CO-CODAMOL 15 MG / 500 MG FILM-COATED TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 15mg/500mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film coated tablet contains: Paracetamol: 500mg

Codeine Phosphate Hemihydrate: 15mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film coated tablet (Tablet).

White to off white oblong shaped, biconvex, film coated tablets with break line on one side and plain on other side.

The break line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

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

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).

Posology

Adults:

Two tablets to be taken every four hours as required, up to a maximum of eight tablets in any 24-hour period.

Paediatric population:

Children aged 16 and over:

Two tablets to be taken every six hours as required, up to a maximum of eight tablets in any 24-hour period.

Children aged 12 to 15 years:

One tablet to be taken every six hours as required, up to a maximum of four tablets in any 24-hour period.

Children under 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).

Elderly:

The adult dose is appropriate (please refer to Section 4.4 for additional information on elderly patients).

The duration of treatment should be limited to three days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

Method of administration

For oral administration.

The break line on the tablet is present to facilitate breaking for ease of swallowing.

4.3 Contraindications

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

This product is contraindicated in patients with raised intracranial pressure or head injury, respiratory depression, acute asthma and acute alcoholism.

Co-codamol 15mg/500mg Tablets are also contraindicated in patients receiving monoamine oxidase inhibitors or who have received these agents within the previous two weeks (see section 4.5).

This product is contraindicated in women during breastfeeding (see section 4.6) and also in patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

Co-codamol 15mg/500mg Tablets are contraindicated 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).

Co-codamol 15mg/500mg Tablets are not recommended for children under 12 years of age.

4.4 Special warnings and precautions for use

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 on-line, 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 also 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.

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 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 commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite, confusion, somnolence, shallow breathing and small pupils. 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:________­_________________

Co-codamol 15mg/500mg Tablets should be used with caution in the elderly and debilitated as these patients may be more sensitive to the effects of opioids, those with prostatic hypertrophy, inflammatory or obstructive bowel disorders or Addison's disease. 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. Dependence of the morphine type may be produced especially with prolonged use of high doses of codeine.

Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms such as restlessness and irritability, once the drug is stopped.

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

Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed serious liver damage. Patients should be advised not to take other paracetamol- or codeine-containing products concurrently.

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):

Can cause addition, contains opioid within a rectangle box

Paediatric population

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.

4.5 Interaction with other medicinal products and other forms of interaction

Co-codamol 15mg/500mg Tablets are contraindicated in patients receiving monoamine oxidase inhibitors or who have received these agents within the previous two weeks (see section 4.3).

The depressant effects of codeine may be enhanced by other central nervous system depressants: anxiolytics, hypnotics, antidepressants, antipsychotics and alcohol. If combined therapy is necessary, the dose of one or both agents should be reduced. Alcohol should be avoided.

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

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

This product should not be used during pregnancy.

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.

Breast-feeding

Administration to nursing women is not recommended as codeine may be secreted in breast milk and may cause respiratory depression in the infant.

Codeine should not be used during breast-feeding (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.

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

Co-codamol 15mg/500mg Tablets may impair mental and/or physical abilities, therefore it may affect the ability to drive and operate machinery.

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

The following undesirable effects have been reported following the use of paracetamol: blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Hypersensitivity, including skin rash, may also occur. Very rare cases of serious skin reactions have been reported.

The following undesirable effects have been reported following the use of codeine: nausea, vomiting, dizziness and drowsiness. These effects are more likely to be experienced by the ambulatory patient and thus may be alleviated if the patient lies down. Other side effects of codeine, which may occur, include bradycardia, miosis, constipation, abdominal pain (rarely codeine-induced pancreatitis has been reported in patients with a history of cholecystectomy), allergic reactions, light-headedness, confusion, euphoria, dysphoria, urinary retention, and pruritus.

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.

Psychiatric disorders:

Frequency unknown: Drug dependence (see section 4.4)

General disorders and administration site conditions:

Uncommon: drug withdrawal syndrome

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

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 Overdose

Paracetamol Overdose:

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, phenobarbitone, 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 of Paracetamol Overdose:

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 of Paracetamol Overdose:

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.

Treatment with activated charcoal should be considered if the overdose has been taken within one 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 24 hours from ingestion should be discussed with the National Poisons Information Centre (NPIC) or a liver unit.

Codeine Overdose

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.

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms of Codeine Overdose

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 of Codeine Overdose

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paracetamol, combinations, excluding psycholeptics ATC Code: N02B E51

Paracetamol has analgesic and antipyretic effects that do not differ significantly from those of aspirin. Its anti-inflammatory action is weak and it has practically no antiplatelet effect. The mechanism of action is unclear, although it is believed to exert its action by inhibition of prostaglandin synthesis.

Codeine is a centrally acting weak analgesic with uses similar to those of morphine, although it is much less potent as an analgesic and has only mild sedative effects. It is used for the relief of cough and pain. Codeine exerts its effects through p opioid receptors, although codeine has a low affinity for these receptors, and its analgesic effect is due to its conversion to morphine; approximately 10% of administered codeine is demethylated to form 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 readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to two hours after oral administration. 90100% of administered drug can be recovered in the urine within the first day.

Practically none is excreted unchanged, most is conjugated in the liver with glucuronic acid or sulphuric acid.

Codeine and its salts are absorbed rapidly from the gastrointestinal tract with peak plasma levels occurring about one hour after oral administration. Codeine is metabolised in the liver and excreted in the urine mainly as a conjugate of glucuronic acid. Approximately 10% of administered codeine is demethylated to form morphine.

Concurrent administration of both drugs does not interfere with the normal metabolic processes of each agent.

5.3 Preclinical safety data

There are no findings of relevance to the prescriber other than those already mentioned elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core Tablet:

Pregelatinised Starch

Povidone (K-30)

Microcrystalline Cellulose PH102

Maize Starch

Crospovidone XL 10

Colloidal Anhydrous Silica

Magnesium Stearate

Coating (Opadry AMB white OY-B-28920):

Polyvinyl Alcohol Part Hydrolyzed

Titanium dioxide (E171)

Talc (E553b)

Lecithin (Soya) (E322)

Xanthan Gum (E415)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 Years.

6.4 Special precautions for storage

The medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

100 Tablets are packed in Alu – PVC/PVdC blister pack. One such blister is packed in a carton along with leaflet (10 × 10’s)

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

RUDIPHARM LIMITED

Unit 6, Salbrook Road Industrial Estate

Salbrook Road, Redhill

Surrey, RH1 5GJ

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 49565/0094