1. Name Of The Medicinal Product
Sevredol®tablets 10 mg , 20 mg, 50 mg.
2. Qualitative And Quantitative Composition
Morphine Sulphate 10 mg, 20 mg, 50 mg
For excipients see 6.1.
3. Pharmaceutical Form
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.
4. Clinical Particulars
4.1 Therapeutic Indications
Sevredol tablets are indicated for the relief of severe pain.
4.2 Posology And Method Of Administration
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:-
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Sevredol tablets 50 mg are not recommended for children.
4.3 Contraindications
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.
4.4 Special Warnings And Precautions For Use
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, 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
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
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
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.
4.7 Effects On Ability To Drive And Use Machines
Treatment with Sevredol tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.
4.8 Undesirable Effects
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
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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
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. Rhabdomyolysis 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. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
5.2 Pharmacokinetic Properties
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.
5.3 Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core
Lactose (anhydrous)
Pregelatinised maize starch
Povidone
Purified water
Magnesium stearate
Talc
Film coat
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6.2 Incompatibilities
None known.
6.3 Shelf Life
Three years.
6.4 Special Precautions For Storage
Do not store above 30oC.
6.5 Nature And Contents Of Container
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.
6.6 Special Precautions For Disposal And Other Handling
None
7. Marketing Authorisation Holder
Napp Pharmaceuticals Ltd
Cambridge Science Park
Milton Road
Cambridge CB4 0GW
8. Marketing Authorisation Number(S)
PL 16950/0063-0065
9. Date Of First Authorisation/Renewal Of The Authorisation
1 May 1999/22 March 2003
10. Date Of Revision Of The Text
November 2007
11 LEGAL CATEGORY
CD (Sch 2), POM
® The Napp device and Sevredol are Registered Trade Marks.
© Napp Pharmaceuticals Limited 2007.
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