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Mundipharma Pharmaceuticals Limited - Formerly Napp Laboratories

Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland
Telephone: +353 1 206 3800
Fax: +353 1 294 5104
Medical Information e-mail: info@mundipharma.ie


Summary of Product Characteristics last updated on medicines.ie: 01/03/2013
SPC SEVREDOL Tablets



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1. NAME OF THE MEDICINAL PRODUCT

Sevredol® 10 mg, 20 mg, 50 mg film-coated tablets


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg, 20 mg or 50 mg morphine sulphate

10 mg tablet: Also contains 207.5 mg lactose.

20 mg tablet: Also contains 197.5 mg lactose.

The film-coating contains a small amount (<1 mg) Sunset Yellow (E110).

50 mg tablet: Also contains 167.5 mg lactose.

For a full list of excipients, see 6.1.


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3. PHARMACEUTICAL FORM

Film-coated tablet

The 10 mg tablets are blue, film-coated, biconvex, capsule-shaped tablets, marked with a scoreline with IR to the left and 10 to the right with a plain reverse side.

The 20 mg tablets are pink, film-coated, biconvex, capsule-shaped tablets, marked with a scoreline with IR to the left and 20 to the right with a plain reverse side.

The 50 mg tablets are pale green, film-coated, biconvex, capsule-shaped tablets, marked with a scoreline with IR to the left and 50 to the right with a plain reverse side.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

For the relief of severe pain.


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4.2 Posology and method of administration

Route of administration

Oral.

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 3-12 years of age

Only Sevredol 10 mg and 20 mg tablets are suitable for children:-

3-5 years

5 mg 4-hourly

6-12 years

5-10 mg 4-hourly

Sevredol tablets 50 mg are not recommended for children.


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4.3 Contraindications

Hypersensitivity to any of the constituents, respiratory depression, head injury, obstructive airways disease, paralytic ileus, acute abdomen, delayed gastric emptying, known morphine sensitivity, or hypersensitivity to any of the tablet constituents, acute hepatic disease, concurrent administration of monoamine oxidase inhibitors or within two weeks of discontinuation of their use. Not recommended during pregnancy.

Not recommended for children below 3 years of age.


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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 and 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 the new post-operative requirement. 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.

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 sulphate may very rarely occur, particularly 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. 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.


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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, gabapentin 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.

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.

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.


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4.6 Pregnancy and lactation

Sevredol tablets are not recommended during 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 new born of mothers undergoing chronic treatment.


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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.


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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

Anaphylactoid reaction

Psychiatric disorders

 

Confusion

Insomnia

Agitation

Euphoria

Hallucinations

Mood altered

Thinking disturbances

Drug dependence

Dysphoria

Nervous system disorders

 

Dizziness

Headache

Involuntary muscle contractions

Somnolence

Convulsions

Hypertonia

Paraesthesia

Syncope

Myoclonus

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

  

Pulmonary oedema

Respiratory depression

Bronchospasm

Cough decreased

Gastrointestinal disorders

Nausea

Constipation

Abdominal pain

Anorexia

Dry mouth

Vomiting

Ileus

Taste perversion

Dyspepsia

 

Hepatobiliary disorders

  

Increased hepatic enzymes

Biliary pain

Exacerbation of pancreatitis

Skin and subcutaneous tissue disorders

 

Hyperhidrosis

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

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.


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4.9 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. Rhabdomyolosis 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.

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.


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5. PHARMACOLOGICAL PROPERTIES

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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.

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 and testosterone. 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.


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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.


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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.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Tablet core

Lactose (anhydrous)

Pregelatinised maize starch

Povidone

Magnesium stearate

Talc

Film coat

10 mg tablet:

Opadry 06B20843 blue containing hypromellose (E464), macrogol 400, titanium dioxide (E171) and brilliant blue FCF lake (E133).

20 mg tablet:

Hypromellose (E464), macrogol 400 and

Opaspray M-1-5503 pink containing hypromellose (E464), titanium dioxide (E171), erythrosine (E127) and Sunset yellow (E110).

50 mg tablet:

Opadry 0Y-21037 green containing hypromellose (E464), macrogol 400, titanium dioxide (E171), quinoline yellow (E104), indigo carmine (E132), iron oxide (E172).


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

Three years.


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6.4 Special precautions for storage

Do not store above 30°C.


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6.5 Nature and contents of container

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


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland


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8. MARKETING AUTHORISATION NUMBER(S)

PA 1688/9/1-3


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10 mg and 20 mg

Date of first authorisation:

29th November 1989

Date of last renewal:

10th June 2006

50 mg

Date of first authorisation:

10th June 1996

Date of last renewal:

10th June 2006


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10. DATE OF REVISION OF THE TEXT

February 2013

® Sevredol, MUNDIPHARMA and the 'mundipharma' device are Registered Trade Marks.

© 2008-2013 Napp Pharmaceuticals Ltd.



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Active Ingredients

 
   Morphine Sulphate