Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Napp Pharmaceuticals Ltd, Cambridge Science Park, Milton Road, Cambridge, CB4 0GW, United Kingdom
Hypersensitivity to the active substance or to any of excipients listed in section 6.1.
Respiratory depression, head injury, paralytic ileus, ‘acute abdomen’, delayed gastric emptying, obstructive airways disease, known morphine sensitivity, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use.
Children under one year of age.
Pre-operative administration of MST CONTINUS suspension is not recommended.
As with all narcotics, a reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal or hepatic function. Use with caution in patients with impaired respiratory function, severe bronchial asthma, convulsive disorders, acute alcoholism, delirum tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency and opiate dependent patients.
Should paralytic ileus be suspected or occur during use, MST CONTINUS suspension should be discontinued immediately.
The major risk of opioid excess is respiratory depression.
Morphine may lower the seizure threshold in patients with a history of epilepsy.
Concomitant use of MST CONTINUS suspension 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 MST CONTINUS suspension concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
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).
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.
Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive MST CONTINUS suspension for 24 hours prior to the intervention. If further treatment with MST CONTINUS suspension is indicated, then the dosage should be adjusted to the new post-operative requirement.
MST CONTINUS suspension should be used with caution post-operatively, and following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.
MST CONTINUS suspension is not recommended preoperatively or within the first 24 hours postoperatively.
It is not possible to ensure bio-equivalence between different brands of prolonged release morphine products. Therefore, it should be emphasised that patients, once titrated to an effective dose, should not be changed from MST CONTINUS preparations to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.
Hyperalgesia that does not respond to a further dose of morphine sulfate may occur in particular in high doses. A morphine sulfate dose reduction or change in opioid may be required.
Morphine has an abuse profile similar to other strong agonist opioids and should be used with particular caution in patients with a history of alcohol and drug abuse. Morphine may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of physical or/and psychological dependence (addiction) or tolerance to opioid analgesics, including morphine. 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.
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.
Some changes that can be seen with long-term use of opioid analgesics include an increase in serum prolactin, and decreases in plasma cortisol, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms include decreased libido, impotence or amenorrhea which may be manifested from these hormonal changes.
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.
The contents of the prolonged release sachets (granules) must be suspended whole or sprinkled on to soft food and drunk immediately after (see section 4.2), but not be broken, crushed or chewed. The administration of broken, chewed or crushed morphine (granules) leads to a rapid release and absorption of a potentially fatal dose of morphine (see section 4.9).
Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.
Concomitant use of alcohol and MST CONTINUS suspension may increase the undesirable effects of MST CONTINUS suspension; concomitant use should be avoided.
The excipient Ponceau 4R may cause allergic reactions.
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 the additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
Drugs which depress the CNS include, but are not limited to: other opioids, anxiolytics, hypnotics and sedatives (including benzodiazepines), antipsychotics, antidepressants, general anaesthetics, phenothiazines, muscle relaxants and antihypertensives.
In a study involving healthy volunteers (N=12), when a 60-mg controlled-release morphine capsule was administered 2 hours prior to a 600-mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.
Alcohol may enhance the pharmacodynamic effects of MST CONTINUS suspension; concomitant use should be avoided.
Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsonians and anti-emetics, may interact with morphine to potentiate anticholinergic adverse events.
Concurrent administration of antacids may result in a more rapid release of morphine than otherwise expected; dosing should therefore be separated by a minimum of two hours. Cimetidine inhibits the metabolism of morphine.
Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.
Plasma concentrations of morphine may be reduced by rifampicin (see section 4.4).
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine, and may possibly decrease plasma concentrations of morphine.
Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.
There are no or limited amount of data from the use of morphine in pregnant women.
MST CONTINUS suspension is not recommended during pregnancy and labour due to the risk of neonatal respiratory depression. 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.
Administration to nursing mothers is not recommended as morphine is excreted in breast milk.
Animal studies have shown that morphine may reduce fertility (see 5.3 Preclinical safety data).
MST CONTINUS suspension may modify the patient’s reactions to a varying extent depending on the dosage and susceptibility. If affected, patients 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:
Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law.
In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with MST CONTINUS suspension but should they occur the suspension could be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.
The following frequencies are the basis for assessing undesirable effects: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
| Very Common | Common | Uncommon | Not known | |
|---|---|---|---|---|
| Immune system disorders | Hypersensitivity | Anaphylactic reaction Anaphylactoid reaction | ||
| Psychiatric disorders | Confusion Insomnia | Agitation Euphoria Hallucinations Mood altered | Drug dependence Dysphoria Thinking disturbances | |
| Nervous system disorders | Dizziness Headache Hyperhidrosis Involuntary muscle contractions Somnolence | Convulsions Hypertonia Myoclonus Paraesthesia Syncope | Allodynia Hyperalgesia (see section 4.4) | |
| Eye disorders | Visual impairment | Miosis | ||
| Ear and labyrinth disorders | Vertigo | |||
| Cardiac disorders | Palpitations | Bradycardia Tachycardia | ||
| Vascular disorders | Facial flushing Hypotension | Hypertension | ||
| Respiratory thoracic and mediastinal disorders | Bronchospasm Pulmonary oedema Respiratory depression | Cough decreased | ||
| Gastrointestinal disorders | Constipation Nausea | Abdominal pain Anorexia Dry mouth Vomiting | Dyspepsia Ileus Taste perversion | |
| Hepatobiliary disorders | Increased hepatic enzymes | Biliary pain Exacerbation of pancreatitis | ||
| Skin and subcutaneous tissue disorders | Rash | Urticaria | ||
| Renal and urinary disorders | Urinary retention | Ureteric spasm | ||
| Reproductive system and breast disorders | Amenorrhoea Decreased libido Erectile dysfunction | |||
| General disorders and administration site conditions | Asthenia Fatigue Malaise Pruritus | Peripheral oedem | Drug tolerance Drug withdrawal (abstinence) syndrome Drug withdrawal (abstinence) syndrome neonatal |
The effects of morphine have led to its abuse and dependence may develop with regular, inappropriate use. This is not a major concern in the treatment of patients with severe pain.
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 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 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.
Not applicable.
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