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Napp Pharmaceuticals Limited

Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire, CB4 0GW
Telephone: +44 (0)1223 424 444
Fax: +44 (0)1223 424 441
WWW: http://www.napp.co.uk
Medical Information Fax: +44 (0)1223 424 912

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Summary of Product Characteristics last updated on the eMC: 14/11/2013
SPC MST Continus tablets 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg


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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.


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2. Qualitative and quantitative composition

Tablets containing Morphine Sulphate 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg.

Excipients with known effect:

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.

60 mg tablet also contains lactose anhydrous 40 mg.

30 mg and 60 mg tablets also contain a small amount (<1 mg) sunset yellow (E110).

For the full list of excipients see section 6.1.


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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


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4. Clinical particulars

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4.1 Therapeutic indications

MST® CONTINUS® 5 mg, 10 mg, 15 mg and 30 mg prolonged release tablets For the prolonged relief of severe and intractable pain, and for the relief of post-operative pain.

MST® CONTINUS® 60 mg, 100 mg, 200 mg prolonged release tablets

For the prolonged relief of severe and intractable pain


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4.2 Posology and method of administration

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 (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.

Posology

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.


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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.


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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 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 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 then indicated, 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).

Abuse of MST CONTINUS tablets by parenteral administration can be expected to result in serious adverse events, which may be fatal.

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 bio-equivalence between different brands of prolonged 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.


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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 depressant including hypnotics or sedatives, 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.

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-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.


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4.6 Fertility, 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 is excreted in breast milk. Withdrawal symptoms may be observed in the new born of mothers undergoing chronic treatment.


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4.7 Effects on ability to drive and use machines

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.


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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 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:

Undesirable Effects

Common (≥ 1%)

Uncommon (< 1%)

Immune system disorders

 

Allergic reaction

Anaphylactic reaction

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Thinking disturbances

Agitation

Drug dependence

Dysphoria

Euphoria

Hallucinations

Mood altered

Nervous system disorders

Headache

Involuntary muscle contractions

Myoclonus

Somnolence

Convulsions

Hypertonia

Paraesthesia

Syncope

Vertigo

Eye disorders

 

Miosis

Visual disturbance

Cardiac disorders

 

Bradycardia

Palpitations

Tachycardia

Vascular disorders

 

Facial flushing

Hypotension

Hypertension

Respiratory, thoracic and mediastinal disorders

Bronchospasm

Cough decreased

Pulmonary oedema

Respiratory depression

Gastrointestinal disorders

Abdominal pain

Anorexia

Constipation

Dry mouth

Dyspepsia

Nausea

Vomiting

Gastrointestinal disorders

Ileus

Taste perversion

Hepatobiliary disorders

Exacerbation of pancreatitis

Biliary pain

Increased hepatic enzymes

Skin and subcutaneous tissue disorders

Hyperhidrosis

Rash

Urticaria

Renal and urinary disorders

 

Ureteric spasm

Urinary retention

Reproductive system and breast disorders

 

Amenorrhea

Decreased libido

Erectile dysfunction

General disorders and administration site conditions

Asthenia

Pruritus

Drug tolerance

Drug withdrawal syndrome

Malaise

Peripheral oedema


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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. 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.


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5. Pharmacological properties

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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 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.


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5.2 Pharmacokinetic properties

Morphine 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 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 is glucuronidation to morphine 3-glucuronide and morphine-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 twelve hourly and a dose of 5.6 g 12 hourly has been recorded.


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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.


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6. Pharmaceutical particulars

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6.1 List of excipients

Tablet core

Lactose Anhydrous

Hydroxyethylcellulose

Purified Water

Cetostearyl Alcohol

Magnesium Stearate

Purified Talc

Film coat

5 mg –Opadry Y-1-7000 white containing E171

Purified water

10 mg - Polyvinyl alcohol, Macrogol 3350, talc, titanium dioxide (E171), iron oxides (E172).

15 mg - Opadry 02B21169 (containing E464, E171, macrogol 400, E104, E133, E132, E172)

Purified Water

30 mg – Opadry OY-6708 violet,

Purified Water

60 mg – Opadry OY-3508 orange,

Purified Water

100 mg – Opadry OY 8215 grey,

Purified Water

200 mg - Opadry 06B21168 (containing E464, E171, E133, E104, macrogol 400)

Macrogol 400

Purified Water


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6.2 Incompatibilities

None stated.


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6.3 Shelf life

Five years.


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6.4 Special precautions for storage

Do not store above 25°C.


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6.5 Nature and contents of container

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


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6.6 Special precautions for disposal and other handling

No special requirements


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7. Marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge CB4 0GW


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8. Marketing authorisation number(s)

PL 16950/0035 - 0041


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9. Date of first authorisation/renewal of the authorisation

1 May 1999


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10. Date of revision of the text

November 2013

® MST, Continus, MST Continus and the NAPP device (logo) are Registered Trade Marks.

© 2009 - 2013 Napp Pharmaceuticals Limited



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