MORPHINE SULFATE INJECTION BP MINIJET 1 MG / ML, MORPHINE SULFATE INJECTION BP RAPIJECT 1 MG / ML - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Morphine Sulfate Injection BP Minijet™

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Morphine Sulfate 1mg/ml

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Sterile aqueous solution for intravenous, intramuscular or subcutaneous injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For intravenous, intramuscular or subcutaneous injection.

For the relief of moderate to severe pain such as in myocardial infarction, severe injuries, neoplastic disease, surgery, renal colic, terminal disease and other conditions where non-narcotic analgesia has failed.

Morphine is effective in the control of post-operative pain and anxiety.

Morphine may be used for its sedative effect in the management of the severe dyspnoea in terminal lung cancer or other terminal respiratory disease.

Morphine should be used as a sedative or hypnotic generally only when pain relief and sedation are required. It is used in pre-anaesthetic medication for surgery, where it reduces anxiety and also the amount of anaesthetic required.

For open-heart surgery, especially in high risk patients with cardiac disease, morphine may be used to produce anaesthesia.

4.2 Posology and method of administration

The dose and dosing regimen should be tailored to the individual patient’s needs.

Adults and children over 12 years:

Intramuscular or subcutaneous administration

5–20 mg every 4 hours as necessary, dependent upon the patient’s response and cause of pain.

For the relief of pain and as pre-anaesthetic, the usual dose is 10mg every 4 hours depending on the severity of the condition and the patient’s response. The usual individual dose range is 5–15mg. The usual daily dose range is 12–120mg.

Acute pain:

2 to 15mg by slow intravenous injection.

or

Loading dose as above, followed by 2.5 – 5mg every hour by infusion. If using Patient Controlled Analgesia (PCA), bolus doses of 1 – 2mg may be given with a lock out of 5 – 20 minutes. A commonly applied dose limit used in PCA is 30mg in 4 hours, although some patients may require higher doses.

or

Frequent small doses ( eg 1 –3 mg every 5 minutes) reaching a maximum cumulative dose of 2 – 3mg/kg. (This is the preferred regimen for patients with myocardial infarction.)

Chronic pain:

Loading doses of 15mg or more. Maintenance doses for infusion are in the range 0.8 –80mg/hour, although higher maintenance doses of 150–200mg/hour may be required.

Open heart surgery

Large doses (0.5 – 3mg/kg) may be administered intravenously by slow continuous infusion as the sole anaesthetic agent.

Morphine should be administered with caution in the elderly and a reduced starting dose titrated to provide optimal pain relief.

Children under 12 years:

Intramuscular or subcutaneous administration:

Up to 6 months          :      up to 10mcg/kg/hour with respiratory support. Bolus

injection to be avoided.

6 months – 12 years      :       10–30mcg/kg/hour. A loading dose of 100–

200mcg/kg may be given initially with bolus top-up doses of 50–100mcg/kg every 4 hours.

6 months – 12 years :       30–60mcg/kg/hour. For the relief of pain in terminal

disease.

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

4.3 Contraindi­cations

Morphine is contraindicated in patients with obstructive airways disease; respiratory depression; known morphine sensitivity; sensitivity to any of the other ingredients; head injuries; coma; convulsive disorders and raised intracranial pressure; biliary colic; acute alcoholism; cerebral oedema; concurrent treatment with monoamine oxidase inhibitors or within two weeks of their discontinuation of treatment with them; phaeochromocytoma, those at risk of paralytic ileus and in patients with acute diarrhoea caused by poisoning or invasive pathogens.

4.4 Special warnings and precautions for use

Morphine is a potent medicine but with considerable potential for harmful effect, including addiction. It should be used only if other drugs with fewer hazards are inadequate, and with the recognition that it may possibly mask significant manifestations of disease which should be identified for proper diagnosis and treatment. It should be used with special caution in patients with a history of drug abuse. Dependence may occur after 1–2 weeks of treatment.

Morphine should be given with caution where there is a reduced respiratory reserve e.g. in conditions including but not restricted to the following: emphysema, asthma, chronic cor pulmonale, kyphoscoliosis, excessive obesity and sleep apnoea. Opiates should also be used cautiously in patients with cardiac arrhythmias, myasthenia gravis or inflammatory or obstructive bowel disorders.

Morphine should be administered with caution or in reduced doses to patients with hypotension, hypothyroidism, adrenocortical insufficiency, impaired kidney or liver function, prostatic hypertrophy, urethral stricture or shock. Morphine should be given with great care to infants, especially neonates. Dosage should be reduced in elderly and debilitated patients.

