PRODUCT SUMMARY

1. TRADE NAME OF THE MEDICAL PRODUCT SEVREDOL tablets 50 mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Morphine Sulfate 50 mg

Excipient with known effect:

Lactose, anhydrous.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Film-coated tablet.

Pale green film coated, capsule shaped, biconvex tablet with a score line on one side. “IR” is marked on the left side and “50” on the right.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

SEVREDOL tablets 50 mg are indicated for the relief of severe pain.

4.2 Posology and method of administration

Posology

Adults and children over 12 years.

The dosage of Sevredol tablets is dependent on the severity of pain and the patient’s previous history of analgesic requirements. One tablet to be taken every four hours or as directed by a physician. Increasing severity of pain or tolerance to morphine will require increased dosage of Sevredol tablets using 10 mg, 20 mg or 50 mg alone or in combination to achieve the desired relief.

Patients receiving Sevredol 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.

Elderly

A reduction in adult dosage may be advisable.

Children

Sevredol tablets 50 mg are not recommended for children.

Route of administration Oral.

4.3 Contraindications

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

Respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdomen, delayed gastric emptying, known morphine sensitivity, acute hepatic disease, concurrent administration of mono-amine oxidase inhibitors or within two weeks of discontinuation of their use. Not recommended during pregnancy.

Not recommended for children below 12 years of age.

4.4 Special warnings and precautions for use

The major risk of opioid excess is respiratory depression.

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, severe bronchial asthma, convulsive disorders, acute alcoholism, delirium 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, adrenocortical insufficiency. Sevredol tablets should not be used where there is a possibility of paralytic ileus occurring. Should paralytic ileus be suspected or occur during use, Sevredol tablets should be discontinued immediately.

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Patients about to undergo additional pain relieving procedures (e.g. surgery, plexus blockade) should not receive Sevredol tablets for 4 hours prior to the intervention. If further treatment with Sevredol tablets is indicated then the dosage should be adjusted to new post-operative requirements. Sevredol tablets should be used with caution preoperatively and within the first 24 hours post-operatively. Sevredol tablets should also be used with caution following abdominal surgery as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.

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 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.

Abuse of oral dosage forms by parenteral administration can be expected to result in serious adverse events, which may be fatal.

4.5 Interaction with other medicinal products and other forms of interaction

Morphine should be used with caution in patients who are concurrently receiving other central nervous system depressants including sedatives or hypnotics, general anaesthetics, phenothiazines, other tranquilisers, muscle relaxants, antihypertensives, and alcohol. 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.

In a study involving healthy volunteers (N = 12), when a 60 mg controlled-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.

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.

Medicinal products that block the action of acetylcholine, for example antihistamines, anti-parkinsons and anti-emetics, may interact with morphine to potentiate the anticholinergic adverse effects.

Cimetidine inhibits the metabolism of morphine.

Monoamine oxidase inhibitors are known to interact with narcotic analgesics producing CNS excitation or depression with hyper- or hypotensive crisis. Morphine should not be co-administered with monoamine oxidase inhibitors or within two weeks of such therapy.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Sevredol tablets are not recommended during pregnancy and labour due to the risk of neonatal respiratory depression.

Breastfeeding

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

Treatment with Sevredol tablets may cause sedation and it is not recommended that patients drive or use machines if they experience drowsiness.

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 Sevredol 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			Allergic reaction	Anaphylactic reaction Anaphylactoi d reaction
Psychiatric disorders		Confusion Insomnia	Agitation Euphoria Hallucination s Mood altered	Drug dependence Dysphoria Thinking disturbances
Nervous system disorders		Dizziness Headache Involuntary muscle contractions Somnolence	Convulsions Hypertonia Myoclonus Paraesthesia Syncope	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			Bronchospas m Pulmonary oedema Respiratory depression	Cough decreased
Gastrointestina l disorders	Constipatio n Nausea	Abdominal pain Anorexia Dry mouth Vomiting	Dyspepsia Ileus Taste perversion

	Very Common	Common	Uncommon	Not known
Hepatobiliary disorders			Increased hepatic enzymes	Biliary pain Exacerbation of pancreatitis
Skin and subcutaneous tissue disorders		Hyperhidrosi s 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		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 and symptoms of morphine 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.

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 (50 g 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.

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 01

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, 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 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 SEVREDOL tablets, however first pass metabolism does occur. Apart from the liver, metabolism also occurs in the kidney and intestinal mucosa. The major urinary metabolite is morphine 3-glucuronide but morphine 6-glucuronide is also formed. The half life for morphine in the plasma is approximately 2.5 - 3.0 hours.

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

Lactose (anhydrous)

Pregelatinised maize starch Povidone Purified Water Magnesium stearate Talc

Film coat

Opadry OY-21037 Green.

(containing hypromellose E464, titanium dioxide E171, macrogol 400, quinoline yellow E104, indigo carmine E132, iron oxide yellow E172).

6.2. Incompatibilities

None known.

6.3. Shelf Life

Three years.

6.4. Special Precautions for Storage

Do not store above 30°C.

6.5. Nature and Contents of Container

PVdC coated PVC blister packs and polypropylene containers with polyethylene lids, containing 56 and 112 tablets.

Medical sample packs containing up to 24 tablets are also available.

6.6. Instruction for Use, Handling and Disposal

None.

7. MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Limited Cambridge Science Park Milton Road Cambridge CB4 0GW

8. MARKETING AUTHORISATION NUMBER

PL 16950/0065

9. DATE OF FIRST AUTHORISATION/RENEWAL AUTHORISATION

1 May 1999

10 DATE OF REVISION OF THE TEXT

02/06/2016