MXL 200 MG PROLONGED-RELEASE CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

MXL 200 mg prolonged release capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains Morphine Sulfate 200 mg.

Excipient with known effect:

Each 200 mg prolonged-release capsule contains 0.015 mg of sodium (sodium dodecyl sulfate)

For the full list of excipients see 6.1.

3. PHARMACEUTICAL FORM

4.1.   Therapeutic Indications

4.2 Posology and method of administration

Posology

MXL prolonged-release 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 prolonged-release capsules.

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

a) 60 mg MXL prolonged-release capsules once-daily if they weigh over 70 kg.

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

Increasing severity of pain will require an increased dosage of MXL prolonged-release 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 prolonged-release 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 prolonged-release 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.

Method of administration

Route of administration: oral

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

Discontinuation of therapy

An abstinence syndrome may be precipitated if opioid administration is suddenly discontinued. Therefore, the dose should be gradually reduced prior to discontinuation.

4.3 Contraindications

MXL prolonged-release capsules are contraindicated in patients with:

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

Severe chronic obstructive pulmonary disease

Severe bronchial asthma

Severe respiratory depression with hypoxia and/or hypercapnia

paralytic ileus

Acute abdomen

Head injury

Delayed gastric emptying

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.

4.4 Special warnings and precautions for use

MXL prolonged-release capsules should be administered with caution in patients with:

Impaired respiratory function

Respiratory depression (see below)

Severe cor pulmonale

Sleep apnoea

CNS depressants co-administration (see below and section 4.5)

Tolerance, physical dependence and withdrawal (see below)

Psychological dependence [addiction], abuse profile and history of substance and/or alcohol abuse (see below)

Acute alcoholism

Delirium tremens

Intracranial lesions or increased intracranial pressure, reduced level of consciousness of uncertain origin

Hypotension with hypovolaemia

Hypothyroidism

Adrenocortical insufficiency

Convulsive disorders

Biliary tract disorders

Pancreatitis

Prostatic hypertrophy

Inflammatory bowel disorders

Severely impaired renal function

Severely impaired hepatic function

Constipation

As with all narcotics, a reduction in dosage may be advisable in the elderly.

MXL prolonged-release capsules should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, MXL prolonged-release capsules should be discontinued immediately.

Respiratory depression

The primary risk of opioid excess is respiratory depression.

Opioids may cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use may increase the risk of CSA in a dose-dependent manner in some patients. Opioids may also cause worsening of preexisting sleep apnoea (see section 4.8). In patients who present with CSA, consider decreasing the total opioid dosage.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of morphine and sedative medicines such as benzodiazepine or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible.

If a decision is made to prescribe morphine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their environment to be aware of these symptoms (see section 4.5).

Tolerance, physical dependence and withdrawal

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. The risk increases with the time the drug is used, and with higher doses. When a patient no longer requires therapy with morphine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal.

Psychological dependence [addiction], abuse profile and history of substance and/or alcohol abuse

There is potential for development of psychological dependence [addiction] to opioid analgesics, including morphine. Morphine has an abuse profile similar to other strong agonist opioids and should be used with particular caution in patients with a history of alcohol and drug abuse. Morphine may be sought and abused by people with latent or manifest addiction disorders.

Parenteral abuse of dosage forms not approved for parenteral administration can be expected to result in serious adverse events, which may be fatal.

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

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD)

Due to a possible association between ACS and morphine use in SCD patients treated with morphine during a vaso-occlusive crisis, close monitoring for ACS symptoms is warranted.

As with all morphine preparations, patients who are to undergo cordotomy or other pain relieving surgical procedures should not receive MXL prolonged-release capsules for 24 hours prior to surgery. If further treatment with MXL prolonged-release capsules is then indicated the dosage should be adjusted to the new postoperative requirement.

MXL prolonged-release capsules 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. MXL prolonged-release capsules are not recommended preoperatively or within the first 24 hours postoperatively.

Oral P2Y12 inhibitor antiplatelet therapy

Within the first day of concomitant P2Y12 inhibitor and morphine treatment, reduced efficacy of P2Y12 inhibitor treatment has been observed (see section 4.5).

