Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
MCR tablets should be administered with caution in patients with:
• impaired respiratory function
• respiratory depression (see below)
• severe cor pulmonale
• sleep apnoea
• CNS depressants co-administration (see below and section 4.5)
• Tolerance, physical dependence and withdrawal (see below)
• Psychological dependence[addiction], abuse profile and history of substance and/or alcohol abuse (see below) • Acute alcoholism
• Delirium tremens
• Intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin.
• hypotension with hypovolaemia
• hypothyroidism
• adrenocortical insufficiency
• convulsive disorders
• biliary tract disorders
• pancreatitis
• prostatic hypertrophy
• inflammatory bowel disorders
• severely impaired renal function
• severely impaired hepatic function
• constipation

As with all narcotics a reduction in dosage may be advisable in the elderly.

Should paralytic ileus be suspected or occur during use, MCR tablets should be discontinued immediately.
Morphine may lower the seizure threshold in patients with a history of epilepsy.

Respiratory Depression
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.


Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of MCR 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 MCR 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).
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.
Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive MCR tablets for 24 hours prior to the intervention. If further treatment with MCR tablets is then indicated, the dosage should be adjusted to the new post-operative requirement.
MCR 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 MCR preparations to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.


Drug dependence, tolerance and potential for abuse
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.
Drug withdrawal syndrome
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
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.
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
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.
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).
The controlled 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 MCR tablets may increase the undesirable effects of MCR tablets; concomitant use should be avoided.

Excipients with known effect:
MCR 10 and MCR 30 tablets contain Lactose.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

MCR 30 tablets contain sunset yellow (E110) which may cause allergic reactions.

Effects on Driving

4.7 Effects on ability to drive and use machines

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.
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.