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UCB (Pharma) Ireland Limited

United Drug House, Magna Drive, Magna Business Park, Citywest Road, Dublin 24, Ireland
Telephone: +353 1 463 7395
Fax: +353 1 463 7396
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Summary of Product Characteristics last updated on medicines.ie: 13/01/2014
SPC Tylex 30mg/500mg Hard Capsules



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1. NAME OF THE MEDICINAL PRODUCT

Tylex 30 mg / 500 mg Hard Capsules


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 500 mg of paracetamol and 30 mg of codeine phosphate hemihydrate.

Excipients: sodium metabisulphite (E223) 0.36 mg/capsule

For full list of excipients see section 6.1.


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3. PHARMACEUTICAL FORM

Capsule, hard.

Hard gelatin capsule with white body and red cap, both with “C30” printed in black.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

Tylex Capsules is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone).


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4.2 Posology and method of administration

Adults:

The capsules are given orally. The usual dose is one or two capsules up to 4 times a day at intervals of not less than 6 hours. Maximum daily dose should not exceed 240 mg of codeine phosphate hemihydrate (i.e. not more than eight capsules per 24 hours should be taken).

Elderly: A reduced dose may be required.

Paediatric population:

Children aged 12 years to 18 years:

The recommended codeine dose for children 12 years and older should be 30 to 60 mg every 6 hours when necessary up to a maximum dose of 240mg daily. The dose is based on the body weight (0.5-1mg/kg).

Children aged less than 12 years:

Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

Codeine should be used at the lowest effective dose for the shortest period of time. Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciably increased incidence of undesirable side effects.

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.


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4.3 Contraindications

Tylex Capsules should not be administered to patients who have previously exhibited hypersensitivity to either paracetamol or codeine, or to any of its excipients.

Tylex Capsules are contraindicated:

- For children under the age of 12 years.

- In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and lifethreatening adverse reactions (see section 4.4)

- In women during breastfeeding (see section 4.6)

- In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.


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4.4 Special warnings and precautions for use

The capsules contain sodium metabisulphite, a sulphite that may cause allergic reactions including anaphylactic symptoms and life threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulphite sensitivity in the general population is unknown and probably low. Sulphite sensitivity is seen more frequently in asthmatic than non-asthmatic people.

These capsules should be used with caution in patients with head injuries, increased intracranial pressure, acute abdominal conditions, the elderly and debilitated, and those with severe impairment of hepatic or renal function, hypothyroidism, Addison's disease and prostatic hypertrophy or urethral stricture, myasthenia gravis, biliary tract disorders (including recent biliary tract surgery) , pre-existing respiratory depression or those with the potential to develop respiratory depression e.g. pulmonary emphysema, known ultra-rapid metabolisers of codeine, reduced blood volume, seizures, shock, ulcerative colitis.

The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Severe liver damage may occur if the maximal daily dose is exceeded, if Tylex is taken together with another paracetamol-containing product, or if Tylex is taken while consuming large amounts of alcohol.

Although paracetamol might logically be presumed to be the best alternative analgesic in patients with aspirin sensitivity, cross reactions have been reported.

CYP2D6 metabolism

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels. General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Population

Prevalence %

African/Ethiopian

29%

African American

3.4% to 6.5%

Asian

1.2% to 2%

Caucasian

3.6% to 6.5%

Greek

6.0%

Hungarian

1.9%

Northern European

1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultrarapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

At high doses codeine has most of the disadvantages of morphine, including respiratory depression. Codeine can produce drug dependence of the morphine type, and therefore has the potential for being abused. Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped. Codeine may impair the mental/or physical abilities required for the performance of potentially hazardous tasks.

Abrupt withdrawal of opioids from persons physically dependent on them precipitates a withdrawal syndrome, the severity of which depends on the individual, the drug used, the size and frequency of the dose, and the duration of drug use.

Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed, serious liver damage. They should be advised not to exceed the recommended dose, not to take other paracetamol-containing products concurrently, to consult their doctor if symptoms persist and to keep the product out of the reach of children.

