TYLEX TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Tylex Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg of codeine phosphate (Ph. Eur) and 500 mg of paracetamol (Ph. Eur).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablets

White, film-coated, capsule-shaped tablets with “TYLEX” printed on both sides

4.1 Therapeutic indications

Tylex Tablets are indicated for use 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).

4.2 Posology and method of administration

Posology

Adults:

Tylex Tablets are given orally. The usual dose is one or two tablets every 4 to 6 hours when necessary to a maximum daily dose of 240 mg codeine and 4 g paracetamol (up to 8 tablets per day).

Duration of treatment:

Codeine should be used at the lowest effective dose for the shortest period of time. 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.

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.

Elderly:

As for adults, however a reduced dose may be required. See warnings.

Paediatric , population:

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).

Children aged 12 to 15 years:

One tablet every 6 hours when necessary to a maximum of 4 tablets in 24 hours.

Children aged 16 to 18 years:

One to two tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

For oral administration.

4.3 Contraindi­cations

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

In 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 life-threatening adverse reactions (see section 4.4).

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

Conditions where morphine and opioids are contraindicated e­.g:

Acute asthma (see section 4.4. and 4.8.)

Respiratory depression (see section 4.8)

Acute alcoholism (see section 4.4 and 4.5.)

Following biliary tract surgery

Head injuries

Raised intra-cranial pressure

Breastfeeding (see section 4.6)

Monoamine oxidase inhibitor therapy, concurrent or within 14 days.

4.4

Special warnings and precautions for use

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

Concomitant use of Tylex 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 Tylex concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

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).

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

Tylex Tablets should be used with caution in patients sensitive to the effects of opioids e.g. the elderly (who may be sensitive to their central and gastro-intestinal effects) and debilitated patients, patients with CNS depression, hypothyroidism, Addison's disease, prostatic hypertrophy or urethral stricture, myasthenia gravis, inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.

Opioid analgesics should be avoided in patients with diseases of the biliary tract.

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 alcoholic liver disease.

Chronic heavy alcohol abusers may be at increased risk of liver toxicity from excessive paracetamol use, although reports of this event are rare. Reports almost invariably involve cases of severe chronic alcoholics and the dosages of paracetamol most often exceed recommended doses and often involve substantial overdose.

Professionals should alert their patients who regularly consume large amounts of alcohol not to exceed recommended doses of paracetamol.

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, great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).

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 and/or physical abilities required for the performance of potentially hazardous tasks.

Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).

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.

CYP 2D6 metabolism

When codeine is administered concurrently with inhibitors of the cytochrome P450 isoenzyme CYP2D6, there may be a reduction or loss of therapeutic effect of codeine (see section 4.5). 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 summarised below:

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 and/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.

Paediatric population:

Tylex should be used with extreme caution in adolescents between 12 and 18 years. An alternative medicine should be considered if at all possible.

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.

Adolescents between 12 and 18 years with compromised respiratory function

Codeine is not recommended for use in adolescents between 12 and 18 years 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 or obesity. These factors may worsen symptoms of morphine toxicity.

4.5 Interaction with other medicinal products and other forms of interaction

Sedative medicines such as benzodiazepines or related drugs:

Patients receiving other central nervous system depressants (including other opioid analgesics, tranquillisers, e.g. Benzodiazepines, sedative hypnotics and alcohol) concomitantly with Tylex capsules may exhibit an additive depressant effect as the effects of CNS depressants (including alcohol) may be potentiated by codeine. When such therapy is contemplated, the dose of one or both agents should be reduced (see section 4.4).

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.

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

Concurrent use of MAOI 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.

Concurrent use of codeine with fluoxetine or paroxetine, bupropion and methadone may result in inhibition of CYP2D6 resulting in a decrease of the morphine concentration and therefore a reduction or loss of analgesic effect of codeine.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of Tylex Tablets is not recommended during pregnancy since safety in pregnant women has not been established.

Codeine:

Codeine has been shown to cross the placental barrier. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers.

As a precautionary measure, use of Tylex tablets should be avoided during the third trimester of pregnancy and during labour.

Breast-feeding

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

Paracetamol is excreted in breast milk but not in a clinically significant amount.

Codeine 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 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 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.

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.

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 under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

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.

A tabulated list of adverse reactions are 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, angioedema and toxic epidermal necrolysis have also been associated with the use of paracetamol.

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

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is stopped.

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 OverdoseParacetamol

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

If the patient 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

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin may occur and the INR may increase. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, hypokalaemia, cerebral oedema, gastrointentinal bleeding and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias, pancreatitis and pancytopenia have been reported.

Management

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. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

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 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.

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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: codeine and paracetamol ATC Code: N02AJ06

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. Acidbased 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 p-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.

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.

5.3 Preclinical safety data

Conventional studies using the currently accepted standards for the evaluation of paracetamol toxicity to reproduction and development are not available.

6.1 List of excipients

Powdered cellulose (grade 40 FCC)

Sodium Starch Glycolate

Maize Starch

Pregelatinized Starch

Magnesium Stearate

Colloidal Silica Anhydrous

Carnauba Wax

Opadry® II White

TekPrint ® SB 1010 N Red

Purified Water

6.2 Incompatibilities

Not applicable

6.3 Shelf life

24 months

6.4 Special precautions for storage

Store at or below 25°C. Protect from light

6.5 Nature and contents of container

Tamper-evident high density polyethylene bottles fitted with low density polyethylene caps, containing 8, 24, 32, 40, 48, 56, 64, 100 or 500 tablets.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00039/0748

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

28 March 1996