CO-CODAMOL 30 MG / 1000 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Co-Codamol 30 mg/1000 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1000 mg of paracetamol and 30 mg of codeine phosphate hemihydrate.

Excipient with known effect:

Lactose monohydrate.

For the full list of excipients, see section 6.1.

Tablets

White to almost white in colour, capsule-shaped, uncoated, biconvex with bevelled edge tablets, with ‘PC6’ debossed on one side and ‘score line’ on the other side of the tablet.

The tablet can be divided into equal doses.

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

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.

Adults

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

Elderly

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 :

^ to one tablet to be taken every six hours when necessary, up to a maximum of four tablets in 24 hours.

Children aged 12 to 15 years:

^ tablet to be taken every six hours when necessary, up to a maximum of two 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).

Method of administration

Oral use.

4.3 Contraindications

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

– Conditions where morphine and opioids are contraindicated e.g., acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure, hepatocellular insufficiency and following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days;

– In all paediatric patients (0–18) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increase risk of developing serious and life threatening adverse reactions (see section 4.4);

– In women during breast-feeding (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 should be observed in administering the product to any patient, whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy, hypothyroidism and those with inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis. Care should also be observed if prolonged therapy is contemplated.

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 summarised 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.

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 alcoholic liver disease.

Patients should be advised not to exceed the recommended dose and not take other paracetamol-containing products concurrently.

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.

– 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 – not boxed):

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

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.

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

Concomitant use of Co-Codamol 15 mg/500 mg 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 Co-Codamol 15 mg/500 mg 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).

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.

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

The effects of CNS depressants (including other opioid analgesics, tranquilisers, sedative hypnotics and alcohol) may be potentiated by codeine. When such therapy is contemplated, the dose of one or both agents should be reduced.

Concurrent use of MAO inhibitors or tricyclic antidepressants with codeine may increase the effect of either the antidepressant or codeine.

Concurrent use of anticholinergics and codeine may produce paralytic ileus.

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).

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.

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.

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

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

Codeine

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

Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.

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.’

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 indicates 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.

As a precautionary measure, it is preferable to avoid the use of Co-Codamol 30 mg/1000 mg Tablets during pregnancy.

Breast-feeding

Codeine

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

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.

Paracetamol

Paracetamol is excreted in breast milk but not in a clinically significant amount.

Fertility

There are no data on the effects of Co-Codamol 30 mg/1000 mg Tablets on human fertility. Fertility was unaffected following paracetamol or codeine treatment in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

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).

General disorders and administration site conditions

Uncommon: drug withdrawal syndrome

Psychiatric disorders

Not known: Drug dependence (see section 4.4).

Blood and the lymphatic system

Not known: blood dyscrasias including thrombocytopenia and agranulocytosis.

Immune system disorders

Not known: anaphylactic shock, angioedema, allergic reactions (hypersensitivity) including skin rash.

Hepatobiliary disorders

Not known: cytolytic hepatitis, which may lead to acute hepatic failure.

Nervous system disorders

Not known: dizziness, light-headedness, confusion, drowsiness.

Ear and labyrinth disorders

Not known: ototoxicity leading to sensorineural hearing loss.

Gastrointestinal disorders

Not known: pancreatitis, constipation, nausea, vomiting.

Skin and subcutaneous tissue disorders

Very rare cases of serious skin reactions have been reported.

Renal and urinary disorders

Not known: urinary retention.

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

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Paracetamol, combinations excl. Psycholeptics, ATC code: N02BE51

Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamol's lack of appreciable anti-inflammatory activity.

Paracetamol also exhibits antipyretic 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.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Concentration in plasma reaches a peak 30–60 minutes. Plasma half-life is 1–4 hours. Paracetamol is relatively uniformly distributed thoughout 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.

The bioavailabilities of paracetamol and codeine, when given as the combination, are similar to those they are given separately.

5.3 Preclinical safety data

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

6.1

6.2

Pregelatinised maize starch Stearic acid

Povidone K 30

Lactose monohydrate

Powdered cellulose

Talc

Magnesium stearate

Not applicable.

6.3

3 years.

6.4 Special precautions for storage

This product does not require any special storage conditions.

6.5 Nature and contents of container

The tablets are packed in Al/PVC blisters.

Pack-sizes: 50 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Alissa Healthcare Research Limited

Unit 5, Fulcrum 1, Solent Way, Whiteley, Fareham, Hampshire,

United Kingdom, PO15 7FE

8 MARKETING AUTHORISATION NUMBER(S)

PL 30322/0033

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/01/2020