This information is intended for use by health professionals

1. Name of the medicinal product

Morphine Sulfate 2mg/ml Solution for Injection

2. Qualitative and quantitative composition

Each ml of sterile solution for injection contains 2mg of Morphine sulfate

Excipient with known effect

Also contains 3.54mg of sodium per ml

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Sterile solution for Injection

Clear,colourless solution and visibly free from particles.

4. Clinical particulars
4.1 Therapeutic indications

Morphine Sulfate Injection 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

Posology

Adults and Children over 12 years

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 for a 70kg adult is: - Loading dose - 5-15mg over 30 minutes then 2.5- 5.0mg every hour

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.

Renal impairment

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.

Hepatic impairment

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.

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore, the dose should be gradually reduced prior to discontinuation.

Method of administration

By slow intravenous injection in Patient Controlled Analgesia (PCA)

The product should not be diluted before use.

4.3 Contraindications

Hypersensitivity to morphine sulfate, other opioid preparations or to any of the excipients listed in section 6.1

Use of Morphine Sulfate Solution for Injection is contra-indicated in patients with respiratory depression, coma, obstructive airways disease, excessive bronchial secretions; during a bronchial asthma attack or in heart failure secondary to chronic lung disease; ulcerative colitis; in presence of a risk of paralytic ileus; biliary and renal tract spasm, phaeochromocytoma, acute abdomen, 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.

Morphine Sulfate Solution for 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.

Use of Morphine Solution for Sulfate Injection during a 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 Solution for 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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Morphine Sulfate 2mg/ml Solution for Injection and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Morphine Sulfate 2mg/ml Solution for Injection concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

ACS symptoms is warranted. Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Decreased Sex Hormones and Increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea

Hyperalgesia that does not respond to a further dose increase of morphine may occur in particular in high doses. A morphine dose reduction or change in opioid may be required.

Morphine has an abuse potential similar to other strong agonist opioids and should be used with particular caution in patients with a history of alcohol or drug abuse.

Dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. The risk increases with the time the drug is used, and with higher doses. Symptoms can be minimised with adjustments of dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8.

This medicinal product contains 3.54 mg sodium per ml equivalent to 0.18 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products 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 its 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. 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.

Both anti-psychotics and morphine sulfate have sedative effects, which can be additive when co-administered.

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.

Sedative medicines such as benzodiazepines or related drugs:

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Pregnancy

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 Solution for Injection is therefore, not recommended for use in pregnancy.

Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal withdrawal (abstinence) syndrome. Treatment may include an opioid and supportive care.

Lactation

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

Fertility

Animal studies have shown that morphine may reduce fertility (see section 5.3.).

4.7 Effects on ability to drive and use machines

Morphine may cause drowsiness and patients should not drive or operate machinery.

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 effects are from published literature and frequencies are not known.

Psychiatric disorders

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

Nervous system disorders

Headache, vertigo, euphoria, dsyphoria, dizziness, taste disturbances, seizures, paraesthesia, raised intracranial pressure, allodynia, hyperalgesia (see section 4.4), hyperhidrosis.

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, dry mouth.

Hepatobiliary disorders

Biliary spasm.

Immune system disorders

Anaphylactic reactions to morphine have been reported rarely, anaphylactoid reactions.

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.

Description of selected adverse reactions

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued, or opioid antagonists administered or can sometimes be experienced between doses. For management, see 4.4.

Physiological withdrawal symptoms include: Body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis. Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms :

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

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.

Management

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. 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Natural opium alkaloids,

ATC Code: N02AA

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 2-3Lkg-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.

In male rats, reduced fertility and chromosomal damage in gametes have been reported.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium Chloride

Water for Injections

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.

Physicochemical incompatibility (formation of precipitates) has been demonstrated between solutions of morphine sulfate and 5- fluorouracil.

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store below 25oC.

Keep the vials in the outer carton in order to protect from light.

6.5 Nature and contents of container

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

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

6.6 Special precautions for disposal and other handling

Morphine Sulfate Solution for Injection is for use as presented (2mg/mL) in IV PCA devices.

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

17/04/2019