1. Name Of The Medicinal Product
MST® CONTINUS® 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg prolonged release tablets.
2. Qualitative And Quantitative Composition
Tablets containing Morphine Sulphate 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg.
3. Pharmaceutical Form
Prolonged release, film-coated, biconvex tablets marked with the NAPP logo on one side and the strength of the preparation on the other.
MST CONTINUS tablets 5 mg are white.
MST CONTINUS tablets 10 mg are golden brown.
MST CONTINUS tablets 15 mg are green.
MST CONTINUS tablets 30 mg are purple.
MST CONTINUS tablets 60 mg are orange.
MST CONTINUS tablets 100 mg are grey.
MST CONTINUS tablets 200 mg are teal green.
4. Clinical Particulars
4.1 Therapeutic Indications
For the prolonged relief of severe and intractable pain. MST CONTINUS tablets 5 mg, 10 mg, 15 mg and 30 mg are additionally indicated for the relief of post-operative pain.
4.2 Posology And Method Of Administration
Route of administration:
Oral.
MST CONTINUS tablets should be swallowed whole and not broken, chewed 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 sulphate (see section 4.9, Overdose).
.
MST CONTINUS tablets should be used at 12-hourly intervals. The dosage is dependent upon the severity of the pain, the patient's age and previous history of analgesic requirements.
Adults:
A patient presenting with severe pain, uncontrolled by weaker opioids (e.g. dihydrocodeine) should normally be started on 30 mg 12-hourly. Patients previously on normal release oral morphine should be given the same total daily dose as MST CONTINUS tablets but in divided doses at 12-hourly intervals.
Increasing severity of pain will require an increased dosage of the tablets. Higher doses should be made, where possible in 30-50% increments as required. The correct dosage for any individual patient is that which is sufficient to control pain with no, or tolerable, side effects for a full 12 hours. It is recommended that the 200 mg strength is reserved for patients who have already been titrated to a stable analgesic dose using lower strengths of morphine sulphate or other opioid preparations.
Patients receiving MST CONTINUS tablets in place of parenteral morphine sulphate 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.
Children:
For children with severe cancer pain, a starting dose in the range of 0.2 to 0.8 mg morphine sulphate per kg bodyweight 12-hourly is recommended. Doses should then be titrated as for adults.
Post-operative pain:
MST CONTINUS tablets are not recommended in the first 24 hours post-operatively or until normal bowel function has returned; thereafter it is suggested that the following dosage schedule be observed at the physician's discretion:
(a) MST CONTINUS tablets 20 mg 12-hourly to patients under 70 kg
(b) MST CONTINUS tablets 30 mg 12-hourly to patients over 70 kg
(c) Elderly - a reduction in dosage may be advisable in the elderly
(d) Children - not recommended.
Supplemental parenteral morphine sulphate may be given if required but with careful attention to the total dosages of morphine sulphate, and bearing in mind the prolonged effects of morphine sulphate in this prolonged release formulation.
4.3 Contraindications
Respiratory depression, head injury, paralytic ileus, 'acute abdomen', delayed gastric emptying, obstructive airways disease, hypersensitivity to any of the tablet constituents, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use. Children under one year of age.
Not recommended for pre-operative use or for the first 24 hours post-operatively.
4.4 Special Warnings And Precautions For Use
As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal or hepatic function. 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, patients with a history of substance abuse, opiate dependent patients, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy and adrenocortical insufficiency.
Morphine sulphate may lower the seizure threshold in patients with a history of epilepsy.
Should paralytic ileus be suspected or occur during use, MST CONTINUS tablets should be discontinued immediately. As with all morphine sulphate preparations, patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive MST CONTINUS tablets for 24 hours prior to the intervention. If further treatment with MST CONTINUS tablets is indicated then the dosage should be adjusted to the new post-operative requirement.
As with all oral morphine sulphate preparations, MST CONTINUS tablets should be used with caution post-operatively and following abdominal surgery, as morphine sulphate impairs intestinal motility and should not be used until the physician is assured of normal bowel function.
The major risk of opioid excess is respiratory depression.
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 sulphate, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.
Morphine sulphate has an abuse profile similar to other strong agonist opioids. Morphine sulphate may be sought and abused by people with latent or manifest addiction disorders. There is potential for development of psychological dependence (addiction) to opioid analgesics, including morphine. The product should be used with particular care in patients with a history of alcohol and drug abuse.
The prolonged 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 sulphate (see section 4.9).
Abuse of MST Continus tablets by parenteral administration can be expected to result in serious adverse events, which may be fatal.
It is not possible to ensure bioequivalence between different brands of prolonged release morphine sulphate products. Therefore, it should be emphasised that patients, once titrated to an effective dose, should not be changed from MST CONTINUS preparations to other slow, sustained or prolonged release morphine sulphate or other potent narcotic analgesic preparations without retitration and clinical assessment.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Morphine sulphate potentiates the effects of tranquillisers, general anaesthetics, phenothiazines, other central nervous system depressants including hypnotics or sedatives, alcohol, muscle relaxants, antihypertensives and gabapentin. 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 sulphate.
