4.1. Therapeutic indications

Morphine is used for the symptomatic relief of severe pain; relief of dyspnoea of left ventricular failure and pulmonary oedema; pre-operative use.

4.2. Posology and method of administration

Posology

Adults

The dosage should be based on the severity of the pain and the response and tolerance of the patient. The usual adult subcutaneous or intramuscular dose is 10 mg every 4 hours if necessary, but may range from 5 mg to 20 mg.

The usual adult intravenous dose is 2.5 mg to 15 mg not more than 4 hourly, where necessary, but dosage and dosing interval must be titrated against the patient's response and adjustments made until analgesia is achieved.

Elderly

Because of the depressant effect on respiration, caution is necessary when giving morphine to the elderly. A reduction of dose is advisable.

Paediatric Population

Not recommended for children under 6 years

For children 6 -12 years (after risk/benefit assessment)

5 - 10 mg by subcutaneous or intramuscular routes only

Hepatic impairment:

A reduction in dosage should be considered in hepatic impairment.

Renal impairment:

The dosage should be reduced in moderate to severe renal impairment.

For concomitant illnesses/conditions where dose reduction may be appropriate see section 4.4

Method of administration

By intramuscular, subcutaneous or intravenous injection.

The subcutaneous route is not suitable for oedematous patients.

The epidural or intrathecal routes must not be used as the product contains a preservative.

Treatment goals and discontinuation

Before initiating treatment with Morphine Sulfate Solution for Injection, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with Morphine Sulfate Solution for Injection it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Duration of treatment

Morphine Sulfate Solution for Injection should not be used longer than necessary.

4.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Acute respiratory depression

• Asthma attack or Chronic Obstructive Airways Disease

• Acute alcoholism

• Biliary colic (see section 4.4)

• Head injuries, comatose patients or increased intracranial pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.

• Heart failure secondary to lung disease

• Monoamine oxidase inhibitors (including moclobemide), or within two weeks of their withdrawal

• Risk of paralytic ileus

• Phaeochromocytoma (due to the risk of pressor response to histamine release).

• Acute diarrhoeal conditions associated with antibiotic-induced pseudomembranous colitis or diarrhoea caused by poisoning (until the toxic material has been eliminated)

4.4. Special warnings and precautions for use

Repeated use can cause tolerance and dependence. Caution in use should be exercised and a reduction in dose may be advisable in the elderly and in the following cases:

• Hypotension

• Hypothyroidism

• Depressed respiratory reserve

• Prostatic hypertrophy

• Hepatic or renal impairment (avoid or reduce dose)

• Convulsive disorders

• Asthma (avoid during attack)

• Adrenocortical insufficiency

• Urethral stricture

• Inflammatory or obstructive bowel disorders

Opioids such as morphine should either be avoided in patients with biliary disorders or they should be given with an antispasmodic.

Hepatobiliary disorders

Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis.

Therefore, in patients with biliary tract disorders morphine may exacerbate pain (use in biliary colic is a contraindication, see 4.3).

In patients given morphine after cholecystectomy, biliary pain has been induced.

Palliative care - in the control of pain in terminal illness, these conditions should not necessarily be a deterrent to use.

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

Concomitant use of Morphine Sulfate 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 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)

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.

Opioid Use Disorder (abuse and dependence)

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as Morphine Sulfate Solution for Injection.

Repeated use of Morphine Sulfate Solution for Injection can lead to Opioid Use Disorder (OUD). A higher dose and longer duration of opioid treatment, can increase the risk of developing OUD. Abuse or intentional misuse of Morphine Sulfate Solution for Injection may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (eg. major depression, anxiety and personality disorders).

Before initiating treatment with Morphine Sulfate Solution for Injection and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.

Patients will require monitoring for signs of drug-seeking behavior (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored, and doses of morphine adjusted during and after treatment with rifampicin

Morphine Sulfate Solution for Injection contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

Oral P2Y12 inhibitor antiplatelet therapy

Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Severe cutaneous adverse reactions (SCARs)

Acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, has been reported in association with morphine treatment. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek medical care if they experience such symptoms.

If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn and an alternative treatment considered.

4.5. Interaction with other medicinal products and other forms of interaction

Alcohol: Enhanced sedative and hypertensive effects.

Anti-arrhythmics: There may be delayed absorption of mexiletine.

Antibacterials: The opioid analgesic papaveretum has been shown to reduce plasma ciprofloxacin concentration. The manufacturer of ciprofloxacin advises that premedication with opioid analgesics be avoided.

Antidepressants, anxiolytics, hypnotics: Severe CNS excitation or depression (hypertension or hypotension) has been reported with the concurrent use of pethidine and monoamine oxidase inhibitors (MAOIs) including selegiline, moclobemide and linezolid. As it is possible that a similar interaction may occur with other opioid analgesics, morphine should be used with caution and consideration given to a reduction in dosage in patients receiving MAOIs.