The long term use of high doses of combined codeine – paracetamol has been associated with the occurrence of deafness.


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4.5 Interaction with other medicinal products and other forms of interaction

Patients receiving other central nervous system depressants (including other opioid analgesics, tranquillisers, sedative hypnotics and alcohol) concomitantly with Tylex may exhibit an additive depressant effect. When such therapy is contemplated, the dose of one or both agents should be reduced.

Concurrent use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine. Concurrent use of anticholinergics and codeine may produce paralytic ileus.

Quinidine may reduce the concentration of morphine, the active metabolite of codeine, by >90% in patients who are known to have extensive metabolism via the cytochrome P452D6 pathway

Concurrent use with centrally acting muscle relaxants may increase the risk of respiratory depression

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

The anti-coagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Plasma-paracetamol concentrations, considered an indication for antidote treatment, should be halved in patients receiving enzyme-inducing drugs such as rifampicin, carbamazepine, phenobarbital, phenytoin, or primidone.


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4.6 Pregnancy and lactation

Tylex Capsules is not recommended during pregnancy since safety in pregnant women has not been established.

Tylex Capsules should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and are unlikely to adversely affect the breast fed infant.

However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

Use of codeine-containing medication during pregnancy may result in neonatal withdrawal symptoms.

Paracetamol is known to pass into breast milk.


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4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.


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4.8 Undesirable effects

Reported adverse reactions seem more prominent in ambulatory than non-ambulatory patients and some of these effects may be alleviated if the patient lies down.

The most commonly (>1/100, <1/10) reported reactions are:

Central nervous system:

Dizziness

Light-headedness

Sedation

Gastro-Intestinal:

Nausea & vomiting

Constipation

Abdominal pain

Psychiatric:

Dysphoria

Euphoria

Respiratory:

Shortness of breath

Asthma

Skin:

Pruritus

Rash

Urticaria

In clinical use of paracetamol-containing products, blood dyscrasias (including thrombocytopenia and agranulocytosis) are reported rarely (<1/10000, >1/1000).

Deafness has been reported in patients after long term use of high doses of codeine – paracetamol.

Anaphylaxis, angiodema and toxic epidermal necrolysis have also been associated with the use of paracetamol.

Drug-induced pancreatitis associated with paracetamol has been reported in literature to be a rare reaction only occurring in patients taking in excess of the recommended doses. Literature reports have also associated cases of pancreatitis with codeine.


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4.9 Overdose

Paracetamol

Acute hepatic necrosis is the most common complication of untreated paracetamol overdose and it usually occurs more than 2 days after ingestion. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue. Toxicity is likely if more than 150 mg/kg of paracetamol is ingested.

The following groups are at risk of liver damage from paracetamol doses above recommended dose:

• patients on long-term treatment with drugs which induce liver enzymes (e.g. barbiturates, St John's Wort)

• people who drink excessive amounts of alcohol

• patients with depleted glutathione levels (e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia)

• Patients with pre-existing hepatitis C.

Symptoms of paracetamol overdose include:

Many patients may remain asymptomatic for the first 24 hours, or at most they may develop abdominal pain, nausea, vomiting, anorexia, diarrhoea and exhibit pallor. Abnormal liver function tests are not usually detectable until at least 18 hours after ingestion and maximum liver damage occurs 72 to 96 hours after ingestion. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage.

Other symptoms of paracetamol overdose include abnormalities of glucose metabolism and metabolic acidosis. Cardiac arrhythmias, pancreatitis and hypokalaemia have also been reported. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death.

Management of overdose

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.

Patients who have ingested more than 150 mg/kg should have gastric lavage performed if they present within an hour of ingestion. Activated charcoal may also be given. A plasma paracetamol level will indicate the likelihood of a patient developing high ALT/AST activities (i.e. > 1,000 i.u. /L) and must be measured at least 4 hours after ingestion. Plasma levels measured less than 4 hours post-ingestion cannot be interpreted. Patients with a plasma level above the treatment line require N-acetylcysteine (NAC). A paracetamol normogram should be employed to determine treatment levels.