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 MXL prolonged-release capsules to other slow, sustained or prolonged release morphine or other potent narcotic analgesic preparations without retitration and clinical assessment.

Hyperalgesia that does not respond to a further dose increase of morphine sulfate may occur in particular in high doses. A morphine sulfate dose reduction or change in opioid may be required.

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include e.g. nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Some changes that can be seen with long-term use of opioid analgesics 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 include decreased libido, impotence or amenorrhea which may be manifested from these hormonal changes.

Plasma concentrations of morphine may be reduced by rifampicin. The analgesic effect of morphine should be monitored and doses of morphine adjusted during and after treatment with rifampicin.

The prolonged release capsules or their contents (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 prolonged-release capsules may increase the undesirable effects of MXL prolonged-release capsules; concomitant use should be avoided.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).

Drugs which depress the CNS include, but are not limited to: other opioids, anxiolytics, sedatives and hypnotics (including benzodiazepines), antiepileptics (including gabapentinoids, e.g. pregabalin), general anaesthetics (including barbiturates), antipsychotics (including phenothiazines), antidepressants, gabapentin, centrally acting anti-emetics, muscle relaxants, antihypertensives and alcohol.

Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

In a study involving healthy volunteers (N = 12), when a 60-mg prolonged -release morphine capsule was administered 2 hours prior to a 600-mg gabapentin capsule, mean gabapentin AUC increased by 44% compared to gabapentin administered without morphine. Therefore, patients should be carefully observed for signs of CNS depression, such as somnolence, and the dose of gabapentin or morphine should be reduced appropriately.

A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients co-administered morphine and a P2Y12 inhibitor (see section 4.4). In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Alcohol may enhance the pharmacodynamic effects of MXL prolonged-release 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 (see section 4.4).

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of morphine in pregnant women.

MXL prolonged-release capsules are not recommended for use in pregnancy and labour due to the risk of neonatal respiratory depression. Newborns whose mothers received opioid analgesics during pregnancy should be monitored for signs of neonatal opioid withdrawal (abstinence) syndrome. Treatment may include an opioid and supportive care.

Breast-feeding

Administration to nursing mothers is not recommended as morphine is excreted in breast milk.

Fertility

Animal studies have shown that morphine may reduce fertility (see section 5.3).

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/…-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 MXL prolonged-release capsules but should they occur the capsules 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).

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.

Drug dependence and withdrawal (abstinence) syndrome

Use of opioid analgesics may be associated with the development of physical and/or psychological dependence or tolerance. An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered, or can sometimes be experienced between doses. For management, see section 4.4.

Physiological withdrawal symptoms include: body aches, tremors, restless legs syndrome, diarrhoea, abdominal colic, nausea, flu-like symptoms, tachycardia and mydriasis. Psychological symptoms include dysphoric mood, anxiety and irritability. In drug dependence, “drug craving” is often involved.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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 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 affect the hypothalamic pituitary adrenal and hypothalamic pituitary gonadal system resulting in adrenal insufficiency or hypogonadism respectively (see section 4.4).

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.

5.2. Pharmacokinetic Properties

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.

5.3 Preclinical safety data

In male rats, reduced fertility and chromosomal damage in gametes have been reported. There are no other pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1 List of excipients

Hydrogenated Vegetable Oil BP

Macrogol 6000 Ph Eur

Talc Ph Eur

Magnesium Stearate Ph Eur

Capsule shells

Gelatin (containing sodium dodecylsulfate)

The following colours are also present: Titanium dioxide (E171); iron oxide (E172)

Printing ink

Shellac

Iron oxide, black (E172)

Propylene glycol

6.2. Incompatibilities

Not applicable

6.3.

Shelf life

6.4. Special Precautions for Storage

Do not store above 25°C.

6.5. Nature and Contents of Container

Polypropylene containers with polyethylene caps, containing: 28 or 30 capsules.

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

6.6. Instruction for Use/Handling

No special requirements

7. MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 16950/0047

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/03/2006