Napp Pharmaceuticals Limited

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.

Section 4.4

The following has been added

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 or 60 mg tablets.

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

Section 4.4

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

Section 4.5
Morphine potentiates the effects of tranquillisers, anaesthetics, phenothiazines, hypnotics, sedatives, muscle relaxants and antihypertensives. 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. The word 'alcohol' has been removed from this sentence.

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

Throughout the doucment "Morphine sulphate" now reads "morphine"
            Section 4.1 Now reads 
            "For the prolonged relief of severe and intractable pain, and for the relief of post-operative pain."

Section 6.1 List of Excipients
Hypromellose (E464) Ph Eur & Macrogol Ph EuR have been removed
Film Coat 
Now reads:
5 mg –Opadry Y-1-7000 white containing E171

Purified water Ph Eur

10 mg - Opaspray M-1-3705B tancontaining IMS, E464, E171, E172.

Polyethylene Glycol 400 NF
Purified Water Ph Eur

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

Purified Water

30 mg – Opadry OY-6708 violet,

Purified Water Ph Eur

60 mg – Opadry OY-3508 orange,

Purified Water Ph Eur

100 mg – Opadry OY 8215 grey,

Purified Water Ph Eur

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

Macrogol 400

Purified Water

Section 1 

The name has been updated to include the pharmaceutical form in line with current guidelines.

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.

 Section 4.8  'The effects of morphine sulphate 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' has been removed.

Section 6.1   Cetostearyl Alcohol BP has been changed to 'Cetostearyl Alcohol Ph Eur'

 5 mg - Titanium dioxide (E171) has been added.

Text in blue has been added to the SPC or taken out with strike through

4.2 (Posology and method of administration

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 any of the tablet constituents known morphine sensitivity

4.4  Special warnings and precautions for use

Use with caution opiate dependent patients and in  patients with impaired respiratory function, 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.

As with all morphine preparations, patients who are about to undergo cordotomy or other additional pain relieving surgical procedures (e.g. surgery, plexus blockade) should not receive MST CONTINUS tablets for 24 hours prior to surgery the intervention.

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.  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).

4.5 (Interaction with other medicinal products and other forms of interaction

Morphine potentiates the effects of tranquillisers, anaesthetics, phenothiazines, hypnotics, sedatives, alcohol, muscle relaxants and antihypertensives. 

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

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.  Cimetidine inhibits the metabolism of morphine.  Monoamine oxidase inhibitors are know ti interact with narcotic analgesics producing CNS excitation or depression with hyper or hypotensive crisis.

4.8  (Undesirable effects)

Dry mount, sweating, vertigo, headache, disorientation, facial flushing, mood changes, palpitation, hallucinations, bronchospasm and colic may occur in a few patients.  Micturition may be difficult and there may be biliary or ureteric spasm.  Overdose may produce respiratory depression.  Rarely, clinically relevant reductions in blood pressure and heart rate have been observed.  Morphine has histamine releasing effects which may be responsible in part for reactions such as urticaria and pruritus.

Common (incidence of >1%) and Uncommon (incidence of < 1%) adverse drug reactions are listed in the table below:

4.9  Overdose

Signs of morphine toxicity and overdosage are
 

4.9  (Overdose)
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.

The pure opioid antagonists are specific antidotes against the effects of opioid overdose.  Other supportive measures should be employed as needed.

5.1  (Pharmacodynamic properties)

Pharmacotherapeutic group: natural opium alkaloid

ATC code: N02A A01

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 centers. 

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.