Tylex 30 mg / 500 mg effervescent tablets

Medocodene 30 mg / 500 mg effervescent tablets

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

For a full list of excipients, see section 6.1

Effervescent tablet.

Round, white or off white tablets.

For the relief of severe pain.

ADULTS

The tablets are given orally and should be dissolved in at least half a tumblerful of water before taking. The usual dose is one or two tablets every four hours as required. The total daily dose should not exceed 240 mg of codeine phosphate (i.e., not more than eight tablets per 24 hours should be taken)

ELDERLY

A reduced dose may be required.

CHILDREN

Use in children under 12 years of age is not recommended.

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.

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

Tylex effervescent is not recommended for children under the age of 12 years.

The risk-benefit of continued use should be assessed regularly by the prescriber.

Because safety and effectiveness in the administration of paracetamol with codeine in children under 12 years of age have not been established, such use is not recommended.

These tablets should be used with caution in patients with head injuries, conditions in which intracranial pressure is raised, in patients sensitive to the effects of opioids, e.g. the elderly and debilitated patients, with CNS depression , hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture, myasthenia gravis, inflammatory or obstructive bowel disorders, pre-existing respiratory depression or those with the potential to develop respiratory depression.

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are 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.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).

These tablets contain 326.6 mg sodium/tablet and this should be taken into account when prescribing for patients for whom sodium restriction is indicated. The product also contains 25 mg aspartame/tablet and therefore care should be taken in phenylketonuria.

Although paracetamol might logically be presumed to be the best alternative analgesic in patients with aspirin sensitivity, cross reactions have been reported. Patients positively identified with aspirin induced asthma, or who have ever experienced an asthmatic reaction to aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) or are at high risk of aspirin induced asthma should avoid all products that contain aspirin or NSAIDs indefinitely. In these patients paracetamol should be recommended in low or moderate dose (< 1000 mg in a single dose) unless contraindicated.

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. Codeine may impair the mental/or physical abilities required for the performance of potentially hazardous tasks.

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 leaflet will state in a prominent position in the 'Before you take' section:

· Do not take for longer than directed by your prescriber

· Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

· Taking a painkiller for headaches too often or for too long can make them worse.

The label will state (To be displayed prominently on outer pack -not boxed):

· Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultrarapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the Caucasian population may be ultra-rapid metabolisers.

The leaflet will state in the "Pregnancy and breast-feeding" subsection of section 2 "Before taking your medicine":

Usually it is safe to take Tylex/Medocodene while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels in their breast milk. If any of the following side effects develop in you or your baby, stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing

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

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

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.

MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of paracetamol to approximately 60 %. Other substances with enzyme-inducing properties, e.g. rifampicin and St. John's wort (hypericum) are also suspected of causing lowered concentrations of paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of paracetamol will be higher in patients being treated with enzyme-inducing agents.

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

The anticoagulant 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.

The use of Tylex effervescent is not recommended during pregnancy or lactation since safety in pregnant women or nursing mothers has not been established.

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

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

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.

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

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.

A tabulated list of adverse reactions is outlined below:

¹ Deafness has been reported in patients after long term use of high doses of codeine – paracetamol.

² 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.

There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

In clinical use of paracetamol-containing products, there have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.

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

Prolonged use of a painkiller for headaches can make them worse.

Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is stopped.

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors

a, Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

Or

b, Regularly consumes ethanol in excess of recommended amounts.

Or

c, Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Management

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

Simultaneous ingestion of alcohol and psychotropic drugs will potentiate the effects of overdosage.

Symptoms of codeine overdose may include:

• Central nervous system depression (including respiratory depression) but this is unlikely to be severe unless the overdose is large, or there is co-ingestion with other sedative agents or alcohol;

• pinpoint sized pupils;

• nausea and vomiting;

• hypotension and tachycardia are possible but unlikely.

Management

General symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within 1 hour after ingesting more than 350 mg or a child more than 5 mg/kg. Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist with a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe patients for at least 4 hours after ingestion.

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 an analgesic with uses similar to those of morphine but has only mild sedative effects. 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.

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.

None stated

Citric Acid Anhydrous E330

Sodium Hydrogen Carbonate E500

Sodium Carbonate Anhydrous E500

Aspartame E951

Macrogol 6000

Magnesium Stearate

Ethanol 96 % (not detected in the finished product)

Not applicable

3 years

Store at or below 25 °C. Store in the original package in a dry place to protect from light and moisture.

Paper/aluminium laminate blister strips packed in cardboard cartons.

Pack sizes: 1, 6, 8, 24, 30, 36, 42, 48, 90, 100 and 102 tablets.

Not all pack sizes may be marketed.

No special requirements

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

PL 00039/750

05/11/2009

01 April 2011