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TYLEX EFFERVESCENT

Active substance(s): CODEINE PHOSPHATE / CODEINE PHOSPHATE / CODEINE PHOSPHATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Tylex 30 mg / 500 mg effervescent tablets
Medocodene 30 mg / 500 mg effervescent tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each effervescent tablet contains 500mg of paracetamol and 30 mg of codeine
phosphate hemihydrate.
Excipients:

Sodium: 326.6 mg per tablet
Aspartame (E951): 25 mg per tablet

For a full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Effervescent tablet.
Round, white or off white tablets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Tylex 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).

4.2

Posology and method of administration

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.

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 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 (i.e., not more than eight tablets 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 240 mg 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).
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.
4.3

Contraindications

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 should not be used
-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 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.
4.4

Special warnings and precautions for use
The risk-benefit of continued use should be assessed regularly by the prescriber.
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 noncirrhotic 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.
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. 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.

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 these
capsules 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 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.

4.6

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

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:

4.8



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

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 is outlined below:

System Organ Class

Adverse Effects (Frequency not know)

Blood and lymphatic system
disorders

Thrombocytopenia, agranulocytosis

Immune system disorders

Anaphylactic reaction, hypersensitivity

Psychiatric disorders

Dysphoria, euphoria

Nervous system disorders

Dizziness, sedation, headache

Ear and labyrinth disorders

Deafness1

Respiratory thoracic and
mediastinal disorders

Bronchospasm, dyspnoea

Gastro-intestinal disorders

Nausea, vomiting, constipation, abdominal

pain, pancreatitis2
Skin and subcutaneous tissue
disorders

Pruritus, rash, urticaria

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.
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

4.9

Overdose
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
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. Abnormalities of glucose metabolism and metabolic acidosis
may occur. In severe poisoning, hepatic failure may progress to encephalopathy,
haemorrhage, hypoglycaemia, hypokalaemia, cerebral oedema, 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 and pancreatitis 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 Nacetylcysteine 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.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
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.

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
None stated

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Citric Acid Anhydrous E330
Sodium Hydrogen Carbonate E500
Sodium Carbonate AnhydrousE500
Aspartame E951
Macrogol 6000
Magnesium Stearate
Ethanol 96 % (not detected in the finished product)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
3 years

6.4

Special precautions for storage

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

6.5

Nature and contents of container
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.

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 00039/0750

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15 October 2009

10

DATE OF REVISION OF THE TEXT
26/08/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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