Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Amdipharm UK Limited, Capital House, 85 King William Street, London EC4N 7BL, UK
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Respiratory depression, paralytic ileus, acute abdomen, delayed gastric emptying, obstructive airways disease, or acute hepatic disease. It is also contra-indicated in the presence of acute alcoholism, head injuries and conditions in which intracranial pressure is raised. Neither should it be given during an attack of bronchial asthma nor heart failure secondary to chronic lung disease.
Patients with excessive bronchial secretions should not be given Rhotard Morphine SR/Morphgesic SR tablets as morphine diminishes the cough response.
Not recommended for pre-operative use or for the first 24 hours post-operatively.
Not recommended during pregnancy and lactation (see section 4.6).
Concurrent administration of monoamine oxidase inhibitors (MAOIs) or within two weeks of discontinuation of their use.
Severe and prolonged respiratory depression may occur in patients with renal impairment given morphine; this is attributed to the accumulation of the active metabolite morphine-6-glucuronide. Therefore Rhotard Morphine SR/Morphgesic SR tablets should not be administered to patients with moderate or severe renal impairment (glomerular filtration rate <20 ml/min).
As with other opioid analgesic containing preparations Rhotard Morphine SR/Morphgesic SR tablets should not be administered to patients with severe hepatic impairment as it may precipitate coma.
Rhotard Morphine SR/Morphgesic SR tablets, as with other opioid containing preparations, is contraindicated in patients with ulcerative colitis, since such preparations may precipitate toxic dilation or spasm of the colon.
Concomitant use of alcohol and Rhotard Morphine SR/Morphgesic SR tablets may increase the undesirable effects of Rhotard Morphine SR/Morphgesic SR tablets, concomitant use should be avoided.
Rhotard Morphine SR/Morphgesic SR tablets should be given with caution or in reduced doses to patients with hypothyroidism, adrenocortical insufficiency, or shock. It should be used with caution in patients with either obstructive bowel disorders or myasthenia gravis.
Caution in patients with convulsive disorders, hypotension with hypovolaemia, the elderly, opioid dependent patients, diseases of the biliary tract, pancreatitis and inflammatory bowel disorders. Use with caution in patients with impaired respiratory function, delirium tremens, severe cor pulmonale and patients with a history of substance abuse. Morphine may lower the seizure threshold in patients with a history of epilepsy.
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.
Should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected to occur during use, treatment should be discontinued immediately.
Extreme caution should be exercised when administering morphine to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.
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.
As with all morphine sulphate preparations, patients about to undergo additional pain relieving procedures (e.g. cordotomy, surgery, plexus blockade) should not receive Rhotard Morphine SR/Morphgesic SR tablets for 24 hours prior to the intervention. If further treatment with Rhotard Morphine SR/ Morphgesic SR tablets is indicated then the dosage should be adjusted to the new post-operative requirement.
The major risk of opioid excess is respiratory depression.
The patient may develop tolerance to the drug with chronic use and require progressively higher doses to maintain pain control. Prolonged use of this product may lead to physical dependence and a withdrawal syndrome may occur upon abrupt cessation of therapy. When a patient no longer requires therapy with morphine sulphate, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
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. Morphine sulphate may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence (addiction) to opioid analgesics, including morphine.
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.
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 sulphate (see section 4.9).
Abuse of Rhotard Morphine SR/Morphgesic SR tablets by parenteral administration can be expected to result in serious adverse events, which may be fatal.
Urinary retention may occur in patients with urethral disease or prostatic hypertrophy.
Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea
It is not possible to ensure bio-equivalence between different brands of controlled release morphine products. Therefore, it should be emphasised that patients, once titrated to an effective dose should not be changed from Rhotard Morphine SR/ Morphgesic SR tablets to other slow, sustained or controlled release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.
Concomitant use of Rhotard Morphine SR/Morphgesic SR 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 Rhotard Morphine SR/Morphgesic SR tablets 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).
Due to a possible association between Acute Chest Syndrome (ACS) and morphine use in Sickle Cell Disease (SCD) patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted
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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Alcohol may enhance the pharmacodynamic effects of Rhotard Morphine SR/Morphgesic SR tablets; concomitant use should be avoided.
Rhotard Morphine SR/Morphgesic SR tablets should not be concurrently administered with monoamine oxidase inhibitors (MAOI’s) or used within two weeks of discontinuation of MAOI use (see section 4.3). The depressant effects of morphine may be enhanced, or the effects of other compounds potentiated, by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics and sedatives, tricyclic antidepressants and phenothiazines, as well as muscle relaxants, gabapentin and antihypertensives. 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 sulphate. The action of morphine may in turn affect the activities of other compounds, for example its gastro-intestinal effects may delay absorption as with mexilitine or may be counteractive as with metoclopramide.
