Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

MST CONTINUS^® 5 mg, 10 mg, 15 mg, 30 mg, 60 mg and 100 mg

Prolonged-release Tablets

Each tablet contains 5 mg, 10 mg, 15 mg, 30 mg, 60 mg or 100 mg morphine sulphate.

5 mg tablet also contains lactose anhydrous 95 mg.

10 mg tablet also contains lactose anhydrous 90 mg.

15 mg tablet also contains lactose anhydrous 85 mg.

30 mg tablet also contains lactose anhydrous 70 mg and Sunset Yellow (E110).

60 mg tablet also contains lactose anhydrous 40 mg and Sunset Yellow (E110).

For excipients, see 6.1.

Film-coated prolonged-release tablets.

Marked with the Napp logo on one side and the strength 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.

For the prolonged relief of severe and intractable pain.

MST CONTINUS tablets 5 mg, 10 mg, 15, mg, 30 mg and 60 mg are additionally indicated in the short term control of post-operative pain.

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 (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 or other opioid preparations.

Patients receiving MST CONTINUS 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.

Children:

For children with severe cancer pain, a starting dose in the range of 0.2 to 0.8 mg morphine 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 may be given if required but with careful attention to the total dosages of morphine, and bearing in mind the prolonged effects of morphine in this prolonged release formulation.

Respiratory depression, head injury, paralytic ileus, 'acute abdomen', delayed gastric emptying, obstructive airways disease, known morphine sensitivity or 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.

Pre-operative administration of MST CONTINUS tablets is not recommended or for the first 24 hours post-operatively.

As with all narcotics a reduction in dosage may be advisable in the elderly, in hypothyroidism and in patients with significantly impaired renal, hepatic or respiratory function. Use with caution in opiate dependent patients and in patients with severe bronchial asthma, a history of substance abuse, convulsive disorders, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy, adrenocortical insufficiency, acute alcoholism and delirium tremens.

Morphine 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 preparations, patients who are 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 preparations, MST CONTINUS tablets should be used with caution post-operatively and following abdominal surgery, as morphine 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, 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. 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 (see section 4.9).

Concomitant use of alcohol and MST CONTINUS tablets may increase the undesirable effects of MST CONTINUS tablets; concomitant use should be avoided.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take the 5 mg, 10 mg, 15 mg, 30 mg and 60 mg tablets.

MST CONTINUS 30 mg and 60 mg prolonged release tablets contain sunset yellow (E110) which may cause allergic reactions.

It is not possible to ensure bioequivalence between different brands of controlled release morphine 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 or other potent narcotic analgesic preparations without retitration and clinical assessment.

Morphine potentiates the effects of tranquillisers, general anaesthetics, phenothiazines, other central nervous system depressants including hypnotics or sedatives, muscle relaxants, antihypertensives and gabapentin.

Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy. 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.

Alcohol may enhance the pharmacodynamic effects of MST CONTINUS tablets; concomitant use should be avoided.

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

Cimetidine inhibits the metabolism of morphine.

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.

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 is excreted in breast milk. Withdrawal symptoms may be observed in the newborn of mothers undergoing chronic treatment.

Morphine 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.

In normal doses, the commonest side effects of morphine 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 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.

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. 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 in an immediate fashion; this might result in a fatal overdose.

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. MST CONTINUS tablets will continue to release and add to the morphine load for up to 12 hours after administration and the management of morphine 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 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, particularly when a prolonged release formulation has been taken.

Pharmacotherapeutic group: Natural opium alkaloid.

ATC code: NO 2A 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. 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 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, on components of the immune system; the clinical significance of these findings is unknown.

Morphine is well absorbed from MST CONTINUS 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. Morphine-3-glucuronide also appears in the bile and is excreted into the intestine, hydrolysed and absorbed as free morphine. The half-life for morphine in 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

Hyetellose

Cetostearyl Alcohol

Magnesium Stearate

Talc

Lactose anhydrous (except for 100 mg)

Hypromellose (E464)

Macrogol 400

Titanium dioxide (E171)

The following tablets have the colourants listed below:

Not applicable

15 mg tablet: 5 years

All other strengths: 3 years.

Do not store above 25°C.

Store in the original package.

Aluminium foil-backed PVdC/PVC blister packs containing 60 tablets.

No special requirements

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

PA 1688/4/1-6

Date of first authorisation:

January 2012

^® MST, CONTINUS, MST CONTINUS, MUNDIPHARMA and the 'mundipharma' device (logo) are Registered Trade Marks.

^©2010 - 2011 Napp Pharmaceuticals.