MST Continus tablets 30 mg

Summary of Product Characteristics Updated 24-Apr-2020 | Napp Pharmaceuticals Limited

1. Name of the medicinal product

MST® CONTINUS® 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg prolonged release tablets.

2. Qualitative and quantitative composition

Each tablet contains Morphine Sulfate 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg, 200 mg.

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.

3. Pharmaceutical form

Prolonged-release tablet.

White, film coated, biconvex tablet marked with the NAPP logo on one side and the strength of the tablet on the other.

MST CONTINUS tablets 5 mg are white

MST CONTINUS tablets 10 mg are golden brown.

MST CONTINUS tablets 15 mg are green.

MST CONTINUS tablets 30 mg are purple.

MST CONTINUS tablets 60 mg are orange.

MST CONTINUS tablets 100 mg are grey.

MST CONTINUS tablets 200 mg are teal green.

4. Clinical particulars
4.1 Therapeutic indications

For the prolonged relief of severe and intractable pain, and for the relief of post-operative 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.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with morphine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

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.

Paediatric population:

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).

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

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.

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

Concomitant use of MST CONTINUS tablets and sedative medicines such as benzodiazepines 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 MST CONTINUS tablets 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 caregivers to be aware of these symptoms (see section 4.5).

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.

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.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with morphine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Adrenal insufficiency

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.

Decreased Sex Hormones and increased prolactin

Some changes that can be seen with long-term use of opioid analgesics 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 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 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 total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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, tranquillisers, general anaesthetics, phenothiazines, hypnotics or sedatives (including benzodiazepines), antipsychotics, antidepressants, muscle relaxants, antihypertensives, gabapentin and alcohol.

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 (see section 4.4).

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

Pregnancy

MST CONTINUS tablets are not recommended during pregnancy and labour. Regular use in pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. If opioid use is required for a prolonged period in pregnant women, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breast feeding

Administration to nursing women is not recommended as morphine is secreted in breast milk and may cause respiratory depression in the infant.

Fertility

Animal studies have shown that morphine may reduce fertility (see 5.3 Preclinical safety data).

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

Hypersensitivity

Anaphylactic reaction

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Agitation

Euphoria

Hallucinations

Mood altered

Drug dependence (see section 4.4)

Dysphoria

Thinking disturbances

Nervous system disorders

Dizziness

Headache

Hyperhidrosis

Involuntary muscle contractions

Somnolence

Convulsions

Hypertonia

Myoclonus

Paraesthesia

Syncope

Allodynia

Hyperalgesia (see section 4.4)

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

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

Asthenia

Fatigue

Malaise

Pruritus

Peripheral oedema

Drug withdrawal syndrome

Drug tolerance

Drug withdrawal (abstinence) syndrome neonatal

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

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

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.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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

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 re-absorption.

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

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. Pharmaceutical particulars
6.1 List of excipients

Tablet core

Lactose Anhydrous

Hydroxyethylcellulose

Purified Water

Cetostearyl Alcohol

Magnesium Stearate

Purified Talc

Film coat

5 mg - Opadry Y-1-7000 white containing E171, Purified water

10 mg - Polyvinyl alcohol, Macrogol 3350, talc, E171, E172.

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

30 mg – Opadry OY-6708 violet, Purified Water

60 mg – Opadry OY-3508 orange, Purified Water

100 mg – Opadry OY 8215 grey, Purified Water

200 mg - Opadry 06B21168 (containing E464, E171, E133, E104, Macrogol 400), Macrogol 400, 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 and other handling

No special requirements

7. Marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing authorisation number(s)

PL 16950/0035, PL 16950/0036, PL 16950/0037, PL 16950/0038, PL 16950/0039, PL 16950/0040, PL 16950/0041

9. Date of first authorisation/renewal of the authorisation

25/02/2009

10. Date of revision of the text

17/04/2020

Company Contact Details
Napp Pharmaceuticals Limited
Address

Cambridge Science Park, Milton Road, Cambridge, Cambridgeshire, CB4 0GW

Telephone

+44 (0)1223 424 444

WWW

http://www.napp.co.uk

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