Mst Continus 60 Mg Prolonged Release Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

MST® CONTINUS® 60 mg prolonged release tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Morphine Sulfate 60 mg.

Excipients with known effect:

Also contains lactose anhydrous 40 mg and a small amount (<1 mg) sunset yellow (E110).

For the full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablet.

Orange, film coated biconvex tablet marked with the NAPP logo on one side and 60 mg on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the prolonged relief of severe and intractable pain.

4.2 Posology and method of administration

Posology

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.

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

(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.

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).

4.3 Contraindications

Hypersensitivity to the active substance or to any of the constituents listed in section 6.1.

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

Should paralytic ileus be suspected or occur during use, MST CONTINUS tablets should be discontinued immediately.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

The major risk of opioid excess is respiratory depression.

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.

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.

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.

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 sulfate may very rarely occur in particular in high doses. A morphine sulfate 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 (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 oral dosage forms 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 this medicine.

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

4.5 Interaction with other medicinal products and other forms of interaction

Morphine sulfate potentiates the effects of tranquillisers, general anaesthetics, phenothiazines, other central nervous system 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 sulfate.

Morphine sulfate 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 sulfate to potentiate anticholinergic adverse events.

Cimetidine inhibits the metabolism of morphine sulfate.

Plasma concentrations of morphine sulfate may be reduced by rifampicin.

Although there are no pharmacokinetic data available for concomitant use of ritonavir with morphine sulfate, ritonavir induces the hepatic enzymes responsible for the glucuronidation of morphine sulfate, and may possibly decrease plasma concentrations of morphine sulfate.

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.

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.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

■ The medicine is likely to affect your ability to drive.

■ Do not drive until you know how the medicine affects you.

■ It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the ‘statutory defence’).

■ This defence applies when:

■ The medicine has been prescribed to treat a medical or dental problem; and

■ You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.

■ Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).”

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

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.

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).

	Very Common	Common	Uncommon	Not known
Immune system disorders			Allergic reaction	Anaphylactic reaction Anaphylactoid reaction
Psychiatric disorders		Confusion Insomnia	Agitation Euphoria Hallucinations Mood altered	Drug dependence Dysphoria Thinking disturbances
Nervous system disorders		Dizziness Headache Involuntary muscle	Convulsions Hypertonia Myoclonus	Hyperalgesia (see section 4.4)

		contractions Somnolence	Paraesthesia Syncope
Eye disorders			Visual disturbance	Miosis
Ear and labyrinth disorders			Vertigo
Cardiac disorders			Palpitations	Bradycardia Tachycardia
Vascular disorders			Facial flushing Hypotension	Hypertension
Respiratory thoracic and mediastinal disorders			Bronchospasm Pulmonary oedema Respiratory depression	Cough decreased
Gastrointestinal disorders	Constipation Nausea	Abdominal pain Anorexia Dry mouth Vomiting	Dyspepsia Ileus Taste perversion
Hepatobiliary disorders			Increased hepatic enzymes	Biliary pain Exacerbation of pancreatitis
Skin and subcutaneous tissue disorders		Hyperhidrosis Rash	Urticaria
Renal and urinary disorders			Urinary retention	Ureteric spasm
Reproductive system and breast disorders				Amenorrhoea Decreased libido Erectile

dysfunction

General disorders and administration site conditions

Asthenic

conditions

Pruritus

Peripheral

oedema

Drug

tolerance

Drug

withdrawal

syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Signs of morphine toxicity and overdose are pin-point pupils, skeletal muscle flaccidity, bradycardia, respiratory depression, hypotension, somnolence and central nervous system depression which can progress to stupor or coma. 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.

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 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, 1 g/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 reestablished. 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 overdose should be modified accordingly.

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.

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 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

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 reabsorption.

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.

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 Hydroxyethylcellulose Purified Water Cetostearyl Alcohol Magnesium Stearate Purified Talc

Film coat

Opadry OY -3508 orange Purified Water

6.2. Incompatibilities

None stated.

6.3 Shelf life

Five years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

No special requirements

MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Limited Cambridge Science Park Milton Road Cambridge CB4 0GW

8. Marketing Authorisation Number

PL 16950/0039

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/02/2009

10 DATE OF REVISION OF THE TEXT

14/12/2015