypnotics sedatives, tricyclics, neuroleptics and phenothiazines. Hyperpyrexia and CNS toxicity may result from an opiate selegiline combination. Such combinations should, therefore, be used with extreme caution.

Combined with alcohol, antidepressants and antipsychotics the hypotensive effect of morphine may be enhanced.

The analgesic effects of opioids tend to be enhanced by the concomitant administration of dexamphetamine, hydroxyzine and some phenothiazines (although the latter may also cause respiratory depression). Morphine may reduce the efficacy of diuretics by inducing the release of the antiduretic hormone. The combination of morphine with anticholinergics may enhance the constipatory effect and urinary retention.

Cimetidine and rantidine appear to interfere with the metabolism of morphine and the metabolism and excretion of morphine may be inhibited by disulfiram. Increased morphine levels may result from the co-administration of cisapride. Metoclopramide and domperidone may antagonise morphine’s gastrointestinal effects and metoclopramide enhances it sedative effect. Ciprofloxacin concentration may be reduced and mexiletine absorption delayed by co-administered opiate. Animal data suggest that propranolol may increase the toxicity of opioids. Animal data suggest that propranolol may increase the toxicity of opioids. Ritonavir can induce the formation of metabolising enzymes made in the liver and can cause increased metabolism of morphine sulfate which can reduce the clinical efficacy of the analgesic.

Co-administration of morphine sulfate with esmolol results in a slight increase in the esmolol levels, but the clinical implications of this increase are not considered very significant.

4.6.    Pregnancy and lactation

There is inadequate evidence on the safety of morphine in human pregnancy nor is there evidence from animal work that morphine is free from hazard. Morphine Sulfate Injection is not, therefore, recommended for use in pregnancy.

Morphine has been shown to suppress lactation, although morphine is secreted in breast milk and may cause respiratory depression in the infant.

4.7.    Effects on ability to drive and use machines

Morphine may modify the patient’s reactions to a varying extent depending on the dosage and individual susceptibility. Ambulatory patients should be warned not to use machines. 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

The side-effects most commonly seen with morphine and other opioids are respiratory depression, nausea, vomiting, constipation, drowsiness and confusion. With long term use these symptoms generally lessen, although constipation frequently persists.

The following adverse events are from published literature and frequencies are not known.

Psychiatric disorders

Restlessness, mood changes, hallucinations, delirium, disorientation, excitation, agitation, sleep disturbance.

Nervous system disorders

Headache, vertigo, euphoria, dysphoria, dizziness, taste disturbances, seizures, paraesthesia, raised intracranial pressure.

Endocrine

Long term use of opioid analgesics can cause adrenal insufficiency. Exacerbation of pancreatitis.

Eye disorders

Visual disturbances, nystagmus, miosis.

Ear and Labyrinth disorders Vertigo.

Cardiac disorders

Bradycardia, tachycardia, palpitations, hypotension, hypertension, syncope.

Vascular disorders

Orthostatic hypotension, facial flushing, oedema.

Gastrointestinal disorders

Dyspepsia, paralytic ileus, abdominal pain, anorexia.

Hepatobiliary disorders Biliary spasm.

Immune system disorders

Anaphylactic reactions to morphine have been reported rarely.

Musculoskeletal, connective tissue and bone disorder

Muscle fasciculation, myoclonus, rhabdomyolysis, muscle rigidity.

Renal and urinary disorders

Difficult micturition, ureteric spasm, urinary retention.

Reproduction and sexual disorders

Long term use of opioid analgesics can cause hypogonadism in both men and women. This can lead to amenorrhoea, reduced libido, infertility, depression and erectile dysfunction.

Respiratory disorders

Bronchospasm (in association with anaphylaxis), inhibition of cough reflex.

Skin and subcutaneous tissue disorders Rashes, urticaria, pruritus.

General disorders and administration site conditions

Dry mouth, sweating, hypothermia, malaise, asthenia, pain and irritation at the injection site.

Long Term Use

Long term use of opioid analgesics has been associated with a state of abnormal pain sensitivity (hyperalgesia).

Tolerance and psychological and physical dependence may occur. Decreased potency may be experienced.

