Special Warning : אזהרת שימוש

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.

Hepatobiliary disorders
Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis.
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.
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 Martindale 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 Martindale 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.

Opioid Use Disorder (abuse and dependence)
Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as Morphine Martindale.

Repeated use of Morphine Martindale can lead to Opioid Use
Disorder (OUD). A higher dose and longer duration of opioid treatment, can increase the risk of developing OUD. Abuse or intentional misuse of Morphine Martindale may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.
Patients will require monitoring for signs of drug-seeking behavior (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines).
For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

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 Martindale 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).
Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Severe cutaneous adverse reactions (SCARs)
Acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, has been reported in association with morphine treatment. Most of these reactions occurred within the first 10 days of treatment. Patients should be informed about the signs and symptoms of AGEP and advised to seek medical care if they experience such symptoms.

If signs and symptoms suggestive of these skin reactions appear, morphine should be withdrawn and an alternative treatment considered.

Effects on Driving

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. 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