Patients who present to an Accident and Emergency Department more than 8 hours after ingesting a paracetamol overdose are at greater risk of developing hepatic damage. In cases of severe poisoning, hepatic failure may progress to encephalopathy, coma and death.

Blood should be taken for a plasma level, but the NAC infusion should be started as soon as possible if more than 150 mg/kg was taken. The NAC infusion should not be delayed while awaiting the result of the plasma paracetamol level. Administration of the antidote should be stopped if the plasma level is subsequently found to be below the treatment line. General supportive measures must be available.

At the end of the NAC infusion, blood should be taken to check the INR and creatinine concentration. If the investigations are abnormal, a further infusion of NAC (at 16 hour dose), to be continued until recovery or death, should be considered.

Codeine

Symptoms of codeine overdose include:

Serious overdose with codeine is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdose with codeine, apnoea, circulatory collapse, cardiac arrest and death may occur.

Management of overdose

Primary attention should be given to the re-establishment of adequate respiratory exchange through the provision of a patent airway and the institution of controlled ventilation. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Opioid antagonists may be employed. Gastric lavage should be considered. Patients should remain under observation, as per hospital guidelines and on a case per case basis.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

ATC Code: N02A A59 codeine combinations; N02B E51 paracetamol combinations excluding psycholeptics.

Paracetamol has analgesic and antipyretic actions similar to those of aspirin with weak anti-inflammatory effects. Paracetamol is only a weak inhibitor of prostaglandin biosynthesis, although there is some evidence to suggest that it may be more effective against enzymes in the CNS than those in the periphery. This fact may partly account for its well documented ability to reduce fever and to induce analgesia, effects that involve actions on neural tissues. Single or repeated therapeutic doses of paracetamol have no effect on the cardiovascular and respiratory systems. Acid-based changes do not occur and gastric irritation, erosion or bleeding is not produced as may occur after salicylates. There is only a weak effect upon platelets and no effect on bleeding time or the excretion of uric acid.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through μ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. The major effect is on the CNS and the bowel. The effects are remarkably diverse and include analgesia, drowsiness, changes in mood, respiratory depression, decreased gastrointestinal motility, nausea, vomiting and alterations of the endocrine and autonomic nervous systems. The relief of pain is relatively selective, in that other sensory modalities, (touch, vibration, vision, hearing etc.) are not obtunded. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.


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5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentration occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours.

Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

Codeine and its salts are absorbed from the gastro-intestinal tract. Ingestion of codeine phosphate produces peak plasma codeine concentrations in about one hour. Codeine is metabolised by O- & N-demethylation in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid.

The plasma half-life has been reported to be between 3 and 4 hours after administration by mouth or intravascular injection.


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5.3 Preclinical safety data

None stated.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Pregelatinised potato starch

Calcium stearate

Aerosol OT-B (docusate sodium, sodium benzoate (E211))

Sodium metabisulphite (E223)

Capsule shell:

Gelatin

Titanium dioxide (E171)

Erythrosine (E127)

Indigo carmine (E132)

Printing ink:

Shellac

Soya lecithin

2-ethoxyethanol

Dimeticone

Iron oxide (E172)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

3 years


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6.4 Special precautions for storage

Do not store above 25°C.

Keep blister in the outer carton.


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6.5 Nature and contents of container

Tamper-evident high-density polyethylene bottles fitted with low-density polyethylene caps, containing 8, 100, 500 capsules.

PVC/foil blisters in strips containing 8, 10 or 20 capsules each, pack sizes: 8, 24 and 100 capsules.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

UCB (Pharma) Ireland Ltd

United Drug House

Magna Business Park

Citywest Road

Dublin 24


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8. MARKETING AUTHORISATION NUMBER(S)

PA 891/14/1


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 February 1997

Date of last renewal: 21 February 2007


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10. DATE OF REVISION OF THE TEXT

December 2013



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Active Ingredients

 
   Paracetamol
   Codeine Phosphate Hemihydrate