Disappearance of opioid analgesic effects, particularly when associated with an unexplained increase in pain, may indicate the development of tolerance or opioid-induced hyperalgesia. An unexplained increase in abdominal pain associated with disturbed intestinal motility, symptoms of constipation, bloating, abdominal distension and increased gastroesophageal reflux during treatment with morphine sulfate, may indicate the development of opioid-induced bowel dysfunction or narcotic bowel syndrome. In such situations consider the use of alternative analgesics and a morphine detoxification.

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.

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

Concomitant use of morphine sulfate 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 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).

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.

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.

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).

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.

4.5 Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors markedly potentiate the action of morphine; morphine should not be administered to patients receiving monoamine oxidase inhibitors (see section 4.3).

Sedative medicines such as benzodiazepines or related drugs:

The sedative effects of morphine may be potentiated and prolonged by central nervous system depressants such as alcohol, anaesthetics, analgesics, antihistamines, barbiturates, narcotics, phenothiazines, sedatives, anxiolytics, hypnotics and tricyclic antidepressants. 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).

Chlorpromazine and some other phenothiazines appear to enhance the sedative action but diminish the analgesic effect of morphine. The use of tricyclic antidepressants, aspirin and other NSAIDs may increase the extent of pain relief of morphine. They also increase the risks of adverse effects.

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

Morphine Sulfate should not be used for pre-medication when ciprofloxacin is given for surgical prophylaxis as serum levels of ciprofloxacin are reduced and adequate cover may not be obtained during surgery

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.

4.6 Fertility, pregnancy and lactation

Fertility

Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).

Pregnancy

There is inadequate evidence of safety in human pregnancy. Morphine is known to cross the placenta and it may cause respiratory depression by this route. It is not advised to administer morphine during pregnancy or during labour. It may reduce uterine contractions, cause respiratory depression in the foetus and neonate, and may have significant effects on the foetal heart rate. 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.

The amount of morphine secreted in breast milk after a single-dose administration seems to be compatible with breast feeding and insufficient to cause major problems or dependence. However long-term treatment with morphine in high doses may cause significant plasma concentration. That is why, caution is advised on the use of morphine in breast-feeding patient and the benefit must outweigh the risk to the infant. If breast feeding is continued, the infant should be observed for possible adverse effects.

4.7 Effects on ability to drive and use machines

Morphine may cause drowsiness. Patients receiving morphine 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

Allodynia (frequency not known), coma, convulsion, drowsiness, headache, increased intracranial pressure, myoclonus, opioid-induced hyperalgesia (or hyperaesthesia) (see section 4.4, frequency not known), vertigo, hyperhidrosis (frequency not known)

confusional state, decreased libido, hallucinations, mood swings, physical and psychological dependence (frequency not known), restlessness

blurred vision, miosis, nystagmus

bronchospasm, pulmonary oedema, which can lead to death, respiratory depression, respiratory failure, which also can lead to death

bradycardia, circulatory failure, palpitations, tachycardia

hypotension, orthostatic hypotension

dry mouth (frequency not known), constipation, intestinal functional disorder, paralytic ileus, narcotic bowel syndrome, nausea, vomiting

biliary spasm, hepatic enzyme increase, spasm of the sphincter of Oddi,

Reproductive system and breast disorders: erectile dysfunction

renal failure, urethral spasm, urinary retention

anaphylactic reaction, anaphylactoid reaction (frequency not known), hypersensitivity

muscle rigidity, rhabdomyolysis

angioedema, contact dermatitis, pruritus, rash, urticaria

5   PHARMACOLOGICAL PROPERTIES

6.1 List of excipients

Disodium edetate

Sulphuric acid (1M; pH adjustment)

Water for Injection

6.2 Incompati­bilities

Morphine salts may be precipitated in alkaline solution. Compatibility should be checked before admixture with other drugs.

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

6.3

Shelf life

24 months

6.4 Special precautions for storage

Do not store above 25°C. Protect from light.

6.5 Nature and contents of container

The solution is contained in a Type I USP glass vial with a rubber closure which meets all the relevant USP specifications for elastomeric closures.

The following volumes are available:

Morphine Sulfate Injection 1mg/ml: 2ml (Minijet™)

10ml (Minijet™)

6.6 Special precautions for disposal

The 2ml and 10ml containers are designed for use with the IMS MinijetTM injector.

The 50ml container is designed for use with a syringe driver.

7 MARKETING AUTHORISATION HOLDER

International Medication Systems (UK) Limited

First Floor, Templeback

10 Temple Back

Bristol

United Kingdom

BS1 6FL

8 MARKETING AUTHORISATION NUMBER(S)

PL 03265/0037

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/1978