Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0GW
MST CONTINUS tablets are contraindicated in patients with:
Children under one year of age.
Not recommended for pre-operative use or for the first 24 hours post-operatively.
MST CONTINUS tablets should be administered with caution in patients with:
As with all narcotics a reduction in dosage may be advisable in the elderly.
Should paralytic ileus be suspected or occur during use, MST CONTINUS tablets should be discontinued immediately.
Morphine may lower the seizure threshold in patients with a history of epilepsy.
The major risk of opioid excess is respiratory depression.
Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of pre-existing sleep apnoea (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.
Concomitant use of MST CONTINUS tablets 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 tablets 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 tablets for 24 hours prior to the intervention. If further treatment with MST CONTINUS tablets is then indicated, the dosage should be adjusted to the new post-operative requirement.
MST CONTINUS tablets 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.
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.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse or addiction.
The clinical need for analgesic treatment should be reviewed regularly.
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with morphine.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
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 and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Some premenopausal women may have low oestrogen 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.
Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5)
The prolonged release tablets must be swallowed whole, and not broken, chewed, dissolved or crushed. The administration of broken, chewed or crushed tablets may lead 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 tablets may increase the undesirable effects of MST CONTINUS tablets; concomitant use should be avoided.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 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, sedatives and hypnotics (including benzodiazepines), antiepileptics (including gabapentinoids, e.g., pregabalin), general anaesthetics (including barbiturates), antipsychotics (including phenothiazines), antidepressants, muscle relaxants, antihypertensives, centrally acting anti-emetics and alcohol.
Morphine sulfate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.
Alcohol may enhance the pharmacodynamic effects of MST CONTINUS tablets; concomitant use should be avoided.
Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine sulfate to potentiate anticholinergic adverse events.
Cimetidine inhibits the metabolism of morphine sulfate.
Plasma concentrations of morphine sulfate may be reduced by rifampicin (see section 4.4).
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.
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulfate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulfate, and may possibly decrease plasma concentrations of morphine sulfate.
MST CONTINUS tablets are not recommended during pregnancy and labour. Regular use in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
Administration to nursing women is not recommended as morphine is secreted in breast milk and may cause respiratory depression in the infant.
Animal studies have shown that morphine may reduce fertility (see 5.3 Preclinical safety data).
Morphine 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 tablets but should they occur the tablets can 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 (see section 4.4) Dysphoria Thinking disturbances | |
| Nervous system disorders | Dizziness Headache Hyperhidrosis Involuntary muscle contractions Somnolence | Convulsions Hypertonia Myoclonus Paraesthesia Syncope | Allodynia Hyperalgesia (see section 4.4) Sleep apnoea syndrome | |
| 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 oedema Drug withdrawal syndrome | Drug tolerance Drug withdrawal (abstinence) syndrome neonatal |
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
None stated.
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