Morphine sulphate should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.
Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine sulphate to potentiate anticholinergic adverse events.
Cimetidine inhibits the metabolism of morphine sulphate.
Plasma concentrations of morphine sulphate may be reduced by rifampicin.
Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulphate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulphate, and may possibly decrease plasma concentrations of morphine sulphate.
4.6 Pregnancy And Lactation
MST CONTINUS 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 sulphate is excreted in breast milk. Withdrawal symptoms may be observed in the newborn of mothers undergoing chronic treatment.
4.7 Effects On Ability To Drive And Use Machines
Morphine sulphate 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.
4.8 Undesirable Effects
In normal doses, the commonest side effects of morphine sulphate are nausea, vomiting, constipation and drowsiness. With chronic therapy, nausea and vomiting are unusual with MST CONTINUS 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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4.9 Overdose
Signs of morphine sulphate 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. Rhabdomyolysis progressing to renal failure has been reported in opioid overdosage.
Crushing and taking the contents of a prolonged release dosage form may lead to the release of morphine sulphate in an immediate fashion; this might result in a fatal overdose.
Treatment of morphine sulphate 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. MST CONTINUS tablets will continue to release and add to the morphine sulphate load for up to 12 hours after administration and the management of morphine sulphate overdosage should be modified accordingly.
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 sulphate overdosage. Naloxone should be administered cautiously to persons who are known, or suspected, to be physically dependent on morphine sulphate. 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, particularly when a prolonged release formulation has been taken.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: natural opium alkaloid
ATC code: N02A A01
Morphine sulphate 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 sulphate are analgesia and sedation (i.e., sleepiness and anxiolysis). Morphine sulphate produces respiratory depression by direct action on brain stem respiratory centers.
Morphine sulphate 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 sulphate 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 sulphate overdose.
Gastrointestinal Tract and Other Smooth Muscle
Morphine sulphate 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 sulphate generally increases smooth muscle tone, especially the sphincters of the gastrointestinal and biliary tracts. Morphine sulphate may produce spasm of the sphincter of Oddi, thus raising intrabiliary pressure.
Cardiovascular System
Morphine sulphate 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 in association with inappropriately low or normal ACTH, LH or FSH levels. Some premenopausal women may have low oestrogen levels. 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 sulphate, on components of the immune system; the clinical significance of these findings is unknown.
5.2 Pharmacokinetic Properties
Morphine sulphate is well absorbed from MST CONTINUS tablets and, in general, peak plasma concentrations are achieved 1-5 hours following administration. The availability is complete when compared to an equivalent dose of immediate release oral solution. Morphine sulphate is subject to a significant first-pass effect which results in a lower bioavailability when compared to an equivalent intravenous dose.
The major metabolic transformation of morphine sulphate is glucuronidation to morphine sulphate-3-glucuronide and morphine sulphate-6-glucuronide which then undergo renal excretion. These metabolites are excreted in bile and may be subject to hydrolysis and subsequent re-absorption.
Patients are titrated to appropriate pain control using the wide range of strengths of MST CONTINUS tablets. Consequently, there is a large inter-patient variation in required dosage, the minimum dosage being 5 mg 12-hourly, and a dose of 5.6 g 12-hourly has been recorded.
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:
Hydroxyethylcellulose Ph Eur
Purified Water Ph Eur
Cetostearyl Alcohol Ph Eur
Magnesium Stearate Ph Eur
Purified Talc Ph Eur
Lactose Anhydrous (except for 100 mg and 200 mg tablets) NF
Hypromellose (E464) Ph Eur
Macrogol Ph Eur
The following tablets have the colourants listed below:
5 mg - Titanium dioxide (E171)
10 mg - Iron oxide (E172), Titanium dioxide (E171)
15 mg - Iron oxide (E172), brilliant blue (E133), quinoline yellow (E104), indigo carmine (E132) Titanium dioxide (E171)
30 mg - Erythrosine (E127), indigo carmine (E132), sunset yellow (E110), Titanium dioxide (E171)
60 mg - Erythrosine (E127), quinoline yellow (E104), sunset yellow (E110), Titanium dioxide (E171)
100 mg - Iron oxide (E172), indigo carmine (E132), Titanium dioxide (E171)
200 mg - Brilliant blue (E133), quinoline yellow (E104), Titanium dioxide (E171.
6.2 Incompatibilities
None stated.
6.3 Shelf Life
Five years.
6.4 Special Precautions For Storage
Do not store above 25oC.
6.5 Nature And Contents Of Container
Aluminium foil-backed PVdC/PVC blister packs. Pack size 60 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Napp Pharmaceuticals Limited
Cambridge Science Park
Milton Road
Cambridge CB4 0GW
8. Marketing Authorisation Number(S)
PL 16950/0035-0041
9. Date Of First Authorisation/Renewal Of The Authorisation
1 May 1999
10. Date Of Revision Of The Text
June 2010
11 LEGAL CATEGORY
CD (Sch 2), POM
® MST, MST CONTINUS, CONTINUS, NAPP and the NAPP devices are Registered Trade Marks.
© Napp Pharmaceuticals Ltd 2010.
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