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MST CONTINUS 60 MG PROLONGED RELEASE TABLETS

Active substance(s): MORPHINE SULPHATE

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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.

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.
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

Immune
system
disorders
Psychiatric
disorders

Nervous
system
disorders

Uncommon

Not known

Allergic
reaction

Anaphylactic
reaction
Anaphylactoid
reaction

Confusion

Agitation

Insomnia

Euphoria

Drug
dependence

Hallucinations

Dysphoria

Mood altered

Thinking
disturbances

Dizziness

Convulsions

Headache

Hypertonia

Hyperalgesia
(see section
4.4)

Involuntary
muscle

Myoclonus

contractions

Paraesthesia

Somnolence

Syncope

Eye disorders

Visual
disturbance

Ear and
labyrinth
disorders

Vertigo

Cardiac
disorders

Palpitations

Vascular
disorders

Facial
flushing

Miosis

Bradycardia
Tachycardia
Hypertension

Hypotension
Bronchospasm Cough
decreased
Pulmonary

Respiratory
thoracic and
mediastinal
disorders

oedema
Respiratory
depression

Gastrointestinal Constipation Abdominal
disorders
pain
Nausea
Anorexia
Dry mouth

Dyspepsia
Ileus
Taste
perversion

Vomiting
Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders
Renal and
urinary
disorders
Reproductive
system and
breast disorders

Increased
hepatic
enzymes

Biliary pain
Exacerbation
of pancreatitis

Hyperhidrosis Urticaria
Rash
Urinary
retention

Ureteric
spasm
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 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 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 3glucuronide 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

7

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

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Source: Medicines and Healthcare Products Regulatory Agency

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