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CO-CODAMOL 15/500 TABLETS

Active substance(s): CODEINE PHOSPHATE HEMIHYDRATE / PARACETAMOL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Co-codamol 15/500 Tablets.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500mg paracetamol and 15mg codeine phosphate
hemihydrate.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Tablet
Co-codamol 15/500 Tablets are white to off-white capsule-shaped tablets,
marked PRO 15 and scored on one side with a plain reverse.

4.1

Therapeutic indications
For the relief of moderate pain.
Codeine 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
Posology
Adults and children aged 16 and over:
Two tablets, to be taken every four hours as required, up to a maximum of
eight tablets in any 24-hour period.
Elderly:

The adult dose is appropriate (please refer to section 4.4 for additional
information on elderly patients).
Paediatric population
Aged 12 to 15 years:
One tablet, to be taken every four hours as required, up to a maximum of four
tablets in any 24-hour period.
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 section 4.3
and 4.4).
Method of administration
For oral administration. The tablets are to be taken whole.
4.3

Contraindications








4.4

Hypersensitivity to the active substances or any of the other excipients
listed in section 6.1.
Conditions where morphine and opioids are contraindicated e.g., acute
asthma, respiratory depression, acute alcoholism, head injuries, raised
intra-cranial pressure, hepatocellular insufficiency and following
biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent
or within 14 days.
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

Special warnings and precautions for use
Care should be observed in administering the product to any patient, whose
condition may be exacerbated by opioids, including the elderly, who may be
sensitive to their central and gastro-intestinal effects, those on concurrent CNS
depressant drugs, those with prostatic hypertrophy and those with
inflammatory or obstructive bowel disorders, Addison’s disease or myasthenia
gravis. Care should also be observed if prolonged therapy is contemplated.

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 summarised
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 postoperatively 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 ultra-rapid 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.
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.

Patients should be advised not to exceed the recommended dose and not take
other paracetamol-containing products concurrently.
The risk-benefit of continued use should be assessed regularly by the
prescriber.
The leaflet will state in a prominent position in the 'before taking' 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.

4.5 Interaction with other medicinal products and other forms of
interaction
The effects of CNS depressants (including other opioid analgesics, tranquilisers,
sedative hypnotics and alcohol) may be potentiated by codeine. 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.
Isoniazid may increase the risk of hepatotoxicity with therapeutic doses of
paracetamol. Antiepileptics, such as carbamazepine, phenobarbital, phenytoin
and primidone can reduce the effects of paracetamol and increase the risk of
hepatotoxicity.
Paracetamol may increase the elimination half-life of chloramphenicol. Oral
contraceptives may increase its rate of clearance. 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 use of paracetamol with increased risk of bleeding;
occasional doses have no significant effect.

4.6

Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of the safety of codeine in human pregnancy, but
there is epidemiological evidence for the safety of paracetamol. Animal
studies with paracetamol and with codeine do not indicate direct or indirect
harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of co-codamol
during pregnancy.
Lactation
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 metabolite 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.
Fertility
There are no data on the effects of co-codamol on human fertility. Fertility was
unaffected following paracetamol or codeine treatment in animal studies (see
section 5.3).

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.

4.8

Undesirable effects




Regular prolonged use of codeine is known to lead to addiction and
tolerance. Symptoms of restlessness and irritability may result when
treatment is then stopped.
Prolonged use of a painkiller for headaches can make them worse.

The information below lists reported adverse reactions, ranked using the following
frequency classification:

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).

Blood and the lymphatic system
Not known: blood dyscrasias including thrombocytopenia and agranulocytosis
Immune system disorders
Not known: anaphylactic shock,
(hypersensitivity) including skin rash

angioedema,

allergic

reactions

Hepatobiliary disorders
Not known: cytolytic hepatitis, which may lead to acute hepatic failure
Nervous system disorders
Not known: dizziness, light-headedness, confusion, drowsiness
Ear and labyrinth disorders
Not known: ototoxicity leading to sensorineural hearing loss.
Gastrointestinal disorders
Not known: pancreatitis, constipation, nausea, vomiting
Skin and subcutaneous tissue disorders
Very rare cases of serious skin reactions have been reported.
Renal and urinary disorders
Not known: urinary retention
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 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:





is on long term treatment with carbamazepine, phenobarbitone, phenytoin,
primidone, rifampicin, St. John’s Wort or other drugs that induce liver
enzymes, or
regularly consumes ethanol in excess of recommended amounts, or
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, 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 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 Nacetylcysteine, 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 National
Poisons Information Service (NPIS) or a liver unit.
Codeine
The effects in overdosage will be potentiated by simultaneous ingestion of
alcohol and psychotropic drugs.
Symptoms
Central nervous system depression, including respiratory depression, may
develop but is unlikely to be severe unless other sedative agents have been coingested, including alcohol, or the overdose is very large. The pupils may be pin-

point in size; nausea and vomiting are common. Hypotension and tachycardia are
possible but unlikely.
Management
This should include general symptomatic and supportive measures including a
clear airway and monitoring of vital signs until stable. Consider activated
charcoal if an adult presents within one hour of ingestion of more than 350mg or
a child more than 5mg/kg.
Give naloxone if coma or respiratory depression is present. Naloxone is a
competitive antagonist and has a short half-life so large and repeated doses may
be required in a seriously poisoned patient. Observe for at least four hours after
ingestion, or eight hours if a sustained release preparation has been taken.

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Paracetamol, combinations excl. Psycholeptics
ATC Code: N02B E51
Paracetamol is an analgesic which acts peripherally, probably by blocking
impulse generation at the bradykinin sensitive chemo-receptors which evoke
pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in
the CNS rather than the periphery appears to be more sensitive to it. This may
explain paracetamol's lack of appreciable anti-inflammatory activity.
Paracetamol also exhibits antipyretic activity.
Codeine is a centrally acting weak analgesic. Codeine exerts its effects through µ
opioid receptors, although codeine has low affinity for these receptors, and its
analgesic effect is due to its conversion to morphine. 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 rapidly and almost completely absorbed from the
gastrointestinal tract. Concentration in plasma reaches a peak in 30-60
minutes. Plasma half-life is 1-4 hours. Paracetamol is relatively uniformly
distributed throughout most body fluids, plasma protein binding is variable.
Codeine phosphate is well absorbed after oral administration and is widely
distributed. About 86% is excreted in the urine in 24 hours; 40-70% if free or
conjugated morphine, 5-15% is free or conjugated norcodeine.

The bioavailabilities of paracetamol and codeine, when given as the combination,
are similar to those when they are given separately.

5.3

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,
toxicity to reproduction and development.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Pregelatinised starch
Maize starch
Povidone
Potassium sorbate
Microcrystalline cellulose
Stearic acid
Purified Talc
Magnesium stearate
Croscarmellose sodium (type A)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Do not store above 25ºC. Store in the original package.

6.5

Nature and contents of container
PVC (250μm)/20μm Aluminium child resistant foil / 15μm PVC blister packs
Or
PVC (250µm)/35gsm glassine/9µm Aluminium child resistant foil blister packs

Pack sizes: 100 tablets.

6.6

Special precautions for disposal
No special requirements

7

MARKETING AUTHORISATION HOLDER
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
United Kingdom
Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS

8

MARKETING AUTHORISATION NUMBER(S)
PL 17780/0500

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
24/08/2011

10

DATE OF REVISION OF THE TEXT
20/11/2014

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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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