Cimetidine inhibits the metabolism 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.
The analgesic effect of opioids tends to be enhanced by co-administration of dexamfetamine, and hydroxyzine.
Medicinal products that block the action of acetylcholine, for example anti-histamines, anti-parkinsonian agents and anti-emetics, may interact with morphine sulphate to potentiate anti-cholinergic adverse events.
Plasma concentrations of morphine sulphate may be reduced by rifampicin.
Morphine may reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Propranolol has been reported to enhance the lethality of toxic doses of opioids in animals, although the significance of this finding is not known for man. Caution should be exercised when these drugs are administered concurrently.
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulphate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulphate, and may possibly decrease plasma concentrations of morphine sulphate.
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).
Rhotard Morphine SR/Morphgesic SR tablets are 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 sulphate is excreted in breast milk (see section 4.3). Withdrawal symptoms may be observed in the new born of mothers undergoing chronic treatment.
Effects of morphine exposure on sexual maturation of male rats, their reproductive capacity and the development of their progeny have been examined. Results indicated that exposure during adolescence led to pronounced inhibition of several indices of sexual maturation (e.g. hormone levels, reduced gonad weights), smaller litters and selective gender specific effects on endocrine function in the offspring.
Animal studies have shown that morphine may reduce fertility (see 5.3. preclinical safety data).
A disruption in ovulation and amenorrhoea can occur in women given morphine.
Rhotard Morphine SR/Morphgesic SR tablets 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:
In normal doses, the most common side effects of morphine are nausea, vomiting, constipation, difficulty in micturition and drowsiness. With chronic therapy, nausea and vomiting are unusual with Rhotard Morphine SR/Morphgesic SR tablets but should they occur the tablets can be readily combined with an anti-emetic if required. Constipation may be treated with appropriate laxatives.
A case of morphine induced thrombocytopenia has been reported.
Morphine has a depressant effect on gonadal hormone secretion which can result in a reduction of testosterone leading to regression of secondary sexual characteristics in men on long-term therapy.
Very Common (incidence ≥1/10), Common (incidence of ≥1%) and Uncommon (incidence of <1%) adverse drug reactions are listed in the table below:
Uncommon: Allergic reaction
Frequency Unknown: Anaphylactic reaction, Anaphylactoid reaction
Common: Confusion, Insomnia
Uncommon: Agitation, Euphoria, Hallucinations, Mood altered
Frequency Unknown: Drug dependence, Dysphoria, Thinking disturbances restlessness
Common: Headache, Involuntary muscle contractions, Somnolence, Dizziness
Uncommon: Convulsions, Hypertonia, Myoclonus, Paraesthesia, Syncope
Frequency Unknown: Raised intracranial pressure, Coma, Hyperalgesia (see section 4.4), hyperaesthesia/allodynia, Hyperhidrosis
Uncommon: Visual disturbance
Frequency Unknown: Miosis
Uncommon: Vertigo
Uncommon: Palpitations
Frequency Unknown: Bradycardia, Tachycardia
Uncommon: Facial flushing, Hypotension
Frequency Unknown: Circulatory failure, Hypertension
Uncommon: Bronchospasm, Pulmonary oedema, Respiratory depression
Frequency Unknown: Cough decreased
Very Common: Constipation, Nausea
Common: Abdominal pain, Anorexia, Vomiting
Uncommon: Dyspepsia, Ileus, Taste perversion
Frequency Unknown: Narcotic bowel syndrome, Dry mouth
Uncommon: Increased hepatic enzymes
Frequency Unknown: Exacerbation of pancreatitis, Biliary pain
Common: Hyperhidrosis, Rash
Uncommon: Urticaria
Uncommon: Urinary retention
Frequency Unknown: Ureteric spasm, Dysuria
Frequency Unknown: Amenorrhea, Decreased libido, Erectile dysfunction
Common: Asthenic conditions, Pruritus
Uncommon: Peripheral oedema
Frequency Unknown: Drug tolerance, Drug withdrawal (abstinence) syndrome, Hypothermia, Anxiety, Dysphoric mood
* Physical and psychological dependence may appear after administration of therapeutic doses for periods of 1 to 2 weeks. Some cases of dependence have been observed after only 2 to 3 days.
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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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