MXL^® 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 200 mg prolonged release capsules

Morphine sulphate 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 200 mg.

For excipients, see 6.1

Capsules, prolonged release

Hard gelatin capsules containing white to off white multiparticulates.

MXL capsules 30 mg are size 4, light blue capsules marked MS OD30.

MXL capsules 60 mg are size 3, brown capsules marked MS OD60.

MXL capsules 90 mg are size 2, pink capsules marked MS OD90.

MXL capsules 120 mg are size 1, olive capsules marked MS OD120.

MXL capsules 150 mg are size 1, blue capsules marked MS OD150.

MXL capsules 200 mg are size 0, rust capsules marked MS OD200

The prolonged relief of severe and intractable pain.

Route of administration

Oral.

The capsules may be swallowed whole or opened and the contents sprinkled on to soft cold food. The capsules and contents should not be crushed or chewed. MXL capsules should be used at 24-hourly intervals. The dosage is dependent upon the severity of the pain, the patient's age and previous history of analgesic requirements.

Adults and elderly

Patients presenting with severe uncontrolled pain, who are not currently receiving opioids, should have their dose requirements calculated through the use of immediate release morphine, where possible, before conversion to MXL capsules.

Patients presenting in pain, who are currently receiving weaker opioids should be started on:

a) 60 mg MXL capsule once-daily if they weigh over 70 kg.

b) 30 mg MXL capsule once-daily if they weigh under 70 kg, are frail or elderly.

Increasing severity of pain will require an increased dosage of MXL capsules using 30 mg, 60 mg, 90 mg, 120 mg, 150 mg or 200 mg alone or in combination to achieve pain relief. Higher doses should be made, where appropriate in 30% - 50% increments as required. The correct dosage for any individual patient is that which controls the pain with no or tolerable side effects for a full 24 hours.

Patients receiving MXL capsules 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 aged 1 year and above

The use of MXL capsules in children has not been extensively evaluated. For severe and intractable pain in cancer a starting dose in the range of 0.4 to 1.6 mg morphine per kg bodyweight daily is recommended. Doses should be titrated in the normal way as for adults.

Hypersensitivity to any of the constituents.

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 (MAOIs) or within two weeks of discontinuation of their use. Not recommended during pregnancy or for pre-operative use or for the first 24 hours post-operatively.

Children under one year of age.

As with all narcotics, a reduction in dosage may be advisable in the elderly, in hypothyroidism, in renal and chronic hepatic disease. Use with caution in patients with impaired respiratory function, convulsive disorders, acute alcoholism, delirum tremens, raised intracranial pressure, hypotension with hypovolaemia, severe cor pulmonale, opioid dependent patients, patients with a history of substance abuse, diseases of the biliary tract, pancreatitis, inflammatory bowel disorders, prostatic hypertrophy and adrenocortical insufficiency. MXL capsules should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, MXL capsules should be discontinued immediately. As with all morphine preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive MXL capsules for 24 hours prior to surgery. If further treatment with MXL capsules is then indicated the dosage should be adjusted to the new post-operative requirement.

It is not possible to ensure bio-equivalence 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 MXL capsules to other slow, sustained or controlled release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.

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 development of psychological dependence to opioid analgesics in properly managed patients with pain has been reported to be rare. However, data are not available to establish the true incidence of psychological dependence in chronic pain patients. The product should be used with particular care in patients with a history of alcohol and drug abuse.

The controlled release granules must be swallowed whole, and not broken, chewed, dissolved or crushed. The administration of broken, chewed or crushed morphine granules leads to a rapid release and absorption of a potentially fatal dose of morphine (see section 4.9).

Concomitant use of alcohol and MXL capsules may increase the undesirable effects of MXL capsules; concomitant use should be avoided.

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

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anesthetics, phenothiazines, other tranquilizers, 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. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

Alcohol may enhance the pharmacodynamic effects of MXL capsules; concomitant use should be avoided.

Mixed agonist/antagonist opioid analgesics (e.g. buprenorphine, nalbuphine, pentazocine) should not be administered to a patient who has received a course of therapy with a pure opioid agonist analgesic.

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.

MXL capsules are not recommended for use in 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 individual 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 MXL capsules but should they occur the capsules 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 drowsiness, 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. Rhabdomyolosis progressing to renal failure has been reported in opioid overdosage.

Crushing and taking the contents of a controlled release dosage form leads to the release of the 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. MXL capsules will continue to release and add to the morphine load for up to 24 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 modified release formulation has been taken.

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 centers.

Morphine depresses the cough reflex by direct effect on the cough center 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 hemorrhagic or ischemic 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, oestrogen and testosterone in association with inappropriately low or normal ACTH, LH or FSH levels. Clinical symptoms may be manifest from these hormonal changes.

Other Pharmacologic 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 the capsules and, in general, peak plasma concentrations are achieved 2-6 hours following administration. The availability is complete when compared to an immediate release oral solution or MST CONTINUS tablets. The pharmacokinetics of morphine are linear across a very wide dose range. Morphine is subject to a significant first-pass effect which results in a lower bioavailability when compared to an equivalent intravenous or intramuscular 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.

Because of the high inter-patient variation in morphine pharmacokinetics, and in analgesic requirements, the daily dosage in individual patients must be titrated to achieve appropriate pain control. Daily doses of up to 11.2 g have been recorded from twelve-hourly MST CONTINUS tablets. For this reason the capsules have been formulated in strengths of 30 mg, 60 mg, 90 mg, 120 mg, 150 mg and 200 mg.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Hydrogenated Vegetable Oil BP

Macrogol 6000 Ph Eur

Talc Ph Eur

Magnesium Stearate Ph Eur

Capsule shells

Gelatin (containing sodium dodecylsulphate)

The following colours are also present:

30 mg: indigo carmine (E132), titanium dioxide (E171);

60 mg: indigo carmine (E132), titanium dioxide (E171), iron oxide (E172);

90 mg: erythrosine (E127), titanium dioxide (E171), iron oxide (E172);

120 mg: indigo carmine (E132), titanium dioxide (E171), iron oxide (E172);

150 mg: erythrosine (E127), indigo carmine (E132), titanium dioxide (E171), iron oxide (E172);

200 mg: titanium dioxide (E171), iron oxide (E172).

Printing ink

Shellac

Iron oxide, black (E172)

Propylene glycol

Not applicable

2 years

Do not store above 25°C

PVdC ( 40 gsm) coated PVC (250 μm) blister strip with aluminium backing foil. The blister strips will be enclosed in a cardboard box. Each box will contain 28 or 30 capsules.

No special requirements

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

United Kingdom

PL 16950/0042-47

31 May 1996 / 29 March 2006

December 2011

CD (Sch 2), POM

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

© 2009 - 2011 Napp Pharmaceuticals Limited.