Summary of medicine characteristics - MORPHINE SULFATE 30 MG IN 1ML SOLUTION FOR INJECTION
1 NAME OF THE MEDICINAL PRODUCT
Morphine Sulfate 30mg in 1ml Solution for Injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1 ml of solution contains 30 mg of Morphine Sulfate
Excipients with known effect:
Also, contains 2.23 mg of sodium per ml and sodium metabisulphite (E223).
For the full list of excipients, see section 6.1.
Solution for Injection
A clear, colourless or almost colourless, particle free solution
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
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 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.
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.
Morphine can cause an increase in intrabiliary pressure as a result of effects on the sphincter of Oddi. 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.
Abrupt withdrawal from persons physically dependent on them precipitates a withdrawal syndrome, the severity of which depends on the individual, the drug used, the size and frequency of the dose and the duration of drug use. Great caution should be exercised in patients with a known tendency or history of drug abuse
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 1mg/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 1mg/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)
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.
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).
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.
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 coadministered 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.
Anaphylactic reactions following intravenous injection have been reported rarely, anaphylactoid reactions.
Bradycardia
Palpitations
Tachycardia
Orthostatic hypotension.
Myoclonus
Mental clouding
Confusion (with large doses)
Hallucinations
Headache
Vertigo
Mood changes including dysphoria
Euphoria
Allodynia
Hyperalgesia (see section 4.4)
Hyperhidrosis
Dry mouth
Biliary spasm
Blurred or double vision or other changes in vision
Miosis
Long term use may lead to a reversible decrease in libido or potency.
Pruritus
Urticaria
Rash
Sweating.
Contact dermatitis has been reported and pain and irritation may occur on injection.
Facial flushing
Muscle rigidity
Difficulty with micturition
Ureteric spasm
Urinary retention
Antidiuretic effect.
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).
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 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
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Natural opium alkaloids,
ATC Code: N02AA01
Morphine is a narcotic analgesic obtained from opium, which acts mainly on the central nervous system and smooth muscle.
Morphine is a potent analgesic with competitive agonist actions at the preceptor, which is thought to mediate many of its other actions of respiratory depression, euphoria, inhibition of gut motility and physical dependence. It is possible that analgesia, euphoria and dependence may be due to the effects of morphine on a p-1 receptor subtype, while respiratory depression and inhibition of gut motility may be due to actions on a p-2 receptor subtype.
Morphine is also a competitive agonist at the K-receptor that mediates spinal analgesia, miosis and sedation. Morphine has no significant actions at the other two major opioid receptors, the 8– and the o-receptors.
Morphine directly suppresses cough by an effect on the cough centre in the medulla. Morphine also produces nausea and vomiting by directly stimulating the chemoreceptor trigger zone in the area postrema of the medulla. Morphine provokes the release of histamine.
5.2 Pharmacokinetic propertiesAbsorption:
Variably absorbed after oral administration; rapidly absorbed after subcutaneous or intramuscular administration.
Blood concentration: After an oral dose of 10mg as the sulfate, peak serum concentrations of free morphine of about 10ng/ml are attained in 15 to 60 minutes; after an intramuscular does of 10mg, peak serum concentrations of 70 to 80ng/ml are attained in 10 to 20 minutes; after an intravenous does of 10mg, serum concentrations of about 60ng/ml are obtained in 15 minutes falling to 30ng/ml after 30 minutes and to 10ng/ml after 3 hours; subcutaneous doses give similar concentrations to intramuscular doses at 15 minutes but remain slightly higher during the following 3 hours; serum concentrations measured soon after administration correlate closely with the ages of the subjects studied and are increased in the aged.
Serum half-life in the period 10 minutes to 6 hours following intravenous administration, 2 to 3 hours; serum half-life in the period 6 hours onwards, 10 to 44 hours.
Widely distributed throughout the body, mainly in the kidneys, liver, lungs and spleen; lower concentrations appear in the brain and muscles; morphine crosses the placenta and traces are secreted in sweat and milk; protein binding, about 35% bound to albumin and to immunoglobulins at concentrations within the therapeutic range.
Mainly glucuronic acid conjugation to form morphine-3 and 6-glucuronides, with sulfate conjugation. N-demethylation, 0-methylation and N-oxide glucuronide formation occurs in the intestinal mucosa and liver; N-demethylation
occurs to a greater extent after oral than parenteral administration; the 0-methylation pathway to form codeine has been challenged and codeine and norcodeine metabolites in urine may be formed from codeine impurities in the morphine sample studied.
After an oral dose, about 60% is excreted in the urine in 24 hours, with about 3% excreted as free morphine in 48 hours; after parenteral dose, about 90% is excreted in 24 hours, with about 10% as free morphine, 65 to 70% as conjugated morphine, 1% as normorphine and 3% as normorphine glucuronide; after administration of large doses to addicts about 0.1% of a dose is excreted as norcodeine; urinary excretion of morphine appears to be pH dependent to some extent: as the urine becomes more acid more free morphine is excreted and as the urine becomes more alkaline more of the glucuronide conjugate is excreted; up to 10% of a dose may be excreted in the bile.
5.3 Preclinical safety data
5.3 Preclinical safety dataIn male rats, reduced fertility and chromosomal damage in gametes have been reported.
6.1 List of excipients
Sodium Chloride,
Sodium Metabisulfite(E223)
Water for Injection.
The pH may be adjusted with Sodium Hydroxide or Sulfuric Acid Solution.
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 aciclovir sodium, doxorubicin, fluorouracil, frusemide, heparin sodium, pethidine hydrochloride, promethazine hydrochloride and tetracyclines. Specialised references should be consulted for specific compatibility information.
Physicochemical incompatibility (formation of precipitates) has been demonstrated between solutions of morphine sulfate and 5– fluorouracil.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the ampoules in the outer carton in order to protect from light.
6.5 Nature and contents of container
6.5 Nature and contents of containerClear, colourless 1ml Ph.Eur type1 glass ampoules containing sufficient solution to permit the removal of 1ml. 10 ampoules are packed into a cardboard carton.
6.6. Special precautions for disposal and other handling
Any solution remaining should be discarded or returned to the pharmacy.