SEVREDOL Tablets *

Section 4.3: Reformatting into a bulleted list, addition of severe bronchial asthma, hypoxia and hypercapnia.

Section 4.4: Reformatting into a bulleted list, addition of pre-existing conditions where caution should be exercised; intracranial lesions and reduced level of consciousness of uncertain origin; constipation. Addition of warning statements regarding risk of respiratory depression and sleep apnoea.

Section 4.5: Reworded to improve clarity

Section 4.8: Addition of sleep apnoea syndrome as a possible side effect, update of the term visual disturbance to visual impairment.

Section 2: (Do not take …) addition of severe asthma

Section 2: (Warnings and precautions) addition of warning for sleep apnoea and constipation.

Section 2: (Other medicines …) reworded to improve clarity

Section 4: (Possible side effects …) addition of sleep apnoea

Section 4.4: Addition of PRAC mandated warnings regarding concomitant use with oral P2Y12 inhibitor antiplatelet therapy.

Section 4.5: Addition of PRAC mandated text describing interaction between morphine and P2Y12 inhibitors.

Correction to section 5.1 'Endocrine System'

Update to SPC in line with the CMDh wording following Morphine PSUSA/00010549/201710 assessment outcome.

Hyperalgesia that will not respond to a further dose increase of morphine sulphate may very rarely occur, particularly in high doses. A morphine sulphate dose reduction or change in opioid may be required.

Section 4.8 Has been rewritten throughout


Section 4.9

Overdosage has been changed to overdose

Signs of morphine toxicity and overdosage are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression and hypotension has been changed to read:

Signs of morphine toxicity and overdose are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression, hypotension, somnolence and central nervous system depression which can progress to stupor or coma.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug - has been deleted

4.4.      Special warnings and precautions for use

Has been replaced with:

The major risk of opioid excess is respiratory depression.

As with all narcotics, a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, convulsive disorders, acute alcoholism, delirium tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy and adrenocortical insufficiency. Sevredol tablets should not be used where there is a possibility of paralytic ileus occurring.  Should paralytic ileus be suspected or occur during use, Sevredol tablets should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Sevredol tablets for 4 hours prior to the intervention. If further treatment with Sevredol tablets is indicated then the dosage should be adjusted to the new post-operative requirement. Sevredol tablets should be used with caution pre-operatively and within the first 24 hours post-operatively. Sevredol tablets should also be used with caution following abdominal surgery.

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, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Morphine has an abuse profile similar to other strong agonist opioids.  Morphine may be sought and abused by people with latent or manifest addiction disorders. The product should be used with particular care in patients with a history of alcohol and drug abuse.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

4.5.      Interaction with other medicinal products and other forms of interaction

Has been replaced with :

                        Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquilisers, muscle relaxants, antihypertensives and alcohol.  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.

                        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.

                        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.

                        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.      

4.6.      Pregnancy and lactation

Has been replaced with:

            Sevredol tablets are not recommended during pregnancy and labour due to the risk of neonatal respiratory depression. Administration to nursing mothers is not recommended as morphine is excreted in breast milk. Withdrawal symptoms may be observed in the new born of mothers undergoing chronic treatment.

4.8.      Undesirable effects

Has been replaced with:

In normal doses, the commonest side effects of morphine are nausea, vomiting, constipation and drowsiness.  With chronic therapy, nausea and vomiting are unusual with Sevredol tablets but should they occur the tablets can be readily combined with an anti-emetic if required.  Constipation may be treated with appropriate laxatives.  

Common (incidence of ¡Ý 1%) and Uncommon (incidence of <1%) adverse drug reactions are listed in the table below:

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.

4.9.      Overdose

Has been replaced with:

Signs of morphine toxicity and overdosage are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression and hypotension. Circulatory failure and deepening coma may occur in more severe cases. Overdosage can result in death.  Rhabdomyolosis progressing to renal failure has been reported in opioid overdosage.

Treatment of morphine overdosage:

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose.  Other supportive measures should be employed as needed.

In the case of massive overdosage, administer naloxone 0.8 mg intravenously.  Repeat at 2-3 minute intervals as necessary, or by an infusion of 2 mg in 500 ml of normal saline or 5% dextrose (0.004 mg/ml).

The infusion should be run at a rate related to the previous bolus doses administered and should be in accordance with the patient's response.  However, because the duration of action of naloxone is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established.

For less severe overdosage, administer naloxone 0.2 mg intravenously followed by increments of 0.1 mg every 2 minutes if required.

Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage.  Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine.  In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Gastric contents may need to be emptied as this can be useful in removing unabsorbed drug.

5.1.      Pharmacodynamic properties

Has been replaced with:

            Pharmacotherapeutic group: Natural opium alkaloid

            ATC code: N02A A01

Morphine acts as an agonist at opiate receptors in the CNS particularly mu and to a lesser extent kappa receptors.  Mu receptors are thought to mediate supraspinal analgesia, respiratory depression, and euphoria, and kappa receptors, spinal analgesia, miosis and sedation. 

Central Nervous System

The principal actions of therapeutic value of morphine are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine produces respiratory depression by direct action on brain stem respiratory centres. 

Morphine depresses the cough reflex by direct effect on the cough centre in the medulla.  Antitussive effects may occur with doses lower than those usually required for analgesia. Morphine causes miosis, even in total darkness.  Pinpoint pupils are a sign of narcotic overdose but are not pathognomonic (e.g., pontine lesions of haemorrhagic or ischaemic origin may produce similar findings).  Marked mydriasis rather than miosis may be seen with hypoxia in the setting of morphine overdose.

Gastrointestinal Tract and Other Smooth Muscle

Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum.  Digestion of food in the small intestine is delayed and propulsive contractions are decreased.  Propulsive peristaltic waves in the colon are decreased, while tone is increased to the point of spasm resulting in constipation.

Cardiovascular System

Morphine may produce release of histamine with or without associated peripheral vasodilation.  Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.

Endocrine System

Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes.  Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacological Effects

In vitro and animal studies indicate various effects of natural opioids, such as morphine, on components of the immune system; the clinical significance of these findings is unknown.