CO-CODAMOL 8/500 EFFERVESCENT TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 8/500 Effervescent Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each effervescent tablet contains 500mg paracetamol and 8mg codeine phosphate.

Excipients with known effect:

Each tablet contains 50mg of sorbitol and 388 mg of sodium

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Effervescent Tablet

Flat white tablets with bevelled edges

4.1 Therapeutic indications

For the relief of most painful and febrile conditions such as headache including migraine, neuralgia, toothache, sore throat, colds, influenza, dysmenorrhoea and rheumatic 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 administrationPosology

Do not take continuously for more than 3 days without consulting your doctor.

Adults:

Two tablets, to be dissolved in a glass of water, every 4 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 16 to 18 years:

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

Children aged 12 to 15 years:

One tablet every 6 hours when necessary to a maximum of four doses in 24 hours.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with codeine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

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 section 4.3 and 4.4).

Co-codamol is contraindicated in children below the age of 12 years for the symptomatic treatment of cold (see sections 4.3).

Children aged 12 years to 18 years: Co-codamol is not recommended for use in children aged 12 years to 18 years with compromised respiratory function for the symptomatic treatment of colds (see section 4.4)

For oral administration.

4.3 Contraindi­cations

Hypersensitivity to paracetamol, codeine phosphate or any of the other constituents.

In children below the age of 12 years for the symptomatic treatment of colds due to an increased risk of developing serious and life-threatening adverse reactions.

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 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

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

The recommended dose should not be exceeded. This medicine should not be taken with any other paracetamol-containing products. If symptoms persist, the patient should be advised to consult their doctor. The patient should be advised to see immediate medical advice in the event of an overdose, even if they feel well, because of the risk of delayed, serious liver damage.

Use with caution in patients with convulsive disorders.

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 your doctor tells you to.

This medicine contains paracetamol. Do not take anything else containing paracetamol while taking this medicine.

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.

Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine even if you feel well.

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:

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

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 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.

Co-codamol 8/500 Effervescent Tablets should be used upon medical advice in patients with:

Mild-to-moderate hepatocellular insufficiency

Severe renal insufficiency

Monitoring after prolonged use should include blood count, liver function and renal function.

This medicinal product contains sodium. This medicinal product contains 388 mg sodium per effervescent tablet, equivalent to 19.4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Each soluble tablet contains sorbitol powder (E420) at 50mg per tablet. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interactions with other medicinal products and other forms of interactions

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.

Patients receiving other narcotic analgesics, antitussive, antihypertensives, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including alcohol) concomitantly with this codeine containing drug may exhibit additive CNS depression.

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dose. A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency. Codeine has been used for many years without apparent ill consequence and animal studies have not shown any hazard.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Results of one case control study suggest that there might be an increased risk of malformations of the respiratory tract in the offspring of women who consumed codeine during the first four months of pregnancy. This increase was statistically not significant. Evidence of other malformations is also reported in epidemiological studies on narcotic analgesics, including codeine.

Patients should follow the advice of their doctor regarding the use of this product.

Breastfeeding

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

Co-codamol 8/500 Effervescent Tablets are contraindicated during breast-feeding (see section 4.3) as codeine may be secreted in breast milk and may cause respiratory depression in the infant.

4.7 Effects on ability to drive and to 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:

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

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely

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 lymphatic system disorders

Not known: agranulocytosis, thrombocytopenia

Immune system disorders

Not known: anaphylactic shock, angioedema

Nervous system disorders

Not known: dizziness, light-headedness, confusion, drowsiness, seizure, headache, somnolence

Gastrointestinal disorders

Not known: pancreatitis, constipation, nausea, vomiting, dry mouth

Respiratory, thoracic and mediastinal disorders

Not known: Respiratory depression

Skin and subcutaneous tissue disorders

Very rare cases of serious skin reactions such as Toxic Epidermal Necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, fixed drug eruption have been reported.

Allergic reactions (hypersensitivity) including skin rash may occur.

Renal and urinary disorders

Not known: urinary retention

Psychiatric disorders:

Not known: Confusional state, dysphoria, euphoria, drug dependence (see section 4.4)

Eye disorders

Not known: Miosis

General disorders and administration site conditions:

Uncommon: drug withdrawal syndrome

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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, gastrointestinal 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 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 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 serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Further measures will depend on the severity, nature and course of clinical symptoms of paracetamol intoxication and should follow standard intensive care protocols.

Codeine

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, 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.

The opioid antagonist naloxone hydrochloride is an antidote to respiratory depression and must be administered intravenously.

Patients should be advised to first consult their healthcare professional before taking codeine if they are taking a benzodiazepine.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations

ATC Code: N02B E51

Paracetamol is a well-established analgesic and antipyretic.

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. 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.

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.

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

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sorbitol,

Saccharin sodium

Sodium hydrogen carbonate (sodium bicarbonate),

Polyvidone (povidone)

Sodium lauryl sulphate

Anhydrous citric acid

Anhydrous sodium carbonate

Dimeticone

6.2. Incompatibilities

Not applicable.

6.3 Shelf life

Paper/PE/Alumi­nium/PE (PPFP laminate) – 48 months

Paper/PE/Alumi­nium/Copolymer (Surlyn laminate) – 36 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5. Nature and contents of container

Individually packed into PPFP or Surlyn laminate strips in cardboard carton.

Pack sizes: 48, 60, 100.

Not all pack sizes may be marketed.

6.6 Special, precautions  for disposal

No special requirements

7. MARKETING AUTHORISATION HOLDER

Zentiva Pharma UK Limited

12 New Fetter Lane

London

EC4A 1JP

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 17780/0511

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15/01/2010