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

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 15/500mg 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 15/500mg Tablets are white capsule shaped tablets, debossed with “CCD 15” on one side and plain on other side.

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 co-codamol in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Posology

Two tablets every four hours when necessary, up to a maximum of eight tablets in 24 hours.

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

Paediatric population

Children aged 16 to 18 years:

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

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

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).

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

For oral administration. The tablets are to be taken whole.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Do not use in children under 12 years of age.

Conditions where morphine and opioids are contraindicated e.g., acute asthma, respiratory depression, obstructive airways disease, acute alcoholism, hepatocellular insufficiency and following biliary tract surgery; monoamine oxidase inhibitor therapy (concurrent or within 14 days); head injury or raised intracranial pressure (in addition to the risk of respiratory depression and increased intracranial pressure, papillary and other responses vital for neurological assessment may be affected).

Comatose patients; Where there is a risk of paralytic ileus; In acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis) or diarrhoea caused by poisoning.

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 who are known to be CYP2D6 ultra-rapid metabolisers.

Concomitant use of monoamine oxidase inhibitors (MAOIs) or within two weeks of MAOI discontinuation as severe CNS excitation or depression (including hypertension or hypotension) may occur

Codeine is also contraindicated in conditions where:

inhibition of peristalsis is to be avoided,

there is a risk of paralytic ileus,

abdominal distension develops,

acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis)

4.4 Special warnings and precautions for use

Co-codamol 15mg/500mg Tablets may cause drowsiness. Co-codamol 15mg/500mg Tablets should be given in reduced doses or with caution to any patient whose condition may be exacerbated by opioids, including the elderly (who may be sensitive to their central and gastro-intestinal effects), debilitated patients or patients on concurrent CNS depressant drugs, those with hypothyroidism, asthma, decreased respiratory reserve, adrenocortical insufficiency, prostatic hypertrophy, hypotension, shock, inflammatory or obstructive bowel disorders, urethral stricture, convulsive disorders, or myasthenia gravis. It should be avoided or the dose reduced in patients with hepatic or renal impairment.

Avoid use during an acute asthma attack.

Risks from concomitant use of opioids and benzodiazepines

Concomitant use of opioids, including codeine, with benzodiazepines may result in sedation, respiratory depression, coma and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe codeine concomitantly with benzodiazepines, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of sedation and respiratory depression (see section 4.5).

Risks from concomitant use of opioids and alcohol

Concomitant use of opioids, including codeine, with alcohol may result in sedation, respiratory depression, coma and death. Concomitant use with alcohol is not recommended (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 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.

Opioid analgesics should be avoided in patients with biliary tract disorders or used in conjunction with an antispasmodic.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).

Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with intravenous busulfan (see section 4.5 Interactions).

Co-codamol 15mg/500mg Tablets enhance the effects of alcohol. Concurrent use should be avoided.

The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.

Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed, serious liver damage. They should be advised not to take other paracetamol-containing products concurrently and to keep the product out of the reach of children.

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

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 co-codamol.

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.

4.5 Interaction with other medicinal products and other forms of interaction

In high doses or with regular treatment, paracetamol may potentiate the effects of warfarin or other coumarins and lead to an increased risk of bleeding. The absorption of paracetamol is reduced by cholestyramine and accelerated by domperidone and metoclopramide.

Cytotoxic drugs: Paracetamol possibly inhibits metabolism of intravenous busulfan (manufacturer of intravenous busulfan advises caution within 72 hours of paracetamol).-

Anaesthetics: sedative antihistamines, sodium oxybate: concomitant administration of codeine may cause increased CNS depression and/or respiratory depression and/or hypotension.

Codeine antagonises the effect of metoclopramide and cisapride on gastrointestinal activity. It delays the absorption of flecainide and mexiletine and potentiates the effect of hypnotics and anxiolytics. The analgesic activity of codeine is likely to be significantly impaired by quinidine which impairs codeine metabolism.

