This information is intended for use by health professionals

1. Name of the medicinal product

Sevredol® tablets 10 mg, 20 mg, 50 mg.

2. Qualitative and quantitative composition

Each tablet contains Morphine Sulfate 10 mg, 20 mg, 50 mg

Excipient with known effect:

Lactose, anhydrous

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablet.

10 mg

Blue, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "10" on the right.

20 mg

Pink, film-coated, capsule-shaped, biconvex tablet with a score line on one side. "IR" is marked on the left side and "20" on the right.

50 mg

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 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.

Paediatric population:

3 - 5 years

6 -12 years

5 mg, 4-hourly

5 -10 mg, 4-hourly

Sevredol tablets 50 mg are not recommended for children below 12 years of age.

Route of administration

Oral.

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 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.

Sevredol 10 mg/20 mg: Not recommended for children below 3 years of age.

Sevredol tablets 50 mg: Not recommended for children below 12 years of age.

4.4 Special warnings and precautions for use

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.

The major risk of opioid excess is respiratory depression.

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

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

Concomitant use of Sevredol 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 Sevredol 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 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 pre-operatively 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.

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

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. There is potential for development of physical and/or psychological dependence (addiction) or tolerance to opioid analgesics, including morphine. The risk increases with the time the drug is used and with higher doses. Symptoms may be minimised with adjustments of the dose or dosage form, and gradual withdrawal of morphine. For individual symptoms, see section 4.8.

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.

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

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

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 (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

Sevredol tablets are not recommended during 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 withdrawal (abstinence) syndrome. Treatment may include an opioid and supportive care.

Breastfeeding

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 5.3 Preclinical safety data).

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

Hypersensitivity

Anaphylactic reaction

Anaphylactoid reaction

Psychiatric disorders

Confusion

Insomnia

Agitation

Euphoria

Hallucinations

Mood altered

Drug dependence

Dysphoria

Thinking disturbances

Nervous system disorders

Dizziness

Headache

Involuntary muscle contractions

Somnolence

Convulsions

Hypertonia

Myoclonus

Paraesthesia

Syncope

Allodynia

Hyperalgesia (see section 4.4)

Hyperhidrosis

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 tolerance

Drug withdrawal (abstinence) syndrome

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.

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, 1g/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 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 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 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

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)

Pregelatinised maize starch

Povidone

Purified water

Magnesium stearate

Talc

Film coat

10 mg tablet:

Opadry (blue) 06B20843 containing Macrogol 400, E464, E133, E171 Purified water

20 mg tablet:

Opadry 85F240092 (pink) containing polyvinyl alcohol (E1203), Macrogol 3350, talc, E171, E127, E110

50 mg tablet:

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 Special precautions for disposal and other handling

None

7. Marketing authorisation holder

Napp Pharmaceuticals Ltd

Cambridge Science Park

Milton Road

Cambridge CB4 0GW

8. Marketing authorisation number(s)

PL 16950/0063-0065

9. Date of first authorisation/renewal of the authorisation

1 May 1999 / 22 March 2003

10. Date of revision of the text

9th November 2018

LEGAL CATEGORY

CD (Sch 2), POM

® SEVREDOL and Napp are Registered Trade Marks.

© 2007 – 2018 Napp Pharmaceuticals Limited.