The sedative effects of morphine (opioid analgesics) are enhanced when used with depressants of the central nervous system such as hypnotics, anxiolytics, tricyclic antidepressants and sedating antihistamines.

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquilisers, muscle relaxants, antihypertensives, gabapentin or pregabalin and alcohol. Interactive effects resulting in respiratory depression, hypotension, profound sedation, or coma may result if these drugs are taken in combination with the usual doses of morphine.

Antipsychotics: possible enhanced sedative and hypotensive effect.

Antidiarrhoeal and antiperistaltic agents (such as loperamide and kaolin): concurrent use may increase the risk of severe constipation.

Antimuscarinics: agents such as atropine antagonise morphine-induced respiratory depression and can partially reverse biliary spasm but are additive to the gastrointestinal and urinary tract effects. Consequently, severe constipation and urinary retention may occur during intensive antimuscarinic analgesic therapy.

Metoclopramide and domperidone: There may be antagonism of the gastrointestinal effects of metoclopramide and domperidone.

Oral P2Y12 inhibitor antiplatelet therapy

A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients co-administered morphine and a P2Y12 inhibitor (see section 4.4). In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

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:

Morphine sulfate should only be used when benefit is known to outweigh risk.

As with all drugs it is not advisable to administer morphine during pregnancy.

Morphine crosses the placental barrier. Administration during labour may cause respiratory depression in the new born infant and gastric stasis during labour, increasing the risk of inhalation pneumonia. Therefore, it is not advisable to administer morphine during labour.

Babies born to opioid-dependent mothers may suffer withdrawal symptoms including CNS hyperirritability, gastrointestinal dysfunction, respiratory distress and vague autonomic symptoms including yawning, sneezing, mottling and fever.

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.

Breast-feeding:

While morphine can suppress lactation, the quantity from therapeutic doses that may reach the neonate via breast milk is probably insufficient to cause major problems of dependence or adverse effects.

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 causes drowsiness so patients should avoid driving or operating 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

It was not affecting your ability to drive safely

4.8. Undesirable effects

The most serious hazard of therapy is respiratory depression (see section 4.9).

The commonest side-effects of morphine are

• Nausea

• Vomiting

• Constipation

• Drowsiness

• Dizziness

Tolerance generally develops with long term use, but not to constipation.

Other side effects include the following:

Psychiatric disorders

• Dependence.

Immune system disorders:

• Anaphylactic reactions following intravenous injection have been reported rarely, anaphylactoid reactions.

Cardiac disorders:

• Bradycardia

• Palpitations

• Tachycardia

• Orthostatic hypotension.

Nervous system disorders:

• Myoclonus

• Mental clouding

• Confusion (with large doses)

• Hallucinations

• Headache

• Vertigo

• Mood changes including dysphoria

• Euphoria

• Allodynia

• Hyperalgesia (see section 4.4)

• Hyperhidrosis

Gastrointestinal disorders:

• Dry mouth

• Biliary spasm

• Pancreatitis

Eye disorders:

• Blurred or double vision or other changes in vision

• Miosis

Reproductive system and breast disorders:

• Long term use may lead to a reversible decrease in libido or potency.

• Central sleep apnoea syndrome

Skin and subcutaneous tissue disorders:

• Pruritus

• Urticaria

• Rash

• Sweating.

• Contact dermatitis has been reported and pain and irritation may occur on injection.

• Facial flushing

• Acute generalised exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

• Muscle rigidity

Hepatobiliary disorders

• Spasm of sphincter of Oddi

Renal and urinary disorders:

• Difficulty with micturition

• Ureteric spasm

• Urinary retention

• Antidiuretic effect.

General disorders and administration site conditions :

• Drug withdrawal (abstinence) syndrome

Tolerance develops to the effects of opioids on the bladder.

The euphoric activity of morphine has led to its abuse and physical and psychological dependence may occur (see section 4.4).

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.

Repeated use of Morphine Sulfate Solution for Injection can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 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

Toxic doses vary considerably with the individual, and regular users may tolerate large doses.

The triad of respiratory depression, coma and constricted pupils is considered indicative of opioid overdosage with dilatation of the pupils occurring as hypoxia develops. Death may occur from respiratory failure

Other opioid overdose symptoms include hypothermia, confusion, severe dizziness, severe drowsiness, hypotension, bradycardia, circulatory failure pulmonary oedema, severe nervousness or restlessness, hallucinations, pneumonia aspiration, convulsions (especially in infants and children). Rhabdomyolysis, progressing to renal failure, has been reported in overdosage.

Death may occur from respiratory failure.

Treatment: The medical management of overdose involves prompt administration of the specific opioid antagonist naloxone if coma or bradypnoea are present using one of the recommended dosage regimens. Both respiratory and cardiovascular support should be given where necessary.