CODIPAR 15 MG / 500 MG TABLETS, COPAZ 15 MG / 500 MG TABLETS, CO-CODAMOL 15 MG / 500 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Copaz 15mg/500mg Tablets

Codipar 15mg/500mg Tablets

Co-codamol 15mg/500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains 15mg codeine phosphate and 500mg paracetamol.

3 PHARMACEUTICAL FORM

Coated tablet

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

Posology

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).

Adults:

The usual dose is one or two tablets every four to six hours when needed, up to a maximum of 8 tablets in any 24 hour period.

Codeine should be used at the lowest effective dose for the shortest period of time. This dose may be taken, up to 4 times a day at intervals of not less than 6 hours. Maximum daily dose should not exceed 240 mg.

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.

Elderly: A reduced dosage may be necessary.

Paediatric population:

Children aged 16–18 years: one to two tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 12 – 15 years: one tablet every 6 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).

Dosage needs to be adjusted according to the severity of pain and the response of the patient.

Method of administration:

Oral.

4.3 Contraindications

Hypersensitivity to either Paracetamol or codeine, or any of the excipients of Copaz tablets. listed in section 6.1

Children under 12 years of age.

Patients who have taken MAOIs within 14 days.

Severe renal or hepatic impairment.

Copaz is contraindicated in patients for whom opiate medications are contraindicated.

This will include some patients with acute asthma, obstructive airway disease, respiratory depression, acute alcoholism, head injuries, raised intracranial pressure and following biliary surgery.

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 efficacy and safety of Copaz tablets in children below the age of 12 years has not been established and use in such children is contraindicated.

Copaz tablets must be used with caution in patients with increased intracranial pressure, acute abdominal conditions, the elderly, the debilitated, impaired hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy and urethral stricture.

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.

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

Concomitant use of Copaz tablets 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 Copaz tablets 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 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 metabolizer 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 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.”

The increased hazard of paracetamol overdosage in patients with alcoholic liver disease.

Patients should be advised not to exceed the recommended dose and not to take other products containing paracetamol or opiate derivatives.

Patients should be advised to consult their doctor if symptoms persist.

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/dihydro­codeine (DHC) regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop taking 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 you prescriber as taking codeine/DHC regularly for a long time can lead to addiction.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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

Patients should be advised not to drive or operate machinery if Copaz causes dizziness or sedation. Codeine may cause visual disturbances.

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

common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100) and not known (cannot be estimated from the available data).

aCodeine can cause respiratory depression particularly in overdosage and in patients with compromised respiratory function.

bLiver damage in association with therapeutic use of paracetamol has been documented; most cases have occurred in conjunction with chronic alcohol abuse.

cSome of these side effects appear more common in ambulatory: rather than non-ambulatory patients. Lying down may alleviate these effects they occur.

*There have been some reports of blood dyscrasias – thrombocytopenia and agranulocytosis, with the use of paracetamol-containing products, but the causal relationship has not been established.

Prolonged use of a pain killer for headaches can make them worse.

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/yellowcardor 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

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:

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) but results should not delay initiation of treatment beyond 8 hours after ingestion, as 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.

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.

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.

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 350 mg or a child more than 5 mg/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: Opioids in combination with non-opioid analgesics,

ATC code: N02AJ06

Paracetamol (N02B E51) has analgesic and antipyretic actions. It is a weak inhibitor of prostaglandin biosynthesis. Single or repeated therapeutic loses of paracetamol do not affect the cardiovascular or respiratory systems. Gastric irritation, erosion, or bleeding is not produced by paracetamol. There is minimal effect on platelets, no effect on bleeding time or excretion of uric acid.

Codeine (N02A A59) is a centrally acting weak analgesic. Codeine exerts its effect through u 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.

Codeine affects the CNS and the gut, including analgesia, drowsiness, mood changes, respiratory depression, reduced gastrointestinal motility, nausea or vomiting, changes in the endocrine and autonomic nervous system. Codeine’s effect on pain relief is selective, and it does not effect other sensations such as touch, vibration, vision, or hearing.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates, with about 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half life varies from about 1–4 hours. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose dependent. A minor hydrolated 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 and peak plasma concentrations are produced in about 1 hour. It is metabolised in the liver to morphine and norcodeines. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The plasma half life is between 3 and 4 hours.

5.3. Preclinical Safety Data

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

Maize Starch

Methylcellulose

Talc

Calcium Stearate

Povidone

Purified Water

Hypromellose

Macrogol 3350

6.2. Incompatibilities

None relevant

6.3. Shelf-Life

36 months

6.4. Special Precautions for Storage

Do not store above 25°C

6.5 Nature and contents of container

Polyethylene capsule container with low density polyethylene child resistant closure.

Or

Aluminium foil over PVC/PVDC or ACLAR film blisters.

In pack sizes of 28, 30, 56, 100 or 112 tablets.

6.6. Instruction for Use, Handling and Disposal

None

7 MARKETING AUTHORISATION HOLDER

Mercury Pharmaceuticals Ltd

Capital House

85 King William Street

London

EC4N 7BL

UK

8. MARKETING AUTHORISATION NUMBER

PL 12762/0056

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

11/03/2009