CO-CODAMOL 30/500 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

2.     Qualitative and Quantitative Composition

3. Pharmaceutical Form

Tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the relief of severe 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

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.

For oral administration:

Adults

Two tablets every four hours. Do not exceed 8 tablets in 24 hours.

Elderly patients:

A reduced dose may be required. (see Section 4.4)

Paediatric population:

Children aged 16 years to 18 years

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

Children aged 12 years to 15 years

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

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).

4.3 Contraindications

Hypersensitivity to paracetamol, codeine or any of the excipients.

Conditions where opioids are contraindicated e.g. acute alcoholism, respiratory depression, head injuries, raised intra-cranial pressure, after biliary tract surgery.

During MAOI treatment or within 14 days of stopping MAOI's.

Children under 12 years.

Acute asthma

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

The patient should be warned:

i) Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor.

ii) Contains paracetamol.

iii) Do not take anything else containing paracetamol while taking this medicine.

iv) Pregnant patients should consult their doctor before taking the medicine.

v) Keep out of the reach of children.

vi) Talk to a doctor at once if you take too much of this medicine, even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

Other Warnings:

Dependence can develop with repeated use of codeine. Care should be exercised if long term treatment is proposed. This product has the potential for being abused. Withdrawal symptoms may appear if the product is withdrawn abruptly.

Caution is advised in treating patients with asthma, Co-codamol Tablets 30/500mg should be avoided during an acute attack.

Codeine may lessen mental or physical capacities that are needed to perform potentially hazardous tasks. If dizziness or sedation occurs, patients should not drive or operate machinery.

Care is advised in the administration of paracetamol-containing products to patients with severe renal or severe hepatic impairment and in those with noncirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease.

Care is advised where the medicine may aggravate a patient’s con­dition. This may occur particularly in the elderly who are sensitive to central and gastrointestinal effects, those also being treated with CNS depressants, those with hypertrophy of the prostate, those with inflammatory or obstructive bowel disorders, those with hypothyroidism and those with Addison's disease.

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

Concomitant use of Codeine 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 Codeine 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).

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 therapeutic 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:

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.

The risk benefit of continues 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 for too often or for too long can make them worse

The label will state (prominently on outer pack, but not in a box):

Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.

4.5 Interactions with other medicinal products

Alcohol, barbiturates, anticonvulsants and tricyclic antidepressants may

increase the hepatotoxicity of paracetamol, particularly after an overdose.

Chloramphenicol – paracetamol may increase the half-life of chloramphenicol.

Colestyramine – may reduce absorption of paracetamol.

Metoclopramide and domperidone – may potentiate the effect of paracetamol.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding.

Alcohol, antipsychotics, anxiolytics and hypnotics may enhance the sedative and hypotensive effects of codeine.

There may be reduced plasma-ciprofloxacin concentrations if ciprofloxacin is administered with codeine.

MAOIs- codeine may cause a hypotensive or hypertensive effect if used with MAOIs. Concomitant use should be avoided and codeine should not be administered until 2 weeks after MAOI discontinuation.

Cisapride, metoclopramide, domperidone- if administered with codeine may lead to an increase in gastrointestinal side effects.

Cimetidine may inhibit the metabolism of opiates.

Ritonavir may reduce the availability of codeine although it can increase the area under the curve for other opioids.

Sedative medicines such as benzodiazepines or related drugs: 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. The dose and duration of concomitant use should be limited (see section 4.4).

4.6 Fertility, pregnancy and lactation

There is inadequate evidence for the safety of codeine in pregnancy but there is epidemiological evidence for the safety of paracetamol. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard.

Nonetheless, careful consideration should be given before giving co-codamol tablets to pregnant mothers particularly during the first trimester. Paracetamol has been detected in breast milk, although it is estimated that less than 0.1% of the maternal dose appears in 100ml of breast milk.

Co-codamol is contraindicated in women 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.

4.7. Effects on ability to drive and use machines

Codeine may cause dizziness and sedation, if affected the patient should not drive or operate machinery. Other drugs including alcohol may enhance the drowsiness caused by codeine (see 4.5).

