Sevredol^® tablets 10 mg , 20 mg, 50 mg.

Morphine Sulphate 10 mg, 20 mg, 50 mg

For excipients see 6.1.

Film-coated tablet.

10 mg

Blue, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "10" on the right.

20 mg

Pink, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "20" on the right.

50 mg

Pale, green film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "50" on the right.

Sevredol tablets are indicated for the relief of severe pain.

Route of administration

Oral.

Adults and children over 12 years.

The dosage of Sevredol tablets is dependent on the severity of pain and the patient's previous history of analgesic requirements. One tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Sevredol tablets using 10 mg, 20 mg or 50 mg alone or in combination to achieve the desired relief.

Patients receiving Sevredol tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 100%. In such patients individual dose adjustments are required.

Elderly:

A reduction in adult dosage may be advisable.

Children 3 -12 years of age:

Only Sevredol 10 mg and 20 mg tablets are suitable for children:-

Sevredol tablets 50 mg are not recommended for children.

Hypersensitivity to any of the constituents, respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdomen, delayed gastric emptying, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use. Not recommended during pregnancy.

Not recommended for children below 3 years of age.

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, severe bronchial asthma, 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, 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 new post-operative requirements. 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 as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

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

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

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. There is potential for development of psychological dependence (addition) to opioid analgesics, including morphine. 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.

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.

In a study involving healthy volunteers (N = 12), when a 60 mg controlled-release morphine capsule was administered 2 hours prior to a 600 mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

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.

Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine to potentiate the anticholinergic adverse effects.

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.

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.

Treatment with Sevredol tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.

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.

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).

Immune system disorders

Not known: Allergic reaction, anaphylactic reaction, anaphylactic reaction

Psychiatric disorders

Common: Confusion, insomnia

Uncommon: Agitation, euphoria, hallucinations, mood altered

Not known: Drug dependence, dysphoria, thinking disturbances

Nervous system disorders

Common: Dizziness, headache, involuntary muscle contractions, somnolence

Uncommon: Convulsions, hypertonia, paraesthesia, syncope, myoclonus

Not known: Hyperalgesia

Eye disorders

Uncommon: Visual disturbance

Not known: Miosis

Ear and labyrinth disorders

Uncommon: Vertigo

Cardiac disorders

Uncommon: Palpitations

Not known: Bradycardia, tachycardia

Vascular disorders

Uncommon: Facial flushing, hypotension

Not known: Hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchospasm, pulmonary oedema, respiratory depression

Not known: Cough decreased

Gastrointestinal disorders

Very common: Nausea

Common: Abdominal pain, anorexia, constipation, dry mouth, vomiting

Uncommon: Dyspepsia, ileus, taste perversion

Hepatobiliary disorders

Uncommon: Increased hepatic enzymes

Not known: Biliary pain, exacerbation of pancreatitis

Skin and subcutaneous tissue disorders

Common: Hyperhidrosis, rash

Uncommon: Urticaria

Renal and urinary disorders

Uncommon: Urinary retention

Not known: Ureteric spasm

Reproductive system and breast disorders

Not known: Amenorrhoea, decreased libido, erectile dysfunction

General disorders and administration site conditions

Common: Asthenic conditions, pruritus

Uncommon: Malaise, peripheral oedema

Not known: Drug tolerance, drug withdrawal syndrome

Signs and symptoms of morphine overdose

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

Treatment of morphine overdose

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

Oral activated charcoal (50g) for adults, 1g/kg for children) may be considered if a substantial amount has been ingested within one hour, provided the airway can be protected.

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 overdose, 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 overdose, 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 overdose. 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.

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 centers.

Morphine depresses the cough reflex by direct effect on the cough center 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 hemorrhagic or ischemic 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.

Morphine generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.

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, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacologic 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.

Morphine is well absorbed from Sevredol tablets, however first pass metabolism does occur. Apart from the liver, metabolism also occurs in the kidney and intestinal mucosa. The major urinary metabolite is morphine-3-glucuronide but morphine-6-glucuronide is also formed. The half life for morphine in the plasma is approximately 2.5 - 3.0 hours.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Tablet core

Lactose (anhydrous)

Pregelatinised maize starch

Povidone

Purified water

Magnesium stearate

Talc

Film coat

None known.

Three years.

Do not store above 30°C.

PVdC coated PVC blister packs and polypropylene containers with polyethylene lids containing 56 and 112 tablets.

Medical sample packs containing up to 24 tablets are also available.

None

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

PL 16950/0063-0065

1 May 1999 / 22 March 2003

04 April 2011

CD (Sch 2), POM

®Sevredol, NAPP and the Napp device (logo) are Registered Trade Marks.

© 2007 – 2011 Napp Pharmaceuticals Limited.