Antidepressants: The depressant effects of opioid analgesics may be enhanced by tricyclic antidepressants. MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Antipsychotics: enhanced sedative and hypotensive effect.

Alcohol: the hypotensive, sedative and respiratory depressive effects of alcohol may be enhanced.

Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation.

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.

Concomitant use of antimuscarinics may lead to paralytic ileus or urinary retention.

Ulcer-healing drugs: Cimetidine may inhibit the metabolism of dihydrocodeine resulting in increased plasma concentrations.

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.

Interference with laboratory tests: Opioids may interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use during labour because of the potential for respiratory depression in the neonate.

The safety of paracetamol-codeine during pregnancy has not been established relative to the possible adverse effects of fetal development.

As with all medication, caution should be exercised during pregnancy, especially in the first trimester.

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.

Codeine

There is inadequate evidence of the safety of codeine in human pregnancy. Animal studies with codeine do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

A possible association with respiratory and cardiac malformations has been reported following first trimester exposure to codeine. Regular use of codeine during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Administration of codeine during labour may depress respiration in the neonate. Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.

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.

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.

Paracetamol

There is epidemiological evidence of safety in human pregnancy. Animal studies with paracetamol do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). 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. 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.

Breastfeeding

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

Paracetamol

Paracetamol is excreted in breast milk but not in clinically significant quantities.

Codeine

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.

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.

Fertility

There are no data relating to the effects of co-codamol on human fertility.

4.7 Effects on ability to drive and use machines

Codeine produces sedation and may also cause changes in vision, including blurred or double vision. If affected, patients should not drive or operate machinery. The effects of alcohol are enhanced by opioid analgesics.

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 of 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

List of adverse reactions

The adverse reactions reported below are classified according to frequency of occurrence as follows: 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)

Effects of withdrawal -abrupt withdrawal precipitates a withdrawal syndrome. Symptoms may include tremor, insomnia, nausea, vomiting, sweating and increase in heart rate, respiratory rate and blood pressure. NOTE tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove fatal.

Other effects -Most reports of adverse reactions to paracetamol relate to overdosage with the drug.

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.

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

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

Symptoms of paracetamol overdose in the first 24 hours are sweating, 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, hypotension, cerebral oedema, coma and death. Prothrombin time may increase with deteriorating liver function. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10 g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested); become irreversibly bound to liver tissue.

Treatment

Immediate treatment is essential in the management of paracetamol overdose. Despite of lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5 g or more of paracetamol in the proceeding 4 hours should 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.

An overdose with codeine is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdose with codeine, apnoea, circulatory collapse, cardiac arrest and death may occur. Primary attention should be given to the re-establishment of adequate respiratory function through the provision of a patent airway and the institution of controlled ventilation. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Opioid antagonists, such as naloxone may be administered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, ATC Code: N02B E51

Paracetamol has analgesic and antipyretic properties.

Codeine phosphate is an opioid analgesic.

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.

5.2 Pharmacokinetic properties

Both paracetamol and codeine phosphate are readily absorbed from the gastrointestinal tract giving peak plasma levels within one hour of administration.

Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half life varies from about one to four hours. At usual therapeutic concentrations plasma-protein binding is negligible.

Codeine is metabolised in the liver to morphine and norcodeine which are both excreted in the urine partly as conjugates with glucuronic acid. Most of the excretion products appear in the urine within six hours and up to 80% of the dose is excreted in 24 hours. About 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine and a further 10% as free or conjugated norcodeine. Only traces are found in the faeces. The plasma half life is approximately three to four hours.

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 and carcinogenic potential. 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

Pregelatinised starch

Povidone

Magnesium stearate

6.2 Incompatibilities

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 25°C. Store in the original package.

6.5 Nature and contents of container

PVC (250^m)/35gsm glassine/9^m Aluminium child resistant foil blister packs.

Pack sizes: 30, 90 or 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 29831/0588

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

03/01/2019