4.8 Undesirable effects

In therapeutic doses, adverse effects to paracetamol are rare, although hypersensitivity reactions such as skin rash may occasionally occur. There have been haematological reactions reported, such as thrombocytopenia,

undergo gastric lavage. Administration of oral methionine or intravenous n-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

Due to Codeine:

Respiratory depression and hypotension with circulatory failure and deepening coma. Convulsion may occur in infants and children.

Treatment:

When over 4 hours have lapsed after overdosing, plasma paracetamol concentration should be measured. Specific treatment is required if the concentration falls above a line drawn between the point 200mg per litre at 4 hours and 30mg per litre at 15 hours after the overdose. Acetylcysteine should be given intravenously or alternatively, methionine may be given by mouth unless the patient is vomiting or is unconscious; both agents are of little value more than 15 hours after the overdose. Patients at risk of hepatic failure should receive a glucose infusion intravenously to prevent hypoglycaemia and established hepatic or renal failure should be managed conventionally. T J Metedith et al, Br Med J, 1986, 293:345. Further reviews on paracetamol overdosage and its management: L F Prescott, Drugs, 1983, 25, 290: (Official Use only). R J Flanagan, Med Toxicol 1987, 2.

Naloxone hydrochloride is indicated if there is coma or bradypnoea – 400^g is given iv repeated at intervals of 2 to 3 minutes if necessary. In children a dose of 5 to I Ong per kg body weight may be given. Alternatively naloxone hydrochloride may be continuously infused and the rate of administration adjusted according to response.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: N02A A59 – Analgesics, opioids, natural opium alkaloids, codeine combinations.

Paracetamol is an analgesic with antipyretic action, it is a weak inhibitor of prostaglandin biosyntheses. However it seems that paracetamol may be more effective in the synthetase system in the CNS rather than in the periphery. The action on neural tissue may explain why paracetamol reduces fever and pain. This may also account for paracetamol lack of anti-inflammatory activity.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through li 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. As an agonist it produces pain relief by acting on opioid binding sites (^-receptors) in the CNS.

5.2. Pharmacokinetic properties

Paracetamol: Paracetamol is rapidly absorbed from the upper gastrointestinal tract after oral administration.

Peak plasma levels of 15–20 micrograms per ml after 1g oral dose occur within 3090 minutes, depending on dosage form. It is rapidly distributed throughout the body and is primarily metabolised in the liver. About 85% is by conjugation with glucuronide and sulphate and about 10% by conjugation with glutathione.

Excretion of the biotransformation products is via the kidney. The elimination halflife is approximately 2–3 hours.

In overdose glucuronide pathways become saturated and excess paracetamol is metabolised via the glutathione pathway. Hepatic glutathione is rapidly depleted and an intermediate hydroxylamine metabolite accumulates and binds to liver proteins causing irreversible damage.

Codeine: Codeine is rapidly absorbed from the gastro-intestinal tract following oral administration. Peak plasma levels are achieved in about 1 hour following oral ingestion and the half-life in plasma is about 2–4 hours.

Codeine is metabolised in the liver by 0– and N-demethylation to morphine norcodeine, normorphine, hydrocodone and other metabolites.

Approximately 10% of a dose of codeine is converted to morphine and accounts for most of the analgesic effect.

Urinary excretion is the main route of elimination of codeine and its metabolites which are mostly excreted as glucuronide conjugates.

5.3 Preclinical safety data

None provided for Co-codamol 30/500mg Tablets.

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

6.1 List of excipients

Starch

Sodium Starch Glycollate

Magnesium Stearate

Povidone (K-30)

Glycerol

Colloidal Silicon Dioxide Talc

Sodium Lauryl sulfate

Purified Water

6.2. Incompatibilities

None known.

6.3. Shelf Life

36 months.

6.4. Special Precautions for Storage

None.

6.5. Nature and Contents of Container

Blister: Lidding material: 50gsm coated paper/ad/9 micron soft temper Aluminium/ compatible heat seal. Base material: 250 micron uPVC coating Pack size 60,100.

6.6. Instruction for Use/Handling

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Sandoz Limited

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR,

United Kingdom.

8. MARKETING AUTHORISATION NUMBER(S)

PL 04416/0378

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

23 July 2002