High doses may produce respiratory depression and hypotension, with deepening coma. Convulsions may occur particularly in infants.

4.9. Overdose

Signs:

The signs of morphine overdosage consist of pin-point pupils, respiratory depression, and hypotension. Circulatory failure and deepening coma may develop in severe cases and death may ensue. Less severe cases may be manifest by nausea, vomiting, tremor, dysphoria, hypothermia, hypotension, confusion and sedation. Rhabdomyolysis progressing to renal failure can also be a consequence of overdosage.

Treatment:

It is vital to maintain and support respiration and circulation. The specific opioid antagonist naloxone should be employed for the reversal of coma and restoration of spontaneous respiration. 400 micrograms of naloxone should be administered intravenously, repeated at 2-3 minute intervals as necessary up to a maximum dose of 10mg.

5. Pharmacological Properties

5.1. Pharmacodynamic properties

Morphine acts as a competitive agonist at opiate receptors in the CNS, particularly mu and to a lesser extent kappa receptors. Activity at the mu-1 subtype receptor is thought to mediate analgesia, euphoria and dependence whilst activity at the mu-2 receptor is thought to be responsible for respiratory depression and inhibition of gut motility. Action at the kappa receptor may mediate spinal analgesia. The analgesic action of morphine is effective at several spinal and supraspinal sites.

5.2. Pharmacokinetic properties

Onset of action is rapid following parenteral administration of morphine with peak analgesic effect occurring within 20 minutes via the intravenous route.

Morphine is widely distributed in the body, with an apparent volume of distribution of 2-3 lkg^-1. Due to its relatively hydrophilic nature, morphine does not readily cross the blood-brain barrier although it is detectable in the cerebrospinal fluid.

Morphine is extensively metabolised by the liver. Renal glucuronidation also takes place. The major metabolite, quantitatively, is morphine-3-glucuronide although morphine-6-glucuronide is significant in terms of potency.

The metabolites are excreted mainly via the renal route.

5.3. Preclinical safety data

The toxicological profile of morphine in animals has not been systematically identified as a result of its established widespread clinical use. Recent animal studies have confirmed some targets for morphine toxicity. A nephrotoxic action has been reported in rats following subcutaneous administration of relatively high levels (up to 96mg/kg) of morphine. Adverse effects of morphine on development of the foetus and newborn have been confirmed in rats and mice. Morphine has been shown to reduce the release of LH from the pituitary causing reductions in serum testosterone levels, reduction in the weight of secondary sex organs and reductions in spermatogenic cell populations. The adverse effects of morphine sulfate in both males and females are consistent with recent findings that morphine exhibits significant genotoxic actions in several in vivo test systems. Immunotoxicity associated with morphine treatment has been reported in animal tests for several parameters which provide possible mechanisms for decreased resistance to a range of infections. Evidence suggests that part of this effect may be mediated via release of endogenous corticosterone.

6. Pharmaceutical Particulars

List of excipients

Sodium chloride

Water for Injections EP

6.2.    Incompatibilities

Morphine Sulfate Injection should not be mixed with other preparations.

Morphine salts are incompatible with aminophylline, sodium salts of barbiturates and phenytoin, aciclovir sodium, frusemide, heparin sodium, pethidine HCl, prochlorperazine edisylate and promethazine HCl.

6.3.    Shelf life

2 years.

6.4. Special precautions for storage

Keep away from light. Store below 25°C.

6.5.    Nature and contents of container

Clear glass ampoules of 1ml, 5ml and 10ml volumes or vials of 50ml volume, with bromobutyl rubber stoppers and tamper-evident aluminium caps.

6.6.    Instruction for use/handling and disposal

Morphine Sulfate Injection is for use as presented (1mg ml ^-1) in IV PCA devices.

7.    MARKETING AUTHORISATION HOLDER

South Devon Healthcare NHS Foundation Trust

Torbay PMU

Long Road

Paignton

Devon

TQ47TW

United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 13079/0001.

9. Date of first authorisation/renewal of authorisation

16/06/1998 / 16/06/2003

10 DATE OF REVISION OF THE TEXT

24/04/2014